Tricyclic PARP1 inhibitors and uses thereof

Abstract

Described herein are tricyclic PARP1 inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of cancer. Also disclosed herein is a method of treating brain 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 compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is brain-penetrating.

Description

[Technical field]

[0001] (cross reference) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 336,078, filed April 28, 2022, and U.S. Provisional Patent Application No. 63 / 381,482, filed October 28, 2022, which are incorporated by reference herein in their entireties. [Background technology]

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

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

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

[0005] Inhibition of PARP family enzymes has been exploited as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have demonstrated that tumor cells harboring deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors are defective in the homologous recombination repair (HRR) pathway and depend on the function of PARP enzymes for survival. Although PARP inhibitor therapy has primarily targeted SRCA-mutated cancers, PARP inhibitors are in clinical trials in non-SRCA-mutated tumors, i.e., tumors that exhibit homologous recombination deficiency (HRD).

[0006] It is believed that PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. It is also believed that selective and potent inhibition of PARP1 leads to trapping of PARP1 in DNA, resulting in DNA double-strand breaks (DSBs) through the collapse of replication forks in S phase. It is also believed that PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells with HRD. Thus, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors with selectivity for PARP1. Summary of the Invention

[0007] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof:

[0008] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, Ring A taken together with X and Y is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X is C, CH, or N; Y is C, CH, or N; Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or two R on the same carbon 1 together to form oxo, n is 0 to 6; Z is N or CR Z and R Z is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; or two R on the same carbon 4 together to form oxo, or or two R on the same or different carbons 4 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 0 to 4; R 5 is 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 is 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 7 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 8is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R a is 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, or heterocycloalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl independently optionally substituted with one or more R; Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O) C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; Or two R on the same atom taken together form an oxo.

[0009] Also disclosed herein are pharmaceutical compositions comprising a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0010] Also disclosed herein is a method of treating a cancer comprising a BRCA1 and / or BRCA2 mutation in a subject in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method of treating a cancer comprising a mutation in a gene that confers a homologous repair deficiency in a subject in need thereof, comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in the gene that confers a homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof. In some embodiments, the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0011] Also disclosed herein is a method of treating cancer present in the brain in a subject in need thereof, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0012] Also disclosed herein is a method of treating brain cancer in a subject in need thereof, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is brain-penetrant.

[0013] (Incorporated 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 PREFERRED EMBODIMENTS

[0014] definition In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments. However, one 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." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0015] 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. Moreover, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense to include "and / or" unless the content clearly dictates otherwise.

[0016] As used herein, the following terms have the following meanings unless otherwise indicated.

[0017] "Oxo" refers to =O.

[0018] "Carboxyl" refers to --COOH.

[0019] "Cyano" refers to -CN.

[0020] "Alkyl" refers to straight or branched chain saturated hydrocarbon monoradicals having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, and the like. Wherever it appears herein, a numerical range such as "C1-C6 alkyl" or "C1-6 alkyl" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is any of the C1- 10In some embodiments, the alkyl is a C1-6 alkyl. In some embodiments, the alkyl is a C1-5 alkyl. In some embodiments, the alkyl is a C1-4 alkyl. In some embodiments, the alkyl is a C1-3 alkyl. Unless otherwise specifically stated herein, an alkyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0021] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Whenever appearing herein, a numerical range such as "C2-C6 alkenyl" or "C2-6 alkenyl" means that the alkenyl group may 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 otherwise specifically stated herein, an alkenyl group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0022] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadinyl, and the like. Whenever it appears herein, a numerical range such as "C2-C6 alkynyl" or "C2-6 alkynyl" means that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated herein, an alkynyl group can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0023] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated herein, an alkylene group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0024] "Alkoxy" means a group of the formula -OR a R refers to the radical of a is an alkyl radical as defined. Unless otherwise specifically stated herein, an alkoxy group can be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0025] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system and may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise specifically stated herein, an aryl 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, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0026] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom) or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3 to C4). 15 Cycloalkyl or C3-C 15Cycloalkenyl, 3 to 10 carbon atoms (C3 to C 10 Cycloalkyl or C3-C 10Examples of cycloalkyl include, but are not limited to, cycloalkyls having 3 to 8 carbon atoms (C3-C8 cycloalkyl or C3-C8 cycloalkenyl), 3 to 6 carbon atoms (C3-C6 cycloalkyl or C3-C6 cycloalkenyl), 3 to 5 carbon atoms (C3-C5 cycloalkyl or C3-C5 cycloalkenyl), or 3 to 4 carbon atoms (C3-C4 cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, cycloalkyls are 3- to 10-membered cycloalkyl or 3- to 10-membered cycloalkenyl. In some embodiments, cycloalkyls are 3- to 6-membered cycloalkyl or 3- to 6-membered cycloalkenyl. In some embodiments, cycloalkyls are 5- to 6-membered cycloalkyl or 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyls include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyls include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0027] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0028] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0029] "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.

[0030] "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.

[0031] "Deuteroalkyl" refers to an alkyl radical, as defined above, that is substituted by 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, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CD3.

[0032] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations 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 1-6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and 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 otherwise specifically stated herein, 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, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heteroalkyl is optionally substituted with halogen.

[0033] "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 otherwise specifically stated in the specification, a heterocycloalkyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, 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, 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 C4). 15 Heterocycloalkyl or C2-C 15 Heterocycloalkenyl, 2 to 10 carbon atoms (C2 to C 10 Heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), heterocycloalkyl having 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), heterocycloalkyl having 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), heterocycloalkyl having 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or heterocycloalkyl having 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 the like. 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, but is not limited to, all ring forms of carbohydrates, including monosaccharides, disaccharides, and oligosaccharides. Unless otherwise stated, heterocycloalkyls have 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is understood that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl.In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically stated herein, a heterocycloalkyl can be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, a heterocycloalkyl is optionally substituted with halogen.

[0034] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, can include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical 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, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoi Examples of aryl groups include, but are not limited to, indolinyl, 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 otherwise specifically stated herein, 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, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe.In some embodiments, the heteroaryl is optionally substituted with halogen.

[0035] The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled 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 can continue indefinitely, as defined, to include an optionally substituted cycloalkyl group, which in turn can continue indefinitely as including an optionally substituted alkyl group). Thus, any substituent described should be understood to generally have a maximum molecular weight of up to about 1,000 daltons, more typically up to about 500 daltons.

[0036] The term "one or more" when referring to optional substituents means that the subject group is optionally substituted with one, two, three, four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.

[0037] An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, that is effective to produce the desired therapeutic effect.

[0038] "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.

[0039] "Synergism" or "synergizing" refers to the effect of the combination being greater than the additive effect of each component alone at the same dose.

[0040] As used herein, a "PARP-associated disease or disorder," or alternatively, a "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.

[0041] As used herein, a "PARP1-associated disease or disorder," or alternatively, a "PARP1-mediated disease or disorder," means any disease or other deleterious condition in which PARP1 or a mutant thereof is known or suspected to play a role.

[0042] compound Described herein are compounds, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, that are useful for the treatment of cancer.

[0043] Disclosed herein is a compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof: [ka] During the ceremony, Ring A taken together with X and Y is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X is C, CH, or N; Y is C, CH, or N; Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or two R on the same carbon 1 together to form oxo, n is 0 to 6; Z is N or CR Z and R Z is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; or R 2 and R 3 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R 4 are independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl; or two R on the same carbon 4 together to form oxo, or or two R on the same or different carbons 4 taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 0 to 4; R 5 is 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 6 is 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R7 is 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, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R a is 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, or heterocycloalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl independently optionally substituted with one or more R; Each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl independently optionally substituted with one or more R; Or R c and R dtogether with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently selected from halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O) C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; Or two R on the same atom taken together form an oxo.

[0044] In some embodiments of the compound of formula (I), ring A together with X and Y is a 5-membered heterocycloalkyl. In some embodiments of the compound of formula (I), ring A together with X and Y is pyrrolidinyl or furanyl. In some embodiments of the compound of formula (I), ring A together with X and Y is a 5-membered heteroaryl. In some embodiments of the compound of formula (I), ring A together with X and Y is pyrrolyl, pyrazolyl, imidazolyl, or triazolyl. In some embodiments of the compound of formula (I), ring A together with X and Y is pyrazolyl or imidazolyl. In some embodiments of the compound of formula (I), ring A together with X and Y is furanyl.

[0045] In some embodiments of the compound of Formula (I), X is C. In some embodiments of the compound of Formula (I), X is CH. In some embodiments of the compound of Formula (I), X is N.

[0046] In some embodiments of the compounds of Formula (I), Y is C. In some embodiments of the compounds of Formula (I), Y is CH. In some embodiments of the compounds of Formula (I), Y is N.

[0047] In some embodiments of the compound of Formula (I), the compound is of Formula (Ia): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0048] In some embodiments of the compound of Formula (I), the compound is of Formula (Ib): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0049] In some embodiments of the compound of Formula (I), the compound is of Formula (Ic): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0050] In some embodiments of the compound of Formula (I), the compound is of Formula (Id): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0051] In some embodiments of the compound of Formula (I), the compound is of Formula (Ie): [ka] In the formula, R 1’ is hydrogen or R1 It is.

[0052] In some embodiments of the compound of Formula (I), the compound is of formula (If): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0053] In some embodiments of the compound of Formula (I), the compound is of Formula (Ig): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0054] In some embodiments of the compound of Formula (I), the compound is of Formula (Ih): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0055] In some embodiments of the compound of Formula (I), the compound is of Formula (Ii): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0056] In some embodiments of the compound of Formula (I), the compound is of Formula (Ij): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0057] In some embodiments of the compound of Formula (I), the compound is of Formula (Ik): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0058] In some embodiments of the compound of Formula (I), the compound is of Formula (II): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0059] In some embodiments of the compound of Formula (I), the compound is of Formula (Im): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0060] In some embodiments of the compound of Formula (I), the compound is of formula (In): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0061] In some embodiments of the compound of Formula (I), the compound is of Formula (Io): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0062] In some embodiments of the compound of Formula (I), the compound is of Formula (Ip): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0063] In some embodiments of the compound of Formula (I), the compound is of formula (Iq): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0064] In some embodiments of the compound of Formula (I), the compound is of Formula (Ir): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0065] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of formula (Ia)-(Il): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0066] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of formula (Ia)-(Ih): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0067] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Ii)-(Il): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0068] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of formula (Im) or (In): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0069] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of formula (Io)-(Ir): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0070] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of Formula (Io) or (Ip): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0071] In some embodiments of the compound of Formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, the compound is of formula (Iq) or (Ir): [ka] In the formula, R 1’ is hydrogen or R 1 It is.

[0072] In some embodiments of compounds of Formula (I) or (Ia)-(Ir), each R 1 is independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where the alkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ir), each R 1 is independently deuterium, 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 (I) or (Ia)-(Ir), each R 1 is independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of a compound of Formula (I) or (Ia)-(Ir), each R 1 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, where alkyl is optionally substituted with one or more R. In some embodiments of a compound of Formula (I) or (Ia)-(Ir), each R 1 is independently deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia)-(Ir), each R 1 is independently halogen or C1-C6 alkyl. In some embodiments of compounds of Formula (I), (Ia)-(Ir), each R 1 is independently a halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), each R 1is independently C1 to C6 alkyl.

[0073] In some embodiments of compounds of Formula (I) or (Ia)-(Ir), each R 1’ is independently halogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or (Ia)-(Ir), R 1’ is independently hydrogen, deuterium, 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 (I) or (Ia)-(Ir), R 1’ is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of Formulae (Ia)-(Ir), each R 1’ is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, where alkyl is optionally substituted with one or more R. In some embodiments of compounds of Formulae (Ia)-(Ir), each R 1’ is independently hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (Ia)-(Ir), each R 1’ is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of Formula (Ia)-(Ir), each R 1’ is independently hydrogen or halogen. In some embodiments of the compounds of Formula (Ia)-(Ir), each R 1’ is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (Ia)-(Ir), each R1’ is hydrogen. In some embodiments of compounds of Formula (Ia)-(Ir), each R 1’ is independently C1 to C6 alkyl.

[0074] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 0-4. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 0-3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 0-2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 0 or 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 3. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), n is 4.

[0075] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), Z is N. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), Z is CR Z It is.

[0076] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R Z is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, where alkylcycloalkyl is optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R Z is C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R Z is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R Z is halogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), RZ is C1-C6 alkyl.

[0077] In some embodiments of compounds of Formula (I) or (Ia)-(Ir), each R 2 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is hydrogen, deuterium, 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 compounds of Formula (I) or (Ia)-(Ir), R 2 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of Formula (I) or (Ia)-(Ir), each R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is hydrogen, deuterium, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is hydrogen or deuterium. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2is deuterium. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is C1-C6 alkyl.

[0078] In some embodiments of compounds of Formula (I) or (Ia)-(Ir), each R 3 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is hydrogen, deuterium, 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 compounds of Formula (I) or (Ia)-(Ir), R 3 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is hydrogen, deuterium, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is hydrogen or deuterium. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is deuterium. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 3 is C1-C6 alkyl.

[0079] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 is hydrogen and R 3 is hydrogen.

[0080] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 2 and R 3 taken together form a cycloalkyl.

[0081] In some embodiments of compounds of Formula (I) or (Ia)-(Ir), each R 4 is independently deuterium, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), each R 4 is independently C1 to C6 alkyl.

[0082] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), two R 4 In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), two R on the same carbon 4 In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), two R on different carbons 4 taken together form a cycloalkyl.

[0083] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), m is 0 to 2. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), m is 0 or 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), m is 0. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), m is 1. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), m is 2.

[0084] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 5 is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 5 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 5 is hydrogen, halogen, or C1 to C6 alkyl.

[0085] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 5 is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 5 is a halogen.

[0086] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 6 is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 6 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 6 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 6is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 6 is a halogen.

[0087] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 7 is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 7 is hydrogen, deuterium, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 7 is hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 7 is hydrogen. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 7 is a halogen.

[0088] In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, where the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 is C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, where alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 is C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 is C1-C6 alkyl or cycloalkyl, where alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), R8 is C1-C6 alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 is C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 In some embodiments of the compounds of Formula (I) or (Ia)-(Ir), R 8 is cyclopropyl.

[0089] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, each alkyl being independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. 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 Ra is independently C1 to C6 alkyl.

[0090] In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, cycloalkyl, or heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, each alkyl being independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen. In some embodiments of the compounds disclosed herein, each Rc and R d is independently C1 to C6 alkyl.

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

[0092] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl), -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl), C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl, or two R on the same atom together form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NH2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuteroalkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -NH2, C1-C3 alkyl, or C1-C3 haloalkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -NH2, C1-C3 alkyl, or two R on the same atom together form oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C3 alkyl.

[0093] 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.

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

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

[0096] The OR label (or) indicates a pure substance, but the absolute configuration of the stereochemical centers is unknown. After chiral separation with isolated pure structures, multiple OR labels with the same numerical value (OR indicates purity) indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical centers is unknown).

[0097] The AND sign (and) indicates that both isomers are present at the depicted stereochemical center. Assigning different numerical values ​​to the AND signs indicates that they are independent of each other. Use of AND signs with the same value indicates that the two stereocenters are relative to each other and can only change in unison.

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

[0099] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds described herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, with each center being present in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, 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 diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical means that does not result in racemization.

[0100] labeled compound In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating 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 are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. l5 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein, and pharma- ceutically 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 C, is incorporated are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability. Additionally, heavy isotopes such as deuterium, i.e., 2 Substitution with, for example, H, may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements.

[0101] 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.

[0102] 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 disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0103] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts, which in some embodiments are prepared in situ during the final isolation and purification of the compounds disclosed herein, or solvates or stereoisomers thereof, or by separately reacting the purified compounds in free form with a suitable acid or base and isolating the salt thus formed.

[0104] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral, organic acid, or inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, 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, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

[0105] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compounds with a pharma- ceutically acceptable inorganic or organic acid, including inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, and the like. These include, but are not limited to, aromatic 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, are not themselves pharmaceutically acceptable but are used in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, their solvates, or stereoisomers, and their pharmaceutically acceptable acid addition salts.

[0106] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates of pharmaceutically acceptable metal cations, ammonia, or pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4, etc.

[0107] 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.

[0108] 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.

[0109] Solvates contain either stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments are formed with pharma- ceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared 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.

[0110] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the scope of the formulas described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, accompanied by the switching of a single bond and an adjacent double bond. In bond configurations where tautomerization is possible, a chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0111] Treatment method Disclosed herein is a method for treating a disease in which inhibition of PARP is beneficial, comprising administering a compound disclosed herein. Also disclosed herein is a method for treating a disease in which inhibition of PARP1 is beneficial, comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer such as gastric cancer and colorectal cancer, or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer. In some embodiments, the cancer is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

[0112] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0113] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0114] In some embodiments, the cancer containing a BRCA1 and / or BRCA2 mutation is bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

[0115] In some embodiments, the cancer is a cancer that is deficient in homologous recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA through a homologous mechanism and reforms continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), and MRE1 1. A (NM_005590), and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulators such as EMSY. In some embodiments, a cancer with a defect in FIR-dependent DNA DSB repair comprises one or more cancer cells that have a reduced or eliminated ability to repair DNA DSBs through the pathway compared to normal cells, i.e., the activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in one or more cancer cells.

[0116] In some embodiments, activity of one or more components of the FIR-dependent DNA DSB repair pathway is impaired in one or more cancer cells of an individual having a cancer that is deficient in FIR-dependent DNA DSB repair.

[0117] In some embodiments, the cancer cells have a BRCA1 and / or BRCA2 deficient phenotype, i.e., BRCA1 and / or BRCA2 activity is reduced or absent in the cancer cells. Cancer cells with this phenotype may be deficient in BRCA1 and / or BRCA2, i.e., BRCA1 and / or BRCA2 expression and / or activity may be reduced or absent in the cancer cells, for example, by mutation or polymorphism in the coding nucleic acid, or by amplification, mutation or polymorphism in a gene encoding a regulator, for example, the EMSY gene encoding the BRCA2 regulator. BRCA1 and BRCA2 are known tumor suppressors whose wild-type alleles are frequently lost in tumors of heterozygous carriers. Amplification of the EMSY gene encoding a BRCA2 binding factor is also known to be associated with breast and ovarian cancer. Carriers of mutations in BRCA1 and / or BRCA2 are also at increased risk of certain cancers, including breast, ovarian, pancreatic, prostate, hematological, gastrointestinal, and lung cancers.

[0118] Also disclosed herein is a method of treating a cancer comprising a mutation in a gene that confers a homologous repair deficiency in a subject in need thereof, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in the gene that confers a homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof.

[0119] Also disclosed herein is a method for treating cancer located in the brain, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0120] In some embodiments, the cancer that resides in the brain arises from a primary peripheral tumor that has metastasized to the brain, hi some embodiments, the cancer that resides in the brain arises from primary brain tissue.

[0121] Also disclosed herein is a method for treating brain cancer, comprising administering a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0122] In some embodiments, the brain cancer is a primary brain tumor that begins in the brain and tends to remain there.

[0123] In some embodiments, the brain cancer is a secondary brain tumor. These cancers begin elsewhere in the body and travel to the brain. Lung, breast, kidney, colon, and skin cancers are the most common cancers that spread to the brain.

[0124] In some embodiments, the compounds disclosed herein, or pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, can penetrate the blood brain barrier (BBB). In some embodiments, the ratio of the compound penetrating the BBB is >0.1, with 1 being complete BBB penetration and 0 being no penetration. In some embodiments, the ratio of the compound penetrating the BBB is >0.2. In some embodiments, the ratio of the compound penetrating the BBB is >0.3. In some embodiments, the ratio of the compound penetrating the BBB is measured using a rat kp,uu assay. In some embodiments, the compound has a ratio of >0.3 (i.e., 0.3 to 1) as determined in a rat kp,uu assay.

[0125] Administration In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, medical history, the patient's health status, weight, and response to the drug, 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.

[0126] In prophylactic applications, compositions containing the compounds described herein are administered to patients 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." In this use, the exact amount also depends on the patient's health, weight, and the like. When used in patients, the effective amount for this use will depend on the severity and course of the disease, disorder or condition, medical history, the patient's health 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 pharma- ceutically 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.

[0127] In certain embodiments where the patient's condition does not improve, at the discretion of the physician, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire lifespan of the patient, to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

[0128] Once the patient's condition has improved, a maintenance dose is administered as needed. In specific embodiments, the dosage or frequency of administration, or both, are then reduced, depending on 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.

[0129] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), etc., but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0130] In general, however, the dose used for adult treatment is typically in the range of 0.01 mg to 5000 mg per day. In one aspect, the dose used for adult treatment is about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as two, three, four or more divided doses per day.

[0131] In one embodiment, a suitable daily dosage for the compounds described herein or pharma- ceutically acceptable salts thereof is about 0.01 to about 50 mg / kg of body weight. In some embodiments, the daily dosage or amount of active agent in the dosage form is lower or higher than the ranges set forth herein, based on a number of variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dosage will vary depending on 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 physician's judgment.

[0132] The toxicity and therapeutic efficacy of such treatment regimens are 10 and ED 90The dose ratio between toxic and therapeutic effects is the therapeutic index, and is known as the LD 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating a therapeutically effective daily dosage range and / or a therapeutically effective unit dosage for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is a daily dosage that provides an ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dosage amount varies within this range depending on the dosage form employed and the route of administration utilized.

[0133] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.Further, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intrathecal injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0134] In certain embodiments, the compounds described herein are administered in a localized manner rather than systemically, for example, via injection of the compound directly into an organ, often in a depot preparation or sustained release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneous or intramuscular) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of an immediate release formulation, an extended release formulation, or an intermediate release formulation. In still other embodiments, the compounds described herein are administered locally.

[0135] Pharmaceutical Compositions / Formulations The compounds described herein are administered to a subject in need of a compound described herein, either alone or in a pharmaceutical composition in combination with a pharma- ceutically acceptable carrier, excipient or diluent, according to standard pharmaceutical practice. In one embodiment, the compounds of the present invention can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0136] In another aspect, provided herein is a pharmaceutical composition comprising the 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 active compound into a preparation that can be used pharmaceutically.The appropriate formulation depends on the route of administration selected. Summary summaries of 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.

[0137] In some embodiments, the pharma- ceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegration agents, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizers, moistening agents, plasticizers, stabilizers, permeation enhancers, wetting agents, antifoaming agents, antioxidants, preservatives, and any combination thereof.

[0138] 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, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0139] Pharmaceutical compositions containing a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or compressing processes.

[0140] Pharmaceutical compositions for oral use can be obtained by mixing one or more solid excipients with one or more compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliary agents if desired to obtain tablets or dragee cores.Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol, cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.If desired, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, are added. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0141] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules contain the active ingredients in a mixture of fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds are dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added.

[0142] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the compounds described herein, or their pharma- ceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical compositions include 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 compositions further include a preservative to prevent the growth of microorganisms.

[0143] combination Disclosed herein are methods of treating cancer using the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0144] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0145] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein. EXAMPLES

[0146] Example 1 [ka] Step 1 and Step 2: Preparation of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide: A solution of 2H-pyrazole-3-carboxylic acid (3.00 g, 26.76 mmol, 1.00 equiv) in SOCl2 (30 mL) was stirred at 90° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with toluene (3×50 mL). The resulting mixture was concentrated under reduced pressure. The crude product 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]dodeca-3,5,9,11-tetraene-2,8-dione (2.3 g) was used directly in the next step without further purification.

[0147] To a stirred solution of 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]dodeca-3,5,9,11-tetraene-2,8-dione (2.30 g, 12.22 mmol, 1.00 equiv) and 3-bromo-2,6-difluoroaniline (5.09 g, 24.45 mmol, 2.00 equiv) in THF (100 mL) was added NaHMDS (2 M, 30.56 mL, 61.12 mmol, 5.00 equiv) dropwise at -10 °C. The resulting mixture was stirred at -10 °C for an additional 2 h. The reaction was monitored by LCMS. The mixture was neutralized to pH 7 with CH3CO2H. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography eluting with PE / EA (0% to 30% gradient in 30 min) to give N-(3-bromo-2,6-difluorophenyl)-2H-pyrazolo-3-carboxamide (6 g, 74.4%). LC-MS: (ES+H, m / z): [M+H] + =301.9; 1H NMR(300MHz,DMSO-d6)δ13.49(s,1H),10.01(s,1H),7.92(d,J=2.4Hz,1H),7.78-7.66(m,1H),7.25(td,J=9.1,1.9Hz,1H),6.77(d,J=2.2Hz,1H).

[0148] Step 3: Preparation of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]-4-quinoxalin-4-one: To a stirred solution of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (5.80 g, 19.20 mmol, 1.00 equiv) in DMA (2 mL) was added NaH (1.15 g, 28.80 mmol, 1.50 equiv, 60% in mineral oil) portionwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was quenched with water (50 mL) at 0° C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in DMSO (20 mL) and purified by reversed-phase flash chromatography (column: C18; mobile phase: MeOH in water (0.1% TFA), gradient 50% to 70% in 40 min; detector, UV 254 nm) to provide 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (1.5 g, 26.3%). LC-MS: (ES+H, m / z): [M+H] + =281.9; 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.13(s,1H),7.89(d,J=8.9Hz,1H),7.58(t,J=7.7Hz,1H),7.21(s,1H).

[0149] Step 4: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one: To a stirred solution of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (1.00 g, 3.54 mmol, 1.00 equiv.) and (tributylstannyl)methanol (1366 mg, 4.25 mmol, 1.20 equiv.) in dioxane (16 mL), XPhos precatalyst 2 (279 mg, 0.35 mmol, 0.10 equiv.) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was filtered, and then the filter cake was washed with DCM / MeOH=(1:5) (3×150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0-7% gradient in 30 min) to give 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (400 mg, 45.9%). LC-MS: (ES+H,m / z): [M+H] + =234.0; 1 H NMR(300MHz,DMSO-d6)δ11.95(s,1H),8.10(d,J=2.1Hz,1H),7.93(dd,J=8.5,1.4Hz,1H),7.38( dd,J=8.5,7.0Hz,1H),7.19(d,J=2.1Hz,1H),5.42(t,J=5.8Hz,1H),4.63(dd,J=5.8,1.5Hz,2H).

[0150] Step 5: Preparation of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one: To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (300 mg, 1.28 mmol, 1.00 equiv.) in DCM (8 mL) was added SOCl2 (765 mg, 6.43 mmol, 5.00 equiv.) and DMF (5 mg, 0.07 mmol, 0.05 equiv.) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with DCM (3×30 mL). The crude product (7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =252.0.

[0151] Step 6: Preparation of 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide: To a stirred mixture of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (180 mg, 0.71 mmol, 1.00 equiv.) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (204 mg, 0.86 mmol, 1.20 equiv.) in MeCN (10 ml), KI (24 mg, 0.14 mmol, 0.20 equiv.) and DIEA (462 mg, 3.57 mmol, 5.00 equiv.) were added at room temperature. The resulting mixture was stirred at 80° C. under 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 (CH2Cl2 / MeOH (gradient 0% to 10% in 30 min)) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide. The crude product was further purified by Prep-HPLC (Column: XBridge Shield RP18 OBD column, 50×250 mm, 10 μm; Mobile phase A: water (0.05% NH3H2O), Mobile phase B: MeCN; Flow rate: 25 mL / min; Gradient: 5% B to 40% B, 40% B in 35 min; Wavelength: 254 / 220 nm; RT1 (min): 30.5) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (204.4 mg, 62.4%). LC-MS: (ES+H, m / z): [M+H] + =454.1; 1H NMR(300MHz,DMSO-d6)δ11.98(s,1H),8.40(q,J=4.7Hz,1H),8.10(d,J=2.1Hz,1H),7.94(dd,J=8.5,1.2Hz,1H),7.84(dd,J=8.1,1.4Hz,1H),7.55(d d,J=10.6,8.1Hz,1H),7.34(dd,J=8.5,6.8Hz,1H),7.19(d,J=2.1Hz,1H), 3.69(s,2H),3.17-3.14(m,4H),2.77(d,J=4.7Hz,3H),2.65-2.57(m,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.57,-131.02.

[0152] The following examples were prepared using procedures similar to those set forth in Example 1. [Table 6-1] [Table 6-2]

[0153] Example 6 [ka] Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate: A solution of methyl 3-amino-2-fluorobenzoate (20.00 g, 118.23 mmol, 1.00 equiv) and NIS (23.94 g, 106.41 mmol, 0.90 equiv) in AcOH (250 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reversed-phase Combiflash chromatography (column: C18 gel; mobile phase: MeOH (0.1% FA) in water, gradient 10% to 50% in 10 min; detector, UV 254 nm) to give methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 11.4%). LC-MS: (ES+H, m / z): [M+H] + =295.80; 1 H NMR (300MHz, DMSO-d6) δ7.52 (dd, J=8.4, 1.5Hz, 1H), 6.81 (dd, J=8.3, 6.7Hz, 1H), 5.43 (s, 2H), 3.83 (s, 3H).

[0154] Step 2: Preparation of methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate: In a 250 mL round bottom flask, methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 13.55 mmol, 1.00 equiv), 3-furoic acid (1.52 g, 13.55 mmol, 1.00 equiv), T3P (43.14 g, 67.78 mmol, 5.00 equiv, 50% in EA), and DIEA (2.08 g, 16.10 mmol, 5.00 equiv) were added at room temperature. The resulting mixture was stirred overnight at 100° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA (0-20% gradient in 30 min)) to give methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate (4.50 g, 85.3%). LC-MS: (ES+H, m / z): [M+H] + =389.85; 1 H NMR(300MHz,DMSO-d6)δ9.99(s,1H),8.40(s,1H),7.91(dd,J=8.4,1.2Hz,1H),7. 83(t,J=1.7Hz,1H),7.61(dd,J=8.4,7.0Hz,1H),7.02-6.96(m,1H),3.86(s,3H).

[0155] Step 3: Preparation of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-2-fluoro-4-iodobenzoate: To a stirred mixture of methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate (2.60 g, 6.68 mmol, 1.00 equiv.) and (Boc)2O (2.92 g, 13.36 mmol, 2.00 equiv.) in DCE (50 mL) was added DMAP (0.82 g, 6.68 mmol, 1.00 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA=5:1, r=0.5). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (0-20% gradient in 30 min) to give methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-2-fluoro-4-iodobenzoate (3.00 g, 91.7%).

[0156] Step 4: Preparation of methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate: To a stirred solution of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-2-fluoro-4-iodobenzoate (3.00 g, 6.13 mmol, 1.00 equiv.) in DMF (30 mL), PCy3 (344 mg, 1.22 mmol, 0.20 equiv.), Pd(OAc)2 (275 mg, 1.22 mmol, 0.20 equiv.), K2CO3 (1.69 g, 12.26 mmol, 2.00 equiv.) were added at room temperature under nitrogen atmosphere. The reaction mixture was irradiated with microwave radiation at 120° C. for 2 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0-20% gradient in 30 min)) to give methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (310 mg, 19.3%). LC-MS: (ES+H,m / z): [M+H+MeCN] + =302.95.

[0157] Step 5: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one: To a stirred solution of methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (150 mg, 0.57 mmol, 1.00 equiv.) in THF (10 mL) was added LiAlH4 (0.46 mL, 1.14 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of HCl (aq) (1 M, 1.2 mL) at 0 °C. The residue was purified by silica gel column chromatography (eluting with CHCl / MeOH (0-10% gradient in 30 min)) to give 6-fluoro-7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (100 mg, 74.6%). LC-MS: (ES+H, m / z): [M+H] + =233.95.

[0158] Step 6: Preparation of 7-(chloromethyl)-6-fluoro-5H-furo[3,2-c]quinolin-4-one: To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (100 mg, 0.42 mmol, 1.00 equiv.) and DMF (2 mg, 0.03 mmol, 0.10 equiv.) in DCM (10 mL) was added SOCl2 (0.24 mL, 3.30 mmol, 10.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-6-fluoro-5H-furo[3,2-c]quinolin-4-one (100 mg, 92.6%). LC-MS: (ES+H, m / z): [M+H] + =252.00.

[0159] Step 7: Preparation of 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide: A solution of 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (95 mg, 0.39 mmol, 1.00 equiv.) in MeCN (5 mL) was treated with DIEA (205 mg, 1.58 mmol, 4.00 equiv.) at room temperature under nitrogen atmosphere for 5 min, followed by the addition of KI (7 mg, 0.04 mmol, 0.10 equiv.), 7-(chloromethyl)-6-fluoro-5H-furo[3,2-c]quinolin-4-one (100 mg, 0.39 mmol, 1.00 equiv.). The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (C18 gel; mobile phase, MeOH in water (0.1% NH3.H2O), gradient 10% to 50% in 10 min; detector, UV 254 nm) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (43.2 mg, 23.8%). LC-MS: (ES+H, m / z): [M+H] + = 454.10; 1 H NMR(400MHz,DMSO-d6)δ11.84-11.57(m,1H),8.39(q,J=4.7Hz,1H),8.13(d,J=2.1Hz,1H),7.84(dd,J=8.1,1.4Hz,1H),7.73(d,J=8.1Hz,1H),7.55( dd,J=10.6,8.1Hz,1H),7.33(dd,J=8.2,6.2Hz,1H),7.11(d,J=2.1Hz,1H) ,3.72(s,2H),3.19-3.16(m,4H),2.77(d,J=4.7Hz,3H),2.62-2.60(m,4H). 19 F NMR (377MHz, DMSO-d6) δ-72.56, δ-132.19.

[0160] The following examples were prepared using procedures similar to those set forth in Example 6. [Table 7]

[0161] Example 7 [ka] Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate: A solution of methyl 3-amino-2-fluorobenzoate (10 g, 59.12 mmol, 1.00 equiv) and NIS (12 g, 53.21 mmol, 0.90 equiv) in AcOH (120 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and poured into NaHCO3 (100 mL) (aq). The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18; mobile phase: MeOH in water (0.1% FA), gradient 10% to 50% in 10 min; detector, UV 254 nm) to give methyl 3-amino-2-fluoro-4-iodobenzoate (2.1 g, 11.98%). LC-MS: (ES+H, m / z): [M+H] + =295.80; 1 H NMR (400MHz, DMSO-d6) δ7.52 (d, J = 8.4, 1.3 Hz, 1H), 6.83-6.78 (m, J = 8.3, 6.7 Hz, 1H), 5.44 (s, 2H), 3.82 (s, 3H).

[0162] Step 2: Preparation of tert-butyl 2-[2-amino-3-fluoro-4-(methoxycarbonyl)phenyl]pyrrole-1-carboxylate: To a stirred solution of methyl 3-amino-2-fluoro-4-iodobenzoate (1 g, 3.39 mmol, 1.00 equiv.) and 1-(tert-butoxycarbonyl)pyrrol-2-ylboronic acid (1 g, 6.78 mmol, 2.00 equiv.) in 1,4-dioxane (120 mL), Pd(dppf)Cl2·CH2Cl2 (276 mg, 0.34 mmol, 0.10 equiv.) and CsF (1 g, 6.78 mmol, 2.00 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was heated and stirred at 100 °C for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18; mobile phase: MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) to give tert-butyl 2-[2-amino-3-fluoro-4-(methoxycarbonyl)phenyl]pyrrole-1-carboxylate (420 mg, 29.84%). LC-MS: (ES+H, m / z): [M+H] + =335.10.

[0163] Steps 3-4: Preparation of 7-fluoro-8-(hydroxymethyl)-6H-pyrrolo[1,2-c]quinazolin-5-one: A mixture of tert-butyl 2-[2-amino-3-fluoro-4-(methoxycarbonyl)phenyl]pyrrole-1-carboxylate (380 mg, 1.14 mmol, 1.00 equiv) with HCl in 1,4-dioxane (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give methyl 7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazoline-8-carboxylate (370 mg, crude).

[0164] To a stirred solution of methyl 7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazolin-8-carboxylate (crude) in THF (10 mL) was added LiAlH4 (0.9 mL, 2.28 mmol, 2.00 equiv., 2.5 M in THF) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 2 h. The reaction was monitored by LCMS. The mixture was poured into water (50 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (3:1 to 1:1)) to give 7-fluoro-8-(hydroxymethyl)-6H-pyrrolo[1,2-c]quinazolin-5-one (160 mg, 40.98%). LC-MS: (ES+H, m / z): [M+H] + =233.1; 1 H NMR(300MHz,DMSO-d6)δ11.54(s,1H),7.74(d,J=8.1Hz,1H),7.64(dd,J=3.1,1.5Hz,1H),7.30-7.23( m,1H),7.04(dd,J=3.6,1.5Hz,1H),6.72-6.68(m,1H),5.37-5.32(m,1H),4.60(dd,J=5.7,1.5Hz,2H).

[0165] Steps 5-6: Preparation of 6-fluoro-5-[4-({7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazolin-8-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide: To a stirred solution of 7-fluoro-8-(hydroxymethyl)-6H-pyrrolo[1,2-c]quinazolin-5-one (130 mg, 0.560 mmol, 1.00 equiv.) and 2 drops of DMF in DCM (15 mL) was added SOCl2 (333 mg, 2.8 mmol, 5.00 equiv.) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification.

[0166] To a stirred mixture of 8-(chloromethyl)-7-fluoro-6H-pyrrolo[1,2-c]quinazolin-5-one (130 mg, crude) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (124 mg, 0.52 mmol, 1.00 equiv., HCl salt) in MeCN (15 mL) was added KI (9 mg, 0.1 mmol, 0.10 equiv.) and DIEA (201 mg, 1.56 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was poured into water (35 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×100 mL) and concentrated under reduced pressure. The crude product (200 mg) was purified by Prep-HPLC (Column: Xselect CSH C18 OBD column 50 x 250 mm 10 μm; Mobile phase A: Water (0.1% NH4HCO3), Mobile phase B: MeCN---preparative; Flow rate: 100 mL / min; Gradient: 35% B to 55% B, 52% B in 30 min; Wavelength: 254 / 220 nm; RT1 (min): 27) to give 6-fluoro-5-[4-({7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazolin-8-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (50.2 mg, 21.2%). LC-MS: (ES+H, m / z): [M+H] + = 453.15; 1 H NMR(300MHz,DMSO-d6)δ11.57(s,1H),8.40(q,J=4.9Hz,1H),7.84(dd,J=8.1,1.5Hz,1H),7.74(d,J=8.1Hz,1H),7.65(dd,J=3.1,1.5Hz,1H),7.61-7.5 2(m,1H),7.28-7.18(m,1H),7.06(dd,J=3.6,1.5Hz,1H),6.75-6.67(m,1H) ,3.67(s,2H),3.25-3.11(m,4H),2.76(d,J=4.7Hz,3H),2.66-2.56(m,4H). 19 F NMR (282MHz, DMSO-d6) δ -72.56, -133.82.

[0167] Example 9 [ka] Step 1: Preparation of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate: To a stirred solution of methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (200 mg, 0.76 mmol, 1.00 equiv) in CF3CH2OH (50 mL) was added Pd / C (163 mg, 10%) at room temperature. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. Upon completion, the resulting mixture was filtered and the filter cake was then washed with CHCl2 / MeOH (10:1, 3×50 mL). The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography eluting with CHCl2 / MeOH (0-10% gradient in 30 min) to give methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (70 mg, 34.7%). LC-MS: (ES+H, m / z): [M+H] + = 263.95; 1 H NMR(300MHz,DMSO-d6)δ11.68(s,1H),7.58(dd,J=8.4,6.1Hz,1H),7.49(d,J=8.5Hz,1H),4.85(t,J=9.4Hz,2H),3.89(s,3H),3.10(t,J=9.4Hz,2H). 19 F NMR (377MHz, DMSO-d6) δ-124.45.

[0168] Step 2: Preparation of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one: To a stirred solution of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (60 mg, 0.22 mmol, 1.00 equiv.) in THF (5 mL) was added LiAlH4 (0.18 mL, 0.45 mmol, 2.00 equiv., 2.5 M in THF) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of HCl (aq) (1 M, 0.5 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0-10% gradient in 30 min) to give 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 93.2%). LC-MS: (ES+H,m / z): [M+H] + =236.0.

[0169] Step 3: Preparation of 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one: To a stirred solution of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 0.21 mmol, 1.00 equiv.) and DMF (2 mg, 0.02 mmol, 0.10 equiv.) in DCM (10 mL) was added SOCl2 (253 mg, 2.13 mmol, 10.00 equiv.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 92.7%). LC-MS: (ES+H, m / z): [M+H] + =254.0.

[0170] Step 4: Preparation of 6-fluoro-5-[4-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide: A solution of 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (47 mg, 0.19 mmol, 1.00 equiv) in MeCN (3 mL) was treated with DIEA (102 mg, 0.78 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere for 5 min, followed by the addition of KI (3 mg, 0.02 mmol, 0.10 equiv) and 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 0.19 mmol, 1.00 equiv). The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0-10% gradient in 30 min)) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (44.0 mg, 47.7%). LC-MS: (ES+H,m / z):[M+H] + = 456.05; 1 H NMR(300MHz,DMSO-d6)δ11.42(s,1H),8.40(d,J=5.0Hz,1H),7.84(dd,J=8.1,1.4Hz,1H),7.55(dd,J=10.6,8.1Hz,1H),7.41(d,J=8.2Hz,1H) ),7.27-7.19(m,1H),4.82(t,J=9.3Hz,2H),3.69(s,2H),3.18-3.15(m,4H),3.07(t,J=9.3Hz,2H),2.76(d,J=4.8Hz,3H),2.60-2.57(m,4H). 19 F NMR (377MHz, DMSO-d6) δ -72.57, -132.99. The following examples were made using procedures similar to those set forth in Example 9. [Table 8-1] [Table 8-2]

[0171] Example 10 [ka] Step 1: Preparation of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)pyrrole-2-carboxylate: To a stirred solution of methylpyrrole-2-carboxylate (1.1 g, 8.791 mmol, 1 equiv.) and K2CO3 (2.4 g, 17.58 mmol, 2 equiv.) in DMF (10 mL) was added 1-bromo-2,4-difluoro-3-nitrobenzene (3.1 g, 13.19 mmol, 1.50 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 150 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc (0-30%)) to give the crude product. The crude product (2.5 g) was further purified by Prep-HPLC (Column: YMC-Triart Prep C18-S, 100×250 mm, S-100 μm, 120A; Mobile phase A: Water (0.05% NH3.H2O + 12.5 mmol / L NH4HCO3), Mobile phase B: MeOH; Flow rate: 120 mL / min; Gradient: 45% B to 85% B, 74% B in 40 min; Wavelength: 254 / 220 nm; RT1 (min): 27;) to give methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)pyrrole-2-carboxylate (1.2 g, 38.8%). LC-MS: (ES+H, m / z): [M+H] + =342.95; 1 H NMR(300MHz,DMSO-d6)δ8.19(dd,J=8.7,7.3Hz,1H),7.53(dd,J=8.7,1.8Hz,1H),7.32(dd ,J=2.8,1.7Hz,1H),7.07(dd,J=3.9,1.7Hz,1H),6.42(dd,J=3.9,2.8Hz,1H),3.64(s,3H).

[0172] Step 2: Preparation of 7-bromo-6-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one: To a stirred solution of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)pyrrole-2-carboxylate (1.1 g, 3.206 mmol, 1 equiv.) and Fe (895 mg, 16.030 mmol, 5 equiv.) in AcOH (10 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 75° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered and then the filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (1:0 to 10:1) to give 7-bromo-6-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (800 mg, 88.7%). LC-MS: (ES+H,m / z): [M+H] + =281.0; 1 H NMR(300MHz,DMSO-d6)δ11.47(s,1H),8.22(dd,J=2.9,1.5Hz,1H),7.89(dd,J=9.0,1.7Hz, 1H),7.50(dd,J=8.9,6.8Hz,1H),7.11(dd,J=3.9,1.4Hz,1H),6.74(dd,J=3.9,2.8Hz,1H).

[0173] Step 3: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrrolo[1,2-a]quinoxalin-4-one: To a stirred solution of 7-bromo-6-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (380 mg, 1.352 mmol, 1.00 equiv.) and (tributylstannyl)methanol (521 mg, 1.622 mmol, 1.2 equiv.) in 1,4-dioxane (10 mL), XPhos Pd G2 (53 mg, 0.068 mmol, 0.05 equiv.) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0-20%)) to give 6-fluoro-7-(hydroxymethyl)-5H-pyrrolo[1,2-a]quinoxalin-4-one (250 mg, 79.6%). LC-MS: (ES+H, m / z): [M+H] + = 233.3; 1 H NMR(300MHz,DMSO-d6)δ11.28(s,1H),8.18(dd,J=2.9,1.5Hz,1H),7.88(dd,J=8.6,1.4Hz,1H),7.26(dd,J=8.5 ,7.2Hz,1H),7.08(dd,J=3.9,1.4Hz,1H),6.71(dd,J=3.9,2.8Hz,1H),5.36(t,J=5.8Hz,1H),4.61-4.59(m,2H).

[0174] Steps 4-5: Preparation of 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrrolo[1,2-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide: To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-pyrrolo[1,2-a]quinoxalin-4-one (150 mg, 0.646 mmol, 1 eq.) and SOCl2 (384 mg, 3.230 mmol, 5 eq.) in DCM (5 mL) was added DMF (9 mg, 0.129 mmol, 0.2 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting crude mixture was used directly in the next step without further purification. To a stirred mixture of 7-(chloromethyl)-6-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (crude) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (142 mg, 0.598 mmol, 1 eq, 1 eq HCl salt) in MeCN (5 mL) was added KI (10 mg, 0.060 mmol, 0.1 eq) and DIEA (232 mg, 1.794 mmol, 3 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 5 h. The reaction was monitored by LCMS. The resulting mixture was poured into water (20 mL) and extracted with CHCl (3×50 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous NaSO, filtered and concentrated. The crude product (300 mg) was purified by Prep-HPLC (Column: Xselect CSH C18 OBD column 30 × 150 mm 5 μm; Mobile phase A: water (0.1% formic acid), Mobile phase B: MeOH----preparative; Flow rate: 60 mL / min; Gradient: 21% B to 36% B, 36% B in 9 min; Wavelength: 254 / 220 nm; RT1 (min): 8.12;) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrrolo[1,2-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (54 mg, 19.3%). LC-MS: (ES+H, m / z): [M+H] + = 453.15; 1H NMR(300MHz,DMSO-d6)δ11.30(s,1H),8.40(q,J=4.9Hz,1H),8.20(dd,J=2.9,1.5Hz,1H),7.96-7.77(m,2H),7.56(dd,J=10.6,8.1Hz,1H),7.23(t, J=8.1Hz,1H),7.09(dd,J=3.9,1.4Hz,1H),6.72(t,J=3.6Hz,1H),3.66(s,2H),3.17(t,J=4.6Hz,4H),2.76(d,J=4.8Hz,3H),2.60(t,J=4.8Hz,4H). 19 F NMR (282MHz, DMSO-d6) δ -72.56, -131.51.

[0175] Examples 19 and 20 [ka] Step 1: Preparation of methyl 2-amino-4-bromo-3-fluorobenzoate: A solution of 2-amino-4-bromo-3-fluorobenzoic acid (15.00 g, 64.09 mmol, 1.00 equiv) in DMF (200 mL) was treated with DIEA (33.14 g, 256.38 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere for 5 min, followed by dropwise addition of CHI (16.38 g, 115.37 mmol, 1.80 equiv) at room temperature. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (1000 mL). The resulting mixture was washed with brine (3×500 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 30 min)) to give methyl 2-amino-4-bromo-3-fluorobenzoate (12.30 g, 73.4%). LC-MS: (ES+H, m / z): [M+H] + = 247.8 / 249.8; 1 H NMR (300MHz, DMSO-d6) δ7.48 (dd, J=8.8, 1.7Hz, 1H), 6.93-6.22 (m, 3H), 3.82 (s, 3H).

[0176] Step 2: Preparation of methyl 4-bromo-2-acetamido-3-fluorobenzoate: To a stirred solution of methyl 2-amino-4-bromo-3-fluorobenzoate (12.30 g, 49.58 mmol, 1.00 equiv) in MeCN (100 mL) was added acetyl chloride (5.84 g, 74.38 mmol, 1.50 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (50 mL) to give methyl 4-bromo-2-acetamido-3-fluorobenzoate (9.00 g, 73.4%). LC-MS: (ES+H, m / z): [M+H] + =290.2 / 290.2.

[0177] Step 3: Preparation of 7-bromo-8-fluoro-4-hydroxy-1H-quinolin-2-one: To a stirred solution of methyl 4-bromo-2-acetamido-3-fluorobenzoate (9.50 g, 32.74 mmol, 1.00 equiv) in THF (80 mL) was added LiHMDS (81 mL, 1.0 mol / L, 2.50 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water at 0° C. The resulting mixture was diluted with water (100 mL) and acidified to pH 5 with HCl (aq). The precipitated solid was collected by filtration and washed with water (2×50 mL) to provide 7-bromo-8-fluoro-4-hydroxy-1H-quinolin-2-one (6.40 g, 76.9%). LC-MS: (ES+H, m / z): [M+H] + =257.8 / 259.8.

[0178] Step 4: Preparation of (3Z)-7-bromo-3-[(dimethylamino)methylidene]-8-fluoro-1H-quinoline-2,4-dione: A solution of 7-bromo-8-fluoro-4-hydroxy-1H-quinolin-2-one (6.50 g, 25.18 mmol, 1.00 equiv.) and DMF-DMA (4.50 g, 37.78 mmol, 1.50 equiv.) in toluene (70 mL) was stirred at 80° C. under nitrogen atmosphere for 24 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration, washed with toluene (3×30 mL), and dried under vacuum to give (3Z)-7-bromo-3-[(dimethylamino)methylidene]-8-fluoro-1H-quinoline-2,4-dione (2.50 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =313.2 / 315.2.

[0179] Step 5: Preparation of 7-bromo-4-chloro-8-fluoro-2-oxo-1H-quinoline-3-carbaldehyde: A solution of (3Z)-7-bromo-3-[(dimethylamino)methylidene]-8-fluoro-1H-quinoline-2,4-dione (2.50 g, 7.98 mmol, 1.00 equiv.) and POCl3 (1.46 g, 9.58 mmol, 1.20 equiv.) in DMF (40 mL) was stirred at 0° C. for 10 min under nitrogen atmosphere. The resulting mixture was stirred at 60° C. for 24 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL) at 0° C. The precipitated solid was collected by filtration and washed with water (3×20 mL) to give 7-bromo-4-chloro-8-fluoro-2-oxo-1H-quinoline-3-carbaldehyde (2.25 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =303.8 / 305.8.

[0180] Step 6: Preparation of 7-bromo-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one: A solution of 7-bromo-4-chloro-8-fluoro-2-oxo-1H-quinoline-3-carbaldehyde (2.25 g, 7.38 mmol, 1.00 equiv.), K2CO3 (2.04 g, 14.77 mmol, 2.00 equiv.), and methylhydrazine (1.28 g, 8.86 mmol, 1.20 equiv.) in DMF (25 mL) was stirred at 80° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with water (3×50 mL). The resulting solid was dried under vacuum to give a mixture of 7-bromo-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (3.50 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H,m / z): [M+H] + =295.9 / 297.9. 1 H NMR (300MHz, DMSO-d6) δ11.38(s,1H),8.15(s,1H),7.97(dd,J=8.8,1.5Hz,1H),7.55(dd,J=8.8,6.5Hz,1H),4.35(s,3H).

[0181] Step 7: Preparation of 6-fluoro-7-(hydroxymethyl)-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 6-fluoro-7-(hydroxymethyl)-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one: A solution of 7-bromo-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (3.5 g, 11.82 mmol, 1.00 equiv.), XPhos precatalyst 2 (930 mg, 1.18 mmol, 0.10 equiv.), and (tributylstannyl)methanol (4.55 g, 14.18 mmol, 1.20 equiv.) in dioxane (20 mL) was stirred overnight at 80° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum and the crude residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (gradient 0% to 10% in 20 min)) to give 6-fluoro-7-(hydroxymethyl)-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 6-fluoro-7-(hydroxymethyl)-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (mixture, 700 mg, 23.9%). LC-MS: (ES+H, m / z): [M+H] + =247.9.

[0182] Step 8: Preparation of 7-(chloromethyl)-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-(chloromethyl)-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one: To a stirred solution of 6-fluoro-7-(hydroxymethyl)-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 6-fluoro-7-(hydroxymethyl)-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (700 mg, 2.83 mmol, 1.00 equiv.) and DMF (20 mg, 0.28 mmol, 0.10 equiv.) in DCM (10 mL), SOCl2 (3368 mg, 28.31 mmol, 10.00 equiv.) was added dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum to give 7-(chloromethyl)-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-(chloromethyl)-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (700 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H,m / z):[M+H] + =265.95.

[0183] Step 9: Preparation of 6-fluoro-5-[4-({6-fluoro-1-methyl-4-oxo-5H-pyrazolo[4,3-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide and 6-fluoro-5-[4-({6-fluoro-2-methyl-4-oxo-5H-pyrazolo[4,3-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide: A solution of 7-(chloromethyl)-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-(chloromethyl)-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (700 mg, 2.63 mmol, 1.00 equiv.), KI (43 mg, 0.26 mmol, 0.10 equiv.), DIEA (1702 mg, 13.17 mmol, 5.00 equiv.), and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (627 mg, 2.63 mmol, 1.00 equiv.) in MeCN (20 mL) was stirred at 80° C. for 3 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with CH3CN (3 x 10 mL) to give the crude product. The crude product was further purified by HPLC (column: YMC-Actus Triart C18 ExRS, 30 x 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MeOH -----preparative; flow rate: 60 mL / min; gradient: 45% B to 56% B, 56% B in 13 min; wavelength: 254 / 220 nm) to give 6-fluoro-5-[4-({6-fluoro-1-methyl-4-oxo-5H-pyrazolo[4,3-c]quinoline]. 6-Fluoro-5-[4-({6-fluoro-2-methyl-4-oxo-5H-pyrazolo[4,3-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (Example 19, 54 mg, 4.35%) and 6-fluoro-5-[4-({6-fluoro-2-methyl-4-oxo-5H-pyrazolo[4,3-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (Example 20, 1.8 mg, 0.14%) were obtained.

[0184] Example 19: LC-MS:(ES+H,m / z):[M+H] + = 468.05; 1H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.40(d,J=5.1Hz,1H),8.13(s,1H),8.02(d,J=8.4Hz,1H),7.84(dd,J=8.0,1.4Hz,1H),7.56(d d,J=10.6,8.1Hz,1H),7.34(t,J=7.5Hz,1H),4.36(s,3H),3.74(s,2H),3.23-3.11(m,4H),2.76(d,J=4.8Hz,3H),2.66-2.56(m,4H). 19 F NMR(377MHz, DMSO-d6)δ-72.56,-131.30.

[0185] Example 20: LC-MS: (ES+H, m / z): [M+H] + =468.0; 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.59(s,1H),8.40(d,J=5.5Hz,1H),7.82(dd,J=16.8,8.0Hz,2H),7.55(t,J=9.4 Hz,1H),7.24(t,J=7.4Hz,1H),4.10(s,3H),3.69(s,2H),3.24-3.08(m,4H),2.76(d,J=4.7Hz,3H),2.66-2.56(m,4H). 19 F NMR (377MHz, DMSO-d6) δ-72.54,-132.86.

[0186] Example 25

change

[0187] Step 2: Preparation of 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylic acid: To a stirred solution of ethyl 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylate (1.30 g, 8.22 mmol, 1.00 equiv) in THF (10 mL) was added LiOH (984 mg, 41.10 mmol, 5.00 equiv, 2M in water) at room temperature. The resulting solution was stirred at room temperature for 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH 3 with 2N HCl (aq), and the resulting mixture was extracted with EtOAc (3×100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylic acid (1.10 g, 95.6%). LC-MS: (ES-H, m / z): [MH] - =219.0.

[0188] Step 3: Preparation of 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-3-fluoro-1H-pyrazole-5-carboxamide: To a stirred solution of 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylic acid (1.00 g, 4.54 mmol, 1.00 equiv) and 3-bromo-2,6-difluoroaniline (1.13 g, 5.44 mmol, 1.20 equiv) in T3P (2 mL, 50% in EA) was added DIEA (1.76 g, 13.62 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 20% gradient in 30 min) to give 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-3-fluoro-1H-pyrazole-5-carboxamide (1.40 g, 96.3%). LC-MS: (ES+H, m / z): [M+H] + = 409.9; 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),7.80-7.78(m,1H),7.39-7.26(m,4H),7.26-7.14(m,2H),6.85(d,J=5.8Hz,1H),5.61(s,2H).

[0189] Step 4: Preparation of ethyl 3-(2-benzyl-5-fluoropyrazole-3-amido)-2,4-difluorobenzoate: To a stirred mixture of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide (800 mg, 1.95 mmol, 1.00 equiv.) and Pd(dppf)Cl2 (142 mg, 0.19 mmol, 0.10 equiv.) in EtOH (6 mL) was added TEA (592 mg, 5.85 mmol, 3.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110° C. under carbon monoxide atmosphere for 2 days. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EtOAc (0-20% gradient in 30 min)) to give ethyl 3-(2-benzyl-5-fluoropyrazole-3-amido)-2,4-difluorobenzoate (300 mg, 38.1%). LC-MS: (ES-H, m / z): [MH] - =402.1; 1 H NMR(300MHz,DMSO-d6)δ10.52(s,1H),7.99-7.91(m,1H),7.45-7.24(m,4H),7.23-7.17( m,2H),6.85(d,J=5.9Hz,1H),5.62(s,2H),4.34(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0190] Step 5: Preparation of ethyl 2,4-difluoro-3-(3-fluoro-1H-pyrazole-5-carboxamido)benzoate: To a stirred solution of ethyl 3-(1-benzyl-3-fluoro-1H-pyrazole-5-carboxamide)-2,4-difluorobenzoate (200 mg, 0.51 mmol, 1.00 equiv) in MeOH (3 mL) and 2M HCl (aq) (0.2 mL) was added Pd(OH)2 / C (72 mg, 0.10 mmol, 0.20 equiv, 20%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under hydrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3×3 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by silica gel column chromatography (PE / EtOAc (0-20% gradient in 30 min)) to give ethyl 2,4-difluoro-3-(3-fluoro-1H-pyrazole-5-carboxamido)benzoate (240 mg, 39.0%). LC-MS: (ES-H, m / z): [MH] - =311.9; 1 H NMR(300MHz,DMSO-d6)δ13.57(d,J=2.2Hz,1H),10.46(s,1H),8.07-7.80(m,1H),7.44- 7.37(m,1H),6.76(dd,J=6.2,2.3Hz,1H),4.34(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0191] Step 6: Preparation of ethyl 2,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate: To a stirred solution of ethyl 2,4-difluoro-3-(5-fluoro-2H-pyrazole-3-amido)benzoate (300 mg, 0.95 mmol, 1.00 equiv) in DMA (4 mL) was added NaH (76 mg, 1.91 mmol, 2.00 equiv, 60% in mineral oil) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 120° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc (0-30% gradient in 30 min) to give ethyl 2,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate (160 mg, 56.9%). LC-MS: (ES-H, m / z): [MH] - =292.0; 1 H NMR (300MHz, DMSO-d6) δ12.32(s,1H),7.88-7.83(m,1H),7.80-7.75(m,1H),7.08(d,J=5.6Hz,1H),4.36(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0192] Step 7: Preparation of 2,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one: To a stirred solution of ethyl 2,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate (150 mg, 0.10 mmol, 1.00 equiv) in THF (4 mL) was added LiEt3BH (1.5 mL, 1.53 mmol, 3.00 equiv, 1M in THF) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (1 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (40-70% gradient in 30 min) to give 2,6-difluoro-7-(hydroxymethyl)pyrazolo[1,5-a]quinoxalin-4(5H)-one (102 mg, crude). LC-MS: (ES-H, m / z): [MH] - =250.0.

[0193] Step 8: Preparation of 7-(chloromethyl)-2,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one: To a stirred solution of 2,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (90 mg, 0.35 mmol, 1.00 equiv.) and DMF (2 mg, 0.03 mmol, 0.10 equiv.) in CHCl (3 mL), SOCl (255 mg, 2.14 mmol, 6.00 equiv.) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The filtrate was concentrated under reduced pressure to give 7-(chloromethyl)-2,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (90 mg, crude). LC-MS: (ES-H, m / z): [MH] - =268.0.

[0194] Step 9: Preparation of 5-[4-({2,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide: To a stirred solution of 7-(chloromethyl)-2,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (90 mg, 0.33 mmol, 1.00 equiv.) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (79 mg, 0.33 mmol, 1.00 equiv.) in MeCN (5 mL) was added DIEA (215 mg, 1.67 mmol, 5.00 equiv.) and KI (5 mg, 0.03 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration and washed with MeOH (3×5 mL). The precipitated solid was purified by trituration with MeOH (6 mL). The precipitated solid was filtered and washed with MeOH (3×5 mL) to give 5-[4-({2,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide (82.3 mg, 50.4%). LC-MS: (ES+H, m / z): [M+H] + = 472.2; 1 H NMR(300MHz,DMSO-d6)δ12.17(s,1H),8.41(d,J=4.9Hz,1H),7.87-7.72(m,2H),7.56(dd,J=10.7,8.1Hz,1H),7. 40-7.30(m,1H),6.98(d,J=5.7Hz,1H),3.69(s,2H),3.18-3.15(m,4H),2.76(d,J=4.8Hz,3H),2.63-2.60(m,4H). 19 F NMR (282MHz, DMSO-d6) δ -72.59, -126.66, -131.30.

[0195] Example 28 [ka] Step 1: Preparation of ethyl 4-fluoro-2H-pyrazole-3-carboxylate: To a stirred solution of 4-fluoro-2H-pyrazole-3-carboxylic acid (850 mg, 6.53 mmol, 1.00 equiv) in EtOH (15 mL) was added SOCl2 (4.66 g, 39.21 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, 96.7%). LC-MS: (ES-H, m / z): [MH] - = 157.1; 1 H NMR (300MHz, DMSO-d6) δ7.60 (d, J = 4.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0196] Step 2: Preparation of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate: To a stirred solution of ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, 6.32 mmol, 1.00 equiv.) and K2CO3 (2.62 g, 18.97 mmol, 3.00 equiv.) in DMF (30 mL) was added (bromomethyl)benzene (2.16 g, 12.64 mmol, 2.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (150 mL), washed with water (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0-30% gradient in 30 min)) to give a mixture of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate (1.30 g, 82.8%). LC-MS: (ES+H, m / z): [M+H] + =249.0; 1H NMR(300MHz,DMSO-d6)δ7.50-7.29(m,6H),7.28-7.20(m,4H),5.69(s,1H),5.32(s,2H),4 .46(q,J=7.2Hz,2H),4.36(q,J=7.1Hz,1H),1.43(t,J=7.1Hz,3H),1.36(t,J=7.1Hz,2H).

[0197] Step 3: Preparation of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid: To a stirred solution of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate (1.30 g, 5.23 mmol, 1.00 equiv) in THF (15 mL) was added LiOH (15 mL, 30.00 mmol, 5.73 equiv, 2M in water) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL) and washed with EtOAc (1×80 mL). The aqueous layer was acidified to pH 6 with citric acid. The aqueous layer was extracted with EtOAc (3×100 mL) and the combined organic layers were dried over Na2SO4, filtered and concentrated to give 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid (1.10 g, 95.4%). LC-MS: (ES-H, m / z): [MH] - =219.1.

[0198] Step 4: Preparation of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide and 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide: To a stirred solution of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid (1.10 g, 4.99 mmol, 1.00 equiv.) in T3P (40 mL, 50% in EA), DIEA (1.94 g, 14.98 mmol, 3.00 equiv.) and 3-bromo-2,6-difluoroaniline (1.25 g, 5.99 mmol, 1.20 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (120 mL). The resulting mixture was washed with 2×100 mL of water, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc (0-30% gradient in 30 min)) to give a mixture of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide and 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide (1.60 g, 78.0%). LC-MS: (ES+H, m / z): [M+H] + = 410.0 / 412.0; 1 H NMR(300MHz,DMSO-d6)δ10.25(s,1H),10.06(s,1H),8.22(d,J=4.4Hz,1H),7.8 4-7.67(m,2H),7.45-7.28(m,7H),7.28-7.15(m,3H),5.56(s,1H),5.40(s,2H).

[0199] Step 5: Preparation of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoate and ethyl 3-(1-benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzoate: To a solution of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide and 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide (1.20 g, 2.92 mmol, 1.00 equiv.) in EtOH (8 mL) was added Pd(dppf)Cl2 (214 mg, 0.29 mmol, 0.10 equiv.) in a pressure tank. The mixture was purged with nitrogen for 10 min and then pressurized to 50 atm with carbon monoxide at 120° C. overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc (0-40% gradient in 40 min)) to give a mixture of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoate and ethyl 3-(1-benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzoate (1.10 g, 93.2%). LC-MS: (ES+H, m / z): [M+H] + =404.1; 1 H NMR(400MHz,DMSO-d6)δ10.18(s,1H),10.00(s,2H),8.21(d,J=4.4Hz,2H),7.99-7.86(m,3H),7.78(d,J=4.3H z,1H),7.46-7.25(m,16H),7.23-7.16(m,2H),5.56(s,2H),5.40(s,4H),4.38-4.3(m,6H),1.35-1.28(m,9H).

[0200] Step 6: Preparation of ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amido)benzoate: To a solution of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoate and ethyl 3-(1-benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzoate (500 mg, 1.24 mmol, 1.00 equiv.) in 20 mL of MeOH / HCl=10:1, Pd(OH)2 / C (1.04 g, 1.49 mmol, 1.20 equiv., 20%) was added in a pressure tank. The mixture was hydrogenated at room temperature under 30 psi hydrogen pressure overnight, then filtered through a Celite® pad and washed with additional DCM:MeOH=10:1 (3×50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (30-60% gradient in 30 min)) to give ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amido)benzoate (150 mg, 38.6%). LC-MS: (ES+H, m / z): [M+H] + =314.1.

[0201] Step 7: Preparation of ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate: To a stirred solution of ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amido)benzoate (160 mg, 0.51 mmol, 1.00 equiv) in DMF (10 mL) was added Cs2CO3 (499 mg, 1.53 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with CHCl2:IPA=10:1 (3×30 mL). The combined organic layers were washed with water (2×40 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0-40% gradient in 40 min) to give ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate (60 mg, 40.0%). LC-MS: (ES-H, m / z): [MH]- =292.0; 1 H NMR(300MHz,DMSO-d6)δ12.11(s,1H),8.32(d,J=3.8Hz,1H),7.99(dd,J=8.8,1.3 Hz,1H),7.77(dd,J=8.8,6.9Hz,1H),4.37(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0202] Step 8: Preparation of 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one: To a stirred solution of ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate (60 mg, 0.20 mmol, 1.00 equiv) in THF (4 mL) was added LiEt3BH (0.61 mL, 0.61 mmol, 3.00 equiv, 1M in THF) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (0.2 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0-10% gradient in 30 min)) to give 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (50 mg, 97.2%). LC-MS: (ES-H, m / z): [MH] - =249.9.

[0203] Step 9: Preparation of 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one: To a stirred solution of 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (50 mg, 0.19 mmol, 1.00 equiv.) and DMF (1 mg, 0.02 mmol, 0.10 equiv.) in DCM (1 mL) was added SOCl2 (118 mg, 0.99 mmol, 5.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (50 mg, crude). LC-MS: (ES-H, m / z): [MH] - =268.0.

[0204] Step 10: Preparation of 5-[4-({3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide: To a stirred solution of 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (50 mg, 0.18 mmol, 1.00 equiv.) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (50 mg, 0.18 mmol, 1.00 equiv.) in MeCN (3 mL) was added KI (3 mg, 0.01 mmol, 0.10 equiv.) and DIEA (95 mg, 0.74 mmol, 4.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with MeCN (5 mL) and the precipitated solid was collected by filtration and washed with MeOH (3×3 mL). The precipitated solid was then purified by trituration with MeOH (4 mL), filtered, and washed with MeOH (3×2 mL). The precipitated solid was then further purified by trituration with hexanes (4 mL). The precipitated solid was collected by filtration and washed with MeOH (3×2 mL) to give 5-[4-({3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide (42 mg, 46.9%). LC-MS: (ES+H, m / z): [M+H] + =472.1; 1 H NMR(300MHz,DMSO-d6)δ11.95(s,1H),8.40(q,J=4.6Hz,1H),8.22(d,J=3.8Hz,1H),7.91(dd,J=8.5,1.3Hz,1H),7.84(dd,J=8.0,1.5Hz, 1H),7.56(dd,J=10.6,8.1Hz,1H),7.35(dd,J=8.6,6.8Hz,1H),3.69(s,2H),3.19-3.16(m,4H),2.76(d,J=4.8Hz,3H),2.63-2.59(m,4H). 19 F NMR (282MHz, DMSO-d6) δ -72.59, -130.76, -168.39.

[0205] The following examples were prepared using procedures similar to those set forth in Example 28. [Table 9]

[0206] Example 31 [ka] Step 1: Preparation of 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione: To a stirred mixture of 2-amino-4-bromo-3-fluorobenzoic acid (50.00 g, 213.65 mmol, 1.00 equiv) in THF (500 mL) was added ditrichloromethyl carbonate (31.70 g, 106.82 mmol, 0.50 equiv) in THF (200 mL) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (100 mL), stirred for 30 min, and then concentrated. The residue was then dissolved in hexane (100 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 min. The precipitated solid was collected by filtration and washed with hexane (3×100 mL). The resulting mixture was concentrated under reduced pressure to give 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione (54 g, 97.2%). LC-MS: (ES-H, m / z): [MH] - = 257.8 / 259.8; 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.68(dt,J=8.6,1.6Hz,1H),7.53(ddd,J=8.4,6.0,1.9Hz,1H). 19 F NMR(377MHz,DMSO-d6)δ-122.54.

[0207] Step 2: Preparation of 3-(2-amino-4-bromo-3-fluorobenzoyl)dihydrofuran-2(3H)-one-5,5-d2: Preparation of dihydrofuran-2(3H)-one-5,5-d2: To a stirred solution of succinic anhydride (10.00 g, 100.02 mmol, 1.00 equiv) in THF (200 mL) was added LiAlD4 (60 mL, 60.01 mmol, 0.60 equiv, 1 M in THF) dropwise at -55 °C under nitrogen atmosphere. The mixture was allowed to warm to 0 °C and stirred for 1.5 h. The reaction was monitored by TLC (PE:EA = 1:1). The reaction was quenched by the addition of HCl (6 M aq.) (35 mL) at -15 °C. The resulting mixture was extracted with CHCl (3 x 500 mL). The combined organic layers were washed with brine (2×300 mL), dried over anhydrous MgSO 4 , filtered and concentrated to give dihydrofuran-2(3H)-one-5,5-d2 (4.5 g, 51.0%). 1 H NMR (400MHz, CDCl3) δ2.56-2.47(m,2H), 2.31-2.20(m,2H).

[0208] To a stirred mixture of 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione (4.50 g, 17.30 mmol, 1.00 equiv.) and dihydrofuran-2(3H)-one-5,5-d2 (2.29 g, 25.95 mmol, 1.50 equiv.) in THF (90 mL) was added LDA (30.29 mL, 60.57 mmol, 3.50 equiv., 2M in THF) dropwise at −70° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (30 mL) at −15° C. 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): [MH] - =301.9 / 303.9.

[0209] Step 3: Preparation of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-2,2-d2)quinolin-2(1H)-one: To a stirred solution of 3-(2-amino-4-bromo-3-fluorobenzoyl)dihydrofuran-2(3H)-one-5,5-d2 (5.3 g, estimated yield 100%, 17.42 mmol, 1.00 equiv) in DMF (100 mL) was added K2CO3 (4.82 g, 34.85 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The mixture was diluted with ice water (800 mL) and then acidified to pH 4 with citric acid. The resulting mixture was stirred at room temperature for 1 h. The precipitated solid was collected by filtration, washed with water (3×100 mL) and dried to give 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-2,2-d2)quinolin-2(1H)-one (3.5 g, 66.0%). LC-MS: (ES+H, m / z): [M+H] + =304.0 / 306.0; 1 H NMR (400MHz, DMSO-d6) δ11.55(s, 1H), 7.60(dd, J=8.7, 1.4Hz, 1H), 7.39(dd, J=8.7, 6.2Hz, 1H), 2.79(s, 2H).

[0210] Step 4: Preparation of 7-bromo-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2: To a stirred mixture of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-2,2-d2)quinolin-2(1H)-one (3.00 g, 9.86 mmol, 1.00 equiv) in DMA (30 mL) was added H2SO4 (3 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 140° C. for 3 h under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with ice water (500 mL) and stirred at room temperature for 1 h. The precipitated solid was collected by filtration and washed with water (3×100 mL). MeOH (30 mL) was added and the precipitated solid was collected by filtration and washed with MeOH (3×5 mL). The resulting solid was dried to give 7-bromo-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2 (1.34 g, 47.4%). LC-MS: (ES+H, m / z): [M+H] + 285.9 / 287.9. 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),7.43(dd,J=8.6,6.0Hz,1H),7.36(dd,J=8.6,1.2Hz,1H),3.05(s,2H).

[0211] Step 5: Preparation of 6-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2: To a stirred solution of 7-bromo-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2 (1.34 g, 4.68 mmol, 1.00 equiv.) and (tributylstannyl)methanol (3.01 g, 9.36 mmol, 2.00 equiv.) in dioxane (10 mL), XPhos precatalyst 2 (737 mg, 0.93 mmol, 0.20 equiv.) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (gradient 0% to 5% in 30 min)) to give 6-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2 (730 mg, 65.7%). LC-MS: (ES-H, m / z): [MH] - =238.0; 1 H NMR(300MHz,DMSO-d6)δ11.38(s,1H),7.40(d,J=8.1Hz,1H),7.26(dd,J=8.2,6.3Hz,1H),5.44(s,1H),4.64(s,2H),3.05(s,2H). 19 F NMR(282MHz,DMSO-d6)δ-134.69.

[0212] Step 6: Preparation of 7-(chloromethyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2: To a stirred solution of 6-fluoro-7-(hydroxymethyl)(2,2-2H2)-3H,5H-furo[3,2-c]quinolin-4-one (711 mg, 2.99 mmol, 1.00 equiv.) in DCM (10 mL) was added SOCl2 (2139 mg, 17.98 mmol, 6.00 equiv.) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2 (779 mg, crude). LC-MS: (ES+H, m / z): [M+H]+ =256.0.

[0213] Step 7: Preparation of 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl-2,2-d2)methyl)piperazin-1-yl)-N-methylpicolinamide: To a stirred mixture of 7-(chloromethyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-2,2-d2 (779 mg, estimated yield 100%, 3.04 mmol, 1.00 equiv.) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (837 mg, 3.04 mmol, 1.00 equiv.) in MeCN (30 mL) was added DIEA (1.58 g, 12.18 mmol, 4.00 equiv.) and KI (51 mg, 0.30 mmol, 0.10 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with MeCN (3×20 mL). The residue was triturated with DMSO (15 mL) and the precipitated solid was collected by filtration and washed with MeOH (3×20 mL). The crude product (400 mg) was purified by Prep-HPLC (Column: XBridge Shield C18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3H2O), Mobile phase B: MeCN; Flow rate: 100 mL / min; Gradient: 10% B to 40% B in 30 min; Wavelength: 254 / 220 nm; RT1 (min): 10) to give 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl-2,2-d2)methyl)piperazin-1-yl)-N-methylpicolinamide (239.5 mg, 17.1% over two steps). LC-MS: (ES+H, m / z): [M+H] + = 458.15; 1H NMR(400MHz,DMSO-d6)δ11.42(s,1H),8.41(d,J=4.9Hz,1H),7.84(dd,J=8.2,1.4Hz,1H),7.55(dd,J=10.6,8.1Hz,1H),7.41(d, J=8.1Hz,1H),7.23(dd,J=8.2,6.1Hz,1H),3.69(s,2H),3.17(d,J=5.1Hz,4H),3.06(s,2H),2.76(d,J=4.8Hz,3H),2.58(s,4H). 19 F NMR (282MHz, DMSO-d6) δ -72.56, -132.97.

[0214] Example 32 [ka] Step 1: Preparation of dihydrofuran-2(3H)-one-4,4-d2: Sodium (1.2 g, 51.76 mmol, 1.54 equiv) was dissolved in methane-d3-ol-d (128 mL). Once the sodium was consumed, butanedioic acid monomethyl ester (4.4 g, 33.61 mmol, 1.00 equiv) was added followed by methane-d3-ol-d (68 mL). The solution was heated to reflux for 24 h, then cooled in ice and acetic acid-d3 acid-d (1.2 g, 18.15 mmol, 0.54 equiv) was added. The solution was stirred for 20 min and then the solvent was removed in vacuo. The white solid was dissolved in water (50 mL) and, while cooling in a water bath, NaBH4 (10.9 g, 289.02 mmol, 8.60 equiv) was added slowly followed by more water (15 mL). The reaction was stirred at room temperature for 12.5 h and then cooled in ice. Concentrated HCl (29 mL) was added, followed by additional concentrated saturated HCl (5.9 mL), and the solution was heated to 110° C. for 1 h. It was then cooled to room temperature, saturated with NaCl, and extracted with DCM (4×150 mL). The combined organic extracts were dried over MgSO4 and concentrated to give dihydrofuran-2(3H)-one-4,4-d2 (1.8 g, 60.8%). 1 H NMR (300MHz, CDCl3) δ4.35(s,2H),2.49(s,2H).

[0215] Steps 2 and 3: Preparation of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-1,1-d2)quinolin-2(1H)-one: To a stirred mixture of 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione (3.00 g, 11.54 mmol, 1.00 equiv) in THF (20 mL) was added dihydrofuran-2(3H)-one-4,4-d2 (1.20 g, 13.85 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The mixture was allowed to cool to -70°C. To the above mixture was added LDA (20 mL, 40.38 mmol, 3.50 equiv, 2M in THF) dropwise over 1 h at -70°C. The resulting mixture was stirred at 0°C for an additional 3 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (20 mL) at 0°C and then concentrated. DMF (50 mL) was added to the residue followed by K2CO3 (3.20 g, 23.15 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for an additional 3 h under nitrogen atmosphere and then cooled to room temperature. The mixture was diluted with ice water (500 mL), acidified to pH 4 with citric acid, and stirred at room temperature for 1 h. The precipitated solid was collected by filtration, washed with water (3×50 mL), and dried at 45° C. to give 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-1,1-d2)quinolin-2(1H)-one (1.9 g, 54.3% over two steps). LC-MS: (ES+H, m / z): [M+H] + =303.9.

[0216] Step 4: Preparation of 7-bromo-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2: To a stirred mixture of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-1,1-d2)quinolin-2(1H)-one (1.90 g, 6.25 mmol, 1.00 equiv) in DMA (30 mL) was added concentrated H2SO4 (3 mL) dropwise at room temperature under nitrogen atmosphere (Caution: exothermic). The resulting mixture was stirred at 140° C. for 3 h under nitrogen atmosphere, cooled to room temperature, and then poured into ice water. The resulting mixture was stirred at room temperature for an additional 30 min. The precipitated solid was collected by filtration, washed with water (3×20 mL), and dried at 45° C. to give 7-bromo-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2 (1.1 g, 61.5%). LC-MS: (ES+H, m / z): [M+H] + = 285.9 / 287.9; 1 H NMR(300MHz,DMSO-d6)δ11.61(s,1H),7.53-7.26(m,2H),4.82(s,2H). 19 F NMR (282MHz, DMSO-d6) δ-121.96.

[0217] Step 5: Preparation of 6-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2: To a stirred solution of 7-bromo-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2 (1.10 g, 3.85 mmol, 1.00 equiv.) and XPhos precatalyst 2 (303 mg, 0.39 mmol, 0.10 equiv.) in dioxane (15 mL), (tributylstannyl)methanol (1.50 g, 4.61 mmol, 1.20 equiv.) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 3 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 10% in 30 min) to give 6-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2 (470 mg, 51.5%). LC-MS: (ES+H, m / z): [M+H] + =238.0; 1 H NMR(300MHz,DMSO-d6)δ11.37(s,1H),7.41(dd,J=8.2,1.0Hz,1H),7.26(dd,J=8 .2,6.3Hz,1H),5.43(t,J=5.8Hz,1H),4.81(s,2H),4.64(dd,J=5.8,1.6Hz,2H). 19 F NMR(282MHz,DMSO-d6)δ-135.04.

[0218] Step 6: Preparation of 7-(chloromethyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2: To a stirred mixture of 6-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2 (470 mg, 1.98 mmol, 1.00 equiv) in DCM (15 mL) was added SOCl2 (0.9 mL, 11.89 mmol, 6.00 equiv) dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 h. The reaction was monitored by LCMS. The resulting mixture was diluted with CH2Cl2 (10 mL) and then concentrated under reduced pressure. The crude product was diluted with THF (40 mL) and then concentrated under reduced pressure. The product was further purified by trituration with MeCN (10 mL) to give 7-(chloromethyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2 (560 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =256.1

[0219] Step 7: Preparation of 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl-3,3-d2)methyl)piperazin-1-yl)-N-methylpicolinamide: To a stirred mixture of 7-(chloromethyl)-6-fluoro-3,5-dihydrofuro[3,2-c]quinolin-4(2H)-one-3,3-d2 (540 mg, 2.11 mmol, 1.00 equiv.) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (580 mg, 2.11 mmol, 1.00 equiv.) in MeCN (15 mL) was added DIEA (1.10 g, 8.45 mmol, 4.00 equiv.) and KI (175 mg, 1.06 mmol, 0.50 equiv.) at room temperature. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with MeCN (10 mL) and the precipitated solid was collected by filtration and washed with MeCN (3×5 mL). The residue was purified by trituration with MeOH (10 mL). The precipitated solid was collected by filtration and washed with MeOH (3×10 mL). The residue was purified by trituration with DMSO (5 mL). The precipitated solid was collected by filtration and washed with MeOH (3×10 mL). The resulting solid was dried under reduced pressure and the crude product (550 mg) was purified by Prep-HPLC (Column: XBridge Shield C18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3H2O), Mobile phase B: MeCN; Flow rate: 100 mL / min; Gradient: 10% B to 40% B in 30 min; Wavelength: 254 / 220 nm) to give 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl-3,3-d2)methyl)piperazin-1-yl)-N-methylpicolinamide (409.8 mg, 42.0%). LC-MS: (ES+H, m / z): [M+H] + = 458.15; 1H NMR(300MHz,DMSO-d6)δ11.42(s,1H),8.40(d,J=5.0Hz,1H),7.84(dd,J=8.0,1.5Hz,1H),7.55(dd,J=10.6,8.1Hz,1H),7.40(d,J=8. 1Hz,1H),7.22(dd,J=8.2,6.1Hz,1H),4.81(s,2H),3.69(s,2H),3.16(d,J=5.4Hz,4H),2.76(d,J=4.8Hz,3H),2.59(d,J=4.8Hz,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.56,-133.00.

[0220] Comparative Example Comparative Example 1 (Example 19 in International Publication No. 2023025307) [ka] Step 1: Preparation of tert-butyl 4-[2-methyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate: A mixture of 5-bromo-N,6-dimethylpyridine-2-carboxamide (1.00 g, 4.37 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (975 mg, 5.23 mmol, 1.20 equiv), BINAP (272 mg, 0.44 mmol, 0.10 equiv), Pd(OAc)2 (98 mg, 0.44 mmol, 0.10 equiv), and Cs2CO3 (3.56 g, 10.91 mmol, 2.50 equiv) in toluene (20.00 mL) was stirred at 80° C. for hours under nitrogen atmosphere. The reaction was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase Combiflash using the following conditions (70% MeOH in water with 0.1% NH3H2O) to give tert-butyl 4-[2-methyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.17 g, 79.9%) as a white solid. LC-MS: (ES+H,m / z):[M+H] + =335.3. 1H NMR (300MHz, CD4OD) δ7.89(d,J=8.2Hz,1H),7.51(d,J=8.3Hz,1H),3.63(t,J=5.0Hz,4H),2.97(d,J=4.4Hz,7H),2.59(s,3H),1.51(s,9H).

[0221] Step 2: Preparation of N,6-dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride: To a stirred solution of tert-butyl 4-[2-methyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (200 mg, 0.60 mmol, 1 equiv) in DCM (4 mL) was added HCl (gas) in 1,4-dioxane (4 mL, 16.00 mmol, 26.75 equiv, 4 M) at room temperature. The resulting solution was stirred at rt for 1 h. LCMS was clean. The resulting mixture was concentrated under reduced pressure to give N,6-dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride (160 mg, crude) as a white solid, which was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =235.2

[0222] Step 3: 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 nitrogen atmosphere. The mixture was allowed to cool to room temperature. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (PE~5:1) 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.

[0223] Step 4: 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)2O (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 at room temperature under nitrogen atmosphere overnight. 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 Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (PE~3:1) to give methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate (5.00 g, 65.63%) as a white solid. 1H 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).

[0224] Step 5: 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 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 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 eluting with PE / EtOAc (100:1 to 1:2) 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.

[0225] Step 6: 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 nitrogen atmosphere. The mixture was hydrogenated under hydrogen atmosphere at room temperature for 2 days. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase silica gel column chromatography using the following conditions: column, C18; mobile phase, MeCN in water, gradient 20% to 50% in 10 min; detector, UV 220 nm 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.

[0226] Step 7: 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 LiAlH4 (0.55 mL, 1.39 mmol, 2.00 equiv, 2.5 M in THF) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h under nitrogen atmosphere. 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 eluting with CHCl / MeOH (10:1 to 2:1) 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) δ 11.38(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).

[0227] Step 8: 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), thionyl chloride (744 mg, 6.26 mmol, 8.00 equiv.) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (30:1 to 10:1) 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.

[0228] Step 9: Preparation of N,6-dimethyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide: A mixture of 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (200 mg, 0.849 mmol, 1.00 equiv.), N,6-dimethyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (299 mg, estimated yield 100%, 1.10 mmol, 1.30 equiv.), DIEA (438.74 mg, 3.396 mmol, 4 equiv.), and KI (14.09 mg, 0.085 mmol, 0.10 equiv.) in MeCN (5 mL) was stirred at 80° C. for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (15 mL) and extracted with CHCl:MeOH=10:1 (3×20 mL). The combined organic layer was washed with CHCl (3×5 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / MeOH (0-10% gradient in 30 min) to give N,6-dimethyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide (100 mg) as a yellow solid. The residue was purified by trituration with MeCN (5 mL). The precipitated solid was collected by filtration and washed with MeCN (1×1 mL) to give N,6-dimethyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide (72 mg, 19.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =434.15. 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.41(q,J=4.8Hz,1H),7.79(d,J=8.2Hz ,1H),7.56(d,J=8.1Hz,1H),7.48(d,J=8.3Hz,1H),7.35(d,J=1.5Hz,1H),7.1 7(dd,J=8.2,1.5Hz,1H),4.79(t,J=9.2Hz,2H),3.62(s,2H),3.04(t,J=9.2Hz ,2H),2.95(t,J=4.7Hz,4H),2.80(d,J=4.8Hz,3H),2.58(s,4H),2.49(s,3H).

[0229] Comparative Example 2 (Example 18 in International Publication No. 2023025307) [ka] Step 1: Preparation of tert-butyl 4-[6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate: To a stirred mixture of methyl 5-bromopyridine-2-carboxylate (10.00 g, 46.28 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (12.93 g, 69.43 mmol, 1.50 equiv) in 1,4-dioxane (100 mL), Cs2CO3 (30.16 g, 92.57 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (1.94 g, 2.31 mmol, 0.05 equiv) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 5 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20-50% in 25 min) and the pure fractions were concentrated in vacuo to give tert-butyl 4-[6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (11 g, Y=67.2%) as a white solid. LC-MS: (ES+H,m / z):[M+H] + =322.2.

[0230] Step 2: Preparation of tert-butyl 4-(6-(methylcarbamoyl)pyridin-3-yl)piperazine-1-carboxylate: A solution of tert-butyl 4-[6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (5.00 g, 15.55 mmol, 1.00 equiv) in MeOH (50 mL) was treated with CH3NH2 (15 mL, 25-30% in water) at room temperature under nitrogen atmosphere for 10 min. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was concentrated under vacuum to give tert-butyl 4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (5 g, Y=96.8%) as a yellow solid. The resulting mixture was used directly in the next step without further purification. LC-MS: (ES+H,m / z):[M+H] + =321.3.

[0231] Step 3: Preparation of tert-butyl 4-[2-chloro-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate: A solution of tert-butyl 4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (5 g, 15.60 mmol, 1.00 equiv.) in MeCN (30 mL) was treated with NCS (2.71 g, 20.28 mmol, 1.30 equiv.) in MeCN (20 mL) at room temperature under nitrogen atmosphere for 10 min. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (20-50% in 25 min) and the pure fractions were concentrated under vacuum to give tert-butyl 4-[2-chloro-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (3.5 g, Y=63.2%) as a yellow solid. LC-MS: (ES+H,m / z):[M+H] + =355.1. 1 H NMR(400MHz,DMSO-d6)δ8.45(q,J=4.7Hz,1H),7.95(d,J=8.1Hz,1H),7.68(d,J=8. 2Hz, 1H), 3.60-3.44 (m, 4H), 3.13-3.01 (m, 4H), 2.79 (d, J=4.8Hz, 3H), 1.43 (s, 9H).

[0232] Step 4: Preparation of 6-chloro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride: A solution of tert-butyl 4-[2-chloro-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (300 mg, 0.84 mmol, 1.00 equiv) in DCM (3 mL) was treated with HCl in 1,4-dioxane (2 mL) at room temperature under nitrogen atmosphere for 1 min. The resulting mixture was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was concentrated in vacuum to give 6-chloro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (251 mg, crude) as a yellow solid. The resulting mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =255.1.

[0233] Step 5: Preparation of 6-chloro-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 mixture of 6-chloro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (203 mg, 0.70 mmol, 1.50 equiv.) and 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (110 mg, 0.46 mmol, 1.00 equiv.) in MeCN (5 mL) was added KI (15 mg, 0.09 mmol, 0.20 equiv.) and DIEA (301 mg, 2.33 mmol, 5.00 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with CHCl / MeOH (10:1, 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 10 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: MeOH; Flow rate: 60 mL / min; Gradient: 53% B to 68% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 9.27). The pure fractions were concentrated under vacuum and lyophilized to give 6-chloro-N-methyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide (77.8 mg, Y = 36.4%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =454.20. 1 H NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.43(q,J=4.7Hz,1H),7.94(d,J=8.1Hz,1H),7.70-7.63(m,1H),7.56(d,J=8.0Hz,1H),7.34(d ,J=1.4Hz,1H),7.16(d,J=8.1,1.7Hz,1H),4.79(t,J=9.2Hz,2H),3.61(s,2H),3.16-2.99(m,6H),2.79(d,J=4.7Hz,3H),2.58(s,4H).

[0234] Comparative Example 3 (Example 64 in International Publication No. 2023025307) [ka] Step 1: Preparation of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate: To a stirred mixture of methyl 4-oxotetrahydrofuran-3-carboxylate (5.00 g, 34.69 mmol, 1.00 equiv) in CHCl (50 mL) was added DIEA (7 mL, 41.63 mmol, 1.20 equiv) dropwise at −78° C. under nitrogen atmosphere. The resulting mixture was stirred at −78° C. for 10 min under nitrogen atmosphere. To the above mixture was added TfO (7 mL, 41.63 mmol, 1.20 equiv) dropwise at −78° C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0-20% gradient in 30 min) to give methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (8.40 g, 87.6%) as a red liquid. 1 H NMR(400MHz,CDCl3)δ4.91(dd,J=5.8,4.5Hz,2H),4.79(dd,J=5.9,4.5Hz,2H),3.83(s,3H). 19 F NMR (377MHz, CDCl3) δ-73.79.

[0235] Step 2: Preparation of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydrofuran-3-carboxylate: To a stirred mixture of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (8.20 g, 29.69 mmol, 1.00 equiv.) and bis(pinacolato)diboron (9.05 g, 35.63 mmol, 1.20 equiv.) in dioxane (300 mL), Pd(dppf)Cl2 (1.09 g, 1.49 mmol, 0.05 equiv.) and KOAc (8.74 g, 89.07 mmol, 3.00 equiv.) were added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. 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 gel column chromatography eluting with PE / EtOAc (10% to 40% gradient in 30 min) to give methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydrofuran-3-carboxylate (4.20 g, 55.6%) as a pale yellow oil. LC-MS: (ES+H, m / z): [M+H] + =255.1. 1 H NMR (300MHz, CDCl3) δ4.93 (td, J=5.2, 4.8, 1.0 Hz, 2H), 4.83 (td, J=5.2, 1.0 Hz, 2H), 3.78 (s, 3H), 1.36 (s, 12H).

[0236] Step 3: Preparation of 4-chloro-2-fluoro-6-nitroaniline: A mixture of 2-fluoro-6-nitroaniline (2.00 g, 12.81 mmol, 1.00 equiv) and NCS (1.80 g, 13.45 mmol, 1.05 equiv) in DMF (20 mL) was stirred at room temperature under nitrogen atmosphere overnight. The resulting mixture was diluted with EtOAc (300 mL). The organic layer was washed with water (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0-20% gradient in 30 min) to give 4-chloro-2-fluoro-6-nitroaniline (1.80 g, 73.7%) as a yellow solid. LC-MS: (ES-H, m / z): [MH]- =189.1. 1 H NMR (400MHz, DMSO-d6) δ7.85 (t, J=2.2Hz, 1H), 7.68 (dd, J=11.0, 2.5Hz, 1H), 7.45 (s, 2H).

[0237] Step 4: Preparation of 2-bromo-5-chloro-1-fluoro-3-nitrobenzene: A mixture of CuBr2 (3.99 g, 17.84 mmol, 2.00 equiv) and tert-butyl nitrite (5.35 mL, 44.61 mmol, 5.00 equiv) in MeCN (15 mL) was stirred at 60° C. for 10 min under nitrogen atmosphere. To the above mixture, 4-chloro-2-fluoro-6-nitroaniline (1.70 g, 8.92 mmol, 1.00 equiv) in MeCN (10 mL) was added dropwise at 60° C. The resulting mixture was stirred at 60° C. for another 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0-5% gradient in 30 min) to give 2-bromo-5-chloro-1-fluoro-3-nitrobenzene (1.70 g, 74.8%) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.19-8.13 (m, 1H), 8.05 (ddt, J = 8.5, 2.3, 0.9Hz, 1H).

[0238] Step 5: Preparation of methyl 4-(4-chloro-2-fluoro-6-nitrophenyl)-2,5-dihydrofuran-3-carboxylate: To a stirred mixture of 2-bromo-5-chloro-1-fluoro-3-nitrobenzene (700 mg, 2.75 mmol, 1.00 equiv) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydrofuran-3-carboxylate (699 mg, 2.75 mmol, 1.00 equiv) in dioxane (20 mL) and HO (1 mL) was added Pd(dppf)Cl2·CH2Cl2 (112 mg, 0.14 mmol, 0.05 equiv) and K2CO3 (1141 mg, 8.25 mmol, 3.00 equiv). The resulting mixture was stirred overnight at 80 °C under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3 x 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. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (gradient 0% to 20% in 30 min) to give methyl 4-(4-chloro-2-fluoro-6-nitrophenyl)-2,5-dihydrofuran-3-carboxylate (300 mg, 36.1%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.22 (t, J = 1.8 Hz, 1H), 8.13 (dd, J = 9.2, 2.0 Hz, 1H), 4.91 (s, 4H), 3.55 (s, 3H).

[0239] Step 6: Preparation of 7-chloro-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one: To a stirred mixture of methyl 4-(4-chloro-2-fluoro-6-nitrophenyl)-2,5-dihydrofuran-3-carboxylate (300 mg, 1.00 mmol, 1.00 equiv) and Fe (245 mg, 4.31 mmol, 10.00 equiv) in EtOH (10 mL) was added CaCl2 (662 mg, 5.97 mmol, 6.00 equiv). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MeCN (3 mL) to give 7-chloro-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (170 mg, 71.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =240.1. 1 H NMR(400MHz,DMSO-d6)δ12.15(s,1H),7.28(dd,J=10.4,1.9Hz,1H),7.24(dd,J=2.0,0.9Hz,1H),5.30(td,J=4.3,2.2Hz,2H),4.92(t,J=4.2Hz,2H).

[0240] Step 7: Preparation of 9-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one: To a stirred mixture of 7-chloro-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (190 mg, 0.79 mmol, 1.00 equiv.) and XPhos 2nd generation precatalyst (62 mg, 0.08 mmol, 0.10 equiv.) in dioxane (6 mL) was added (tributylstannyl)methanol (509 mg, 1.59 mmol, 2.00 equiv.). The resulting mixture was stirred at 100° C. for 2 h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CHCl / MeOH (10:1) (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0-10% gradient in 30 min) to give 9-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (80 mg, 42.9%) as a white solid. LC-MS: (ES+H,m / z):[M+H] + =236.1. 1 H NMR(400MHz,DMSO-d6)δ12.06(s,1H),7.22(s,1H),6.95(d,J=11.3Hz,1H),5.51(t,J= 5.7Hz,1H), 5.32(tt,J=3.9,1.8Hz,2H),4.93(t,J=4.2Hz,2H),4.57(d,J=5.7Hz,2H).

[0241] Step 8: Preparation of 7-(chloromethyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one: To a stirred mixture of 9-fluoro-7-(hydroxymethyl)-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (60 mg, 0.26 mmol, 1.00 equiv.) and DMF (2 mg, 0.03 mmol, 0.10 equiv.) in CHCl (4 mL), SOCl (0.06 mL, 0.77 mmol, 3.00 equiv.) was added dropwise at 0° C. under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (50 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =253.9.

[0242] Step 9: Preparation of 6-fluoro-5-(4-((9-fluoro-4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide: To a stirred mixture of 7-(chloromethyl)-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (45 mg, 0.18 mmol, 1.00 equiv.) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (73 mg, 0.27 mmol, 1.50 equiv.) in MeCN (3 mL) was added KI (6 mg, 0.04 mmol, 0.20 equiv.) and DIEA (115 mg, 0.89 mmol, 5.00 equiv.). The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 h. 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 eluting with CHCl / MeOH (0-10% gradient in 30 min) to give the crude product (70 mg). The crude product (70 mg) was purified by Prep-HPLC under the following conditions (Column: Xselect CSH C18 OBD column 30 × 150 mm, 5 μm; Mobile phase A: water (0.1% HCOOH), Mobile phase B: MeCN; Flow rate: 60 mL / min; Gradient: 4% B to 15% B in 8 min; Wavelength: 254 nm / 220 nm; RT1 (min): 12.82). The pure fractions were concentrated under reduced pressure and lyophilized to give 6-fluoro-5-(4-((9-fluoro-4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (28.0 mg, 34.2%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =456.10. 1 H NMR(300MHz,DMSO-d6)δ12.03(s,1H),8.41(q,J=4.7Hz,1H),7.85(dd,J=8.0,1.5Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),7.22(s,1H),7.03(d ,J=11.2Hz,1H),5.32(d,J=5.1Hz,2H),4.93(t,J=4.2Hz,2H),3.62(s,2H),3.26-3.11(m,4H),2.77(d,J=4.7Hz,3H),2.57(t,J=4.6Hz,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.508,-118.241.

[0243] Comparative Example 4 (Example 4 in Chinese Patent Application Publication No. 115232129(A)) [ka] Example A: Cell proliferation inhibition assay The purpose of this experiment is to evaluate the effect of the compounds disclosed herein on cell proliferation through cell viability assays in DLD-1 BRCA2(- / -) and parental isogenic pairs and MDA-MB-436 (mutated BRCA1) cell lines. The CellTiter-Glo (CellTiter-Glo, CTG) based cell viability assay is designed to determine the number of viable cells in culture due to compound effects by quantifying ATP, which indicates the presence of metabolically active cells.

[0244] DLD-1 BRCA2(- / -) and parental isogenic pairs were cultured in RPMI1640 supplemented with 10% fetal bovine serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS, both at 37°C and 5% CO2. Compounds of the invention were dispensed into 384-well plates (Corning, 3764) using an Echo acoustic liquid handler to form final concentrations serially diluted 1:3 with a top dose of 10 or 30 μM. Cells were seeded into plates at a density of 50 cells / well (DLD-1 parental), 200 cells / well (DLD-1 BRCA2- / -), or 500 cells / well (MDA-MB-436). After a brief rotation, cells were cultured undisturbed for 7 days at 37°C in a fully humidified incubator with 5% CO2. Cell viability was measured by CellTiter Glo2.0 assay kit (Promega, G9243), and the percentage of proliferation inhibition was calculated and plotted against the final compound concentration, and the data was fitted with Xfit to obtain IC 50 was generated.

[0245] Example B: Biochemical (FP) Assay Fluorescent polarization (FP)-based assays are widely used in drug discovery due to their homogenous format, robust performance, and lack of interference seen in other assays. To characterize the present compounds, the inventors utilized an assay that measures the displacement of a commercially available fluorescently labeled PARP1 / 2 inhibitor (PARPi-FL, Tocris Biosciences, #6461), as exemplified in the assays performed in WO 2014 / 064149 and WO 2021 / 013735(A1). The assay was performed using the following method.

[0246] Compounds were dissolved in DMSO and serially diluted in the desired concentration range in Optiplate-384F plates utilizing an Echo550 liquid handler. 100% DMSO was used for high (with protein) and low (without protein) control samples. 20 nL of compound or DMSO alone was added to individual assay plate wells.

[0247] PARP1 and PARP2 proteins were expressed, purified and diluted to a final concentration of 20 nM in assay buffer containing 50 mM Tris, pH 8.0, 0.001% Triton® X-100, 10 mM MgCI2, 150 mM NaCI. PARPi-FL was then added to a final concentration of 3 nM.

[0248] The assay plate is centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 4 hours.

[0249] Fluorescence polarization is read using an Envision plate reader using the following settings: Excitation Filter-FITC FP480-Ex Slot 3 Emission Filter-FITC FP P-pol535-Em Slot 4 Second emission filter - FITC FP S-pol535-Em slot 3 Mirror Module - FITC FP Dual Enhance - Slot 1

[0250] The inhibition rate is calculated using the percentage of the permuted Mahalanobis distance greater than the control sample (mP value) according to the following formula: [Table 10]

number

[0251] IC reported for each compound using XLFit (Eq. 201) 50 Calculate.

[0252] The data from Examples A and B are shown in Table 2. [Table 2]

[0253] Example C: In vitro human transporter efflux Example C1: MDR1 and BCRP Madin-Darby canine kidney (MDCKII) cells expressing either MDR1 or BCRP were plated on Corning HTS Transwell® 96-well polycarbonate permeable (0.4 μm pore) supports at 545,000 cells / cm. 2Cells were seeded at a density of 100 μM. Prior to the assay, cells were incubated for 4-8 days and the integrity of the monolayer was assessed by measuring the transepithelial electrical resistance (TEER). Test and reference compounds were diluted in transport buffer (HBSS HEPES pH 7.4) to concentrations of 10 μM and 1 μM, respectively. The final organic solvent concentration was 0.5% (v / v). Bidirectional (apical to basolateral and basolateral to apical) flux of test and reference compounds was determined over a 2-h incubation at 37 °C and 5% CO2, 95% relative humidity. At the end of the incubation, samples were taken from the apical and basolateral sides and then precipitated with acetonitrile containing an internal standard. After centrifugation at 3200 × g, the supernatant was diluted 1:1 (v / v) with water and subjected to analysis by HPLC-MS / MS. The integrity of the cell monolayer during the assay was confirmed by using the marker Lucifer Yellow at a final concentration of 100 μM.

[0254] Example C2: Caco-2 Corning 96-well HTS Transwell® permeable support plates were seeded with 34,300 Caco-2 cells (ATCC) per well after a 1-h equilibration period in cell culture medium maintained at 37°C in an incubator containing a 5% CO2 atmosphere with 95% relative humidity. After seeding, plates were cultured for 14–18 days with cell culture medium changes every other day starting within 24 hours. Monolayer barrier integrity was monitored throughout the culture period using transepithelial electrical resistance (TEER) measurements performed with a Millicell Epithelial Volt-Ohm system. Caco-2 monolayers maintained TEER values ​​>230 ohm cm 2The plate was considered ready for use when the concentration was 0.5-1.5 mM. Working stocks of the individual test substances were prepared at a concentration of 5 μM by diluting 1 mM stocks prepared in DMSO into 10 mM HEPES. Prior to performing the assay, the Caco-2 plates were washed twice with pre-warmed 10 mM HEPES and then equilibrated in 10 mM HEPES for 30 min at 37 °C. Following equilibration, test substance flux was tested in both directions (in both apical to basolateral and basolateral to apical directions) by adding the test substance working stock to either the apical or basolateral chamber. A blank, 10 mM HEPES, was added to the opposite side. The plate was then incubated for 2 h at 37 °C. At the end of the incubation, aliquots from both sides of each monolayer were quenched with 4 volumes of ACN containing an internal standard. After a centrifugation step, the supernatant was diluted with pure water before being analyzed via LC-MS / MS.

[0255] Apparent Permeability (P app , ×10 -6 The transport velocity (Vp) was calculated for all transport assays using the following formula:

number

[0256] The outflow ratio is the ratio of apical to basolateral P app Basolateral to apical P app The ratio of

number

[0257] Data from Examples C1 and C2 are provided in Table 3. [Table 3]

[0258] Example D: In vivo determination of rat Kp,uu Determination of unbound fraction (Pu) in plasma

[0259] The in vitro binding of test articles and reference compounds to plasma proteins was investigated using equilibrium dialysis. Plasma samples containing 5 μM test article or blank dialysis buffer solution (PBS, pH 7.4) were added to separate chambers of the dialysis well of a high-throughput equilibrium dialysis (HTD) device. The dialysis plate was sealed and placed in a 37°C incubator with 5% CO2 for 6 hours with shaking at approximately 100 rpm. All experiments were performed in duplicate. Ketoconazole (5 μM) was used as a reference compound. After incubation, the seal was removed and 50 μL of post-dialysis samples were pipetted from both the buffer and plasma chambers into a new 96-well plate. Samples were equimatrilyzed by either adding blank plasma to the buffer samples or blank buffer to the plasma samples. Subsequently, 400 μL (4 volumes) of acetonitrile containing internals was added to all samples to precipitate proteins and determine the relative concentrations of the test articles before analysis by UPLC-MS / MS. The unbound fraction in plasma was calculated using the concentrations of test article in the buffer and plasma samples according to the following formula:

number

[0260] Determination of the unbound fraction in brain homogenate (Bu)

[0261] The equilibrium dialysis method was used to study the in vitro binding of test articles and reference compounds to rodent brain homogenates. Brains removed from naive animals were weighed and homogenized in 4 volumes of PBS, pH 7.4. Brain homogenate samples containing 1 μM test article or blank dialysis buffer solution (PBS, pH 7.4) were added to separate chambers of the dialysis wells of a high-throughput equilibrium dialysis (HTD) device. The dialysis plate was sealed and placed in a 37°C incubator with 5% CO2 for 6 hours with shaking at approximately 100 rpm. All experiments were performed in duplicate. Telmisartan (5 μM) was used as the reference compound. After incubation, the seals were removed and 50 μL of post-dialysis samples were pipetted from both the buffer and brain homogenate chambers into a new 96-well plate. Samples were equimatrilysin treated by adding blank homogenate to the buffer samples or blank buffer to the homogenate samples. 400 μL (4 volumes) of acetonitrile containing an internal standard was then added to all samples to precipitate proteins before analysis by UPLC-MS / MS to determine the relative concentration of the test article. The unbound fraction in the diluted brain homogenates was calculated using the concentrations of the test article in the buffer and homogenate samples according to the following formula:

number

[0262] Correction for the unbound rate in undiluted brain was performed using the following formula:

number

[0263] Determination of brain-to-plasma partition coefficients (Kp) and drug-unbound Kp (Kp,uu) of drugs in rats

[0264] Compounds were formulated individually or in cassettes (as a mixture) at a concentration of 0.1 mg / mL / compound in sterile water containing 0.5% (w / v) methylcellulose 400 cP and administered to male Sprague-Dawley rats by oral gavage at a dose volume of 10 mL / kg. One animal was sacrificed at each time point 0.5, 1, 2, 4, 8, and 24 hours after dosing, and brain and blood samples were collected. Plasma was prepared from the blood via refrigerated centrifugation, and plasma samples were stored frozen at -80°C until bioanalysis. Brain samples were rinsed with saline to remove residual blood and blotted dry with paper wipes. Brain samples were then weighed, homogenized with 3 volumes (v / w) of water, and stored frozen at -80°C until bioanalysis.

[0265] Prior to bioanalysis, plasma and brain samples were extracted with 4 volumes of acetonitrile containing an internal standard and centrifuged for 15 minutes. The supernatant was diluted with 2 volumes of water and injected for analysis by HPLC-MS / MS. Plasma and brain homogenate drug concentrations were determined against a calibration curve constructed by spiking blank rat plasma or brain homogenate with drug over the appropriate concentration range. Brain homogenate concentrations were corrected for the homogenization buffer dilution factor to obtain the total brain drug concentration.

[0266] The brain-to-plasma partition coefficient (Kp) for each compound was determined as follows: AUC brain:AUC plasma, where t was the same in each matrix. If the drug concentration versus time profile for one matrix fell below the lower limit of quantification at an earlier time point than the other matrix, the brain Kp was calculated as the average of the ratios of the total brain drug concentration to the total plasma drug concentration measured at each time point where drug concentrations in both matrices were quantifiable.

[0267] Kp,uu was then calculated from Kp using the following formula: Kp,uu=Kp×(unbound fraction in brain homogenate / unbound fraction in plasma).

[0268] Data from Example D is provided in Table 4. [Table 4]

[0269] Example E: HLM and hHEP Assays HLM Working stocks of individual test substances were prepared at a concentration of 100 μM by diluting 10 mM stocks prepared in DMSO 100-fold (v:v) into ACN. Thawed liver microsomes were suspended in 100 mM potassium phosphate buffer, pH 7.4, to a microsomal protein concentration of 0.562 mg / mL. The diluted microsomes were combined with a solution of 10 mM NADPH, and the mixture was prewarmed to 37° C. for 8 min. The reaction was initiated by the addition of test substance working stock to achieve a final test substance concentration of 1 μM. Final microsomal protein and NADPH concentrations were 0.5 mg / mL and 1 mM, respectively. Incubations containing NADPH were performed in duplicate. Test substance loss mediated by non-CYP mechanisms was evaluated in a parallel set of incubations performed in the absence of NADPH. Incubations lacking NADPH consisted of one replicate per test substance. After incubation in a 37°C water bath, aliquots of each reaction were quenched with cold ACN containing internal standard at 0.5, 15, 30, 60, 90, and 120 min. Precipitated proteins were pelleted by refrigerated centrifugation. Supernatants were diluted in an equal volume of pure water and mixed thoroughly before analysis by LC-MS / MS. In vitro specific clearance (CL) in μL / min / mg was calculated. int ) was determined for each incubation from the calculated in vitro half-life, which was determined using a standard log-linear regression approach. In vitro CL int Values ​​were scaled up using the following physiological scaling factors: 40 mg microsomal protein / g human liver and 25.7 g human liver / kg body weight. Finally, predicted human liver clearance (CL hep,predScaled intrinsic clearance values ​​were introduced into a well-stirred liver model to calculate the intrinsic clearance (in mL / min / kg) in mL / min / kg. A human hepatic blood flow of 21 mL / min / kg was assumed, and no correction was made for test substance binding to red blood cells, plasma proteins, or components of the incubation system.

[0270] hHEP Working stocks of individual test substances were prepared at a concentration of 100 μM by diluting 10 mM stocks prepared in DMSO 100-fold (v:v) with ACN / HO (50 / 50, v:v). Human cryopreserved hepatocytes were thawed in a 37°C water bath for less than 2 min, suspended in thawing medium, and then centrifuged at 100 × g for 10 min. The thawing medium was aspirated and 1.5 × 10 pelleted hepatocytes were collected. 6 Cell viability was determined using acridine orange / propidium iodide staining, and hepatocytes were resuspended in incubation medium at 0.5 × 10 cells / mL. 6 The cells were further diluted to viable cells / mL. 198 μL of hepatocyte aliquots were added to wells of a 96-well plate and test substance incubation was initiated by the addition of 2 μL of 100 μM working stock. Plates were incubated on an orbital shaker at 300 rpm at 37° C. and 95% relative humidity in a 5% CO2 atmosphere. Incubations were performed in duplicate. After incubation, aliquots of each reaction were terminated by the addition of ACN containing internal standard at 0, 30, 60, 90, 120, and 240 min. Precipitated proteins were pelleted by refrigerated centrifugation. The supernatant was diluted in an equal volume of pure water and mixed thoroughly before analysis by LC-MS / MS. μL / min / 10 6 In vitro intrinsic clearance (CL) in cells int ) was determined for each incubation from the calculated in vitro half-life, which was determined using standard log-linear regression methods. In vitro CL int The values ​​are scaled according to the following physiological scaling factor: 99×10 6Scale-up was performed using 25.7 g human liver / kg body weight and 25.7 g human liver / g cell. Finally, the predicted human liver clearance (CL hep,pred Scaled intrinsic clearance values ​​were introduced into a well-stirred liver model to calculate the intrinsic clearance (in mL / min / kg) in mL / min / kg. A human hepatic blood flow of 21 mL / min / kg was assumed, and no correction was made for test substance binding to red blood cells, plasma proteins, or components of the incubation system.

[0271] Data from Example E is provided in Table 5. [Table 5]

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, 【Chemistry 45】 During the ceremony, Ring A taken together with X and Y is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X is C, CH, or N; Y is C, CH, or N; Each R １ are independently deuterium, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Or two R on the same carbon １ together to form oxo, n is 0 to 6; Z is N or CR Ｚ and R Ｚ But hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ２ But hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ３ But hydrogen, deuterium, halogens, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Or R ２ and R ３ taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; Each R ４ are independently deuterium, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, or C ２ ~C ６ alkynyl, or Or two R on the same carbon ４ together to form oxo, or or two R on the same or different carbons ４ taken together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R; m is 0 to 4; R ５ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ６ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ７ is hydrogen, deuterium, halogen, -CN, -OH, -OR ａ , -NR ｃ R ｄ , C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; R ８ is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R; Each R ａ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, each alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl independently optionally substituted with one or more R; Each R ｃ and R ｄ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Deuteroalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Aminoalkyl, C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ alkynyl, cycloalkyl, or heterocycloalkyl, each of which is independently optionally substituted with one or more R; Or, R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; Each R is independently a halogen, —CN, —OH, —OC １ ~C ３ Alkyl, -OC １ ~C ３ Haloalkyl, -SC １ ~C ３ Alkyl, -S(=O)C １ ~C ３ Alkyl, -S(=O) ２ C １ ~C ３ Alkyl, -S(=O) ２ N.H. ２ , -S(=O) ２ N.H.C. １ ~C ３ Alkyl, -S(=O) ２ N (C １ ~C ３ Alkyl) ２ , -NH ２ , -NHC １ ~C ３ Alkyl, -N(C １ ~C ３ Alkyl) ２ , -C(=O)C １ ~C ３ Alkyl, -C(=O)OH, -C(=O)OC １ ~C ３ Alkyl, -C(=O)NH ２ , -C(=O)NHC １ ~C ３ Alkyl, -C(=O)N(C １ ~C ３ Alkyl) ２ , C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Deuteroalkyl, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Aminoalkyl, C １ ~C ３ Heteroalkyl, or C ３ ~C ６ cycloalkyl, or or two R on the same atom taken together form oxo, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

2. The compound is of formula (Ia) 【Chemistry 46】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

3. The compound is of formula (Ib) 【Chemistry 47】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

4. The compound is of formula (Ic) 【Chemistry 48】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

5. The compound is of formula (Id) 【Chemistry 49】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

6. The compound is of formula (Ie) 【Chemistry 50】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

7. The compound is of formula (If) 【Chemistry 51】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

8. The compound is of formula (Ig) 【Chemistry 52】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

9. The compound is of formula (Ih), 【Chemistry 53】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

10. The compound is of formula (Ii) 【Chemical 54】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

11. The compound is of formula (Ij) 【Chemistry 55】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

12. The compound is of formula (Ik) 【Chemistry 56】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

13. The compound is of formula (II) 【Chemistry 57】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

14. The compound is of formula (Im) 【Chemistry 58】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

15. The compound is of formula (In) 【Chemistry 59】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

16. The compound is of formula (Io) 【Chemistry 60】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

17. The compound is of formula (Ip) 【Chemistry 61】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

18. The compound is of formula (Iq) 【Chemistry 62】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

19. The compound is of formula (Ir) 【Chemistry 63】 In the formula, R １’ is hydrogen or R １ 2. The compound of claim 1, wherein:

20. Each R １ are independently halogen or C １ ~C ６ 20. The compound of any one of claims 1 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

21. 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0 or 1.

22. Each R １’ The compound of any one of claims 2 to 19, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

23. 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein Z is N.

24. Z is CR Ｚ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

25. R Ｚ is hydrogen, deuterium, halogen, or C １ ~C ６ 25. The compound of any one of claims 1 to 22 or 24, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

26. R ２ is hydrogen, deuterium, or C １ ~C ６ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

27. R ３ is hydrogen, deuterium, or C １ ~C ６ 27. The compound of any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

28. R ２ and R ３ 27. The compound of any one of claims 1 to 26, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: taken together form a cycloalkyl.

29. Each R ４ are independently deuterium, C １ ~C ６ Alkyl, or C １ ~C ６ 28. The compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, which is haloalkyl.

30. Each R ４ But independently, C １ ~C ６ 30. The compound of any one of claims 1 to 29, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

31. 31. The compound of any one of claims 1 to 30, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein m is 0 to 2.

32. R ５ is hydrogen, halogen, or C １ ~C ６ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

33. R ５ The compound of any one of claims 1 to 32, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is halogen.

34. R ６ is hydrogen, halogen, or C １ ~C ６ 34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein: R is an alkyl group;

35. R ６ 35. The compound of any one of claims 1 to 34, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

36. R ７ is hydrogen, halogen, or C １ ~C ６ 36. The compound of any one of claims 1 to 35, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

37. R ７ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein is hydrogen.

38. R ８ But, C １ ~C ６ 38. The compound of any one of claims 1 to 37, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl or cycloalkyl, and said alkyl and cycloalkyl are optionally substituted with one or more R.

39. R ８ But, C １ ~C ６ 39. The compound of any one of claims 1 to 38, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, wherein R is an alkyl group.

40. A compound selected from the compounds disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

41. 41. A pharmaceutical composition comprising a compound according to any one of claims 1 to 40, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

42. 41. A method of treating cancer in a subject in need thereof, said method comprising administering a compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

43. 43. The method of claim 42, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, or lung cancer.

44. 41. A method of treating a cancer harboring a BRCA1 and / or BRCA2 mutation in a subject in need thereof, said method comprising administering a compound according to any one of claims 1 to 40, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

45. 41. A method of treating a cancer comprising a mutation in a gene that confers a homologous repair deficiency in a subject in need thereof, said method comprising administering a compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

46. 46. ​​The method of claim 45, wherein the mutation in a gene that confers homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof.

47. 47. The method of any one of claims 42 to 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, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.

48. The method of any one of claims 42 to 47, wherein the cancer is a metastatic cancer.

49. The method of any one of claims 42 to 48, wherein the cancer has metastasized to the brain.

50. 41. A method of treating cancer present in the brain in a subject in need thereof, said method comprising administering a compound according to any one of claims 1 to 40, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

51. 41. A method of treating brain cancer in a subject in need thereof, said method comprising administering a compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

52. 52. The method of any one of claims 42-51, wherein the compound, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is brain penetrant.

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