PARP1 inhibitors and uses thereof

Abstract

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

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 63 / 301,907, filed on January 21, 2022, and U.S. Provisional Application No. 63 / 376,338, filed on September 20, 2022, which are hereby incorporated by reference in their entirety.

Background Art

[0002] Poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) synthase (PARS) plays an important role in promoting DNA repair, regulating RNA transcription, mediating cell death, and modulating the immune response. Due to these actions, PARP inhibitors are targets for a wide range of diseases. PARP inhibitors have demonstrated efficacy in numerous models of disease, particularly in models of ischemia-reperfusion injury, inflammatory diseases, degenerative diseases, protection from the harmful effects of cytotoxic compounds, and enhancement of cytotoxic cancer therapy. PARP has also been implicated in retroviral infection, and thus inhibitors may be useful for anti-retroviral therapy. PARP inhibitors are effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurological injuries, organ transplantation, and reperfusion of the eye, kidney, intestine, and skeletal muscle. The 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 some models of degenerative diseases including diabetes (and its complications) and Parkinson's disease. PARP inhibitors can alleviate liver toxicity after acetaminophen overdose, cardiac and renal toxicity from doxorubicin and platinum-based anti-cancer drugs, and skin damage following sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cancer cell death, limiting tumor growth, reducing metastasis, and prolonging the survival of animals with tumors.

[0003] PARP1 and PARP2 are the most widely studied PARPs with respect to their roles 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 DNA damage.

[0004] Following completion of the role of this mobilization, PARP auto-PARylation releases the bound PARP from DNA, allowing access to other DNA repair proteins to complete the repair. Therefore, the binding of PARP to the damage site, its catalytic activity, and its final release from DNA are all important steps for cancer cells to respond to DNA damage caused by chemotherapeutic agents and radiotherapy.

[0005] Inhibition of PARP family enzymes has been utilized as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have demonstrated that tumor cells with deleterious alterations in BRCA1 or BRCA2, important 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 lack the homologous recombination repair (HRR) pathway and rely on the function of PARP enzymes for survival. PARP inhibitor therapy mainly targets SRCA mutant cancers, but PARP inhibitors are being clinically tested in non-SRCA mutant tumors, i.e., tumors showing homologous recombination deficiency (HRD). Subjects are being clinically tested.

[0006] PARP inhibitors with improved selectivity for PARP1 are thought to have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. Also, when PARP1 is strongly and selectively inhibited, it is thought that PARP1 is trapped on DNA and DNA double-strand breaks (DSBs) occur due to the collapse of replication forks in the S phase. Moreover, PARP1-DNA trapping is thought to be an effective mechanism for selectively killing tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors having selectivity for PARP1. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0007] Compounds of formula (I), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are disclosed herein,

Chemical formula

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

[0009] Also disclosed herein are methods of doing so in a subject in need of treatment for cancer comprising a BRCA1 and / or BRCA2 mutation, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein are methods of doing so in a subject in need of treatment for cancer comprising a mutation in a gene conferring homologous repair deficiency, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in the gene conferring 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 lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0010] A method of doing so in a subject in need of treatment for cancer present in the brain, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. A method of treating brain cancer in a subject in need of treatment for brain cancer, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0011] Incorporation by reference All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The present invention provides, for example, the following items. (Item 1) A compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Mode for Carrying Out the Invention

[0012] Definition In the following description, specific specific details are set forth in order to provide a complete understanding of the various embodiments. However, those skilled in the art will understand that the present invention can be practiced without these details. In other instances, well-known structures are not shown in detail or described in order to avoid unnecessarily obscuring the description of the embodiments. Unless the context requires otherwise, throughout the following specification and claims, the word "comprise" and its variations, such as "comprises" and "comprising" ) shall be construed in an open and inclusive sense, i.e., "including but not limited to". Further, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

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

[0014] The following terms, as used in this specification, have the following meanings unless otherwise indicated.

[0015] "Oxo" refers to =O.

[0016] "Carboxyl" refers to -COOH.

[0017] "Cyano" refers to -CN.

[0018] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon monoradical 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, and longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this specification, numerical ranges such as "C1-C6 alkyl" or "C1-6 alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C1- 10It is alkyl. In some embodiments, the alkyl is C1-6 alkyl. In some embodiments, the alkyl is C1-5 alkyl. In some embodiments, the alkyl is C1-4 alkyl. In some embodiments, the alkyl is C1-3 alkyl. Unless otherwise specifically described herein, the alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, 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.

[0019] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. This group can be in either the cis or trans conformation with respect to the double bond and is to 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, etc. Whenever it appears in this specification, numerical ranges such as "C2-C6 alkenyl" or "C2-6 alkenyl" mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkenyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0020] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadynyl, etc. Whenever it appears in this specification, numerical ranges such as "C2-C6 alkynyl" or "C2-6 alkynyl" mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0021] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, the alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0022] "Alkoxy" refers to a radical of the formula -OR a wherein R a is an alkyl radical as defined. Unless otherwise specified herein, the alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0023] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, and may include a fused ring system (when fused with a cycloalkyl or heterocycloalkyl ring, aryl is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, aryl is a 6- to 10-membered aryl. In some embodiments, aryl is a 6-membered aryl (phenyl). Examples of aryl radicals include, but are not limited to, aryl radicals derived from hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, perylene, pyrene, and triphenylene. Unless otherwise specified herein, aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, aryl is optionally substituted with halogen.

[0024] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring that may include a fused ring system (when fused with an aryl ring or heteroaryl ring, cycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. In some embodiments, cycloalkyl is fully saturated. Representative cycloalkyls include those having 3 to 15 carbon atoms (C3 - C 15 cycloalkyl or C3 - C 15(cycloalkenyl), 3 to 10 carbon atoms (C3 - C 10 cycloalkyl or C3 - C 10Cycloalkyl 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) is exemplified, but not limited thereto. In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated herein, the cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

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

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

[0027] "Hydroxyalkyl" refers to an alkyl radical as defined above substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted by one hydroxyl. In some embodiments, the alkyl is substituted by 1, 2, or 3 hydroxyls. Examples of hydroxyalkyl include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] "Aminoalkyl" refers to an alkyl radical as defined above substituted by one or more amines. In some embodiments, the alkyl is substituted by one amine. In some embodiments, the alkyl is substituted by 1, 2, or 3 amines. Examples of aminoalkyl include aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0029] "Deuterioalkyl" refers to an alkyl radical as defined above that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted by one deuterium. In some embodiments, the alkyl is substituted by 1, 2, or 3 deuteriums. In some embodiments, the alkyl is substituted by 1, 2, 3, 4, 5, or 6 deuteriums. Examples of deuterioalkyl include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterioalkyl is CD3.

[0030] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the rest of the molecule by a carbon atom of the heteroalkyl. In one embodiment, the heteroalkyl is a C1-C6 heteroalkyl, and the heteroalkyl is composed of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is attached to the remainder of the molecule by a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated herein, the 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, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0031] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring radical containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogens. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, the heterocycloalkyl contains 1 nitrogen. In some embodiments, the heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise specifically stated herein, the heterocycloalkyl radical may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, may include fused ring systems (when fused with an aryl ring or heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), or bridged ring systems. The nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2 - C 15 heterocycloalkyl or C2 - C 15 heterocycloalkenyl), 2 to 10 carbon atoms (C2 - C 10 heterocycloalkyl or C2 - C 10heterocycloalkyl having from 2 to 8 carbon atoms (C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), from 2 to 7 carbon atoms (C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), from 2 to 6 carbon atoms (C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), from 2 to 5 carbon atoms (C2-C5 heterocycloalkyl or C2-C5 heterocycloalkenyl), or from 2 to 4 carbon atoms (C2-C4 heterocycloalkyl or C2-C4 heterocycloalkenyl), but are not limited thereto. 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, 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, but are not limited thereto. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyl has from 2 to 10 carbons in the ring. When referring to the number of carbon atoms in heterocycloalkyl, it is understood that the number of carbon atoms in heterocycloalkyl is not the same as the total number of atoms (i.e., the skeletal atoms of the heterocycloalkyl ring) that make up the heterocycloalkyl (including heteroatoms). In some embodiments, 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 described herein, the heterocycloalkyl may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0032] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, heteroaryl contains 1 to 3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heteroaryl contains 1 to 3 nitrogens. In some embodiments, heteroaryl contains 1 or 2 nitrogens. In some embodiments, heteroaryl contains 1 nitrogen. The heteroaryl radical may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, may include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, heteroaryl is bonded through an aromatic ring atom), or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. In some embodiments, heteroaryl is 5- to 10-membered heteroaryl. In some embodiments, heteroaryl is 5- to 6-membered heteroaryl. In some embodiments, heteroaryl is 6-membered heteroaryl. In some embodiments, heteroaryl is 5-membered heteroaryl. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, Benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 - oxoazepinyl, oxazolyl, oxiranyl, 1 - oxidopyridinyl, 1 - oxidopyrimidinyl, 1 - oxidopyranidinyl, 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) are included, but not limited thereto. Unless otherwise specifically described herein, heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, - CN, - COOH, COOMe, - CF3, - OH, - OMe, - NH2, or - NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, - CN, - CF3, - OH, or - OMe. In some embodiments, heteroaryl is optionally substituted with halogen.

[0033] The term "optionally" or "optionally substituted" means that the event or situation described thereafter may or may not occur, and that the description includes both the case where the event or situation occurs and the case where the event or situation does not occur. For example, "optionally substituted alkyl" means either "alkyl" as defined above or "substituted alkyl". Further, a group that is optionally substituted may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F), or substituted at any level between full substitution and mono-substitution (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). One of ordinary skill in the art will understand that for any group containing one or more substituents, such a group is not intended to introduce any substitution or substitution pattern that is sterically unrealistic and / or synthetically infeasible (e.g., a substituted alkyl that contains an optionally substituted cycloalkyl group, which in turn contains an optionally substituted alkyl group, and so on ad infinitum). Thus, any substituent described is generally understood to have a maximum molecular weight of about 1,000 Daltons, more typically about 500 Daltons.

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

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

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

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

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

[0039] Compound Compounds useful for the treatment of cancer, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are described herein.

[0040] Compounds of formula (I), or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are disclosed herein, [Chemical Formula] Wherein, R 1 is hydrogen, deuterium, halogen, -CN, -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, and the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R, R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, X is N or CR 3 and Y is N or CR 4 and Z is N or CR 5 and R 3 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs, R 4 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs, R 5 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs, Each R 6 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs, or, two Rs 6combine to form a cycloalkyl or heterocycloalkyl, each optionally being deuterium, halogen, -CN, -OH, -OR a -NR c R d and being substituted by C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, each R 7 is independently deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, or C2-C6 alkynyl, or two Rs on the same carbon combine to form an oxo, or 7 two Rs on the same or different carbons combine to form a cycloalkyl or heterocycloalkyl, each optionally being substituted by one or more Rs, n is 0-4, 7 T is N or CR n is from 0 to 4, T is N or CR 8 and U is N or CR 9 and R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a -NR c R d C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted by one or more Rs, R 9is 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, and the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs, R 10 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, and the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs, R 11 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, and the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs, R 12 is cyano or halogen, each R ais, independently, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is, independently, optionally substituted with one or more Rs, each R b is, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is, independently, optionally substituted with one or more Rs, each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rs, or, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more Rs, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, or two Rs on the same atom together form an oxo, provided that when X is CR 3 and Y is CR 4 and Z is CR 5 one of R 3 R 4 and R 5 is not hydrogen and R 4 is not -OMe, provided that when X is CH, Y is CH, and Z is CH, R 2 is not hydrogen.

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

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

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

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

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

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

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

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

[0049] In some embodiments of the compound of formula (I), X is N. In some embodiments of the compound of formula (I), X is CR 3 and is.

[0050] In some embodiments of the compound of formula (I), Y is N. In some embodiments of the compound of formula (I), Y is CR 4 and is.

[0051] In some embodiments of the compound of formula (I), Z is N. In some embodiments of the compound of formula (I), Z is CR 5 and is.

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

[0053] In some embodiments of the compound of formula (I), the compound is of formula (Ia).

Chemical formula

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

Chemical formula

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

Chemical formula

[0056] In some embodiments of the compound of formula (I), the compound is of formula (Id),

Chemical formula

[0057] In some embodiments of the compound of formula (I), the compound is of formula (Ie),

Chemical formula

[0058] In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, and the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs.

[0059] In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, and the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs. In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, and the alkyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more Rs. In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl, and the alkyl, alkynyl, and cycloalkyl are optionally substituted with one or more Rs. In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 1is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is C1-C6 alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is methyl or ethyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is methyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is ethyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is cyclopropyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is difluoromethyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is halogen, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is halogen or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1is fluoro or chloro. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 1 is chloro.

[0060] In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is hydrogen, halogen, -OR a , or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is fluoro. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is methyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is -OR a . In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is -OCF3. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C1-C2 alkyl, C1-C2 haloalkyl, or C1-C2 deuteroalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is hydrogen, halogen, -OR a , or C1-C2 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 2 is halogen, -OR a, or is C1-C2 alkyl. In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 2 is halogen or C1-C2 alkyl.

[0061] In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 3 is hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 3 is hydrogen, halogen, -OR a , or C1-C6 alkyl. In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 3 is hydrogen, or halogen, or C1-C6 alkyl.

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

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

[0064] In some embodiments of the compound of formula (I) or (Ia)-(Ie), R 4 is hydrogen, deuterium, halogen, -CN, -NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, or heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 4 is hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 4 is hydrogen, halogen, -OR a , or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 4 is hydrogen, or halogen, or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 4 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 4 is halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 4 is hydrogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 4 is not hydrogen.

[0065] In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 5 is hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterated alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 5 is hydrogen, halogen, -OR a , or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 5is hydrogen, or a halogen, or C1-C6 alkyl.

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

[0067] In some embodiments of the compounds of formula (I) or (Ia)-(Ie), each R 6 is independently hydrogen, deuterium, a halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), each R 6 is independently hydrogen, deuterium, or C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), one R 6 is hydrogen and the other R 6 is C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), each R 6 is deuterium. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), each R 6 is independently C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), each R 6 is hydrogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), two Rs 6 together form a cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), two Rs 6 together form a cyclopropyl.

[0068] In some embodiments of the compounds of formula (I) or (Ia)-(Ie), each R7 is independently C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuterioalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), each R 7 is independently C1-C6 alkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), two Rs on the same carbon or different carbons 7 together form cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), two Rs on the same carbon or different carbons 7 together form cyclopropyl.

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

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

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

[0072] In some embodiments of the compounds of formula (I) or (Ia)-(Ie),

Chemical formula

Chemical formula

[0073] In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 deuteroalkyl, or cycloalkyl. In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 8 is hydrogen, halogen, -CN, -OR a , C1 - C6 alkyl, or C1 - C6 haloalkyl. In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 8 is hydrogen, halogen, -CN, -OR a , or C1 - C6 haloalkyl. In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 8 is hydrogen, halogen, or C1 - C6 haloalkyl. In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 8 is hydrogen or halogen. In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 8 is hydrogen.

[0074] In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 deuteroalkyl, or cycloalkyl. In some embodiments of the compound of formula (I) or (Ia) - (Ie), R 9is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 9 is hydrogen, halogen, -C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 9 is hydrogen, halogen, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 9 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 9 is hydrogen.

[0075] In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 10 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 dideuteroalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 10 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 10 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 10 is hydrogen.

[0076] In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 11 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterioalkyl, or cycloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 11 is hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 11 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or (Ia)-(Ie), R 11 is hydrogen.

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

[0078] In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 haloalkyl.

[0079] In some embodiments of the compounds disclosed herein, each Rb is, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is, independently, optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is, independently, optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R b is, independently, hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R bis independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b is independently C1-C6 haloalkyl.

[0080] In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), and each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, and each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Rc and R d is, independently, hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d is, independently, hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d is hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d is, independently, C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d is, independently, C1-C6 haloalkyl.

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

[0082] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuteroalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl, or two Rs on the same atom together form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 deuteroalkyl, or two Rs on the same atom together form an oxo. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl, or two Rs on the same atom together form an oxo.

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

[0084] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selected from the compounds of Table 1.

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

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

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

[0087] The AND label (and) indicates the presence at the stereochemical center where both isomers are shown. Assigning different numerical values to the AND labels indicates that they are independent of each other. The use of AND labels with the same value indicates that the two stereocenters are related to each other and can only change in concert.

[0088] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof,

Chemical formula

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

[0090] Labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled forms. 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 a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those recited herein, except that one or more atoms are replaced by atoms 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, for example, 2 H, 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl. Compounds described herein containing the foregoing isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of the invention. Certain isotopically labeled compounds, for example, 3 H and 14 C, etc., incorporating radioactive isotopes are useful in drug and / or substrate tissue distribution assays. Tritium labeling, i.e., 3 H and carbon-14, i.e., 14 C isotopes are particularly preferred because of the ease of their preparation and detectability. Further, substitution with heavy isotopes, such as deuterium, i.e., 2 H, etc., provides certain therapeutic advantages such as increased metabolic stability, e.g., longer in vivo half-life or reduced required dosage.

[0091] In some embodiments, the compounds described herein are labeled by other means including, but not limited to, the use of a chromophore or fluorophore, a bioluminescent label, or a chemiluminescent label.

[0092] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0093] In some embodiments, the compounds described herein have an acidic or basic group and thus react with any of several inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or of their solvates or stereoisomers, or by separately reacting the purified compound in free form with a suitable acid or base and isolating the salt thus formed.

[0094] Examples of pharmaceutically acceptable salts include salts prepared by reacting a compound described herein with a mineral, organic acid, or inorganic base, such salts including 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, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodate, 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, sebacate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate. Examples of pharmaceutically acceptable salts include salts prepared by reacting a compound described herein with a mineral, organic acid, or inorganic base, such salts including 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, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodate, 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, sebacate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylenesulfonate.

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

[0096] In some embodiments, the compounds described herein that contain a free acid group react with a suitable base such as a hydroxide, carbonate, bicarbonate, sulfate, etc. of a pharmaceutically acceptable metal cation, ammonia, or a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali or alkaline earth salts such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts, etc. Specific examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1~4 alkyl)4, etc.

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

[0098] Solvate In some embodiments, the compounds described herein exist as solvates. The present invention provides a method of treating a disease by administering such a solvate. The present invention further provides a method of treating a disease by administering such a solvate as a pharmaceutical composition.

[0099] Solvates contain a solvent in either stoichiometric or non-stoichiometric amounts and, in some embodiments, are formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, and the like. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of mere illustration, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated and solvated forms. Generally, the solvated forms are considered to be equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

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

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

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

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

[0104] In some embodiments, cancers that include BRCA1 and / or BRCA2 mutations are bladder cancer, brain and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

[0105] In some embodiments, the cancer is a cancer that lacks homologous recombination (HR)-dependent DNA DSB repair activity. The HR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms and reforms an intact DNA helix. Components of the HR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51L1 (NM_002877), RAD51C (NM_002876), RAD51L3 (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), MRE11A (NM_005590), and NBS1 (NM_002485). HR-dependent DNA Other proteins involved in the DSB repair pathway include regulatory factors such as EMSY. In some embodiments, the cancer that lacks HR-dependent DNA DSB repair includes one or more cancer cells that have a reduced or lost ability to repair DNA DSBs via that pathway, i.e., the activity of the HR-dependent DNA DSB repair pathway can be reduced or lost in one or more cancer cells.

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

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

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

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

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

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

[0112] In some embodiments, the brain cancer is a primary brain tumor that begins in the brain and tends to remain there.

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

[0114] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, can permeate the blood brain barrier (BBB) In some embodiments, the ratio of the compound that permeates the BBB is >0.1, where 1 is complete BBB permeation and 0 is no permeation. In some embodiments, the ratio of the compound that permeates the BBB is >0.2. In some embodiments, the ratio of the compound that permeates the BBB is >0.3. In some embodiments, the ratio of the compound that permeates the BBB is measured using the rat kp,uu assay. In some embodiments, the compound has a ratio of >0.3 (i.e., 0.3 - 1) when determined by the rat kp,uu assay.

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

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

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

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

[0119] Once the patient's condition has improved, a maintenance dosage is administered as needed. Thereafter, in a specific embodiment, the dosage or dosing frequency, or both, are reduced, depending on the symptoms, to a level at which the improved disease, disorder or condition is maintained. However, in certain embodiments, the patient will require intermittent or daily treatment over the long term upon any recurrence of symptoms.

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

[0121] However, generally, the dosages used for the treatment of adults typically range from 0.01 mg to 5000 mg per day. In one aspect, the dosages used for the treatment of adults are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently presented as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example, as 2, 3, 4 or more divided doses per day.

[0122] In one embodiment, an appropriate daily dosage for the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is about 0.01 to about 50 mg / kg per body weight. In some embodiments, the daily dosage or amount of the active substance in the dosage form is lower or higher than the range indicated herein, based on the number of variables regarding the individual treatment regimen. In various embodiments, the daily dosage and unit dosage are varied according to several variables including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the physician.

[0123] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals including, but not limited to, the determination of LD 10 and ED 90 . The dose ratio between toxicity and therapeutic effect is the therapeutic index and is expressed as the ratio between LD 50 and ED 50 . In certain embodiments, data obtained from cell culture assays and animal experiments are used in formulating a therapeutically effective daily dosage range and / or therapeutically effective unit dosage for use in mammals including humans. In some embodiments, the daily dosage of the compounds described herein is within the range of blood concentrations that include an ED 50 with minimal toxicity. In certain embodiments, the daily dosage range and / or unit dosage vary within this range depending on the dosage form used and the route of administration utilized.

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

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

[0126] In any of the foregoing embodiments, further embodiments include multiple administrations of an effective amount of the compound, where (i) the compound is administered continuously or intermittently as a single dose, (ii) the time between multiple administrations is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the subject every 12 hours, (v) the compound is administered to the subject every 24 hours. Further or alternative embodiments include a washout period, during which administration of the compound is temporarily interrupted or the dose of the compound administered is temporarily reduced, and at the end of the washout period, administration of the compound is resumed. In one embodiment, the length of the washout period varies from 2 days to 1 year.

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

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

[0129] Pharmaceutical Composition / Formulation The compounds described herein are administered, according to standard medical practice, to a subject in need of the compounds described herein, alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. In one embodiment, the compounds of the invention can be administered to an animal. The compounds can be administered orally or parenterally (including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and local routes of administration).

[0130] In another aspect, provided herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, 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 processing the active compound into a pharmaceutically usable preparation. Appropriate formulations depend on the chosen route of administration. An overview 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, N.Y., 1980, and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), and such disclosures are hereby incorporated by reference into this specification.

[0131] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, moistening agents, plasticizers, stabilizers, permeation enhancers, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

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

[0133] The pharmaceutical compositions containing the compounds described in this specification, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are merely exemplary and are manufactured in conventional ways, such as by conventional mixing, dissolving, granulating, tablet coating, wet grinding (levigating), emulsifying, encapsulating, entrapping, or compression processes.

[0134] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more of the compounds described in this specification, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries if desired, to obtain tablets or tablet 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. Disintegrants such as cross-linked - sodium carboxymethyl starch, polyvinylpyrrolidone, agar, or salts of alginic acid or sodium alginate are added if desired. In some embodiments, dyes or pigments are added to the tablet or tablet coating for identification or to characterize different combinations of the active compound dosage.

[0135] Oral pharmaceutical compositions include push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in a mixture of a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and an optional stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid (e.g., fatty oil, liquid paraffin, or liquid polyethylene glycol). In some embodiments, a stabilizer is added.

[0136] Pharmaceutical compositions for parenteral use are formulated as injections or infusions. In some embodiments, a pharmaceutical composition suitable for injection or infusion comprises a sterile aqueous solution, dispersion, or sterile powder containing a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium comprising, for example, water, physiological saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent the growth of microorganisms.

[0137] Combination A method of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent is disclosed herein.

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

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

Example

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

Chemical formula

Chemical formula

[0141] Example 1

Chemical formula

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

[0143] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL), NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by TLC (Pet. ether: EtOAc = 5:1, Rf fMonitored by TLC (Rf = 0.2). The reaction mixture was quenched by adding saturated aqueous sodium bisulfite (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H).

[0144] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL), SnCl2 (26.25 g, 134.09 mmol, 5.00 equiv) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, over 3 steps). LC-MS: (ES + H, m / z): [M + H] + = 311.0

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

[0146] Step 6: Preparation of ethyl 7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A mixture of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.50 g, 5.05 mmol, 1.00 equiv), tert-butyl(ethynyl)dimethylsilane (850 mg, 6.05 mmol, 1.20 equiv), CuI (0.19 g, 1.01 mmol, 0.20 equiv), Et3N (1.53 g, 15.15 mmol, 3 equiv), and Pd(PPh3)2Cl2 (0.35 g, 0.51 mmol, 0.10 equiv) in DMF (45 mL) was stirred at 50 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (450 mL). The resulting mixture was extracted with EtOAc (3 × 450 mL). The combined organic layers were washed with brine (3 × 450 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.5 g, 83%). LC-MS: (ES + H, m / z): [M + H] + = 357.2.

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

[0148] Step 8: Preparation of 3-[2-(tert-Butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (92 mg, 0.29 mmol, 1.00 equiv) and DMF (1 mg, 0.01 mmol, 0.05 equiv) in DCM (5 mL) was added dropwise SOCl2 (0.06 mL, 0.88 mmol, 3.00 equiv, 1.64 g / mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (97 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H + MeCN] += 374.2.

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

[0150] Step 10: Preparation of 5-{4-[(7-ethynyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile: A stirred mixture of 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridin-3-yl}methyl)piperazin-1-yl]pyridine-2-carbonitrile (120 mg, 0.24 mmol, 1.00 equiv) in THF (2.5 mL) was added dropwise with TBAF (0.27 mL, 0.27 mmol, 1.10 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by prepHPLC to give 5-{4-[(7-ethynyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile (31.3 mg, 34%). LC-MS: (ES + H, m / z): [M + H] + = 369.1; 1 H NMR (300 MHz, DMSO-d6) δ 12.17 (s, 1H), 8.48 (d, 1H), 8.42 (d, 1H), 8.15 (s, 1H), 7.75 (d, 1H), 7.64 (d, 1H), 7.36 (dd, 1H), 4.51 (s, 1H), 3.67 (s, 2H), 3.47 - 3.38 (m, 4H), 2.60 - 2.52 (m, 4H).

[0151] Example 2

Chemical Structure

[0152] Step 2: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate: To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL) was added NH4Cl (25 mL, saturated aqueous solution) and Fe (5.03 g, 90.01 mmol, 4.00 equiv). The reaction mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with CH2Cl2 / 2-propanol (5:1, 200 mL) and washed with water (250 mL) and brine (250 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This afforded methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90.17%) which was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] + =193.15; 1 H NMR (300 MHz, DMSO-d6) δ 8.29 (d, 1H), 7.60 (d, 1H), 5.51 - 5.47 (m, 1H), 5.41 (s, 2H), 5.39 - 5.36 (m, 1H), 3.84 (s, 3H), 2.08 (t, 3H).

[0153] Step 3: Preparation of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was added to a solution of methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et3N (6.16 g, 60.87 mmol, 3.00 equiv) in toluene (40 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C overnight under nitrogen. The reaction was monitored by LCMS. The reaction was quenched with MeOH (30 mL) at 0 °C. The resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2 / 2-propanol (5:1, 3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.80 g, 40.66%). LC-MS: (ES + H, m / z): [M + H] + = 219.1.; 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.92 (d, 1H), 8.15 (d, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.48 (s, 3H).

[0154] Step 4: Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A solution of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH3COOH (7 mL) was added dropwise with 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 93.5%). LC-MS: (ES + H, m / z): [M + H] + =253.0; 1 1H NMR (300 MHz, DMSO-d6) δ 8.90 (d, 1H), 8.13 (d, 1H), 3.93 (s, 3H), 2.60 (s, 3H).

[0155] Step 5: Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL) was added dropwise LiAlH4 (2 mL, 2.5 M in THF, 4.75 mmol, 2.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (1 mL, 12 M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (230 mg, 43.1%). LC-MS: (ES + H, m / z): [M + H] + =225.1; 11H NMR (300 MHz, DMSO-d6) δ 12.24 (br, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 5.69 (s, 1H), 4.63 (s, 2H), 2.63 (s, 3H).

[0156] Step 6: Preparation of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equiv) and DMF (7 mg, 0.09 mmol, 0.10 equiv) in DCM (10 mL) was added dropwise SOCl2 (318 mg, 2.67 mmol, 3.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (98 mg, 45.2%). LC-MS: (ES + H, m / z): [M + H] + = 243.0.

[0157] Step 7: Preparation of 4-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}benzonitrile: A solution of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (25 mg, 0.10 mmol, 1.00 equiv), DIEA (66 mg, 0.51 mmol, 5.00 equiv), KI (4 mg, 0.02 mmol, 0.20 equiv), and 4-(piperazin-1-yl)benzonitrile (19 mg, 0.10 mmol, 1.00 equiv) in MeCN (2 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure. The pure fractions were concentrated and then lyophilized to give 4-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}benzonitrile (12 mg, 29.6%). LC-MS: (ES-H, m / z): [M-H] - =392.15; 1 H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 3.67 (s, 2H), 3.38 - 3.34 (m, 4H), 2.64 (s, 3H), 2.57 - 2.54 (m, 4H).

[0158] Example 3

Chemical Structure

[0159] Step 2: Preparation of methyl 6-formyl-5-nitropyridine-3-carboxylate: A mixture of methyl 6-methyl-5-nitropyridine-3-carboxylate (35 g, 178.42 mmol, 1.00 equiv) and SeO2 (30 g, 267.64 mmol, 1.50 equiv) in dioxane (200 mL) was stirred at 110 °C overnight under a nitrogen atmosphere. The resulting mixture was then filtered and the filter cake was washed with EtOAc (5 × 200 mL). The filtrate was concentrated under reduced pressure and then the crude product was dissolved in THF (200 mL). The resulting mixture was filtered and the filter cake was washed with THF (3 × 100 mL). The filtrate was concentrated under reduced pressure to give nitropyridine-3-carboxylate (40 g, crude). LC-MS: (ES + H, m / z): [M + H] + = 211.1.

[0160] Step 3: Preparation of methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate: To a stirred solution of NaH (11.42 g, 285.52 mmol, 1.50 equiv, 60 wt%) in THF (500 mL) was added dropwise ethyl 2-(diethoxyphosphoryl)butanoate (72 g, 285.52 mmol, 1.50 equiv) in THF (50 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 10 minutes, then warmed to 40 °C and stirred for 10 minutes under a nitrogen atmosphere. The resulting mixture was cooled to -78 °C, and then methyl 6-formyl-5-nitropyridine-3-carboxylate (40 g, 190.35 mmol, 1.00 equiv) in THF (50 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (100 mL) at 0 °C. 400 mL of water was added to the resulting mixture, and the mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (20 g, 36%, 2 steps) and methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate (8.8 g). Data for methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate: LC-MS: (ES + H, m / z): [M + H] + = 309.1; 1H NMR (300 MHz, chloroform-d) δ 9.27 (d, 1H), 8.88 (d, 1H), 7.10 (t, 1H), 4.22 - 4.16 (m, 2H), 4.03 (s, 3H), 2.59 (qd, 2H), 1.25 (t, 3H), 1.19 (t, 3H). Data for methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinate: LC-MS: (ES + H, m / z): [M + H] + = 309.1; 11H NMR (300 MHz, chloroform-d) δ 9.45 (d, 1H), 8.88 (d, 1H), 7.87 (s, 1H), 4.34 (q, 2H), 4.05 (s, 3H), 2.67 (q, 2H), 1.39 (t, 3H), 1.15 (t, 3H).

[0161] Step 4: Preparation of ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a stirred mixture of methyl 6-[(1Z)-3-ethoxy-2-ethyl-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (9.00 g, 29.19 mmol, 1.00 equiv) and Fe (16.30 g, 291.93 mmol, 10.00 equiv) in EtOH (200 mL), CaCl2 (19.44 g, 175.16 mmol, 6.00 equiv) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, the filter cake was washed with EtOAc (5 × 100 mL), and the combined filtrates were concentrated. The resulting mixture was added to 250 mL of water and extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with brine (1 × 250 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (5.2 g, 72%). LC-MS: (ES + H, m / z): [M + H] + = 247.1; 1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 8.90 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 4.38 (q, 2H), 2.58 (q, 2H), 1.36 (t, 3H), 1.20 (t, 3H).

[0162] Step 5: Preparation of 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (4.00 g, 16.24 mmol, 1.00 equiv) in THF (50 mL) was added dropwise LiAlH4 (13 mL, 32.49 mmol, 2.00 equiv, 2.5 M in THF) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of 1 M aqueous HCl (16 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography to afford 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (2.00 g, 60%). LC-MS: (ES + H, m / z): [M + H] + = 204.8; 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 8.38 (d, 1H), 7.74 (s, 1H), 7.62 (d, 1H), 5.49 (t, 1H), 4.62 (d, 2H), 2.55 (dd, 2H), 1.18 (t, 3H).

[0163] Step 6: Preparation of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (300 mg, 1.47 mmol, 1.00 equiv) and DMF (11 mg, 0.15 mmol, 0.10 equiv) in DCM (10 mL) was added dropwise SOCl2 (1.05 g, 8.81 mmol, 6.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography to afford 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (300 mg, 92%). LC-MS: (ES + H, m / z): [M + H] + = 222.8; 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.50 (d, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 4.93 (s, 2H), 2.56 (td, 2H), 1.19 (t, 3H).

[0164] Step 7: Preparation of 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile: To a stirred mixture of 5-(piperazin-1-yl)pyridine-2-carbonitrile, HCl salt (600 mg) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (500 mg, 2.25 mmol, 1.00 equiv) in ACN (4 mL) were added DIEA (1.45 g, 11.25 mmol, 5.00 equiv) and KI (75 mg, 0.45 mmol, 0.20 equiv) portionwise at room temperature. The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction mixture was poured into water (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile (650 mg, 77%). LC-MS: (ES + H, m / z): [M + H] + = 375.2; 1 H NMR (300 MHz, DMSO-d6) δ 11.86 (s, 1H), 8.41 - 8.35 (m, 2H), 7.75 (t, 2H), 7.61 (s, 1H), 7.36 (dd, 1H), 3.64 (s, 2H), 3.52 - 3.42 (m, 4H), 2.61 - 2.54 (m, 6H), 1.18 (t, 3H).

[0165] Example 5

Chemical formula

[0166] Step 2: Preparation of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one: To a stirred mixture of Fe (5.00 g, 89.52 mmol, 5.00 equiv) in AcOH (100 mL), methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butanoate (6.00 g, 17.90 mmol, 1.00 equiv) in AcOH (20 mL) was added dropwise at 80 °C under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by TLC (CH2Cl2 / MeOH = 10 / 1). The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with water (3 × 100 mL). The precipitated solid was collected by filtration and washed with water (3 × 20 mL). Thereby, 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.5 g, 92%) was obtained. 1 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 6.99 (d, 1H), 6.72 (s, 1H), 6.17 (s, 1H), 3.78 (d, 1H), 1.72 - 1.62 (m, 2H), 0.88 (t, 3H).

[0167] Step 3: Preparation of 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one: To a stirred solution of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.40 g, 16.11 mmol, 1.00 equiv) in DCM (100 mL), DDQ (4.39 g, 19.33 mmol, 1.20 equiv) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NaHCO3 (aqueous solution) (100 mL) at 0 °C. The residue was purified by trituration with saturated NaHCO3 (aqueous solution) (5 × 100 mL). The precipitated solid was collected by filtration and washed with water (3 × 100 mL) to give 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one (3.50 g, 80%). LC-MS: (ES-H, m / z): [M-H] - = 269.0;1 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.44 (d, 1H), 7.24 (s, 1H), 2.79 (q, 2H), 1.21 (t, 3H).

[0168] Step 4: Preparation of 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde: To a solution of 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one (2.90 g, 10.70 mmol, 1.00 equiv) in toluene (100 mL) was added TMEDA (1.49 g, 12.84 mmol, 1.20 equiv), bis(adamantan-1-yl)(butyl)phosphane (0.77 g, 2.14 mmol, 0.20 equiv), and Pd(OAc)2 (0.24 g, 1.07 mmol, 0.10 equiv) in a pressure tank. The mixture was purged with nitrogen for 5 minutes and then pressurized to 30 atm with (CO:H2 = 1:1). The mixture was stirred at 100 °C overnight. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under vacuum to give 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde (1.40 g, 59%). LC-MS: (ES-H, m / z): [M-H] - = 219.0; 1 1H NMR (300 MHz, DMSO-d6) δ 12.74 (s, 1H), 10.01 (d, 1H), 7.65 - 7.47 (m, 2H), 2.86 (q, 2H), 1.24 (t, 3H).

[0169] Step 5: Preparation of 6-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile: A stirred solution of 6-(piperazin-1-yl)pyridine-3-carbonitrile (200 mg, 1.06 mmol, 1.00 eq) and 2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (304 mg, 1.38 mmol, 1.30 eq) in THF (10 mL) was added Ti(OiPr)4 (453 mg, 1.60 mmol, 1.50 eq) at room temperature under a nitrogen atmosphere. After 2 h, NaBH(AcO)3 (901 mg, 4.25 mmol, 4.00 eq) was added at 0 °C and the reaction was warmed to room temperature. After 2 h, the reaction was quenched by adding water (10 mL) at 0 °C. The aqueous layer was extracted with EtOAc (5 × 30 mL). The combined organic phases were concentrated under reduced pressure and the crude product was purified by prepHPLC to give 6-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile (56.1 mg, 13%). LC-MS: (ES + H, m / z): [M + H] + = 393.2; 1H NMR (300 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.16 - 7.04 (m, 2H), 6.93 (d, 1H), 3.77 - 3.52 (m, 6H), 2.87 - 2.75 (m, 2H), 2.50 - 2.43 (m, 4H), 1.22 (t, 3H); 19 19F NMR (282 MHz, DMSO-d6) δ -125.38.

[0170] Example 12

Chemical Structure

[0171] Step 2: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate: To a stirred mixture of methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate (12.00 g, 38.18 mmol, 1.00 equiv) in MeOH (180 mL) and EtOAc (30 mL), Pd(OH)2 / C (2.40 g) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. When complete, the resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 300 mL). The filtrate was concentrated and purified by silica gel column chromatography (Pet. ether / EtOAc) to afford methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (8 g, 83%). LC-MS: (ES + H, m / z): [M + H] + = 253.0; 1 H NMR (400 MHz, DMSO-d6) δ 10.44 (s, 1H), 7.25 - 7.20 (m, 1H), 7.19 - 7.14 (s, 1H), 4.00 - 3.91 (m, 1H), 3.75 (s, 3H), 1.76 - 1.60 (m, 2H), 0.94 - 0.86 (m, 3H).

[0172] Step 3: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate: To a stirred mixture of methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (7.00 g, 27.75 mmol, 1.00 equiv) in DCM (70 mL) at room temperature was added DDQ (7.56 g, 33.30 mmol, 1.20 equiv) in DCM (70 mL). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The residue was then dissolved in saturated aqueous NaHCO3 (200 mL). The precipitated solid was collected by filtration and washed with saturated aqueous NaHCO3 (3 × 200 mL) and water (3 × 200 mL). The solid was purified by trituration with EtOAc (30 mL) / hexane (100 mL). The resulting mixture was filtered and the filter cake was washed with hexane (3 × 100 mL). The filter cake was dried under reduced pressure to give methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate (6 g, 86%). LC-MS: (ES+H, m / z): [M+H] + =251.1; 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.78 (d, 1H), 7.63 (d, 1H), 3.89 (s, 3H), 2.82 (q, 2H), 1.23 (t, 3H).

[0173] Step 4: Preparation of 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one: To a stirred mixture of methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate (5.00 g, 19.98 mmol, 1.00 eq) in THF (100 mL) was added dropwise LiAlH4 (40 mL, 39.96 mmol, 2.00 eq, 1 moL / L in THF) at 0 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding water (1.5 mL), 15% NaOH (1.5 mL), and water (4.5 mL) at 0 °C. The precipitated solid was collected by filtration and washed with water (3 × 30 mL). The solid was dissolved in water (500 mL) and EtOAc (200 mL). The resulting mixture was extracted with EtOAc (8 × 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with MeOH (5 mL) and EtOAc (20 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 10 mL). The solid was dried under reduced pressure to give 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (1.2 g, 27%). LC-MS: (ES + H, m / z): [M + H] + =223.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.38 (s, 1H), 7.48 (d, 1H), 7.41 (d, 1H), 5.52 (brs, 1H), 4.64 (s, 2H), 2.80 (q, 2H), 1.18 (t, 3H).

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

[0175] Step 6: Preparation of 6-{4-[(2-Ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: A mixture of 7-(bromomethyl)-3-ethyl-6-fluoro-1H-quinoxalin-2-one (190 mg, 0.67 mmol, 1.00 equiv), 6-(piperazin-1-yl)pyridine-3-carbonitrile (150 mg, 0.80 mmol, 1.20 equiv), and DIEA (431 mg, 3.33 mmol, 5.00 equiv) in NMP (5 mL) was stirred at 80 °C for 1 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction mixture was poured into water (30 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product (200 mg) was purified by prepHPLC to give 6-{4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (100.2 mg, 38%). LC-MS: (ES + H, m / z): [M + H] + = 393.1; 1 H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.54 (d, 1H), 7.38 (d, 1H), 6.94 (d, 1H), 3.75 - 3.67 (m, 6H), 2.81 (q, 2H), 2.56 - 2.51 (m, 4H), 1.21 (t, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -124.28.

[0176] Example 16

Chem.

[0177] Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate: A solution of ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 24.14 mmol, 1.00 equiv) and triethyl phosphite (5.22 g, 31.39 mmol, 1.30 equiv) was stirred at 130 °C for 24 h under a nitrogen atmosphere. The residue was purified by reverse-phase combi flash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 38%). 11H NMR (300 MHz, chloroform-d) δ 4.26 - 4.07 (m, 6H), 2.19 (dd, 1H), 1.30 (dt, 10H), 0.71 (dddd, 1H), 0.60 (ddddd, 1H), 0.47 - 0.37 (m, 1H), 0.24 (ddtd, 1H).

[0178] Step 3: Preparation of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate: To a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv, 60 wt%) in THF (20 mL) was added dropwise ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 10 minutes, then warmed to 40 °C and stirred for 10 minutes under a nitrogen atmosphere. The resulting mixture was cooled to -78 °C, and then methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (5 mL) at 0 °C. 20 mL of water was added to the resulting mixture, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (700 mg, 46%). LC-MS: (ES + H, m / z): [M + H] + = 320.8.

[0179] Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv) and Fe (1.04 g, 18.73 mmol, 10.00 equiv) in EtOH (10 mL) was added with CaCl2 (1.24 g, 11.24 mmol, 6.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (2 × 50 mL). The filtrate was concentrated under reduced pressure. 50 mL of water was added to the resulting mixture and extracted with EtOAc (2 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (200 mg, 41%). LC-MS: (ES + H, m / z): [M + H] + = 259.0.

[0180] Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (160 mg, 0.62 mmol, 1.00 equiv) was added dropwise LiAlH4 (0.50 mL, 1.23 mmol, 2.00 equiv, 2.5 M in THF) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (1 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (100 mg, 75%). LC-MS: (ES + H, m / z): [M + H] + = 217.2.

[0181] Step 6: Preparation of 6,7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.37 mmol, 1.00 equivalent) and DMF (3 mg, 0.04 mmol, 0.10 equivalent) in DCM (10 mL) was added SOCl2 (264 mg, 2.22 mmol, 6.00 equivalents) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 235.0.

[0182] Step 7: Preparation of 3-cyclopropyl-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one: To a stirred solution of 1-(5-fluoropyridin-2-yl)piperazine (100 mg, 0.55 mmol, 1.00 equivalent) and 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (130 mg, 0.55 mmol, 1.00 equivalent) in ACN (3 mL) were added DIEA (357 mg, 2.76 mmol, 5.00 equivalents) and KI (18 mg, 0.11 mmol, 0.20 equivalent) at room temperature. The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature and then poured into H2O (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated and the crude product was purified by prepHPLC to give 3-cyclopropyl-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one (122.8 mg, 58%). LC-MS: (ES + H, m / z): [M + H] + = 380.3; 11H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 8.38 (d, 1H), 8.09 (d, 1H), 7.61 (d, 1H), 7.55 - 7.45 (m, 1H), 7.42 (s, 1H), 6.86 (dd, 1H), 3.62 (s, 2H), 3.49 - 2.38 (m, 4H), 2.50 - 2.45 (m, 4H), 2.20 - 2.08 (m, 1H), 1.02 - 0.92 (m, 2H), 0.86 - 0.78 (m, 2H); 19 19F NMR (282 MHz, DMSO-d6) δ -143.41.

[0183] Examples 28 and 29 [Chemical formula] Step 1: Preparation of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred mixture of 7-bromo-3-methyl-1H-1,5-naphthyridin-2-one (3.00 g, 12.54 mmol, 1.00 equiv) and tributyl(1-ethoxyethenyl)stannane (13.60 g, 37.64 mmol, 3.00 equiv) in 1,4-dioxane (20 mL) was added Pd(PPh3)2Cl2 (0.44 g, 0.62 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. When complete, the reaction was cooled to room temperature and the resulting solution was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 231.1

[0184] Step 2: Preparation of 7-acetyl-3-methyl-1,5-naphthyridin-2(1H)-one: The solution of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one from Step 1 was cooled to 0 °C and treated by dropwise addition of concentrated HCl (4 mL). The resulting reaction mixture was stirred at room temperature for 1 hour and then basified to pH 8 with saturated NaHCO3 (aqueous solution). The resulting mixture was then diluted with water (100 mL) and extracted with CH2Cl2 (3 × 200 mL). The combined organic layers were washed with brine (1 × 300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 7-acetyl-3-methyl-1,5-naphthyridin-2(1H)-one (1.39 g, 55% in two steps). LC-MS: (ES + H, m / z): [M + H] + =203.2

[0185] Step 3: Preparation of 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile: 7-Acetyl-3-methyl-1H-1,5-naphthyridin-2-one (350 mg, 1.73 mmol, 1.00 equiv) was added to a solution of 6-[(2R)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile (455 mg, 2.25 mmol, 1.30 equiv) in CH2Cl2 (8 mL). The resulting mixture was then concentrated under reduced pressure. To the above mixture, Ti(OiPr)4 (4.6 mL, 15.58 mmol, 9.00 equiv) was added dropwise at room temperature. The resulting mixture was stirred at 80 °C for an additional 4 hours and then cooled to room temperature. To the above mixture, EtOH (5 mL) and NaBH3CN (217 mg, 3.46 mmol, 2.00 equiv) were added portionwise at room temperature. The resulting mixture was stirred at 80 °C for an additional 2 hours and then cooled to room temperature. The reaction mixture was poured into water (100 mL), stirred for 1 hour, filtered through a plug of celite, and washed with DCM / MeOH (3 / 1, 300 mL). The aqueous layer was extracted with DCM / i-PrOH (5 / 1, 2 × 100 mL), and the combined organic layers were washed with brine (2 × 50 mL), Na2SO 4.It was dried, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (280 mg, 41.6%). LC-MS: (ES-H, m / z): [M+H] + = 389.1. The diastereomers were separated by chiral-HPLC to obtain rel-6-[(2R)-2-methyl-4-[(1R*)-1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (Example 28, 90.6 mg, de = 100%) and rel-6-[(2R)-2-methyl-4-[(1S*)-1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (Example 29, 69.5 mg, de = 100%). Data for Example 28: LC-MS: (ES+H, m / z): [M+H] + = 389.2; 1 1H NMR (300 MHz, DMSO-d6) δ 11.90 (s, 1H), 8.48 - 8.43 (dd, 2H), 7.85 - 7.82 (m, 2H), 7.65 - 7.64 (d, 1H), 6.86 - 6.83 (d, 1H), 4.51 (s, 1H), 4.26 - 4.22 (d, 1H), 3.59 - 3.57 (q, 1H), 3.14 - 3.11 (m, 2H), 2.58 - 2.50 (d, 1H), 2.18 - 2.06 (m, 5H), 1.36 - 1.34 (d, 3H), 1.18 - 1.15 (d, 3H). Data for Example 29: LC-MS: (ES+H, m / z): [M+H] + = 389.1; 11H NMR (300 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.48 - 8.46 (dd, 2H), 7.85 - 7.81 (m, 2H), 7.66 (d, 1H), 6.86 - 6.83 (d, 1H), 4.62 (s, 1H), 4.16 - 4.12 (d, 1H), 3.70 - 3.64 (q, 1H), 3.11 - 3.01 (td, 1H), 2.88 - 2.76 (dd, 2H), 2.26 - 2.03 (m, 5H), 1.34 (d, 3H), 1.22 (d, 3H). The relative stereochemistry of Examples 28 and 29 was arbitrarily assigned.

[0186] Example 36 [Chemical formula] Step 1: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate: A mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (10.00 g, 46.17 mmol, 1.00 equivalent), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.52 g, 92.34 mmol, 2.00 equivalents), K2CO3 (12.76 g, 92.34 mmol, 2.00 equivalents), and Pd(dppf)Cl2 (3.38 g, 4.62 mmol, 0.10 equivalent) in dioxane (150 mL) and water (15 mL) was stirred at 100 °C for 3 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was brought to room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated NaCl (aqueous solution) (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 49%) as a pale yellow oil. LC-MS: (ES + H, m / z): [M + H] + = 222.95.

[0187] Step 2: Preparation of methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate: To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL) was added NH4Cl (25 mL, saturated aqueous solution) and Fe (5.03 g, 90.01 mmol, 4.00 equiv). The reaction mixture was stirred at 80 °C for 4 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to come to room temperature and then concentrated under reduced pressure. The residue was diluted with CH2Cl2 / 2-propanol (5:1, 200 mL) and washed with water (250 mL) and brine (250 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. This afforded methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90%) which was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] + = 193.15. 1 H NMR (300 MHz, DMSO-d6) δ 8.29 (d, 1H), 7.60 (d, 1H), 5.51 - 5.47 (m, 1H), 5.41 (s, 2H), 5.39 - 5.36 (m, 1H), 3.84 (s, 3H), 2.08 (t, 3H).

[0188] Step 3: Preparation of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: A solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was added to a solution of methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et3N (6.16 g, 60.87 mmol, 3.00 equiv) in toluene (40 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 60 °C overnight under nitrogen. The reaction was monitored by LCMS. The reaction was quenched with MeOH (30 mL) at 0 °C. The resulting mixture was diluted with water (200 mL) and extracted with CH2Cl2 / 2-propanol (5:1, 3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.80 g, 41%). LC-MS: (ES + H, m / z): [M + H] + =219.1; 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 8.92 (d, 1H), 8.15 (d, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.48 (s, 3H).

[0189] Step 4: Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a solution of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH3COOH (7 mL), dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 94%). LC-MS: (ES + H, m / z): [M + H]+ = 253.0; 1 1H NMR (300 MHz, DMSO-d6) δ 8.90 (d, 1H), 8.13 (d, 1H), 3.93 (s, 3H), 2.60 (s, 3H).

[0190] Step 5: Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL) was added LiAlH4 (2 mL, 2.5 M in THF, 4.75 mmol, 2.00 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (1 mL, 12 M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (230 mg, 43%). LC-MS: (ES + H, m / z): [M + H] + = 225.1; 1 1H NMR (300 MHz, DMSO-d6) δ 12.24 (br, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 5.69 (s, 1H), 4.63 (s, 2H), 2.63 (s, 3H).

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

[0192] Step 7: Preparation of 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: To a stirred mixture of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (85 mg, 0.35 mmol, 1.00 equiv) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 equiv) in ACN (1 mL) were added DIEA (136 mg, 1.05 mmol, 3.00 equiv) and KI (1 mg, 0.01 mmol, 0.10 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 1 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a crude product (90 mg), which was further purified by prepHPLC to give 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (52.5 mg, 28%). LC-MS: (ES + H, m / z): [M + H] + = 395.10; 11H NMR (300 MHz, DMSO-d6) δ 12.30 (broad, 1H), 8.50 (multiplet, 2H), 7.85 (doublet of doublets, 1H), 7.69 (doublet, 1H), 6.94 (doublet, 1H), 3.67 - 3.62 (multiplet, 6H), 2.65 (singlet, 3H), 2.50 - 2.49 (multiplet, 4H).

[0193] Example 42

Chem.

[0194] Step 2: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred solution of methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 2.42 mmol, 1.00 eq) in THF (65 mL) was added dropwise a solution of LiAlH4 (2.5 M in THF, 3.9 mL, 9.75 mmol, 4.00 eq) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated aqueous NH4Cl solution (10 mL) at 0 °C and dried over anhydrous Na2SO4. The mixture was filtered and washed with CH2Cl2 / MeOH (10:1, 100 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (520 mg, 89%). LC-MS: (ES + H, m / z): [M + H] + = 241.1. 1 H NMR (400 MHz, Methanol-d4) δ 8.58 (d, 1H), 7.73 (d, 1H), 7.20 (t, 1H), 4.79 (s, 2H), 2.81 (t, 3H).

[0195] Step 3: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (320 mg, 1.33 mmol, 1.00 eq) and DMF (5 mg, 0.07 mmol, 0.05 eq) in CH2Cl2 (32 mL) was added dropwise SOCl2 (475 mg, 4.00 mmol, 3.00 eq) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was brought to room temperature and then concentrated under reduced pressure to afford 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (crude, 400 mg). LC-MS: (ES + H, m / z): [M + H] + = 259.1

[0196] Step 4: Preparation of 6-(4-{[7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile: A mixture of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (380 mg, 1.47 mmol, 1.00 equiv), 6-(piperazin-1-yl)pyridine-3-carbonitrile (415 mg, 2.20 mmol, 1.50 equiv), KI (365 mg, 2.20 mmol, 1.50 equiv), and DIEA (569 mg, 4.40 mmol, 3.00 equiv) in MeCN (4 mL) was stirred at 80 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to come to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous Na2SO4. The mixture was filtered, washed with EtOAc (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by prepHPLC to give 6-(4-{[7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (31 mg, 5%). LC-MS: (ES + H, m / z): [M + H] + = 411.2; 1 1H NMR (300 MHz, DMSO-d6) δ 12.17 (br, 1H), 8.57 (d, 1H), 8.41 (d, 1H), 7.85 (dd, 1H), 7.68 (d, 1H), 7.24 (t, 1H), 6.94 (d, 1H), 3.80 - 3.60 (m, 6H), 2.72 (s, 3H), 2.60 - 2.40 (m, 4H); 19 19F NMR (282 MHz, DMSO-d6) δ -115.51.

[0197] Example 47

Chemical formula

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

[0199] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: A stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was treated portionwise with NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by TLC (Pet. ether:EtOAc = 5:1, R f = 0.2). The reaction was quenched by the addition of saturated aqueous sodium bisulfite (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H).

[0200] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: A stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 equiv) in EtOH (100 mL) was added SnCl2 (26.25 g, 134.09 mmol, 5.00 equiv) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5%, in 3 steps). LC-MS: (ES + H, m / z): [M + H] + =311.0

[0201] Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equiv) in DMF (10 mL) was added CuCl (0.57 g, 5.78 mmol, 1.50 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was washed with 3 × 30 mL of water (10% NH3·H2O). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 77.78%). LC-MS: (ES + H, m / z): [M + H] + =267.0; 11H NMR (300 MHz, DMSO-d6) δ 9.27 (d, 1H), 8.63 (d, 1H), 8.57 (s, 1H), 4.41 (q, 2H), 4.12 (s, 3H), 1.37 (t, 3H).

[0202] Step 6: Preparation of Ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate: To a stirred mixture of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CH3CN (8 mL) was added TMSI (1.80 g, 9.00 mmol, 3.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The aqueous layer was washed with 3 × 50 mL of water (10% Et3N). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 97.64%). LC-MS: (ES + H, m / z): [M + H] + = 252.9; 1 1H NMR (300 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 8.20 (s, 1H), 4.39 (q, 2H), 1.36 (t, 3H).

[0203] Step 7: Preparation of 3-Chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: A stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv) in THF (6 mL) was added dropwise with LiAlH4 (2.5 mL, 5.85 mmol, 2.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for an additional 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1 M HCl (aqueous solution). The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 40.53%). LC-MS: (ES + H, m / z): [M + H] + = 211.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.69 (d, 1H), 5.53 (t, 1H), 4.64 (d, 2H).

[0204] Step 4: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 1.18 mmol, 1.00 equiv) in CH2Cl2 (5 mL) was added dropwise SOCl2 (423 mg, 3.56 mmol, 3.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This afforded 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 228.95.

[0205] Step 9: Preparation of 3-chloro-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (200 mg, 0.87 mmol, 1.00 equiv) and 1-(5-fluoropyridin-2-yl)piperazine (126 mg, 0.69 mmol, 0.80 equiv) in CH3CN (5 mL), DIEA (564 mg, 4.36 mmol, 5 equiv) and KI (14 mg, 0.08 mmol, 0.10 equiv) were added at room temperature. The resulting mixture was stirred at 50 °C for 2 h. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature and poured into 20 mL of water. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prepHPLC to give 3-chloro-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one (42.7 mg, 13.08%). LC-MS: (ES + H, m / z): [M + H] + = 374.0; 1 1H NMR (300 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.48 (d, 1H), 8.29 (s, 1H), 8.09 (d, 1H), 7.70 (d, 1H), 7.55 - 7.47 (m, 1H), 6.87 (dd, 1H), 3.66 (s, 2H), 3.46 - 3.42 (m, 4H), 2.53 - 2.50 (m, 4H); 19 19F NMR (282 MHz, DMSO-d6) δ -143.39.

[0206] Example 48

Chemical Structure

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

[0208] Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred solution of ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate (230 mg, 0.85 mmol, 1.00 equiv) in THF (5 mL), LiAlH4 (0.69 mL, 2.5 mol / L in THF, 2.00 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with MeOH (10 mL), and then DCM (50 mL) was added. The solution was filtered and the filter cake was washed with DCM / MeOH (5:1) (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH) to give 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (50 mg, 26%). LC-MS: (ES + H, m / z): [M + H] + = 227.0; 1 1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 8.50 (d, 1H), 8.16 (d, 1H), 7.70 (s, 1H), 6.98 (t, 1H), 5.57 (t, 1H), 4.67 (d, 2H).

[0209] Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.35 mmol, 1.00 eq) and DMF (1 mg, 0.02 mmol, 0.05 eq) in DCM (4 ml), SOCl2 (126 mg, 1.06 mmol, 3.00 eq) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 245.0.

[0210] Step 5: Preparation of 6-(4-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile: To a stirred solution of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (86 mg, assumed yield 100%, 0.35 mmol, 1.00 eq), 6-(piperazin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 eq), and KI (11 mg, 0.07 mmol, 0.20 eq) in ACN (5 ml), DIEA (227 mg, 1.76 mmol, 5.00 eq) was added dropwise at room temperature. The resulting solution was stirred at 80 °C for 1 h. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL). The solution was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product (80 mg). The crude product was purified by prepHPLC to give 6-(4-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (42.9 mg, 33% over 2 steps). LC-MS: (ES + H, m / z): [M + H] + = 397.1; 11H NMR (300 MHz, DMSO-d6) δ 12.33 (s, 1H), 8.54 (d, 1H), 8.48 (d, 1H), 8.16 (s, 1H), 7.85 (dd, 1H), 7.71 (d, 1H), 7.20 - 6.73 (m, 2H), 3.72 - 3.68 (m, 4H), 3.67 (s, 2H), 2.51 - 2.49 (m, 4H); 19 19F NMR (282 MHz, DMSO-d6) δ -119.30.

[0211] Example 49 [Chemical formula] Step 1: Preparation of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propanoate: To a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.01 mmol, 1.00 equiv) and methyl 2-aminopropanoate hydrochloride (2.93 g, 21.00 mmol, 1.00 equiv) in NMP (200 mL) was added dropwise DIEA (27.15 g, 210.09 mmol, 5.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by TLC (Pet. ether / EtOAc = 10 / 1). The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (1 L). The resulting mixture was washed with water (3 × 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propanoate (7.5 g, 56%) as a red oil. 1 1H NMR (400 MHz, DMSO-d6) δ 8.08 (t, 1H), 7.87 (dd, 1H), 7.77 (dd, 1H), 4.67 - 4.55 (m, 1H), 3.68 (s, 3H), 1.48 (dd, 3H); 19 19F NMR (377 MHz, DMSO-d6) δ -122.19.

[0212] Step 2: Preparation of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one: To a stirred solution of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propanoate (6.00 g, 18.68 mmol, 1.00 equiv) in HOAc (200 mL) was added Fe (5.22 g, 93.43 mmol, 5.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was filtered and the filter cake was washed with DCM:MeOH = 4:1 (3 × 100 mL). The filtrate was concentrated under reduced pressure. The pH of the residue was adjusted to pH 7 with saturated NaHCO3 (aqueous solution). The resulting mixture was then extracted with CH2Cl2 (3 × 300 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.2 g, 87%). LC-MS: (ES-H, m / z): [M-H] - = 257.1; 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 7.01 (dd, 1H), 6.76 (t, 1H), 6.20 (s, 1H), 3.90 - 3.80 (m, 1H), 1.28 (d, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -132.99.

[0213] Step 3: Preparation of 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one: To a stirred solution of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.50 g, 17.36 mmol, 1.00 eq) in DCM (500 mL) was added DDQ (4.34 g, 19.10 mmol, 1.10 eq) at room temperature. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with saturated NaHCO3 (aqueous solution) (500 mL). The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was filtered and the filter cake was washed with saturated NaHCO3 (aqueous solution) (3 × 100 mL). The filter cake was dried under reduced pressure. The residue was purified by silica gel column chromatography to afford 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one (3 g, 67%). LC-MS: (ES-H, m / z): [M-H] - =255.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 7.49 - 7.40 (m, 1H), 7.24 (q, 1H), 2.40 (q, 3H).

[0214] Step 4: Preparation of 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde: To a solution of 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one (500 mg, 1.94 mmol, 1.00 equiv) in toluene (100 mL) were added bis(adamantan-1-yl)(butyl)phosphane (349 mg, 0.97 mmol, 0.50 equiv), TMEDA (1.13 g, 9.72 mmol, 5.00 equiv), and Pd(OAc)2 (218 mg, 0.97 mmol, 0.50 equiv) in a pressure tank. The mixture was purged with nitrogen for 5 minutes and then pressurized to 30 Mpa with CO2:H2 = 1:1 at room temperature. The resulting mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde (300 mg, 74.8%). LC-MS: (ES-H, m / z): [M-H] - =205.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 10.02 (q, 1H), 7.67 - 7.52 (m, 2H), 2.49 - 2.44 (m, 3H).

[0215] Step 5: Preparation of 6-{4-[(8-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: A stirred mixture of 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde (200 mg, 0.97 mmol, 1.00 equiv) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (274 mg, 1.45 mmol, 1.50 equiv) in THF (20 mL) was added with titanium tetrakis(2-propanolate) (551 mg, 1.94 mmol, 2.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. To the above mixture, NaBH(OAc)3 (822 mg, 3.88 mmol, 4.00 equiv) was added at room temperature. The resulting mixture was stirred at room temperature for an additional 4 h. The reaction was monitored by LCMS. The reaction was quenched by adding water (80 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, followed by trituration with MeCN (5 mL) to afford 6-{4-[(8-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (51.1 mg, 14%). LC-MS: (ES + H, m / z): [M + H] + =379.2; 1 H NMR (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.09 (d, 2H), 6.93 (d, 1H), 3.68 (t, 4H), 3.60 - 3.55 (m, 2H), 2.47 (d, 4H), 2.41 (s, 3H); 19 F NMR (377 MHz, DMSO-d6) δ -125.51.

[0216] Example 60

Chemical Structure

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

[0218] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropicolinaldehyde: A stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)ethenyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was added portionwise with NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by TLC (PE:EA = 5:1, R f = 0.2). The reaction was quenched by the addition of saturated aqueous sodium bisulfite (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H).

[0219] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate: To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropanoate (20.40 g, 107.27 mmol, 4.00 eq) in EtOH (100 mL), SnCl2 (26.25 g, 134.09 mmol, 5.00 eq) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 90 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford the crude product. The crude product was purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% yield over 3 steps). LC-MS: (ES+H, m / z): [M+H] + = 311.0 / 313.0; 1 H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 4.42 (q, 2H), 4.12 (s, 3H), 1.39 (t 3H).

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

[0221] Step 6: Preparation of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (450 mg, 1.51 mmol, 1.00 equiv) in THF (8 mL) was added dropwise LiAlH4 (1.21 mL, 3.03 mmol, 2.00 equiv, 2.5 M in THF) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (3.03 mL, 3.03 mmol, 2.00 equiv) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (220 mg, 56.9%). LC-MS: (ES + H, m / z): [M + H] + = 255.0 / 257.0.

[0222] Step 7: Preparation of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (230 mg, 0.90 mmol, 1.00 equiv) and DMF (6 mg, 0.09 mmol, 0.10 equiv) in DCM (7 mL), SOCl2 (321 mg, 2.70 mmol, 3.00 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (220 mg, 89.2%). LC-MS: (ES + H, m / z): [M + H] + = 272.9 / 274.9.

[0223] Step 8: Preparation of 6-{4-[(7-bromo-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: To a stirred mixture of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (150 mg, 0.54 mmol, 1.00 equiv), DIEA (354 mg, 2.74 mmol, 5.00 equiv), and 6-(piperazin-1-yl)pyridine-3-carbonitrile (113 mg, 0.60 mmol, 1.10 equiv) in MeCN (7 mL), KI (18 mg, 0.11 mmol, 0.20 equiv) was added portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC, the pure fractions were concentrated, and then lyophilized to give 6-{4-[(7-bromo-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (25.6 mg, 10.9%). LC-MS: (ES + H, m / z): [M + H] + = 425.00 / 427.00; 11H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.47 (s, 3H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.68 (s, 1H), 6.93 (d, J = 9.1 Hz, 1H), 3.78 - 3.59 (m, 6H), 2.48 (d, J = 4.7 Hz, 4H).

[0224] Examples 68 and 69

Chemical Structure

[0225] Step 2: Preparation of methyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate: To a stirred solution of ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-naphthyridine-3-carboxylate (1.30 g, 4.30 mmol, 1.00 equiv) in MeCN was added HBr in AcOH (0.25 mL, 33 wt%, 2.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 0.5 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL) and basified to pH 8 with Et3N. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate (730 mg, 58.89%). LC-MS: (ES + H, m / z): [M + H] + = 289.10; 1 1H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 4.96 - 4.87 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.12 - 4.04 (m, 1H), 3.91 - 3.79 (m, 1H), 2.48 - 2.32 (m, 1H), 1.99 - 1.81 (m, 2H), 1.74 - 1.63 (m, 1H), 1.36 (t, J = 7.1 Hz, 3H).

[0226] Step 3: Preparation of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one: To a stirred mixture of ethyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate (730 mg, 2.53 mmol, 1.00 equiv) in THF (8 mL) was added dropwise LiAlH4 (192 mg, 5.06 mmol, 2.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M HCl (1 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (280 mg, 44.90%). LC-MS: (ES + H, m / z): [M + H] + = 247.00; 1 H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 5.48 (t, J = 5.6 Hz, 1H), 4.98 - 4.84 (m, 1H), 4.63 (d, J = 5.3 Hz, 2H), 4.18 - 4.01 (m, 1H), 3.91 - 3.75 (m, 1H), 2.45 - 2.31 (m, 1H), 2.02 - 1.78 (m, 2H), 1.74 - 1.58 (m, 1H).

[0227] Step 4: Preparation of 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one: To a stirred solution of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (280 mg, 1.13 mmol, 1.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv) in DCM, SOCl2 (0.25 mL, 3.41 mmol, 3.00 equiv) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (300 mg, crude). LC-MS: (ES + H, m / z): [M + H] + = 265.05.

[0228] Step 5: Preparation of 6-(4-{[6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile: To a stirred mixture of 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (150 mg, 0.56 mmol, 1.00 equiv) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (106 mg, 0.56 mmol, 1.00 equiv) in MeCN (10 mL), DIEA (292 mg, 2.26 mmol, 4.00 equiv) and KI (18 mg, 0.11 mmol, 0.20 equiv) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to give 6-(4-{[6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (88 mg, 37.29%). LC-MS: (ES + H, m / z): [M + H] +=417.10. The racemate (88 mg) was separated by prep-chiral-HPLC under the following conditions: Column: CHIRALPAK IH, 2 × 25 cm, 5 μm; Mobile phase A: Hex (10 mM NH3-MeOH), Mobile phase B: EtOH:ACN = 5:1; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 12 min; Wavelength: 218 / 282 nm; RT1 (min): 4.62; RT2 (min): 6.76; Sample solvent: MeOH:DCM = 1:1 - HPLC; Injection volume: 0.75 mL; Number of runs: 6. The pure fractions were concentrated under vacuum and then lyophilized to obtain Example 68 (34.2 mg, purity 99.7%, ee = 100%) and Example 69 (34.1 mg, purity 99.3%, ee = 99.7%). Example 68: LC-MS: (ES + H, m / z): [M + H] + =417.10; 1 1H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.47 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 1.8 Hz, 1H), 7.84 (dd, J = 9.1, 2.4 Hz, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H), 4.89 (t, J = 6.8 Hz, 1H), 4.10 - 4.03 (m, 1H), 3.87 - 3.79 (m, 1H), 3.73 - 3.62 (m, 6H), 2.58 - 2.49 (m, 4H), 2.43 - 2.30 (m, 1H), 2.02 - 1.77 (m, 2H), 1.73 - 1.57 (m, 1H). Example 69: LC-MS: (ES + H, m / z): [M + H] + =417.10; 11H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.48 (d, J = 2.4 Hz, 1H), 8.43 (d, J = 1.8 Hz, 1H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.64 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 4.90 (t, J = 6.8 Hz, 1H), 4.15 - 4.00 (m, 1H), 3.92 - 3.76 (m, 1H), 3.74 - 3.59 (m, 6H), 2.50 - 2.45 (m, 4H), 2.44 - 2.31 (m, 1H), 2.02 - 1.78 (m, 2H), 1.74 - 1.57 (m, 1H).

[0229] Example 71 [Chemical Structure] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide: A solution of α-methylcinnamic acid (2.56 g, 15.78 mmol, 1.00 equiv) in DCM (30 mL) was treated with DIEA (8.16 g, 63.15 mmol, 4.00 equiv) and T3P (15.07 g, 23.68 mmol, 1.50 equiv, 50 wt% in DCM) at room temperature for 5 min under a nitrogen atmosphere, followed by the addition of 3-bromo-2-fluoroaniline (3.00 g, 15.78 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 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 to obtain (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide (2.00 g, 37.9%). LC-MS: (ES + H, m / z): [M + H] + = 333.95 / 335.95; 11H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.62 - 7.41 (m, 7H), 7.21 - 7.13 (m, 1H), 6.85 - 6.69 (m, 1H), 2.12 (d, J = 1.4 Hz, 3H).

[0230] Step 2: Preparation of 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one: To a stirred solution of (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide (2.00 g, 5.98 mmol, 1.00 equiv) in chlorobenzene (20 mL) was added AlCl3 (2.39 g, 17.95 mmol, 3.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-8-chloro-3-methyl-1H-quinolin-2-one (1.00 g, 65.2%). LC-MS: (ES + H, m / z): [M + H] + = 255.80 / 257.80; 1 1H NMR (400 MHz, DMSO-d6) δ 11.94 (s, 1H), 7.82 (s, 1H), 7.44 - 7.34 (m, 2H), 2.09 (s, 3H).

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

[0232] Step 4: Preparation of 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one: To a stirred solution of 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one (400 mg, 1.93 mmol, 1.00 equiv) and DMF (14 mg, 0.19 mmol, 0.10 equiv) in DCM (5 mL) was added SOCl2 (2.30 g, 19.30 mmol, 10.00 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (400 mg, 91.8%). LC-MS: (ES + H, m / z): [M + H] + =226.3

[0233] Step 5: Preparation of 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: A solution of 6-(piperazin-1-yl)pyridine-3-carbonitrile hydrochloride (229 mg, estimated yield 100%, 0.88 mmol, 1.00 equiv) in MeCN (10 mL) was treated with DIEA (573 mg, 4.43 mmol, 5.00 equiv) at room temperature for 5 min under a nitrogen atmosphere, followed by the addition of KI (17 mg, 0.10 mmol, 0.10 equiv) and 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (200 mg, 0.88 mmol, 1.00 equiv). The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (92.1 mg, 23.8%). LC-MS: (ES + H, m / z): [M + H] + = 378.10; 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.47 (d, J = 4.0 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.1, 6.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.66 - 3.65 (m, 6H), 2.51 - 2.48 (m, 4H), 2.10 (d, J = 1.3 Hz, 3H). 19 F NMR (377 MHz, DMSO-d6) δ -135.84.

[0234] Example 82

Chemical Structure

[0235] Step 2: Preparation of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate: To a stirred solution of 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl) malonate (45.00 g, 115.62 mmol, 1.00 equiv) in CH2Cl2 (300 mL) was added TFA (200 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (100 mL). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (35 g, crude). LC-MS: (ES+H, m / z): [M+H] + =290.9

[0236] Step 3: Preparation of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate: To a stirred solution of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (35.00 g, 121.07 mmol, 1.00 equiv) and Fe (79.72 g, 1219.36 mmol, 7.50 equiv) in EtOH (250 mL), saturated aqueous NH4Cl solution (250 mL) was added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (300 mL). The resulting mixture was stirred at room temperature for 10 min. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 70 mL). The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL) and then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (9.3 g, 29.7%) as a pale yellow oil. LC-MS: (ES + H, m / z): [M + H] + = 259.1

[0237] Step 4: Preparation of ethyl 2-(5-bromo-3-(2,2-dimethoxypropanamide)pyridin-2-yl)acetate: To a stirred solution of methyl 2,2 - diethoxypropanoate (12.00 g, 80.99 mmol, 1.00 equiv) in MeOH (120 mL) was added dropwise NaOH (9.72 g, 242.98 mmol, 3.00 equiv) in H2O (120 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 h under a nitrogen atmosphere. The reaction was monitored by TLC. The mixture was acidified to pH 8 with HCl (2 M in water). The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOH (500 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered and the filter cake was washed with EtOH (3 × 100 mL). The filtrate was concentrated under reduced pressure to give sodium 2,2 - dimethoxypropanoate (8.5 g, 78.2%). 1 1H NMR (300 MHz, D2O) δ 3.12 (d, J = 1.7 Hz, 6H), 1.33 (s, 3H).

[0238] To a stirred solution of sodium 2,2 - dimethoxypropanoate (7.59 g, 48.63 mmol, 1.50 equiv) in dioxane (100 ml) were added DIEA (12.57 g, 97.26 mmol, 3.00 equiv) and T3P (30.95 g, 97.26 mmol, 3.00 equiv, 50 wt% in EtOAc) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under a nitrogen atmosphere. To the above mixture was added methyl 2 - (3 - amino - 5 - bromopyridin - 2 - yl)acetate (8.40 g, 32.42 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at 100 °C overnight. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 2 - (5 - bromo - 3 - (2,2 - dimethoxypropanamide)pyridin - 2 - yl)acetate (9.3 g, 79.4%). LC - MS: (ES + H, m / z): [M + H] + = 375.1

[0239] Step 5: Preparation of Ethyl 7-Bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxylate: To a stirred solution of ethyl 2-(5-chloro-3-(2,2-dimethoxypropanamide)pyridin-2-yl)acetate (7.00 g, 18.65 mmol, 1.00 eq) in TFA (100 mL) was added H2O (7 mL), followed by 2 drops of fresh I2 solution (30 mg of I2 suspended in TFA (10 mL)) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C overnight under a nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in toluene (100 mL) and piperidine (6 mL). The resulting mixture was refluxed at 120 °C for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl 7-bromo-3-methyl-2-oxo-1H-1,5-naphthyridine-4-carboxylate (3.3 g, 56.9%). LC-MS: (ES + H, m / z): [M + H] + = 313.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.06 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). Step 6: Preparation of 7-Bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred solution of ethyl 7-bromo-3-methyl-2-oxo-1H-1,5-naphthyridine-4-carboxylate (3.00 g, 9.64 mmol, 1.00 eq) in THF (50 mL), LiEt3BH (30 mL, 1 M in THF) was added dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding water / ice (6 mL) at 0 °C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (gradient from 0 to 10:1 in 30 min) to afford 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (1.8 g, 69.4%). LC-MS: (ES-H, m / z): [M-H] - =267.0 / 269.0; 1 H NMR (300 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.90 (d, J = 5.2 Hz, 2H), 2.21 (s, 3H).

[0240] Step 7: Preparation of 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde: To a stirred mixture of 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (1.80 g, 6.68 mmol, 1.00 equiv) in THF (20 mL) was added 1,1-bis(acetyloxy)-3-oxo-3H-1λ[5],2-benziodoxole-1-yl acetate (3.40 g, 8.02 mmol, 1.20 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The precipitated solid was collected by filtration and washed with water (3 × 5 mL). The residue was purified by reverse phase combiflash chromatography to afford 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde (760 mg, 42.5%). LC-MS: (ES-H, m / z): [M-H] - =264.9; 1 H NMR (300 MHz, DMSO-d6) δ 12.28 (s, 1H), 10.88 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 2.25 (s, 3H).

[0241] Step 8: Preparation of 7-bromo-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred solution of 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde (750 mg, 2.80 mmol, 1 equiv) in THF (5 mL) was added dropwise BAST (2.49 g, 11.23 mmol, 4 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The reaction was quenched at 0 °C with saturated NH4Cl (aqueous solution) (3 mL). The resulting mixture was extracted with EtOAc (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-4-(difluoromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (320 mg, 39.4%). LC-MS: (ES-H, m / z): [M-H] - =287.0

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

[0243] Step 10: Preparation of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one: To a stirred solution of 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (185 mg, 0.25 mmol, 1.00 equiv) and DMF (2 mg, 0.02 mmol, 0.10 equiv) in CH2Cl2 (3 mL) was added dropwise SOCl2 (183 mg, 1.54 mmol, 6.00 equiv) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (195 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 259.0

[0244] Step 11: Preparation of 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile: A stirred solution of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (104 mg, 0.40 mmol, 1.00 equiv) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (91 mg, 0.48 mmol, 1.20 equiv) in MeCN (5 ml) was added with DIEA (260 mg, 2.01 mmol, 5.00 equiv) and KI (13 mg, 0.08 mmol, 0.20 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (crude). The crude product was further purified by trituration with MeOH (6 mL) to give 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (28.3 mg, 16.6%). LC-MS: (ES + H, m / z): [M + H] + =411.10; 1 H NMR (300 MHz, DMSO-d6) δ 12.25 (s, 1H), 8.48 (t, J = 1.8 Hz, 2H), 8.14 - 7.74 (m, 2H), 7.70 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 3.39 - 3.67 (m, 6H), 2.50 - 2.48 (m, 4H), 2.33 (t, J = 2.8 Hz, 3H). 19 F NMR (282 MHz, DMSO-d6) δ -117.71.

[0245] Example 83

Chemical Structure

[0246] Step 2: Preparation of 7-bromo-8-fluoro-1H-quinolin-2-one: A mixture of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (17.00 g, 59.00 mmol, 1.00 equiv) in H2SO4 (85 mL) was stirred at room temperature for 3 hours under a nitrogen atmosphere. The resulting mixture was added dropwise to ice water (1 L) and stirred for 1 hour. The precipitated solid was collected by filtration and washed with water (3 × 200 mL). The resulting mixture was concentrated under reduced pressure to give 7-bromo-8-fluoro-1H-quinolin-2-one (14.30 g, crude). LC-MS: (ES + H, m / z): [M + H] + = 242.0 / 244.0。

[0247] Step 3: Preparation of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one: To a stirred mixture of 7-bromo-8-fluoro-1H-quinolin-2-one (3.00 g, 12.39 mmol, 1.00 equiv) and NCS (2.65 g, 19.83 mmol, 1.60 equiv) in CH3COOH (50 mL) was added dropwise dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, crude). LC-MS: (ES + H, m / z): [M + H] + = 275.9 / 277.9; 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.52 - 7.42 (m, 2H).

[0248] Step 4: Preparation of 3-chloro-7-ethyl-8-fluoro-1H-quinolin-2-one: To a stirred mixture of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, 8.97 mmol, 1.00 equiv), CsF (4.09 g, 26.91 mmol, 3.00 equiv), Pd(dppf)Cl2 (0.33 g, 0.44 mmol, 0.05 equiv), and 2-ethenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 8.97 mmol, 1.00 equiv) in dioxane (50 mL) was added dropwise H2O (5 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES + H, m / z): [M + H] + = 224.0; 11H NMR (300 MHz, DMSO-d6) δ 12.38 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.53 - 7.46 (m, 2H), 6.95 (dd, J = 17.7, 11.2 Hz, 1H), 6.07 (dd, J = 17.7, 1.0 Hz, 1H), 5.57 (dd, J = 11.2, 1.0 Hz, 1H).

[0249] Step 5: Preparation of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde: To a stirred mixture of 3-chloro-7-ethenyl-8-fluoro-1H-quinolin-2-one (750 mg, 3.35 mmol, 1.00 equiv), K2OsO2(OH)4 (123 mg, 0.33 mmol, 0.10 equiv), NaIO4 (2.87 g, 13.41 mmol, 4.00 equiv), and 2,6-dimethylpyridine (718 mg, 6.70 mmol, 2.00 equiv) in THF (15 mL), H2O (1.5 mL) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (630 mg, 83.2%). LC-MS: (ES-H, m / z): [M-H] - = 224.1.

[0250] Step 6: Preparation of 6-{4-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile: A mixture of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (150 mg, 0.66 mmol, 1.00 eq) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (137 mg, 0.73 mmol, 1.10 eq) in DCM (2 mL) was stirred at room temperature for 10 minutes. The resulting mixture was concentrated under reduced pressure. To the resulting mixture was added HOAc (19 mg, 0.33 mmol, 0.50 eq) in EtOH (3 mL), and the mixture was stirred at 50 °C for 4 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. To the above mixture, NaBH3CN (83 mg, 1.33 mmol, 2.00 eq) was added portionwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with EtOH (3 × 2 mL). The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure to give 6-{4-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (69.3 mg, 26.2%). LC-MS: (ES + H, m / z): [M + H] + = 398.10; 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 1.5 Hz, 1H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 8.1, 6.3 Hz, 1H), 6.97 - 6.87 (m, 1H), 3.71 - 3.63 (m, 6H), 2.50 - 2.44 (m, 4H); 19 F NMR (282 MHz, DMSO-d6) δ -134.50.

[0251] The following compounds were synthesized as described above.

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

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

[0253] DLD-1 BRCA2(- / -) and parental isogenic pairs were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both were cultured at 37 °C with 5% CO2. The compounds of the present invention were dispensed into 384-well plates (Corning, 3764) using an Echo acoustic liquid handler to form a final concentration serially diluted 1:3 with a maximum dose of 10 or 30 μM. Cells were seeded onto the plates at a density of 50 cells / well (DLD-1 parent), 200 cells / well (DLD-1 BRCA2- / -), or 500 cells / well (MDA-MB-436). After brief rotation, the cells were cultured without disturbance at 37 °C with 5% CO2 in a well-humidified incubator for 7 days. Cell viability was measured by the CellTiter Glo2.0 assay kit (Promega, G9243), the growth inhibition rate was calculated, plotted against the final compound concentration, and the data was fitted to Xfit to generate IC 50 values.

[0254] Example B: Biochemical (FP) Assay Assays based on fluorescent polarization (FP) are widely used in drug discovery due to their homogeneous format, robust performance, and lack of interference seen in other assays. Compounds were characterized using an assay that measures the displacement of a commercially available fluorescently labeled PARP1 / 2 inhibitor (PARPi-FL, Tocris Biosciences, No. 6461) as exemplified in the assays conducted in International Publication Nos. 2014 / 064149 and 2021 / 013735 (A1). The assay was performed using the following method. The compound was dissolved in DMSO and serially diluted in an Optiplate-384F plate at the desired concentration range using an Echo550 liquid handler. 100% DMSO was used for the high (protein present) and low (protein absent) control samples. 20 nL of the compound or DMSO alone was added to individual assay plate wells.

[0255] PARP1 and PARP2 proteins were expressed, purified, and diluted to a final concentration of 20 nM in an assay buffer containing 50 mM Tris, pH 8.0, 0.001% Triton® X-100, 10 mM MgCl2, and 150 mM NaCl. Then, PARPi-FL was added at a final concentration of 3 nM.

[0256] The assay plate was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 4 hours.

[0257] Fluorescent polarization was read using an Envision plate reader using the following settings.

[0258] 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 Enh - Slot 1

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

Table 5

Number

[0260] Using XLFit (Equation 201), the reported IC 50 was calculated for each compound.

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

Table 3-1

Table 3-2

[0262] Example C: Human Transporter Efflux in Vitro Madin-Darby canine kidney (MDCKII) cells expressing MDR1 and BCRP were seeded at a density of 545,000 cells / cm2 on a Corning HTS Transwell® 96-well polycarbonate permeable (0.4 μm pore) support. Cells were incubated for 4 - 8 days prior to the assay, and monolayer integrity was evaluated by measuring trans-epithelial electrical resistance (TEER). Test compounds and reference compounds were diluted in transport buffer (HBSS HEPES pH 7.4) to concentrations of 10 and 1 μM, respectively. The final organic solvent concentration was 0.5% (v / v). Bidirectional (apical to basolateral and basolateral to apical) fluxes of test compounds and reference compounds were determined over a 2-hour incubation at 37 °C and 5% CO2 at 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. Integrity

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

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

[0265] The in vitro binding of the test article and reference compound to plasma proteins was examined using the equilibrium dialysis method. Plasma samples containing 5 μM of the test article or blank dialysis buffer (PBS, pH 7.4) were added to separate chambers of the dialysis wells of a high-throughput equilibrium dialysis (HTD) apparatus. The dialysis plate was sealed and placed in an incubator with 5% CO2 at 37 °C and shaken at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Ketoconazole (5 μM) was used as the reference compound. After incubation, the seals were removed and 50 μL of the post-dialysis samples were pipetted from both the buffer and plasma chambers into fresh 96-well plates. The samples were equimatrilyzed by addition either to the buffer sample of the blank sample or to the plasma sample of the blank buffer. . Subsequently, 400 μL (4 volumes) of acetonitrile containing internal standard was added to all samples to precipitate the protein, and then the relative concentration of the test article was determined by analysis by UPLC-MS / MS. The unbound fraction in plasma was calculated using the concentrations of the test article in the buffer and plasma samples according to the following formula.

Equation

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

[0267] The in vitro binding of the test article and reference compound to rodent brain homogenates was examined using the equilibrium dialysis method. Brains collected from naive animals were weighed and homogenized in 4 volumes of PBS, pH 7.4. Brain homogenate samples containing 1 μM of the test article or blank dialysis buffer (PBS, pH 7.4) were added to separate chambers of the dialysis wells of a high-throughput equilibrium dialysis (HTD) apparatus. The dialysis plate was sealed and placed in an incubator with 5% CO2 at 37 °C and shaken at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Telmisartan (5 μM) was used as the reference compound. After incubation, the seals were removed and 50 μL of the post-dialysis samples were pipetted into a new 96-well plate from both the buffer and brain homogenate chambers. The samples were equilibrated by either addition of the buffer sample to the blank homogenate or addition of the blank buffer to the homogenate sample. Subsequently, 400 μL (4 volumes) of acetonitrile containing internal standard was added to all samples to precipitate the proteins, which were then analyzed by UPLC-MS / MS to determine the relative concentration of the test article. The unbound fraction in the diluted brain homogenate was calculated using the concentrations of the test article in the buffer and homogenate samples according to the following equation.

Number

[0268] Correction for the unbound percentage in the undiluted brain was achieved using the following equation.

Number

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

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

[0271] Prior to bioanalysis, the plasma samples 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 generated by spiking blank rat plasma or brain homogenate with the drug over an appropriate concentration range. Brain homogenate concentrations were corrected for the homogenization buffer dilution factor to obtain total brain drug concentrations.

[0272] The brain-to-plasma partition coefficient (Kp) for each compound was determined by calculating AUCbrain: AUCplasma, provided that tlast was the same for each matrix. If the drug concentration vs. time profile for one matrix dropped below the lower limit of quantification at an earlier time point than the other, the brain Kp was calculated as the mean of the ratios of the total brain drug concentration to the total plasma drug concentration measured at each time point where the drug concentrations in both matrices were quantifiable.

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

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

Table 4

Claims

【Claim 1】 The invention described in the specification of this application.

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