PARP1 inhibitors and uses thereof

Abstract

PARP1 inhibitors and pharmaceutical compositions comprising the same are described herein.The subject compounds and compositions are useful for treating cancer.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 301,907, filed on January 21, 2022, and U.S. Provisional Application Serial No. 63 / 376,338, filed on September 20, 2022, which are hereby incorporated by reference in their entirety. Background Art

[0003] Poly (ADP-ribose) polymerase (PARP) or poly (ADP-ribose) synthase (PARS) plays an important role in promoting DNA repair, controlling RNA transcription, mediating cell death and regulating immune responses. These effects make PARP inhibitors targeted drugs for a wide variety of diseases. PARP inhibitors have demonstrated efficacy in many disease models, particularly in models of ischemia-reperfusion injury, inflammatory diseases, and degenerative diseases, demonstrating protection against the adverse effects of cytotoxic compounds and synergistic effects of cytotoxic cancer therapy. PARP is also suitable for retroviral infection, so inhibitors can be used in antiretroviral therapy. PARP inhibitors are effective in preventing ischemia-reperfusion injury in models of myocardial infarction, stroke, other neurological trauma, organ transplantation, and reperfusion of the eye, kidney, intestine, and skeletal muscle. Inhibitors are effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown benefit in several models of degenerative diseases, including diabetes (and complications) and Parkinson's disease. PARP inhibitors can ameliorate liver toxicity following acetaminophen overdose, cardio- and renal toxicity from doxorubicin and platinum-based antineoplastic agents, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to enhance radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, reducing metastasis, and prolonging survival of tumor-bearing animals.

[0004] PARP1 and PARP2 are the most extensively studied PARPs due 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 lesions.

[0005] After this recruitment is complete, PARP autoPARylation triggers the release of bound PARP from DNA to allow access to other DNA repair proteins to complete the repair. Therefore, the binding of PARP to the damage site, its catalytic activity and its eventual release from DNA are all important steps in the cancer cell response to DNA damage caused by chemotherapeutic agents and radiation therapy.

[0006] Inhibition of PARP family enzymes has been developed as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have demonstrated that tumor cells carrying deleterious alterations in BRCA1 or BRCA2, key tumor suppressor proteins involved in double-strand DNA break (DSB) repair by homologous recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors have defective homologous recombination repair (HRR) pathways and rely on the function of PARP enzymes for survival. Although PARP inhibitor therapy primarily targets SRCA mutant cancers, clinical trials of PARP inhibitors have been conducted in non-SRCA mutant tumors that exhibit homologous recombination deficiency (HRD).

[0007] It is believed that PARP inhibitors with improved selectivity for PARP1 may have improved efficacy and reduced toxicity compared to other clinical PARP1 / 2 inhibitors. It is also believed that selective and strong inhibition of PARP1 will lead to the capture of PARP1 on DNA, resulting in DNA double-strand breaks (DSBs) through S-phase replication fork collapse. It is also believed that PARP1-DNA capture is an effective mechanism for selective killing of tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors that are selective for PARP1. Summary of the invention

[0008] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0009]

[0010] in:

[0011] R 1 Hydrogen, deuterium, halogen, -CN, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0012] R 2 Hydrogen, deuterium, halogen, -CN, -OR a 、-NR c R d, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0013] X is N or CR 3 ;

[0014] Y is N or CR 4 ;

[0015] Z is N or CR 5 ;

[0016] R 3 Hydrogen, deuterium, halogen, -CN, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0017] R 4 Hydrogen, deuterium, halogen, -CN, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0018] R 5 Hydrogen, deuterium, halogen, -CN, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0019] Each R 6 are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0020] Or two R 6together to form a cycloalkyl or heterocycloalkyl group; each optionally substituted by deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0021] Each R 7 are independently deuterium, halogen, -CN, -OH, -OR a 、-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 or C2-C6 alkynyl;

[0022] Or two R on the same carbon 7 Together they form an oxo group;

[0023] or two R on the same carbon or on different carbons 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0024] n is 0 to 4;

[0025] T is N or CR 8 ;

[0026] U is N or CR 9 ;

[0027] R 8 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0028] R 9 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0029] R 10 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0030] R 11 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0031] R 12 is cyano or halogen;

[0032] Each R a is independently 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, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0033] Each R bis independently hydrogen, 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, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; and

[0034] Each R c and R d is independently hydrogen, 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, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0035] or R c and R d together with the atoms to which they are attached form a heterocycloalkyl group, optionally substituted with one or more R;

[0036] 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0037] Or two R on the same atom together form an oxo group;

[0038] The prerequisite is that when X is CR 3 When Y is CR 4 and Z is CR 5 ; then R 3 , R 4 and R 5 One of them is not hydrogen and R 4 is not -OMe; and

[0039] The prerequisite is that when X is CH, Y is CH, and Z is CH; then R 2 Not hydrogen.

[0040] 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.

[0041] Also disclosed herein is a method for treating a cancer comprising a BRCA1 and / or BRCA2 mutation in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method for treating a cancer comprising a mutation in a gene causing homologous repair deficiency in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in the gene causing 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 cancer 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 a metastatic cancer. In some embodiments, the cancer has metastasized in the brain.

[0042] Also disclosed herein is a method of treating cancer present in the brain of a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0043] Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0044] Incorporated by Reference

[0045] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0046] definition

[0047] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, those skilled in the art will appreciate that the present invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the subsequent claims, the word "include" and its variations such as "comprises" and "containing" should be interpreted in an open, inclusive sense, i.e., interpreted as "including but not limited to". In addition, the titles provided herein are for convenience only and do not explain the scope or meaning of the claimed invention.

[0048] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in multiple places throughout this specification do not necessarily all refer to the same embodiment. In addition, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner. In addition, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense including "and / or" unless clearly specified otherwise.

[0049] As used herein, unless otherwise indicated, the following terms have the following meanings:

[0050] "Oxo" refers to =0.

[0051] "Carboxyl" refers to -COOH.

[0052] "Cyano" refers to -CN.

[0053] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monovalent radical having one to about ten carbon atoms, more preferably one to six 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, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this document, a numerical range such as "C1-C6 alkyl" or "C 1-6The term "alkyl" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the definition also covers the occurrence of the term "alkyl" in which no numerical range is specified. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C 1-6 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise specifically stated in the specification, alkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkyl is optionally substituted by halogen.

[0054] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in a cis or trans conformation about the double bond, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkenyl" or "C 2-6 "Alkenyl" means that the alkenyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkenyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkenyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0055] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C 2-6 "Alkynyl" means that the alkynyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkynyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0056] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, alkylene may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0057] "Alkoxy" refers to a group of the formula -OR a A group in which R a It is an alkyl group as defined. Unless specifically stated otherwise in the specification, alkoxy may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0058] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6-10 membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group (phenyl). Aryl groups include, but are not limited to, aryl groups derived from anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, The aryl group of the hydrocarbon ring system of fluoranthene, fluorene, asymmetric indene, symmetric indene, indane, indene, naphthalene, phenanthene, phenanthrenes, pyrenes, pyrene and triphenylene. Unless otherwise specifically stated in the specification, the aryl group may be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the aryl group is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the aryl group is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the aryl group is optionally substituted by halogen.

[0059] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C3-C 15 Cycloalkyl or C3-C 15 cycloalkenyl), cycloalkyl (C3-C 10 Cycloalkyl or C3-C 10In some embodiments, the cycloalkyl group is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, 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]heptane. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0060] "Halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, halogen is fluorine or chlorine. In some embodiments, halogen is fluorine.

[0061] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0062] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0063] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0064] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0065] "Assorted alkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof). Assorted alkyl groups are connected to the rest of the molecule at the carbon atom of the assorted alkyl group. In one aspect, assorted alkyl groups are C1-C6 assorted alkyl groups, wherein the assorted alkyl group is composed of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof), wherein the assorted alkyl group is connected to the rest of the molecule at the carbon atom of the assorted alkyl group. The example of such assorted alkyl groups is, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, heteroalkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0066] "Heterocycloalkyl" refers to a 3 to 24-membered partially or fully saturated cyclic group 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, heterocycloalkyl is fully saturated. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heterocycloalkyl contains one to three nitrogens. In some embodiments, heterocycloalkyl contains one or two nitrogens. In some embodiments, heterocycloalkyl contains one nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, heterocycloalkyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having two to fifteen carbon atoms (C2-C 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), heterocycloalkyl (C2-C10 Heterocycloalkyl or C2-C 10C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrrolid ... Oxazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 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.Term heterocycloalkyl also includes all ring forms of carbohydrate, including but not limited to monosaccharide, disaccharide and oligosaccharide.Unless otherwise indicated, heterocycloalkyl has 2 to 10 carbons in the ring.It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) (that is, the skeleton atoms of heterocycloalkyl ring) constituting heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkenyl. Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heterocycloalkyl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0067] "Heteroaryl" refers to a 5 to 14 ring system group containing one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl group contains one to three nitrogens. In some embodiments, the heteroaryl group contains one or two nitrogens. In some embodiments, the heteroaryl group contains one nitrogen. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded by an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl group is a 5 to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5 to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, aza benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone , benzothiophenyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine The heteroaryl group may be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0068] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes instances in which the event or situation occurs and instances in which the event or situation does not occur. For example, "optionally substituted alkyl" refers to "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It should be understood by those skilled in the art that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which is in turn defined to include optionally substituted alkyl, possibly infinite). Therefore, any substituent described is generally understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons.

[0069] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by one, two, three or four substituents. In some embodiments, the subject group is optionally substituted by one, two or three substituents. In some embodiments, the subject group is optionally substituted by one or two substituents. In some embodiments, the subject group is optionally substituted by one substituent. In some embodiments, the subject group is optionally substituted by two substituents.

[0070] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.

[0071] As used herein, the terms "treatment", "therapeutic" refer to therapeutic treatment, in which the purpose is to alleviate (mitigate) an undesirable physiological condition, disorder or disease, or to obtain a beneficial or desired clinical result. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, relief of symptoms; alleviation of the degree of condition, disorder or disease; stabilization of the condition, disorder or disease state (i.e., not worsening); delay in the onset of the condition, disorder or disease or slowing down of the progression; improvement of the condition, disorder or disease state; and relief (whether partial or complete) of the condition, disorder or disease, whether detectable or undetectable or enhanced or improved. Treatment includes causing a clinically significant response without excessive side effects. Treatment also includes prolonging survival compared to the expected survival if not receiving treatment. As used herein, the terms "treatment", "therapeutic" and words derived therefrom do not necessarily mean 100% or complete treatment. On the contrary, there are different degrees of treatment that are considered by those of ordinary skill in the art to have potential benefits or therapeutic effects. In this regard, the disclosed methods can provide treatment of any amount or any level of illness in mammals. For example, a disorder (including symptoms or conditions thereof) can be reduced, for example, by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. "Synergy" or "acting synergistically" means that the effect of the combination is greater than the sum of the effects of each component alone at the same dose.

[0072] As used herein, a "disease or disorder associated with PARP" or alternatively a "PARP-mediated disease or disorder" means any disease or other deleterious condition in which PARP or a mutant thereof is known or suspected to play a role.

[0073] As used herein, a "disease or disorder associated with PARP1" or alternatively a "PARPl-mediated disease or disorder" means any disease or other deleterious condition in which PARP1 or a mutant thereof is known or suspected to play a role.

[0074] Compound

[0075] Described herein are compounds useful for treating cancer, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0076] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0077]

[0078] in:

[0079] R 1 Hydrogen, deuterium, halogen, -CN, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0080] R 2 Hydrogen, deuterium, halogen, -CN, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl;

[0081] X is N or CR 3 ;

[0082] Y is N or CR 4 ;

[0083] Z is N or CR 5 ;

[0084] R 3 Hydrogen, deuterium, halogen, -CN, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0085] R 4 Hydrogen, deuterium, halogen, -CN, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0086] R 5 Hydrogen, deuterium, halogen, -CN, -ORa 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0087] Each R 6 are independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0088] Or two R 6 together to form a cycloalkyl or heterocycloalkyl group; each optionally substituted by deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;

[0089] Each R 7 are independently deuterium, halogen, -CN, -OH, -OR a 、-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 or C2-C6 alkynyl;

[0090] Or two R on the same carbon 7 Together they form an oxo group;

[0091] or two R on the same carbon or on different carbons 7 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0092] n is 0 to 4;

[0093] T is N or CR 8 ;

[0094] U is N or CR 9 ;

[0095] R 8 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NRc 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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0096] R 9 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0097] R 10 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0098] R 11 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0099] R 12 is cyano or halogen;

[0100] Each R ais independently 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, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0101] Each R b is independently hydrogen, 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, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R; and

[0102] Each R c and R d is independently hydrogen, 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, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R;

[0103] or R c and R d together with the atoms to which they are attached form a heterocycloalkyl group, optionally substituted with one or more R;

[0104] 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl;

[0105] Or two R on the same atom together form an oxo group;

[0106] The prerequisite is that when X is CR 3 When Y is CR 4 and Z is CR 5 ; then R 3 , R 4 and R 5 One of them is not hydrogen and R 4 is not -OMe; and

[0107] The prerequisite is that when X is CH, Y is CH, and Z is CH; then R 2 Not hydrogen.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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 .

[0117] 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 .

[0118] 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 .

[0119] In some embodiments of the compound of formula (I), X is N; Y is N or CR 4 ; and Z is N or CR 5 In some embodiments of the compound of formula (I), X is N or CR 3 ; Y is N; and Z is N or CR 5 In some embodiments of the compound of formula (I), X is N or CR 3 ; Y is N or CR 4 ; and Z is N. In some embodiments of compounds of formula (I), one of X, Y or Z is N. In some embodiments of compounds of formula (I), both of X, Y or Z are N. In some embodiments of compounds of formula (I), X is CR 3 ; Y is CR 4 ; and Z is CR 5 In some embodiments of the compound of formula (I), X is CH; Y is CH; and Z is CH. In some embodiments of the compound of formula (I), X is CR 3 ; Y is N; and Z is CR 5In some embodiments of the compound of formula (I), X is CH; Y is N; and Z is CH. In some embodiments of the compound of formula (I), X is N; 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.

[0120] In some embodiments of the compound of Formula (I), the compound has Formula (Ia):

[0121]

[0122] In some embodiments of the compound of Formula (I), the compound has Formula (Ib):

[0123]

[0124] In some embodiments of the compound of Formula (I), the compound has Formula (Ic):

[0125]

[0126] In some embodiments of the compound of Formula (I), the compound has Formula (Id):

[0127]

[0128] Where R 3 , R 4 and R 5 One of them is not hydrogen and R 4 Not for -OMe.

[0129] In some embodiments of the compound of Formula (I), the compound has Formula (Ie):

[0130]

[0131] Where R 2 Deuterium, halogen, -CN, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl.

[0132] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 1 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; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R.

[0133] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein alkyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), R 1 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein alkyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl or cycloalkyl; wherein alkyl, alkynyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkynyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (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) to (Ie), R 1 is C1-C6 alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 is a C1-C6 haloalkyl group. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 is halogen, C1-C6 haloalkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 is halogen or cycloalkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 1 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 1 For chlorine.

[0134] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 2 For hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 For hydrogen, halogen, -OR a or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 2 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 For-OR a In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 2 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 Hydrogen, deuterium, halogen, -CN, -OR a 、-NR c R d, C1-C2 alkyl, C1-C2 haloalkyl or C1-C2 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 For hydrogen, halogen, -OR a or C1-C2 alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 Halogen, -OR a or C1-C2 alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 2 It is halogen or C1-C2 alkyl.

[0135] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 3 For hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), R 3 For hydrogen, halogen, -OR a or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 3 It is hydrogen, halogen or C1-C6 alkyl.

[0136] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 3 is hydrogen or halogen.

[0137] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 3 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 3 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 3 Not hydrogen.

[0138] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 4 For 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 alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4For hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), R 4 For hydrogen, halogen, -OR a or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 4 is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 4 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 4 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 4 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 4 Not hydrogen.

[0139] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 5 For hydrogen, deuterium, halogen, -OR a , C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), R 5 For hydrogen, halogen, -OR a or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 5 It is hydrogen, halogen or C1-C6 alkyl.

[0140] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 5 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 5 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 5 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 5 Not hydrogen.

[0141] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), each R 6 is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), each R 6is independently hydrogen, deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (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 Formula (Ia) to Formula (Ie), each R 6 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), each R 6 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), each R 6 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), two R 6 In some embodiments of compounds of Formula (I) or Formula (Ia) to Formula (Ie), two R 6 Together they form a cyclopropyl group.

[0142] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), each R 7 is independently C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), each R 7 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), two R on the same carbon or different carbons are 7 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), two R on the same carbon or different carbons are 7 Together they form a cyclopropyl group.

[0143] In some embodiments of compounds of Formula (I) or (Ia)-(Ie), n is 0 or 1. In some embodiments of compounds of Formula (I) or (Ia)-(Ie), n is 0 to 2. In some embodiments of compounds of Formula (I) or (Ia)-(Ie), n is 1 or 2. In some embodiments of compounds of Formula (I) or (Ia)-(Ie), n is 1. In some embodiments of compounds of Formula (I) or (Ia)-(Ie), n is 2. In some embodiments of compounds of Formula (I) or (Ia)-(Ie), n is 3. In some embodiments of compounds of Formula (I) or (Ia)-(Ie), n is 4.

[0144] In some embodiments of the compound of Formula (I) or Formula (Ia)-Formula (Ie), T is N. In some embodiments of the compound of Formula (I) or Formula (Ia)-Formula (Ie), T is CR 8.

[0145] 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 .

[0146] In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), for In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ie), for

[0147] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 8 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 8 Hydrogen, halogen, -CN, -OR a , C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 8 Hydrogen, halogen, -CN, -OR a or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 8 is hydrogen, halogen or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 8 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 8 For hydrogen.

[0148] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 9 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 9 is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 9is hydrogen, halogen, -C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 9 is hydrogen, halogen or cycloalkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 9 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 9 For hydrogen.

[0149] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 10 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 10 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 10 is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 10 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 10 For hydrogen.

[0150] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 11 Hydrogen, deuterium, halogen, -CN, -OH, -OR a , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 11 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 11 is hydrogen, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 11 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 11 For hydrogen.

[0151] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R12 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 12 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 12 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 12 In some embodiments of the compounds of Formula (I) or (Ia) to (Ie), R 12 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ie), R 12 is fluorine or bromine.

[0152] In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl) or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R a R 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 In some embodiments of the compounds disclosed herein, each R a are independently C1-C6 haloalkyl.

[0153] In some embodiments of the compounds disclosed herein, each R bR 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); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R b R 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 R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b R is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. b is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R b In some embodiments of the compounds disclosed herein, each R b In some embodiments of the compounds disclosed herein, each R b are independently C1-C6 haloalkyl.

[0154] In some embodiments of the compounds disclosed herein, each R c and R d R 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); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each Rc and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R 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 c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. 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 In some embodiments of the compounds disclosed herein, each R c and R d In some embodiments of the compounds disclosed herein, each R c and R d are independently C1-C6 haloalkyl.

[0155] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached they form a heterocycloalkyl group optionally substituted with one or more R.

[0156] 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 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; or two R on the same atom together form an oxo group. 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 deuterated alkyl; or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl; or two R on the same atom are taken together to form an oxo group.

[0157] Any combination of the various groups of variables described above is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0158] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selected from the compounds of Table 1.

[0159] Table 1

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170] The absolute designation (abs) is added to the chiral center to indicate that it is unequivocally a pure sample of the drawn stereoisomer.

[0171] The OR notation (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 notations with the same value (OR stands for purity) will indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0172] The AND symbol (and) indicates that two isomers exist at the depicted stereochemical center. The assignment of different numerical values ​​to the AND symbols indicates that they are independent of each other. The use of AND symbols with the same value indicates that two stereocenters are relative to each other and can only change simultaneously.

[0173] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from:

[0174]

[0175] Other forms of the compounds disclosed herein

[0176] Isomers / stereoisomers

[0177] 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 provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in R configuration or S configuration. The compounds described herein include all diastereomers, enantiomers and diastereomeric forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or diastereoisomer mixtures produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, a pair of diastereomeric compounds are formed by reacting the racemic mixture of the compound with an optically active resolving agent, separating the diastereomers and recovering the optically pure enantiomers, and the compounds described herein are prepared as their individual stereoisomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on solubility differences. In some embodiments, optically pure enantiomers and resolving agents are then recovered by any practical means that do not result in racemization.

[0178] Labeled compounds

[0179] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically 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, such as 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 and pharmaceutically acceptable salts, solvates or stereoisomers thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Particularly preferred are tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes because of their ease of preparation and detectability. In addition, heavy isotopes such as deuterium (i.e., 2 H) Substitutions may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0180] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0181] Pharmaceutically acceptable salts

[0182] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0183] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified compound in its free form with a suitable acid or base separately and isolating the salt thus formed.

[0184] Examples of pharmaceutically acceptable salts include those prepared by reacting a compound described herein with an inorganic, organic or inorganic base, such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate , hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0185] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, 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, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable in themselves, are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0186] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate), with ammonia or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0187] 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 the 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.

[0188] Solvate

[0189] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0190] Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments, are formed during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the process of the methods described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents including but not limited to dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in non-solvated forms as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0191] Tautomer

[0192] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of hydrogen atoms, with the conversion of single bonds and adjacent double bonds. In the bonding arrangements where tautomerism may occur, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0193] Treatment

[0194] 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 cancer 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.

[0195] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0196] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0197] In some embodiments, the cancer comprising a BRCA1 and / or BRCA2 mutation 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.

[0198] In some embodiments, the cancer is a cancer that lacks Flomologous Recombination (FIR)-dependent DNA DSB repair activity.The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE1 (NM_007068). 1A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulatory factors such as EMSY. In some embodiments, the cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells whose ability to repair DNA DSB by this pathway is reduced or eliminated relative to normal cells, that is, the activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in the one or more cancer cells.

[0199] In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is abolished in one or more cancer cells of an individual suffering from a cancer deficient in FIR-dependent DNA DSB repair.

[0200] In some embodiments, the cancer cells have a BRCA1 and / or BRCA2 defective phenotype, i.e., the activity of BRCA1 and / or BRCA2 is reduced or eliminated in the cancer cells. Cancer cells with this phenotype may lack BRCA1 and / or BRCA2, i.e., the expression and / or activity of BRCA1 and / or BRCA2 in the cancer cells may be reduced or eliminated, for example, by mutations or polymorphisms in the encoding nucleic acid, or by amplification, mutation or polymorphism of genes encoding regulatory factors (e.g., the EMSY gene encoding BRCA2 regulatory factors). BRCA1 and BRCA2 are known tumor suppressor genes, and their wild-type alleles are often lost in tumors of heterozygous carriers. It is also known that the amplification of the EMSY gene encoding BRCA2 binding factors is associated with breast cancer and ovarian cancer. Carriers of BRCA1 and / or BRCA2 mutations are also at high risk for certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.

[0201] Also disclosed herein is a method of treating a cancer comprising a mutation in a gene that causes homology repair deficiency in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the mutation in the gene that causes homology repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof.

[0202] 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.

[0203] 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.

[0204] Also disclosed herein is a method for treating brain cancer, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0205] In some embodiments, the brain cancer is a primary brain tumor that begins in the brain and tends to remain in the brain.

[0206] In some embodiments, brain cancer is a secondary brain tumor. These cancers begin elsewhere in the body and metastasize to the brain. Lung cancer, breast cancer, kidney cancer, colon cancer, and skin cancer are the most common cancers that spread to the brain.

[0207] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or stereoisomers are capable of penetrating the blood-brain barrier (BBB). In some embodiments, the ratio of the compound penetrating the BBB is>0.1, where 1 is complete BBB penetration, and 0 is no penetration. In some embodiments, the ratio of the compound penetrating the BBB is>0.2. In some embodiments, the ratio of the compound penetrating the BBB is>0.3. In some embodiments, the ratio of the compound penetrating the BBB is measured using the rat kp, uu assay. In some embodiments, as determined in the rat kp, uu assay, the ratio of the compound>0.3 (i.e., 0.3 to 1).

[0208] Drug administration

[0209] In certain embodiments, compositions containing compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress at least one of the symptoms of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, previous treatment, the patient's health, body weight, and response to the drug, and 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.

[0210] In preventive applications, compositions containing compounds described herein are administered to patients who are susceptible to or otherwise at risk for a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the patient's health, weight, etc. When used for a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health and response to the drug, and the judgment of the treating physician. In one aspect, preventive treatment includes administering a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof to a mammal that has previously experienced at least one symptom or risk factor for the disease being treated and is currently in a state of remission to prevent the recurrence of symptoms of the disease or condition.

[0211] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is chronic, i.e., for an extended period of time, including the entire duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0212] In certain embodiments where the patient's condition does improve, the dose of the administered drug is temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, for example, only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example, the dose reduction during the drug holiday is only 10%-100%, including, for example, only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0213] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, as symptoms change, the dose or frequency of administration, or both, is reduced to a level that maintains the improved disease, disorder, or condition. However, in certain embodiments, after any recurrence of symptoms, the patient requires long-term intermittent or daily treatment.

[0214] The amount of a given agent that corresponds to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., weight, sex), but will still be determined according to the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0215] However, in general, dosages for adult treatment are generally in the range of 0.01 mg to 5000 mg per day. In one aspect, dosages for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., two, three, four or more sub-doses per day.

[0216] In one embodiment, the daily dose suitable for the compound described herein or its pharmaceutically acceptable salt, solvate or stereoisomer is about 0.01 mg / kg body weight to about 50 mg / kg body weight. In some embodiments, based on multiple variables related to individual treatment regimens, the amount of active substance in the daily dose or dosage form is lower or higher than the range indicated herein. In various embodiments, the daily dose and unit dose vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the doctor.

[0217] Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to LD 10 and ED90 The dose ratio between toxic and therapeutic effects is the therapeutic index, expressed as LD 50 With ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range that includes the ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or the unit dosage varies within this range, depending on the dosage form employed and the route of administration employed.

[0218] In any of the foregoing aspects are further embodiments wherein an effective amount of a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered to a mammal by injection; and / or (e) administered topically to a mammal; and / or (f) administered non-systemically or topically to a mammal.

[0219] Within any of the foregoing aspects are additional embodiments comprising a single administration of an effective amount of the compound, including additional embodiments wherein (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times over the course of a day.

[0220] In any of the foregoing aspects are further embodiments comprising multiple administrations of an effective amount of the compound, including further embodiments wherein (i) the compound is administered continuously or intermittently: such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to a subject every 12 hours; (v) the compound is administered to a subject every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0221] Route of administration

[0222] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal and topical administration. In addition, for example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic and intranasal injection.

[0223] In certain embodiments, the compounds as described herein are applied in a local rather than systemic manner, for example, by injecting the compound directly into an organ, usually in the form of a reservoir formulation or a sustained release formulation. In a specific embodiment, the long-acting preparation is applied by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such an embodiment, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In other embodiments, the compounds as described herein are applied topically.

[0224] Pharmaceutical compositions / preparations

[0225] According to standard pharmaceutical practice, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in the form of a pharmaceutical composition to a subject in need thereof. In one embodiment, the compounds of the invention can be administered to animals. These compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0226] In another aspect, provided herein is a pharmaceutical composition comprising a compound as 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 of the active compound into a pharmaceutically usable formulation. Appropriate formulations depend on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventeenth Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0227] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0228] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal routes of administration. Pharmaceutical formulations described herein include but are not limited to aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and mixed immediate release formulations and controlled release formulations.

[0229] Pharmaceutical compositions containing a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0230] The pharmaceutical composition for oral use is obtained in such a way that one or more solid excipients are mixed with one or more compounds described herein, the resulting mixture is optionally ground, and if necessary, the granular mixture is processed after adding suitable auxiliary agents to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants are added, such as cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, agar or alginic acid or its salts such as sodium alginate. In some embodiments, colorants or pigments are added to tablets or dragee coatings to identify or characterize different combinations of active compound doses.

[0231] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0232] The pharmaceutical composition for parenteral use is formulated as an infusion or injection. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution, dispersion or sterile powder comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or a liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides and any combination thereof. In some embodiments, the pharmaceutical composition also includes a preservative to prevent microbial growth.

[0233] combination

[0234] Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0235] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0236] In some embodiments, the additional therapeutic agent is administered simultaneously 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 before the compounds disclosed herein are administered. In some embodiments, the additional therapeutic agent is administered after the compounds disclosed herein are administered.

[0237] Example

[0238] The compounds described herein were synthesized as generally described in General Schemes 1 and 2.

[0239] General Scheme 1

[0240]

[0241] General Scheme 2

[0242]

[0243] Example 1

[0244]

[0245] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine :

[0246] To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv) in MeOH (50 mL) was added dropwise NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30 wt %) at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether: EtOAc = 1: 1, R f=0.4). After completion, the reactant was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0247] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethylene-1-amine Preparation :

[0248] 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. under nitrogen atmosphere overnight. The reaction was monitored by TLC (petroleum ether: EtOAc=1:1, R f =0.5). The mixture was cooled to room temperature and then concentrated under reduced pressure to give crude (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethene-1-amine. The crude product was used directly in the next step without further purification.

[0249] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropyridine aldehyde :

[0250] To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was added NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by TLC (petroleum ether: EtOAc = 5: 1, R f =0.2). The reaction was quenched by adding saturated sodium thiosulfate (aqueous solution) (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 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0251] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0252] To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carboxaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (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) in batches at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled 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 layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product. The crude product was further purified by trituration with hexanes (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% over three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0

[0253] Step 5: Preparation of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0254] To a solution of 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylic acid ethyl ester (5.00 g, 16.07 mmol, 1.00 equiv) in ACN (400 mL) was added TMSI (13.8 mL, 96.42 mmol, 6.00 equiv) dropwise at room temperature. The final reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The mixture was cooled 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 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid ethyl ester (3.8 g, 80%). LC-MS: (ES+H, m / z): [M+H] + =296.95.

[0255] Step 6: 7-[2-(tert-Butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid ethyl Preparation of esters :

[0256] 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 under nitrogen atmosphere for 2 hours. The mixture was cooled 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.

[0257] Step 7: 3-[2-(tert-Butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one Preparation :

[0258] 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 nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. 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-naphthyridine-2-one (840 mg, 79%). LC-MS: (ES+H, m / z): [M+H] + =315.0.

[0259] Step 8: 3-[2-(tert-Butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one Preparation :

[0260] 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 nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 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.

[0261] Step 9: 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridine-3- Preparation of pyridine-2-carbonitrile :

[0262] To a stirred mixture of 5-(piperazin-1-yl)pyridine-2-carbonitrile hydrochloride (119 mg, 0.53 mmol, 1.48 equiv), DIEA (232 mg, 1.80 mmol, 5.00 equiv) and 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (120 mg, 0.36 mmol, 1.00 equiv) in MeCN (5 mL) was added KI (11 mg, 0.07 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridin-3-yl}methyl)piperazin-1-yl]pyridine-2-carbonitrile (120 mg, 69%).

[0263] Step 10: 5-{4-[(7-ethynyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2- Preparation of methyl nitrile :

[0264] To a stirred mixture of 5-[4-({7-[2-(tert-butyldimethylsilyl)ethynyl]-6-oxo-5H-1,5-naphthyridin-3-yl}methyl)piperazin-1-yl]pyridine-2-carbonitrile (120 mg, 0.24 mmol, 1.00 equiv) in THF (2.5 mL) was added TBAF (0.27 mL, 0.27 mmol, 1.10 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. 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 preparative HPLC 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): [MH] - =369.1; 1 H NMR(300MHz,DMSO-d6)δ12.17(s,1H),8.48(d,1H),8.42(d,1H),8.15(s,1H),7.75(d,1H), 7.64(d,1H),7.36(dd,1H),4.51(s,1H),3.67(s,2H),3.47-3.38(m,4H),2.60-2.52(m,4H).

[0265] Example 2

[0266]

[0267] Step 1: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate :

[0268] A mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (10.00 g, 46.17 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.52 g, 92.34 mmol, 2.00 equiv), K2CO3 (12.76 g, 92.34 mmol, 2.00 equiv) and Pd(dppf)Cl2 (3.38 g, 4.62 mmol, 0.10 equiv) in dioxane (150 mL) and water (15 mL) was stirred at 100 °C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with saturated NaCl (aq.) (3 x 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 and eluted with PE / EA (1:1) to give methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 48.74%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H] + =222.95; 1 H NMR (300MHz, DMSO-d6) δ9.25(d,1H),8.74(d,1H),5.41–5.47(m,1H),5.13–5.21(m,1H),3.94(s,3H),2.16(dd,3H).

[0269] Step 2: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate :

[0270] To a stirred solution of 5-nitro-6-(prop-1-ene-2-yl)pyridine-3-carboxylic acid methyl ester (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 was stirred at 80 ° C under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The mixture was allowed to reach 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 gave 5-amino-6-(prop-1-ene-2-yl)pyridine-3-carboxylic acid methyl ester (3.90 g, 90.17%) that was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] + =193.15; 1H NMR (300MHz, DMSO-d6) δ8.29(d,1H),7.60(d,1H),5.51-5.47(m,1H),5.41(s,2H),5.39–5.36(m,1H),3.84(s,3H),2.08(t,3H).

[0271] Step 3: Preparation of 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester :

[0272] At 0°C under nitrogen atmosphere, a solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was added to a solution of 5-amino-6-(prop-1-ene-2-yl)pyridine-3-carboxylic acid methyl ester (3.90 g, 20.29 mmol, 1.00 equiv) and Et3N (6.16 g, 60.87 mmol, 3.00 equiv) in toluene (40 mL). The resulting mixture was stirred overnight at 60°C 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 layer was 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 (400MHz, DMSO-d6) δ11.92(s,1H),8.92(d,1H),8.15(d,1H),6.79(s,1H),3.93(s,3H),2.48(s,3H).

[0273] Step 4: Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0274] To a solution of 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH3COOH (7 mL) was added 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ° C. under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (650 mg, 93.5%). LC-MS: (ES+H, m / z): [M+H] + =253.0; 1 H NMR (300MHz, DMSO-d6) δ8.90(d,1H),8.13(d,1H),3.93(s,3H),2.60(s,3H).

[0275] Step 5: Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0276] To a stirred solution of 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (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 nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. 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-naphthyridine-2-one (230 mg, 43.1%). LC-MS: (ES+H, m / z): [M+H] + =225.1; 1 H NMR (300MHz, DMSO-d6) δ12.24(br,1H),8.48(d,1H),7.77(d,1H),5.69(s,1H),4.63(s,2H),2.63(s,3H).

[0277] Step 6: Preparation of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0278] 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 SOCl2 (318 mg, 2.67 mmol, 3.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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.

[0279] Step 7: 4-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}benzonitrile Preparation :

[0280] 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 under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting mixture was concentrated under reduced pressure. The pure fractions were concentrated and then lyophilized to give 4-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}benzonitrile (12 mg, 29.6%). LC-MS:(ES-H,m / z):[MH] - =392.15; 1 H NMR (400MHz, DMSO-d6) δ12.30(s,1H),8.51(d,J=1.8Hz,1H),7.69(d,J=1.9Hz,1H),7.58(d,J=8. 7Hz,2H),7.02(d,J=8.7Hz,2H),3.67(s,2H),3.38–3.34(m,4H),2.64(s,3H),2.57-2.54(m,4H).

[0281] Example 3

[0282]

[0283] Step 1: Preparation of methyl 6-methyl-5-nitropyridine-3-carboxylate :

[0284] To a stirred mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (5 g, 273.08 mmol, 1.00 equiv) and methylboronic acid (2.75 g, 46.17 mmol, 2.00 equiv) in toluene (60 mL) and H2O (3 mL) at room temperature under nitrogen atmosphere was added Pd(dppf)Cl2 (0.83 g, 1.15 mmol, 0.05 equiv) and CsF (7 g, 46.17 mmol, 2.00 equiv). The resulting mixture was stirred at 100°C under nitrogen atmosphere overnight. To the resulting mixture was added 500 mL of water and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography to give methyl 6-methyl-5-nitropyridine-3-carboxylate (2.9 g, 64%). LC-MS: (ES+H, m / z): [M+H] + =197.0; 1H NMR (400 MHz, CHLOROFORM-d) δ9.29 (d, 1H), 8.84 (d, 1H), 4.01 (s, 3H), 2.94 (s, 3H).

[0285] Step 2: Preparation of methyl 6-formyl-5-nitropyridine-3-carboxylate :

[0286] 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 under a nitrogen atmosphere overnight. The resulting mixture was then filtered and the filter cake was washed with EtOAc (5×200 mL). The organic layer was concentrated under reduced pressure, and 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.

[0287] Step 3: Preparation of (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinic acid methyl ester :

[0288] To a stirred solution of NaH (11.42 g, 285.52 mmol, 1.50 equiv., 60 wt. %) in THF (500 mL) at 0°C under nitrogen was added dropwise THF (50 mL) containing ethyl 2-(diethoxyphosphoryl)butanoate (72 g, 285.52 mmol, 1.50 equiv.). The resulting mixture was stirred at 0°C for 10 minutes, then warmed to 40°C and stirred under nitrogen for 10 minutes. The resulting mixture was cooled to -78°C, then THF (50 mL) containing methyl 6-formyl-5-nitropyridine-3-carboxylate (40 g, 190.35 mmol, 1.00 equiv.) was added dropwise. The resulting mixture was stirred at -78°C under nitrogen for 30 minutes. 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 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 (Z)-6-(2-(ethoxycarbonyl)but-1-ene-1-yl)-5-nitronicotinic acid methyl ester (20 g, 36% for two steps) and (E)-6-(2-(ethoxycarbonyl)but-1-ene-1-yl)-5-nitronicotinic acid methyl ester (8.8 g). Data for (Z)-6-(2-(ethoxycarbonyl)but-1-ene-1-yl)-5-nitronicotinic acid methyl ester: LC-MS: (ES+H, m / z): [M+H] + =309.1; 1H NMR (300 MHz, chloroform-d) δ9.27 (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 (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nitronicotinic acid methyl ester: LC-MS: (ES+H, m / z): [M+H] + =309.1; 1 H NMR (300 MHz, CHLOROFORM-d) δ 9.45 (d, 1H), 8.88 (d, 1H), 7.87 (s, 1H), 4.34 (q, 2H), 4.05 (s, 3H), 2.67 (q, 2H), 1.39 (t, 3H), 1.15 (t, 3H).

[0289] Step 4: Preparation of ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0290] To a stirred mixture of 6-[(1Z)-3-ethoxy-2-ethyl-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylic acid methyl ester (9.00 g, 29.19 mmol, 1.00 equiv) and Fe (16.30 g, 291.93 mmol, 10.00 equiv) in EtOH (200 mL) was added CaCl2 (19.44 g, 175.16 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ° C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (5×100 mL), and the combined filtrate was concentrated. The resulting mixture was added to 250 mL of water and extracted with EtOAc (3×250 mL). The combined organic layer was washed with brine (1×250 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (5.2 g, 72%). LC-MS: (ES+H, m / z): [M+H] + =247.1; 1H NMR (400MHz, DMSO-d6) δ12.06(s,1H),8.90(s,1H),8.16(s,1H),7.83(s,1H),4.38(q,2H),2.58(q,2H),1.36(t,3H),1.20(t,3H).

[0291] Step 5: Preparation of 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0292] 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 nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (16 mL) at 0°C. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridine-2-one (2.00 g, 60%). LC-MS: (ES+H, m / z): [M+H] + =204.8; 1H NMR (400MHz, DMSO-d6) δ11.91(s,1H),8.38(d,1H),7.74(s,1H),7.62(d,1H),5.49(t,1H),4.62(d,2H),2.55(dd,2H),1.18(t,3H).

[0293] Step 6: Preparation of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one :

[0294] 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 SOCl2 (1.05 g, 8.81 mmol, 6.00 equiv) dropwise at 0°C under 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 give 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (300 mg, 92%). LC-MS: (ES+H, m / z): [M+H] + =222.8; 1H NMR (400MHz, DMSO-d6) δ11.99(s,1H),8.50(d,1H),7.76(s,1H),7.70(d,1H),4.93(s,2H),2.56(td,2H),1.19(t,3H).

[0295] Step 7: 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carboxylate Preparation of nitrile :

[0296] To a stirred mixture of 5-(piperazine-1-yl)pyridine-2-carbonitrile, HCl salt (600 mg) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (500 mg, 2.25 mmol, 1.00 equiv) in ACN (4 mL) was added DIEA (1.45 g, 11.25 mmol, 5.00 equiv) and KI (75 mg, 0.45 mmol, 0.20 equiv) in batches at room temperature. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reactant was poured into water (20 mL). The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile (650 mg, 77%). LC-MS: (ES+H, m / z): [M+H] + =375.2; 1 H NMR(300MHz,DMSO-d6)δ11.86(s,1H),8.41-8.35(m,2H),7.75(t,2H),7.61(s,1H) ),7.36(dd,1H),3.64(s,2H),3.52-3.42(m,4H),2.61-2.54(m,6H),1.18(t,3H).

[0297] Example 5

[0298]

[0299] Step 1: Preparation of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butyrate :

[0300] To a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.02 mmol, 1.00 equiv) and methyl 2-aminobutyrate hydrochloride (6.43 g, 42.02 mmol, 1.00 equiv) in NMP (200 mL) was added DIEA (27.15 g, 210.10 mmol, 5.00 equiv) dropwise at room temperature. The resulting mixture was diluted with water (500 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (8×300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the pure fractions were concentrated in vacuo to give methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butyrate (13.00 g, 92%). LC-MS: (ES+H, m / z): [M+H] + =334.9; 1 H NMR (400MHz, DMSO-d6) δ8.09(t,1H),7.88(dd,1H),7.79(dd,1H),4.56(dtd,1H),3.69(s,3H),1.97–1.79(m,2H),0.91(t,3H).

[0301] Step 2: Preparation of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one :

[0302] To a stirred mixture of Fe (5.00 g, 89.52 mmol, 5.00 equiv) in AcOH (100 mL) at 80 ° C under a nitrogen atmosphere, AcOH (20 mL) containing 2-[(4-bromo-2-fluoro-6-nitrophenyl) amino] butyric acid methyl ester (6.00 g, 17.90 mmol, 1.00 equiv) was added dropwise. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 hours. The reaction was monitored by TLC (CH2Cl2 / MeOH=10 / 1). The mixture was cooled 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 grinding with water (3×100 mL). The precipitated solid was collected by filtration and washed with water (3×20 mL). This gave 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.5 g, 92%). 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),6.99(d,1H),6.72(s,1H),6.17(s,1H),3.78(d,1H),1.72–1.62(m,2H),0.88(t,3H).

[0303] Step 3: Preparation of 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one :

[0304] To a stirred solution of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxaline-2-one (4.40 g, 16.11 mmol, 1.00 equiv) in DCM (100 mL) was added DDQ (4.39 g, 19.33 mmol, 1.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. 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-quinoxaline-2-one (3.50 g, 80%). LC-MS: (ES-H, m / z): [MH] - =269.0; 1 HNMR (400MHz, DMSO-d6) δ12.51(s,1H),7.44(d,1H),7.24(s,1H),2.79(q,2H),1.21(t,3H).

[0305] Step 4: Preparation of 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde :

[0306] In a pressure tank, TMEDA (1.49 g, 12.84 mmol, 1.20 equiv), bis(adamantan-1-yl)(butyl)phosphine (0.77 g, 2.14 mmol, 0.20 equiv), Pd(OAc)2 (0.24 g, 1.07 mmol, 0.10 equiv) were added to a solution of 7-bromo-3-ethyl-5-fluoro-1H-quinoxaline-2-one (2.90 g, 10.70 mmol, 1.00 equiv) in toluene (100 mL). 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 in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde (1.40 g, 59%). LC-MS: (ES-H, m / z): [MH]- =219.0; 1 H NMR (300MHz, DMSO-d6) δ12.74(s,1H),10.01(d,1H),7.65–7.47(m,2H),2.86(q,2H),1.24(t,3H).

[0307] Step 5: 6-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)oxazol Preparation of nitrile :

[0308] To a stirred solution of 6-(piperazin-1-yl)pyridine-3-carbonitrile (200 mg, 1.06 mmol, 1.00 equiv) and 2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxaline-6-carbaldehyde (304 mg, 1.38 mmol, 1.30 equiv) in THF (10 mL) at room temperature under nitrogen atmosphere was added Ti(OiPr)4 (453 mg, 1.60 mmol, 1.50 equiv). After 2 h, NaBH(AcO)3 (901 mg, 4.25 mmol, 4.00 equiv) was added at 0 °C and the reaction was warmed to room temperature. After 2 h, the reaction was quenched by the addition of 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 preparative HPLC to give 6-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile (56.1 mg, 13%). LC-MS: (ES+H, m / z): [M+H] + =393.2;1H NMR(300MHz,DMSO-d6)δ12.43(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 F NMR(282MHz,DMSO-d6)δ-125.38.

[0309] Example 12

[0310]

[0311] Step 1: Preparation of methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate :

[0312] To a stirred mixture of methyl 2,4-difluoro-5-nitrobenzoate (10.00 g, 46.06 mmol, 1.00 equiv) and methyl 2-aminobutyrate, HCl salt (5.40 g, 46.06 mmol, 1.00 equiv) in NMP (100 mL) was added DIEA (48.1 mL, 276.34 mmol, 6.00 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The reaction was quenched by adding water (200 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (8×200 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography to give methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate (12 g, 83%). LC-MS: (ES+H, m / z): [M+H] + =315.1; 1 H NMR(400MHz,DMSO-d6)δ8.80-8.56(m,2H),7.21-6.99(m,1H),4.84-4.74(m,1H ),3.85-3.81(s,3H),3.77-3.74(s,3H),2.05–1.82(m,2H),0.91-0.85(m,3H).

[0313] Step 2: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate :

[0314] To a stirred mixture of methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate (12.00 g, 38.18 mmol, 1.00 equiv) in MeOH (180 mL) and EtOAc (30 mL) was added Pd(OH)2 / C (2.40 g) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. After completion, the resulting mixture was filtered and the filter cake was washed with EtOAc (3×300 mL). The filtrate was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc) to give methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (8 g, 83%). LC-MS: (ES+H, m / z): [M+H] + =253.0; 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),7.25-7.20(m,1H),7.19-7.14(s,1H),4.00-3.91(m,1H),3.75(s,3H),1.76–1.60(m,2H),0.94-0.86(m,3H).

[0315] Step 3: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate :

[0316] To a stirred mixture of 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylic acid methyl ester (7.00 g, 27.75 mmol, 1.00 equiv) in DCM (70 mL) was added DDQ (7.56 g, 33.30 mmol, 1.20 equiv) in DCM (70 mL) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The residue was then dissolved in a saturated NaHCO3 aqueous solution (200 mL). The precipitated solid was collected by filtration and washed with a saturated NaHCO3 aqueous solution (3×200 mL) and water (3×200 mL). The solid was purified by grinding 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 obtain 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 HNMR (400MHz, DMSO-d6) δ12.44(s,1H),7.78(d,1H),7.63(d,1H),3.89(s,3H),2.82(q,2H),1.23(t,3H).

[0317] Step 4: Preparation of 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one :

[0318] To a stirred mixture of 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylic acid methyl ester (5.00 g, 19.98 mmol, 1.00 equiv) in THF (100 mL) was added dropwise LiAlH4 (40 mL, 39.96 mmol, 2.00 equiv, 1 moL / L THF solution) 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 grinding with MeOH (5 mL) and EtOAc (20 ml). The resulting mixture was filtered and the filter cake was washed with EtOAc (3×10 mL). The solid was dried under reduced pressure to give 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (1.2 g, 27%). LC-MS: (ES+H, m / z): [M+H] + =223.2; 1 H NMR (400MHz, DMSO-d6) δ12.38(s,1H),7.48(d,1H),7.41(d,1H),5.52(brs,1H),4.64(s,2H),2.80(q,2H),1.18(t,3H).

[0319] Step 5: Preparation of 7-(bromomethyl)-3-ethyl-6-fluoro-1H-quinoxalin-2-one :

[0320] To a stirred solution of 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (150 mg, 0.68 mmol, 1.00 equiv) in HBr (4 mL, 33 wt% in AcOH) was added at room temperature under nitrogen. The resulting mixture was stirred at 80 °C under nitrogen for 1 hour. The reaction was monitored by LCMS. The mixture was cooled 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.

[0321] Step 6: 6-{4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-yl Preparation of methyl nitrile :

[0322] 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. under nitrogen atmosphere for 1 hour. The mixture was allowed to cool to room temperature. The reaction 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 preparative HPLC to give 6-{4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (100.2 mg, 38%). LC-MS: (ES+H, m / z): [M+H] + =393.1; 1 H NMR(300MHz,DMSO-d6)δ12.31(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(282MHz,DMSO-d6)δ-124.28.

[0323] Example 16

[0324]

[0325] Step 1: Preparation of ethyl 2-bromo-2-cyclopropylacetate :

[0326] At -78 ° C under nitrogen atmosphere, LDA (42.9 mL, 85.82 mmol, 1.10 equivalents, 2.0 M THF solution) was added dropwise to a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equivalents) in THF (100 mL). The reactant was stirred for 1 hour, then TMSCl (8.48 g, 78.02 mmol, 1.00 equivalents) was added dropwise, and the reactant was stirred for 3 hours while being warmed to room temperature. The reaction was cooled to -78 ° C, and NBS (15.28 g, 85.82 mmol, 1.10 equivalents) was added dropwise in 50 mL THF. The reactant was then stirred for 2 hours and allowed to warm to room temperature. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH4Cl (aqueous solution) (50 mL) at 0 ° C. The resulting mixture was extracted with Et2O (3 × 200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combined flash chromatography to give ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 31%). 1 H NMR (300 MHz, CHLOROFORM-d) δ 4.25 (q, 2H), 3.58 (d, 1H), 1.65–1.55 (m, 1H), 1.31 (t, 3H), 0.92–0.76 (m, 2H), 0.61–0.53 (m, 1H), 0.48–0.40 (m, 1H).

[0327] Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate :

[0328] 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. under a nitrogen atmosphere for 24 hours. The residue was purified by reverse phase combined flash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 38%). 1 HNMR (300MHz, chloroform-d) δ4.26–4.07(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).

[0329] Step 3: 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylic acid Preparation of methyl ester :

[0330] To a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv., 60 wt%) in THF (20 mL) was added ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv.) at 0°C under nitrogen. The resulting mixture was stirred at 0°C for 10 minutes, then warmed to 40°C and stirred under nitrogen for 10 minutes. The resulting mixture was cooled to -78°C, followed by the addition of methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv.) in THF (20 mL). The resulting mixture was stirred at -78°C under nitrogen for 30 minutes. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated NH4Cl (aq.) (5 mL) at 0°C. 20 mL of water was added to the resulting mixture and 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 give methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (700 mg, 46%). LC-MS: (ES+H, m / z): [M+H] + =320.8.

[0331] Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0332] To a stirred mixture of 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-ene-1-yl]-5-nitropyridine-3-carboxylic acid methyl ester (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 CaCl2 (1.24 g, 11.24 mmol, 6.00 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled 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 layer was 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.

[0333] Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one:

[0334] 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 nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding 1 M aqueous HCl (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridine-2-one (100 mg, 75%). LC-MS: (ES+H, m / z): [M+H] + =217.2.

[0335] Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one :

[0336] To a stirred mixture of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.37 mmol, 1.00 equiv) and DMF (3 mg, 0.04 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl2 (264 mg, 2.22 mmol, 6.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-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.

[0337] Step 7: 3-Cyclopropyl-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one Preparation :

[0338] To a stirred solution of 1-(5-fluoropyridin-2-yl)piperazine (100 mg, 0.55 mmol, 1.00 equiv) and 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one (130 mg, 0.55 mmol, 1.00 equiv) in ACN (3 mL) was added DIEA (357 mg, 2.76 mmol, 5.00 equiv) and KI (18 mg, 0.11 mmol, 0.20 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was cooled 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 preparative HPLC 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; 1 H NMR(300MHz,DMSO-d6)δ11.88(s,1H),8.38(d,1H),8.09(d,1H),7.61(d,1H),7.55-7.45(m,1H),7.42(s,1H),6.86( dd,1H),3.62(s,2H),3.49-2.38(m,4H),2.50-2.45(m,4H),2.20-2.08(m,1H),1.02–0.92(m,2H),0.86–0.78(m,2H); 19 F NMR(282MHz,DMSO-d6)δ-143.41.

[0339] Example 28 and Example 29

[0340]

[0341] Step 1: Preparation of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0342] 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-ethoxyvinyl)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 under nitrogen atmosphere for 2 hours. After the reaction was completed, the reactants were 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

[0343] Step 2: Preparation of 7-acetyl-3-methyl-1,5-naphthyridin-2(1H)-one :

[0344] The solution of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one obtained from step 1 was cooled to 0°C and treated with concentrated HCl (4 mL) added dropwise. The resulting reaction mixture was stirred at room temperature for 1 hour and then basified to pH 8 with saturated NaHCO3(aq). 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% over two steps). LC-MS: (ES+H, m / z): [M+H] + =203.2

[0345] Step 3: 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazine- Preparation of 1-methyl]pyridine-3-carbonitrile :

[0346] 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. Ti(OiPr)4 (4.6 mL, 15.58 mmol, 9.00 equiv) was added dropwise to the above mixture at room temperature. The resulting mixture was stirred at 80°C for another 4 hours and then cooled to room temperature. EtOH (5 mL) and NaBH3CN (217 mg, 3.46 mmol, 2.00 equiv) were added to the above mixture in portions at room temperature. The resulting mixture was stirred at 80°C for another 2 hours and then cooled to room temperature. The reaction mixture was poured into water (100 mL) and 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), then the combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4., filtered and concentrated. The residue was purified by silica gel column chromatography to give 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (280 mg, 41.6%). LC-MS: (ES-H, m / z): [M+H] + =389.1. The diastereomers were separated by chiral HPLC to give rel-6-[(2R)-2-methyl-4-[(1R*)-1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (Example 28: 90.6 mg, de=100%) and rel-6-[(2R)-2-methyl-4-[(1R*)-1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (Example 29: 69.5 mg, de=100%). Data for Example 28: LC-MS: (ES+H, m / z): [M+H] + =389.2; 1HNMR (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; 1 H 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 for Example 28 and Example 29 is arbitrarily assigned.

[0347] Embodiment 36

[0348]

[0349] Step 1: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate :

[0350] A mixture of methyl 6-chloro-5-nitropyridine-3-carboxylate (10.00 g, 46.17 mmol, 1.00 equiv), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.52 g, 92.34 mmol, 2.00 equiv), K2CO3 (12.76 g, 92.34 mmol, 2.00 equiv) and Pd(dppf)Cl2 (3.38 g, 4.62 mmol, 0.10 equiv) in dioxane (150 mL) and water (15 mL) was stirred at 100 °C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtoAc (3×300 mL). The combined organic layers were washed with saturated NaCl (aq.) (3 x 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 give methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 49%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H] + =222.95.

[0351] Step 2: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate :

[0352] To a stirred solution of 5-nitro-6-(prop-1-ene-2-yl)pyridine-3-carboxylic acid methyl ester (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 was stirred at 80 ° C under a nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The mixture was allowed to reach 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 gave 5-amino-6-(prop-1-ene-2-yl)pyridine-3-carboxylic acid methyl ester (3.90 g, 90%) that was used directly without further purification. LC-MS: (ES+H, m / z): [M+H] + =193.15. 1 H NMR (300MHz, DMSO-d6) δ8.29(d,1H),7.60(d,1H),5.51-5.47(m,1H),5.41(s,2H),5.39–5.36(m,1H),3.84(s,3H),2.08(t,3H).

[0353] Step 3: Preparation of 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester:

[0354] At 0°C under nitrogen atmosphere, a solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was added to a solution of 5-amino-6-(prop-1-ene-2-yl)pyridine-3-carboxylic acid methyl ester (3.90 g, 20.29 mmol, 1.00 equiv) and Et3N (6.16 g, 60.87 mmol, 3.00 equiv) in toluene (40 mL). The resulting mixture was stirred overnight at 60°C 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 layer was 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 (400MHz, DMSO-d6) δ11.92(s,1H),8.92(d,1H),8.15(d,1H),6.79(s,1H),3.93(s,3H),2.48(s,3H).

[0355] Step 4: Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0356] To a solution of 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH3COOH (7 mL) was added 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ° C overnight and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (650 mg, 94%). LC-MS: (ES+H, m / z): [M+H] + =253.0; 1 H NMR (300MHz, DMSO-d6) δ8.90(d,1H),8.13(d,1H),3.93(s,3H),2.60(s,3H).

[0357] Step 5: Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0358] To a stirred solution of 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (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 nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. 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-naphthyridine-2-one (230 mg, 43%). LC-MS: (ES+H, m / z): [M+H] + =225.1; 1 H NMR (300MHz, DMSO-d6) δ12.24(br,1H),8.48(d,1H),7.77(d,1H),5.69(s,1H),4.63(s,2H),2.63(s,3H).

[0359] Step 6: Preparation of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0360] 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 SOCl2 (318 mg, 2.67 mmol, 3.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 10 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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.

[0361] Step 7: 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine- Preparation of 3-carbonitrile :

[0362] To a stirred mixture of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (85 mg, 0.35 mmol, 1.00 equiv) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 equiv) in ACN (1 mL) was added DIEA (136 mg, 1.05 mmol, 3.00 equiv) and KI (1 mg, 0.01 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C for 1 hour. The reaction was monitored by LCMS. The mixture was cooled 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 preparative HPLC to give 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (52.5 mg, 28%). LC-MS: (ES+H, m / z): [M+H] + =395.10; 1 H NMR (300MHz, DMSO-d6) δ12.30(br,1H),8.50(m,2H),7.85(dd,1H),7.69(d,1H),6.94(d,1H),3.67-3.62(m,6H),2.65(s,3H),2.50-2.49(m,4H).

[0363] Embodiment 42

[0364]

[0365] Step 1: Preparation of methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0366] A mixture of 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (800 mg, 3.67 mmol, 1.00 equiv), sodium difluoromethanesulfinate (1012 mg, 7.33 mmol, 2.00 equiv), 2-methylpropane-2-peroxy alcohol (991 mg, 11.00 mmol, 3.00 equiv) and TFA (418 mg, 3.67 mmol, 1.00 equiv) in CH2Cl2 / H2O (2.5:1, 120 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was then diluted with water (100 mL) and extracted with CH2Cl2 / 2-propanol (5:1, 3×100 mL). The combined organic layers were washed with water (3×50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to give methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 66%). LC-MS: (ES+H, m / z): [M+H] + =269.1; 1 H NMR (400MHz, DMSO-d6) δ12.39(s,1H),8.99(d,1H),8.19(m,1H),7.26(t,1H),3.94(s,3H),2.72(s,3H).

[0367] Step 2: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0368] To a stirred solution of 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylic acid methyl ester (650 mg, 2.42 mmol, 1.00 equiv) in THF (65 mL) was added dropwise LiAlH4 solution (2.5 M in THF, 3.9 mL, 9.75 mmol, 4.00 equiv) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding a saturated NH4Cl aqueous 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 layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridine-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).

[0369] Step 3: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0370] To a stirred mixture of 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (320 mg, 1.33 mmol, 1.00 equiv) and DMF (5 mg, 0.07 mmol, 0.05 equiv) in CH2Cl2 (32 mL) was added dropwise SOCl2 (475 mg, 4.00 mmol, 3.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature and then concentrated under reduced pressure to give 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (crude, 400 mg). LC-MS: (ES+H, m / z): [M+H] + =259.1

[0371] Step 4: 6-(4-{[7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazine-1- Preparation of 3-(2-(2-(4-(2-yl)pyridine)carbonitrile :

[0372] A mixture of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (380 mg, 1.47 mmol, 1.00 equiv), 6-(piperazine-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 under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was allowed to reach room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×10 mL) and dried over anhydrous Na2SO4. The mixture was filtered and washed with EtOAc (50 mL), and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC 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; 1H NMR(300MHz,DMSO-d6)δ12.17(br,1H),8.57(d,1H),8.41(d,1H),7.85(dd,1H),7.68 (d,1H),7.24(t,1H),6.94(d,1H),3.80-3.60(m,6H),2.72(s,3H),2.60-2.40(m,4H); 19 FNMR(282MHz,DMSO-d6)δ-115.51.

[0373] Embodiment 47

[0374]

[0375] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine :

[0376] To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv) in MeOH (50 mL) was added dropwise NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30 wt %) at 0°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether: EtOAc = 1: 1, R f =0.4). After completion, the reactant was concentrated under reduced pressure and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (1×200 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0377] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethylene-1-amine Preparation :

[0378] 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. under nitrogen atmosphere overnight. The reaction was monitored by TLC (petroleum ether: EtOAc=1:1, R f=0.5). The mixture was cooled to room temperature and then concentrated under reduced pressure to give crude (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethene-1-amine. The crude product was used directly in the next step without further purification.

[0379] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropyridine aldehyde :

[0380] To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was added NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by TLC (petroleum ether: EtOAc = 5: 1, R f =0.2). The reaction was quenched by adding saturated sodium thiosulfate (aqueous solution) (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 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0381] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0382] To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carboxaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (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) in batches at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled 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 layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain a crude product. The crude product was further purified by trituration with hexanes (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% over three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0

[0383] Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0384] To a stirred mixture of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (1.20 g, 3.85 mmol, 1.00 equiv) in DMF (10 mL) was added CuCl (0.57 g, 5.78 mmol, 1.50 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120 ° C overnight. The reaction was monitored by LCMS. The mixture was cooled 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; 1 HNMR (300MHz, DMSO-d6) δ9.27(d,1H),8.63(d,1H),8.57(s,1H),4.41(q,2H),4.12(s,3H),1.37(t,3H).

[0385] Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0386] 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 nitrogen atmosphere. The resulting mixture was stirred at 50 ° C for 2 hours. The reaction was monitored by LCMS. The mixture was cooled 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 HNMR (300MHz, DMSO-d6) δ12.61(s,1H),8.94(d,1H),8.37(d,1H),8.20(s,1H),4.39(q,2H),1.36(t,3H).

[0387] Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0388] To a stirred mixture of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate (740 mg, 2.92 mmol, 1.00 equiv) in THF (6 mL) was added LiAlH4 (2.5 mL, 5.85 mmol, 2.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for another 2 hours at 0°C. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1M HCl. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridine-2-one (250 mg, 40.53%). LC-MS: (ES+H, m / z): [M+H] + =211.0; 1 H NMR (400MHz, 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).

[0389] Step 4: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one :

[0390] 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 nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =228.95.

[0391] Step 9: Preparation of 3-chloro-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one Preparation :

[0392] 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) was added DIEA (564 mg, 4.36 mmol, 5 equiv) and KI (14 mg, 0.08 mmol, 0.10 equiv) at room temperature. The resulting mixture was stirred at 50 °C for 2 hours. 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 preparative HPLC 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 1HNMR(300MHz,DMSO-d6)δ12.48(s,1H),8.48(d,1H),8.29(s,1H),8.09(d,1H),7.70(d, 1H),7.55–7.47(m,1H),6.87(dd,1H),3.66(s,2H),3.46–3.42(m,4H),2.53–2.50(m,4H); 19 F NMR(282MHz,DMSO-d6)δ-143.39.

[0393] Embodiment 48

[0394]

[0395] Step 1: Preparation of ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0396] A solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (300 mg, 0.96 mmol, 1.00 equiv), [1,3-bis[2,6-bis(isopropyl)phenyl]-2-imidazolidinylidene]difluoromethylsilver(I) (97 mg, 0.17 mmol, 1.10 equiv), [2-[2-(diphenylphosphino)phenoxy]phenyl]diphenylphosphine (181 mg, 0.33 mmol, 0.35 equiv) and Pd(dba)2 (177 mg, 0.30 mmol, 0.32 equiv) in toluene (5 ml) was stirred at 80 °C under nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was filtered and the filter cake was washed with EtOAc (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / EtOAc 5:1) to give ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate (235 mg, 86%). LC-MS: (ES+H, m / z): [M+H] + =283.1; 1 H NMR (300MHz, DMSO-d6) δ9.25(d,1H),8.59(d,1H),8.53(s,1H),7.24(t,1H),4.42(q,2H),4.12(s,3H),1.40(t,3H); 19 F NMR(282MHz,DMSO-d6)δ-117.83.

[0397] Step 2: Preparation of ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0398] To a solution of ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate (240 mg, 0.85 mmol, 1.00 equiv) in ACN (7 mL) was added TMSI (680 mg, 3.40 mmol, 4.00 equiv) dropwise at room temperature. The reaction mixture was then stirred at 50 °C under nitrogen for 5 hours, cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum 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.

[0399] Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0400] To a stirred solution of ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate (230 mg, 0.85 mmol, 1.00 equiv) in THF (5 ml) was added dropwise LiAlH4 (0.69 mL, 2.5 mol / L THF solution, 2.00 equiv) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. 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-naphthyridine-2-one (50 mg, 26%). LC-MS: (ES+H, m / z): [M+H] + =227.0; 1 H NMR (400MHz, DMSO-d6) δ12.36(s,1H),8.50(d,1H),8.16(d,1H),7.70(s,1H),6.98(t,1H),5.57(t,1H),4.67(d,2H).

[0401] Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one :

[0402] To a stirred solution of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (80 mg, 0.35 mmol, 1.00 equiv) and DMF (1 mg, 0.02 mmol, 0.05 equiv) in DCM (4 ml) was added dropwise SOCl2 (126 mg, 1.06 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 hours. 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.

[0403] Step 5: 6-(4-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyrrolidone Preparation of 3-pyridinecarbonitrile :

[0404] To a stirred solution of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one (86 mg, assuming 100% yield, 0.35 mmol, 1.00 equiv), 6-(piperazine-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 equiv), KI (11 mg, 0.07 mmol, 0.20 equiv) in ACN (5 ml) was added DIEA (227 mg, 1.76 mmol, 5.00 equiv) dropwise at room temperature. The resulting mixture was stirred at 80 °C for 1 hour. The reaction was monitored by LCMS. The mixture was cooled 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 a crude product (80 mg). The crude product was purified by preparative HPLC to give 6-(4-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (42.9 mg, 33% over two steps). LC-MS: (ES+H, m / z): [M+H] + =397.1; 1 H NMR(300MHz,DMSO-d6)δ12.33(s,1H),8.54(d,1H),8.48(d,1H),8.16(s,1H),7.85(dd, 1H),7.71(d,1H),7.20–6.73(m,2H),3.72–3.68(m,4H),3.67(s,2H),2.51–2.49(m,4H); 19 F NMR(282MHz,DMSO-d6)δ-119.30.

[0405] Embodiment 49

[0406]

[0407] Step 1: Preparation of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propanoate :

[0408] To a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.01 mmol, 1.00 equiv) and 2-alanine methyl ester hydrochloride (2.93 g, 21.00 mmol, 1.00 equiv) in NMP (200 mL) was added DIEA (27.15 g, 210.09 mmol, 5.00 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 ° C for 2 hours under a nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether / EtOAc=10 / 1). The mixture was cooled 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 HNMR(400MHz,DMSO-d6)δ8.08(t,1H),7.87(dd,1H),7.77(dd,1H),4.67-4.55(m,1H),3.68(s,3H),1.48(dd,3H); 19 F NMR(377MHz,DMSO-d6)δ-122.19.

[0409] Step 2: Preparation of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one :

[0410] 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 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled 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 NaHCO (aqueous solution). The resulting mixture was then extracted with CH2Cl2 (3×300 mL). The combined organic layer was washed with brine (1×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.2 g, 87%). LC-MS: (ES-H, m / z): [MH] - =257.1; 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.01(dd,1H),6.76(t,1H),6.20(s,1H),3.90-3.80(m,1H),1.28(d,3H). 19 F NMR (377MHz, DMSO-d6) δ-132.99.

[0411] Step 3: Preparation of 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one :

[0412] To a stirred solution of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxaline-2-one (4.50 g, 17.36 mmol, 1.00 equiv) in DCM (500 mL) was added DDQ (4.34 g, 19.10 mmol, 1.10 equiv) at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. 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 minutes. 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 give 7-bromo-5-fluoro-3-methyl-1H-quinoxaline-2-one (3 g, 67%). LC-MS: (ES-H, m / z): [MH] - =255.0; 1 H NMR (400MHz, DMSO-d6) δ12.52(s,1H),7.49-7.40(m,1H),7.24(q,1H),2.40(q,3H).

[0413] Step 4: Preparation of 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde :

[0414] In a pressure tank, bis(adamantan-1-yl)(butyl)phosphine (349 mg, 0.97 mmol, 0.50 equiv), TMEDA (1.13 g, 9.72 mmol, 5.00 equiv) and Pd(OAc)2 (218 mg, 0.97 mmol, 0.50 equiv) were added to a solution of 7-bromo-5-fluoro-3-methyl-1H-quinoxaline-2-one (500 mg, 1.94 mmol, 1.00 equiv) in toluene (100 mL). The mixture was purged with nitrogen for 5 minutes and then pressurized to 30 MPa with CO2:H2=1:1 at room temperature. The resulting mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde (300 mg, 74.8%). LC-MS: (ES-H, m / z): [MH] - =205.2; 1 H NMR (400MHz, DMSO-d6) δ12.75(s,1H),10.02(q,1H),7.67–7.52(m,2H),2.49–2.44(m,3H).

[0415] Step 5: 6-{4-[(8-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-yl Preparation of methyl nitrile :

[0416] To a stirred mixture of 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde (200 mg, 0.97 mmol, 1.00 equiv) and 6-(piperazine-1-yl)pyridine-3-carbonitrile (274 mg, 1.45 mmol, 1.50 equiv) in THF (20 mL) was added tetrakis(propan-2-yloxy)titanium (551 mg, 1.94 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. NaBH(OAc)3 (822 mg, 3.88 mmol, 4.00 equiv) was added to the above mixture at room temperature. The resulting mixture was stirred for another 4 hours at room temperature. 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 and then triturated with MeCN (5 mL) to give 6-{4-[(8-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazine-1-yl}pyridine-3-carbonitrile (51.1 mg, 14%). LC-MS: (ES+H, m / z): [M+H]+ =379.2; 1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.48(d,1H),7.85(dd,1H),7.09(d,2 H),6.93(d,1H),3.68(t,4H),3.60-3.55(m,2H),2.47(d,4H),2.41(s,3H); 19 F NMR (377MHz, DMSO-d6) δ-125.51.

[0417] Embodiment 60

[0418]

[0419] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine :

[0420] To a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 equiv) in MeOH (50 mL) was added NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30 wt%) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The results were analyzed by TLC (PE:EA=1:1, R f =0.4) to monitor the reaction. The resulting mixture was concentrated under reduced pressure, and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3×100 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 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400MHz, DMSO-d6) δ8.66(s,1H),4.04(s,3H),2.70(s,3H).

[0421] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethylene-1-amine Preparation :

[0422] 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. under nitrogen atmosphere overnight. f =0.5) to monitor the reaction. Allow the mixture to cool to room temperature. Concentrate the resulting mixture under reduced pressure. The crude product is used directly in the next step without further purification.

[0423] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropyridine aldehyde :

[0424] To a stirred mixture of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)vinyl]dimethylamine (18.01 g, crude) in THF (100 mL) and H2O (100 mL) was added NaIO4 (28.00 g, 131.07 mmol, 2.20 equiv) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The precipitate was purified by TLC (PE:EA=5:1, R f =0.2) to monitor the reaction. The reaction was quenched by adding saturated sodium thiosulfate (aqueous solution) (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 H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.87(s,1H),4.10(s,3H).

[0425] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0426] To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carboxaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (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) in batches at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled 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 obtain a crude product. The crude product was purified by trituration with hexanes (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% yield over three steps). LC-MS: (ES+H, m / z): [M+H] + =311.0 / 313.0; 1 H NMR (400MHz, DMSO-d6) δ9.22(s,1H),8.78(s,1H),8.58(s,1H),4.42(q,2H),4.12(s,3H),1.39(t 3H).

[0427] Step 5: Preparation of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0428] To a solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv) in ACN (400 mL) was added TMSI (13.8 mL, 96.42 mmol, 6.00 equiv) dropwise at room temperature. The final reaction mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. 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 under the following conditions: column, silica gel; mobile phase, DCM containing EA, 45% to 60% gradient in 20 minutes; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure to give ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (3.8 g, 79.5%). LC-MS: (ES+H, m / z): [M+H] + =296.95 / 298.95

[0429] Step 6: Preparation of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0430] 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 nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding HCl (3.03 mL, 3.03 mmol, 2.00 equiv) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridine-2-one (220 mg, 56.9%). LC-MS: (ES+H, m / z): [M+H] + =255.0 / 257.0.

[0431] Step 7: Preparation of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one :

[0432] To a stirred mixture of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (230 mg, 0.90 mmol, 1.00 equiv) and DMF (6 mg, 0.09 mmol, 0.10 equiv) in DCM (7 mL) was added SOCl2 (321 mg, 2.70 mmol, 3.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (220 mg, 89.2%). LC-MS: (ES+H, m / z): [M+H] + =272.9 / 274.9.

[0433] Step 8: 6-{4-[(7-bromo-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile Preparation :

[0434] To a stirred mixture of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (150 mg, 0.54 mmol, 1.00 equiv), DIEA (354 mg, 2.74 mmol, 5.00 equiv) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (113 mg, 0.60 mmol, 1.10 equiv) in MeCN (7 mL) was added KI (18 mg, 0.11 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC, and the pure fractions were concentrated and then lyophilized to give 6-{4-[(7-bromo-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (25.6 mg, 10.9%). LC-MS: (ES+H, m / z): [M+H] + =425.00 / 427.00; 1 H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.47(s,3H),7.85(dd,J=9.1,2.4Hz,1H) ,7.68(s,1H),6.93(d,J=9.1Hz,1H),3.78–3.59(m,6H),2.48(d,J=4.7Hz,4H).

[0435] Example 68 and Example 69

[0436]

[0437] Step 1: Preparation of ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-naphthyridine-3-carboxylate :

[0438] To a stirred solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equiv) and (4-methoxyphenyl)[4-(trifluoromethyl)phenyl]methanone (1.12 g, 4.01 mmol, 0.25 equiv) in THF was added 5,5'-dimethyl-2,2'-bipyridine (0.74 g, 4.01 mmol, 0.25 equiv), nickel acetylacetonate (1.03 g, 4.01 mmol, 0.25 equiv) and Na2CO3 (1.70 g, 16.07 mmol, 1.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was placed approximately ~3 cm from two 40 W blue LEDs and stirred at room temperature under nitrogen atmosphere for 7 days. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (50 mL) and 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-methoxy-7-(oxacyclopentane-2-yl)-1,5-naphthyridine-3-carboxylate (1.6 g, 32.93%). LC-MS: (ES+H, m / z): [M+H] + =303.15; 1 H NMR(400MHz, DMSO-d6)δ9.20(d,J=2.0Hz,1H),8.57(dd,J=2.1,0.8Hz,1H),8.27–8.10(m,1H),5.13–5.04(m,1H),4.41(q,J=7.1Hz,2H ),4.18–4.09(m,1H),4.09(s,3H),3.95–3.85(m,1H),2.49–2.39(m,1H),2.05–1.82(m,2H),1.79–1.67(m,1H),1.39(t,J=7.1Hz,3H).

[0439] Step 2: Preparation of ethyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate :

[0440] To a stirred solution of ethyl 6-methoxy-7-(oxacyclopentane-2-yl)-1,5-naphthyridine-3-carboxylate (1.30 g, 4.30 mmol, 1.00 equiv) in MeCN was added AcOH (0.25 ml, 33 wt %, 2.00 equiv) containing HBr 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-(oxacyclopentane-2-yl)-5H-1,5-naphthyridine-3-carboxylate (730 mg, 58.89%). LC-MS: (ES+H, m / z): [M+H] + =289.10; 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.91(d,J=1.9Hz,1H),8.18(d,J=1.9Hz,1H),7.84(d,J=1.1Hz,1H),4.96–4.87(m,1H),4.39(q ,J=7.1Hz,2H),4.12–4.04(m,1H),3.91–3.79(m,1H),2.48–2.32(m,1H),1.99–1.81(m,2H),1.74–1.63(m,1H),1.36(t,J=7.1Hz,3H).

[0441] Step 3: Preparation of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one :

[0442] 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 nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding 1M 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-naphthyridine-2-one (280 mg, 44.90%). LC-MS: (ES+H, m / z): [M+H] + =247.00; 1H NMR (300MHz, DMSO-d6) δ11.97(s,1H),8.40(d,J=1.9Hz,1H),7.80(s,1H),7.64(d,J=1.9Hz,1H),5.48(t,J=5.6Hz,1H),4.98–4. 84(m,1H),4.63(d,J=5.3Hz,2H),4.18–4.01(m,1H),3.91–3.75(m,1H),2.45–2.31(m,1H),2.02–1.78(m,2H),1.74–1.58(m,1H).

[0443] Step 4: Preparation of 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one :

[0444] To a stirred solution of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (280 mg, 1.13 mmol, 1.00 equiv) and DMF (8 mg, 0.11 mmol, 0.10 equiv) in DCM was added SOCl2 (0.25 mL, 3.41 mmol, 3.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 hours. 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.

[0445] Step 5: 6-(4-{[6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazine-1-yl Preparation of 3-(2-(2-(4-(2-yl)pyridine)carbonitrile :

[0446] 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) at room temperature under nitrogen atmosphere was added DIEA (292 mg, 2.26 mmol, 4.00 equiv) and KI (18 mg, 0.11 mmol, 0.20 equiv). The resulting mixture was stirred at 80 °C under nitrogen atmosphere. Stir for 2 hours. Allow the mixture to cool to room temperature. Monitor the reaction by LCMS. Extract the resulting mixture with EtOAc (3×20 mL). Wash the combined organic layers with brine (20 mL) and dry over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give 6-(4-{[6-oxo-7-(oxacyclopentane-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazine-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 preparative 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 minutes; wavelength: 218 / 282 nm; RT1 (minute): 4.62; RT2 (minute): 6.76; sample solvent: MeOH:DCM=1:1--HPLC; injection volume: 0.75 mL; number of runs: 6, the pure fractions were concentrated in vacuo and then lyophilized to give Example 68 (34.2 mg, 99.7% purity, ee=100%) and Example 69 (34.1 mg, 99.3% purity, ee=99.7%). Example 68: LC-MS: (ES+H, m / z): [M+H] + =417.10; 11H 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; 1 1H 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).

[0447] Embodiment 71

[0448]

[0449] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide :

[0450] 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), T3P (15.07 g, 23.68 mmol, 1.50 equiv, 50 wt% in DCM) for 5 minutes at room temperature under 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 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 give (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide (2.00 g, 37.9%). LC-MS: (ES+H, m / z): [M+H] + =333.95 / 335.95; 1 H NMR (400MHz, DMSO-d6) δ9.89 (s, 1H), 7.62–7.41 (m, 7H), 7.21 -7.13 (m, 1H), 6.85–6.69 (m, 1H), 2.12 (d, J = 1.4Hz, 3H).

[0451] Step 2: Preparation of 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one :

[0452] 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 nitrogen atmosphere. The resulting mixture was stirred at 120°C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one (1.00 g, 65.2%). LC-MS: (ES+H, m / z): [M+H] + =255.80 / 257.80; 1 H NMR (400MHz, DMSO-d6) δ11.94(s,1H),7.82(s,1H),7.44-7.34(m,2H),2.09(s,3H).

[0453] Step 3: Preparation of 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one :

[0454] A solution of 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one (800 mg, 3.12 mmol, 1.00 equiv) and (tributyltinyl)methanol (1.10 g, 3.43 mmol, 1.10 equiv), second generation XPhos precatalyst (123 mg, 0.15 mmol, 0.05 equiv) in 1,4-dioxane (10 mL) was stirred overnight at 80 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled 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

[0455] Step 4: Preparation of 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one :

[0456] 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 nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under 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

[0457] Step 5: 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carboxylate Preparation of nitrile :

[0458] A solution of 6-(piperazine-1-yl)pyridine-3-carbonitrile hydrochloride (229 mg, assuming 100% yield, 0.88 mmol, 1.00 equiv) in MeCN (10 mL) was treated with DIEA (573 mg, 4.43 mmol, 5.00 equiv) for 5 min at room temperature under 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 under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (92.1 mg, 23.8%). LC-MS: (ES+H, m / z): [M+H] + =378.10; 1 H NMR (400MHz, DMSO-d6) δ11.77(s,1H),8.47(d,J=4.0Hz,1H),7.87–7.76(m,2H),7.38(d,J=8.1Hz,1H),7.18 (dd,J=8.1,6.4Hz,1H),6.91(d,J=8.0Hz,1H),3.66–3.65(m,6H),2.51-2.48(m,4H),2.10(d,J=1.3Hz,3H). 19 F NMR (377MHz, DMSO-d6) δ-135.84.

[0459] Embodiment 82

[0460]

[0461] Step 1: Preparation of 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate :

[0462] To a stirred solution of potassium tert-butoxide (21.27 g, 189.52 mmol, 1.50 equiv) in THF (500 ml) was added dropwise 1-tert-butyl 3-ethyl malonate (35.67 g, 189.52 mmol, 1.50 equiv) at room temperature under nitrogen atmosphere. 5-bromo-2-chloro-3-nitropyridine (30.00 g, 126.34 mmol, 1.00 equiv) in THF (50 ml) was added dropwise at 60°C over 15 minutes. The resulting mixture was stirred at 60°C for another 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The resulting mixture was diluted with HCl (1 M in water) (200 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 1-(tert-butyl)3-ethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (45 g, 91.5%). LC-MS: (ES-H, m / z): [MH] - =387.1

[0463] Step 2: Preparation of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate :

[0464] 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 nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 solution (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

[0465] Step 3: Preparation of ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate :

[0466] To a stirred solution of ethyl 2-(5-bromo-3-nitropyridine-2-yl)acetate (35.00 g, 121.07 mmol, 1.00 equiv) and Fe (79.72 g, 1219.36 mmol, 7.50 equiv) in EtOH (250 ml) was added saturated aqueous NH4Cl solution (250 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (300 mL). The resulting mixture was stirred at room temperature for 10 minutes. 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 layer was 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

[0467] Step 4: Preparation of ethyl 2-(5-bromo-3-(2,2-dimethoxypropionamido)pyridin-2-yl)acetate :

[0468] To a stirred solution of methyl 2,2-dimethoxypropionate (12.00 g, 80.99 mmol, 1.00 equiv) in MeOH (120 mL) was added dropwise H2O (120 mL) containing NaOH (9.72 g, 242.98 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 4 hours under nitrogen atmosphere. The reaction was monitored by TLC. The mixture was acidified to pH 8 with HCl (2M 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 hours. 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-dimethoxypropionate (8.5 g, 78.2%). 1 H NMR (300MHz, D2O) δ3.12 (d, J = 1.7Hz, 6H), 1.33 (s, 3H).

[0469] To a stirred solution of sodium 2,2-dimethoxypropanoate (7.59 g, 48.63 mmol, 1.50 equiv) in dioxane (100 ml) was added DIEA (12.57 g, 97.26 mmol, 3.00 equiv) and T3P (30.95 g, 97.26 mmol, 3.00 equiv, 50 wt% in EtOAc) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. To the above mixture was added ethyl 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 cooled 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-dimethoxypropionamido)pyridin-2-yl)acetate (9.3 g, 79.4%). LC-MS: (ES+H, m / z): [M+H] + =375.1

[0470] Step 5: Preparation of ethyl 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxylate :

[0471] To a stirred solution of ethyl 2-(5-bromo-3-(2,2-dimethoxypropionamido)pyridin-2-yl)acetate (7.00 g, 18.65 mmol, 1.00 equiv) in TFA (100 ml) was added H2O (7 mL) followed by 2 drops of fresh I2 solution (30 mg of I2 was suspended in TFA (10 mL)) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C under nitrogen atmosphere overnight. The resulting mixture was concentrated in vacuo. The residue was dissolved in toluene (100 mL) and piperidine (6 mL). The resulting mixture was refluxed at 120°C for 2 hours and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-bromo-3-methyl-2-oxo-1H-1,5-naphthyridine-4-carboxylate (3.3 g, 56.9%). LC-MS: (ES+H, m / z): [M+H] + =313.0; 1 H NMR (400MHz, DMSO-d6) δ12.20 (s, 1H), 8.55 (d, J = 2.1Hz, 1H), 7.86 (d, J = 2.1Hz, 1H), 4.42 (q, J = 7.1Hz, 2H), 2.06 (s, 3H), 1.33 (t, J = 7.1Hz, 3H).

[0472] Step 6: Preparation of 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0473] To a stirred solution of ethyl 7-bromo-3-methyl-2-oxo-1H-1,5-naphthyridine-4-carboxylate (3.00 g, 9.64 mmol, 1.00 equiv) in THF (50 ml) was added dropwise LiEt3BH (30 ml, 1 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by adding water / ice (6 mL) at 0°C. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (0 to 10:1 gradient over 30 minutes) to give 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridine-2(1H)-one (1.8 g, 69.4%). LC-MS: (ES-H, m / z): [MH] - =267.0 / 269.0; 1 H NMR (300MHz, DMSO-d6) δ 11.95 (s, 1H), 8.57 (d, J = 2.1Hz, 1H), 7.83 (d, J = 2.1Hz, 1H), 5.04 (t, J = 5.5Hz, 1H), 4.90 (d, J = 5.2Hz, 2H), 2.21 (s, 3H).

[0474] Step 7: Preparation of 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde :

[0475] To a stirred mixture of 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridine-2(1H)-one (1.80 g, 6.68 mmol, 1.00 equiv) in THF (20 ml) was added 1,1-bis(acetoxy)-3-oxo-3H-11^[5],2-benzidoyl-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 under a nitrogen atmosphere for 2 hours. 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 combined flash chromatography to give 7-bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde (760 mg, 42.5%). LC-MS:(ES-H,m / z):[MH] - =264.9; 1 H NMR (300MHz, DMSO-d6) δ12.28(s,1H),10.88(s,1H),8.62(d,J=2.1Hz,1H),7.89(d,J=2.1Hz,1H),2.25(s,3H).

[0476] Step 8: Preparation of 7-bromo-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0477] 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 eq.) in THF (5 ml) was added BAST (2.49 g, 11.23 mmol, 4 eq.) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 50°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched with saturated NH4Cl (aqueous solution) (3 ml) at 0°C. 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-naphthyridine-2-one (320 mg, 39.4%). LC-MS: (ES-H, m / z): [MH] - =287.0

[0478] Step 9: Preparation of 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0479] 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 (tributyltinyl)methanol (959 mg, 2.98 mmol, 2.40 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80° C. under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 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.

[0480] Step 10: Preparation of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0481] 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 nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo 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

[0482] Step 11: 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) Preparation of piperazine-1-yl)nicotinonitrile :

[0483] To a stirred solution of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (104 mg, 0.40 mmol, 1.00 equiv) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (91 mg, 0.48 mmol, 1.20 equiv) in MeCN (5 ml) was added DIEA (260 mg, 2.01 mmol, 5.00 equiv) and KI (13 mg, 0.08 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was cooled 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; 1H NMR (300MHz, DMSO-d6) δ12.25(s,1H),8.48(t,J=1.8Hz,2H),8.14–7.74(m,2H),7.70(d,J=1. 9Hz, 1H), 6.94 (d, J = 9.1Hz, 1H), 3.39-3.67 (m, 6H), 2.50-2.48 (m, 4H), 2.33 (t, J = 2.8Hz, 3H). 19 F NMR(282MHz,DMSO-d6)δ-117.71.

[0484] Embodiment 83

[0485]

[0486] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxypropene-2-amide :

[0487] Pyridine (14.99 g, 189.45 mmol, 1.80 equiv) was added dropwise to a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 equiv) in DCM (300 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. (2E)-3-ethoxyprop-2-enoyl chloride (21.24 g, 157.88 mmol, 1.50 equiv) was added dropwise to the above mixture within 5 minutes at room temperature. The resulting mixture was stirred for another 2 hours at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL). The resulting mixture was washed with water (3×500 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (24.6 g, 81.1%). LC-MS: (ES+H, m / z): [M+H] + =288.0 / 290.0.

[0488] Step 2: Preparation of 7-bromo-8-fluoro-1H-quinolin-2-one :

[0489] 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 under nitrogen for 3 hours. 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.

[0490] Step 3: Preparation of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one :

[0491] 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 2,2-dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled 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 product). LC-MS: (ES+H, m / z): [M+H] + =275.9 / 277.9; 1 H NMR (400MHz, DMSO-d6) δ12.52 (s, 1H), 8.38 (d, J = 1.6Hz, 1H), 7.52–7.42 (m, 2H).

[0492] Step 4: Preparation of 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one :

[0493] 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-vinyl-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 nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled 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-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES+H, m / z): [M+H] + =224.0; 1HNMR(300MHz,DMSO-d6)δ12.38(s,1H),8.34(d,J=1.6Hz,1H),7.53-7.46(m,2H),6.95 (dd,J=17.7,11.2Hz,1H), 6.07 (dd,J=17.7,1.0Hz,1H), 5.57 (dd,J=11.2,1.0Hz,1H).

[0494] Step 5: Preparation of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde :

[0495] To a stirred mixture of 3-chloro-7-vinyl-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-lutidine (718 mg, 6.70 mmol, 2.00 equiv) in THF (15 mL) was added dropwise H2O (1.5 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (630 mg, 83.2%). LC-MS: (ES-H, m / z): [MH] - =224.1.

[0496] Step 6: 6-{4-[(3-chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile Preparation :

[0497] A mixture of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carboxaldehyde (150 mg, 0.66 mmol, 1.00 equiv) and 6-(piperazine-1-yl)pyridine-3-carbonitrile (137 mg, 0.73 mmol, 1.10 equiv) in DCM (2 ml) was stirred at room temperature for 10 minutes. The resulting mixture was concentrated under reduced pressure. EtOH (3 mL) containing HOAc (19 mg, 0.33 mmol, 0.50 equiv) was added to the resulting mixture and stirred for 4 hours at 50° C. under a nitrogen atmosphere. The mixture was cooled to room temperature. NaBH3CN (83 mg, 1.33 mmol, 2.00 equiv) was added to the stirred mixture in batches 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 HNMR (400MHz, DMSO-d6) δ12.46(s,1H),8.47(d,J=2.0Hz,1H),8.36(d,J=1.5Hz,1H),7.85(dd,J=9.1,2.4Hz,1H ),7.49(d,J=8.1Hz,1H),7.28(dd,J=8.1,6.3Hz,1H),6.97–6.87(m,1H),3.71–3.63(m,6H),2.50–2.44(m,4H); 19 F NMR(282MHz,DMSO-d6)δ-134.50.

[0498] The following compounds were synthesized as described above.

[0499] Table 2. Characterization data

[0500]

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509] Example A: Cell Growth Inhibition Assay

[0510] Cell proliferation was measured by cell viability assay using DLD-1BRCA2(- / -) and parental isogenic pairs and MDA-MB-436 (mutated BRCA1) cell lines. The CellTiter-Glo (CTG) based cell viability assay is designed to determine the number of viable cells in culture affected by a compound by quantifying ATP, which indicates the presence of metabolically active cells.

[0511] DLD-1BRCA2 (- / -) and parent 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 distributed into 384-well plates (Corning, 3764) using an Echo sonic liquid handler to form a final concentration of 1:3 serial dilutions, with a maximum dose of 10 μM or 30 μM. Cells were seeded into plates at a density of 50 cells / well (DLD-1 parent), 200 cells / well (DLD-1BRCA2- / -) or 500 cells / well (MDA-MB-436). After a short period of centrifugation, cells were cultured undisturbed at 37°C and 5% CO2 in a fully humidified incubator for 7 days. Cell viability was measured by CellTiterGlo 2.0 assay kit (Promega, G9243), and growth inhibition was calculated and plotted against final compound concentration, and the data were fitted in Xfit to generate IC 50 value.

[0512] Example B: Biochemical (FP) assay

[0513] Fluorescence polarization (FP)-based assays have been widely used in drug discovery due to homogeneous format, robust performance, and lack of interference observed in other assays. Compounds were characterized using an assay measuring displacement of a commercially available fluorescently labeled PARP 1 / 2 inhibitor (PARPi-FL, Tocris Biosciences, #6461), as exemplified in assays performed in WO2014 / 064149 and WO2021 / 013735A1. The assay was performed using the following method:

[0514] Compounds were dissolved in DMSO and serially expanded over the desired concentration range in Optiplate-384F plates using an Echo 550 liquid handler. 100% DMSO was used for high (with protein) and low (without protein) control samples. 20 nL of compound or DMSO alone was added to each assay plate well.

[0515] PARP1 and PARP2 proteins were expressed, purified and diluted to a final concentration of 20 nM in assay buffer containing 50 mM Tris pH 8.0, 0.001% Triton X-100, 10 mM MgCl2, 150 mM NaCl. PARPi-FL was then added at a final concentration of 3 nM.

[0516] The assay plate was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 4 hours.

[0517] Fluorescence polarization was read using an Envision microplate reader using the following settings:

[0518] Excitation filter - FITC FP 480 - Excitation slot 3

[0519] Emission filter - FITC FP P-pol 535 - emission slot 4

[0520] 2nd emission filter - FITC FP S-pol 535 - emission slot 3

[0521] Mirror Module - FITC FP Dual Enh - Slot 1

[0522] The inhibition rate was calculated using the percentage of aligned Mahalanobis distances greater than the control sample (mP value) according to the following equation:

[0523] <![CDATA[mP c :mP value of the compound]]> <![CDATA[mP L :mP value of low control]]> <![CDATA[mP H : mP value of high control]]>

[0524]

[0525] The reported IC for each compound was calculated using XLFit (Eq. 201). 50 .

[0526] The data for Example A and Example B are provided in Table 3.

[0527] Table 3

[0528]

[0529]

[0530] Example C: In vitro human transporter efflux

[0531] Madin-Darby canine kidney (MDCKII) cells expressing MDR1 and BCRP were seeded at a density of 545,000 cells / cm2 on a Corning HTS on 96-well polycarbonate permeable (0.4 μm pore) supports. Cells were incubated for 4 to 8 days prior to the assay and monolayer integrity was assessed by measuring transmembrane electrical resistance (TEER). Test and reference compounds were diluted to a concentration of 10 μM and 1 μM, respectively, with transport buffer (HBSS HEPES pH 7.4). The final organic solvent concentration was 0.5% (v / v). Bidirectional (apical to basolateral and basolateral to apical) fluxes of test and reference compounds were determined during incubation for 2 h at 37°C and 5% CO2 and 95% relative humidity. At the end of 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 analyzed by HPLC-MS / MS. Integrity

[0532] The apparent permeability (Papp, in ×10-6 cm / s) was calculated using the following equation:

[0533] Papp=(dQ / dt) / (AxD0)

[0534] where dQ / dt is the drug transport rate (pmol / s), A is the surface area of ​​the membrane (0.143 cm 2 ), and D0 is the initial donor concentration (nM or pmol / cm3).

[0535] Outflow ratio = Papp(B→A) / Papp(A→B)

[0536] 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.

[0537] Example D: In vivo determination of rat Kp,uu

[0538] Determination of unbound fraction (Pu) in plasma

[0539] The equilibrium dialysis method is used to study the in vitro binding of test articles and reference compounds to plasma proteins. Plasma samples containing 5 μM test articles or blank dialysis buffer solutions (PBS, pH 7.4) are added to the individual chambers of the dialysis wells of the high-throughput equilibrium dialysis (HTD) device. The dialysis plate is sealed and placed in an incubator containing 5% CO2 at 37°C, and shaken at about 100 rpm for 6 hours. All experiments are performed in duplicate. Ketoconazole (5 μM) is used as a reference compound. After incubation, the seal is removed, and 50 μL of the post-dialysis sample is pipetted from the buffer chamber and the plasma chamber to a fresh 96-well plate. By adding blank plasma to the buffer sample or adding blank buffer to the plasma sample, the sample is subjected to iso-matrixization. Subsequently, before the relative concentration of the test article is determined by UPLC-MS / MS analysis, 400 μL (4 volumes) of acetonitrile containing an internal standard are added to all samples to precipitate protein. According to the following equation, the concentration of the test article in the buffer sample and the plasma sample is used to calculate the unbound fraction in the plasma:

[0540]

[0541] Determination of the unbound fraction in brain homogenate (Bu)

[0542] Balance dialysis is used to study the in vitro binding of test articles and reference compounds to rodent brain homogenates. The brain collected from the original animal is weighed and homogenized in 4 volumes of PBS (pH 7.4). Brain homogenate samples containing 1 μM test article or blank dialysis buffer solution (PBS, pH 7.4) are added to the individual chambers of the dialysis wells of the high-throughput equilibrium dialysis (HTD) device. The dialysis plate is sealed and placed in an incubator containing 5% CO2 at 37°C and shaken at about 100 rpm for 6 hours. All experiments are performed in duplicate. Telmisartan (5 μM) is used as a reference compound. After incubation, the seal is removed and 50 μL of the dialyzed sample is pipetted from the buffer chamber and the brain homogenization chamber to a fresh 96-well plate. The sample is iso-matrixed by adding a blank homogenate to the buffer sample or adding a blank buffer to the homogenate sample. Subsequently, 400 μL (4 volumes) of acetonitrile containing an internal standard was added to all samples to precipitate the protein prior to analysis 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 concentration of the test article in the buffer sample and the homogenate sample according to the following equation:

[0543]

[0544] Correction for the percent unbound in undiluted brain was achieved by the following equation:

[0545]

[0546] Determination of drug brain-plasma partition coefficient (Kp) and drug unbound Kp (Kp,uu) in rats

[0547] Compounds were prepared individually or in boxes (as a mixture) at a concentration of 0.1 mg / mL / compound in sterile water containing 0.5% (w / v) methylcellulose 400 cP, and administered to male Sprague-Dawley rats via gavage at a dose volume of 10 mL / kg. One animal was killed at each of the following time points: 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration, and brain samples and blood samples were collected. Plasma was prepared from blood via refrigerated centrifugation, and plasma samples were stored frozen at -80°C until bioanalysis. Brain samples were rinsed with saline to remove residual blood and blotted with wipes. The brain samples were then weighed, homogenized with 3 volumes (v / w) of water, and stored frozen at -80°C until bioanalysis.

[0548] Prior to bioanalysis, plasma and brain samples were extracted with 4 volumes of acetonitrile containing an internal standard and centrifuged for 15 minutes. The supernatant was diluted with 2 volumes of water and injected for analysis via HPLC-MS / MS. Plasma drug concentrations and brain homogenate drug concentrations were determined against calibration curves generated by spiking drug into blank rat plasma or brain homogenate over the entire appropriate concentration range. Brain homogenate concentrations were corrected for the homogenate buffer dilution factor to obtain total brain drug concentrations.

[0549] The brain-plasma partition coefficient (Kp) was determined for each compound and calculated as: AUC brain: AUC plasma, provided that tlast was the same in each matrix. If the drug concentration versus time curve for one matrix dropped below the lower limit of quantitation at an earlier time point than the other matrix, the brain Kp was calculated as the average of the ratios of the total brain drug concentration to the total plasma drug concentration measured at each time point at which the drug concentration could be quantified in both matrices.

[0550] Kp is then calculated from Kp using the following formula: Kp,uu: Kp,uu = Kp*(unbound fraction in brain homogenate / unbound fraction in plasma).

[0551] The data from Example C and Example D are provided in Table 4.

[0552] Table 4

[0553]

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof.

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