PARP1 inhibitor and application thereof

Abstract

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

Description

[0001] This application is a divisional application of a Chinese patent application with an application date of January 20, 2023, an application number of 202380016582.X (PCT application number PCT / US2023 / 011268), and an invention title of "PARP1 Inhibitors and Their Uses".

[0002] Cross - References

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 301,907, filed January 21, 2022, and U.S. Provisional Application Serial No. 63 / 376,338, filed September 20, 2022, which are hereby incorporated by reference in their entireties. Background of the Invention

[0004] Poly(ADP - ribose) polymerase (PARP) or poly(ADP - ribose) synthase (PARS) plays important roles in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These roles make PARP inhibitors targeted drugs for a variety of diseases. PARP inhibitors have shown 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 potentiation of cytotoxic cancer therapies. PARP is also applicable to retroviral infections, and thus inhibitors can be used in antiretroviral therapy. In models of myocardial infarction, stroke, other nerve traumas, organ transplantation, and reperfusion of the eye, kidney, intestine, and skeletal muscle, PARP inhibitors are effective in preventing ischemia - reperfusion injury. The inhibitors are effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis, and uveitis. PARP inhibitors have also shown benefits in several degenerative disease models, including diabetes (and its complications) and Parkinson's disease. PARP inhibitors can improve hepatotoxicity after acetaminophen overdose, cardiotoxicity and nephrotoxicity from doxorubicin and platinum - based anti - tumor agents, and skin damage secondary to sulfur mustard gas. In various cancer models, PARP inhibitors have been shown to enhance radiotherapy and chemotherapy by increasing cancer cell death, restricting tumor growth, reducing metastasis, and prolonging the survival of tumor - bearing animals.

[0005] PARP1 and PARP2 are the most widely studied PARPs due to their roles in DNA damage repair. PARP1 is activated by DNA damage breaks and catalyzes the addition of poly(ADP - ribose) (PAR) chains to target proteins. This post - translational modification (termed PARylation) mediates the recruitment of additional DNA repair factors to DNA lesions.

[0006] After this recruitment function is completed, auto-PARylation of PARP triggers the release of the bound PARP from DNA to allow access to other DNA repair proteins to complete the repair. Thus, the binding of PARP to the damage site, its catalytic activity, and its ultimate release from DNA are all important steps in the response of cancer cells to DNA damage caused by chemotherapeutic agents and radiotherapy.

[0007] Inhibition of PARP family enzymes has been developed as a strategy for selectively killing cancer cells by inactivating the complementary DNA repair pathway. 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 PARP family DNA repair enzymes. Such tumors have a defective homologous recombination repair (HRR) pathway and rely on the function of PARP enzymes for survival. Although PARP inhibitor therapy mainly targets SRCA mutant cancers, clinical trials of PARP inhibitors have been conducted in non-SRCA mutant tumors that exhibit homologous recombination deficiency (HRD).

[0008] 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 strong inhibition of PARP1 selectivity will lead to the trapping of PARP1 on DNA, resulting in DNA double-strand breaks (DSBs) caused by S-phase replication fork collapse. It is also believed that PARP1-DNA trapping is an effective mechanism for selectively killing tumor cells with HRD. Therefore, there is an unmet medical need for effective and safe PARP inhibitors. In particular, PARP inhibitors selective for PARP1. SUMMARY OF THE INVENTION

[0009] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0010]

[0012] Wherein:

[0013] R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0014] R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;

[0015] X is N or CR 3 ;

[0016] Y is N or CR 4 ;

[0017] Z is N or CR 5 ;

[0018] R 3 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0019] R 4are hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0020] R 5 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0021] Each R 6 is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0022] or two Rs 6 together form cycloalkyl or heterocycloalkyl; each optionally substituted by deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl substituted;

[0023] each R 7 independently is deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

[0024] or two Rs on the same carbon 7 together form an oxo group;

[0025] or two Rs on the same or different carbons 7 together form cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs;

[0026] n is from 0 to 4;

[0027] T is N or CR 8 ;

[0028] U is N or CR 9 ;

[0029] R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0030] R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0031] R 10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0032] R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0033] R 12 is cyano or halogen;

[0034] each R a independently is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2-C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkylene(cycloalkyl), C 1 -C 6 Alkylene(heterocycloalkyl), C 1 -C 6 Alkylene(aryl) or C 1 -C 6 Alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0035] Each R b Is independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkylene(cycloalkyl), C 1 -C 6 Alkylene(heterocycloalkyl), C 1 -C 6 Alkylene(aryl) or C 1 -C 6 Alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; and

[0036] Each R c And R d Is independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, hetero cycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hetero cycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0037] or R c and R d together with the atom to which they are attached form a hetero cycloalkyl, optionally substituted by one or more R;

[0038] each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 -, -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 -, -NHC(=O)OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 alkyl, -C(=O)NH 2 -, -C(=O)N(C 1 -C 6 alkyl) 2 -, -C(=O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C1 -C 6 heteroalkyl;

[0039] or two Rs on the same atom together form an oxo group;

[0040] provided that when X is CR 3 then Y is CR 4 and Z is CR 5 ; then one of R 3 , R 4 and R 5 is not hydrogen and R 4 is not -OMe; and

[0041] provided that when X is CH, Y is CH, and Z is CH; then R 2 is not hydrogen.

[0042] 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.

[0043] Also disclosed herein is a method of treating cancer in a subject in need thereof comprising a BRCA1 and / or BRCA2 mutation, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. Also disclosed herein is a method of treating cancer in a subject in need thereof comprising a mutation in a gene that results in homologous repair deficiency, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the mutation in the gene that results in 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, gastric cancer, thyroid cancer or uterine cancer. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0044] Also disclosed herein is a method of treating cancer present in the brain in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0045] The present disclosure also provides a method for 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.

[0046] Incorporated by reference

[0047] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Detailed Description

[0048] Definition

[0049] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the following claims, the word "comprise" and variations such as "comprises" and "comprising" are to be construed in an open, inclusive sense, i.e., as "including, but not limited to." Additionally, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0050] As used herein, unless otherwise specified, the following terms have the following meanings:

[0051] As used herein, unless otherwise indicated, the following terms have the following meanings:

[0052] "oxo group" means ═O.

[0053] "carboxyl group" means -COOH.

[0054] "cyano group" means -CN.

[0055] "Alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon monovalent group having from one to about ten carbon atoms, more preferably from 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, and longer alkyl groups such as heptyl, octyl, etc. Whenever it appears herein, a numerical range such as "C 1 -C 6 alkyl" or "C 1-6 alkyl" means that the alkyl can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses the occurrence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl is C 1-10 alkyl. In some embodiments, the alkyl is C 1-6 alkyl. In some embodiments, the alkyl is C 1-5 alkyl. In some embodiments, the alkyl is C 1-4 alkyl. In some embodiments, the alkyl is C 1-3 alkyl. Unless specifically stated otherwise in the specification, the alkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, the alkyl is optionally substituted by halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted by halogen.

[0056] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon monovalent group having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. The group can be in the cis or trans conformation with respect to the double bond, and it should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH 2 ), 1-propenyl (-CH 2 CH=CH 2 ), isopropenyl [-C(CH 3 )=CH2 , butenyl, 1,3 - butadienyl, etc. Whenever it appears herein, numerical ranges such as "C 2 -C 6 enyl" or "C 2-6 enyl" mean that the enyl can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also covers the occurrence of the term "enyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, the enyl can be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the enyl is optionally substituted by oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, the enyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the enyl is optionally substituted by halogen.

[0057] "Alkynyl" refers to a straight - chain or branched - chain 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, etc. Whenever it appears herein, numerical ranges such as "C 2 -C 6 alkynyl" or "C 2-6 alkynyl" mean that the alkynyl can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but this definition also covers the occurrence of the term "alkynyl" where no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl can be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl is optionally substituted by oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, the alkynyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl is optionally substituted by halogen.

[0058] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, the alkylene may be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkylene is optionally substituted by oxo group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 substitution. In some embodiments, the alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkylene is optionally substituted by halogen.

[0059] "Alkoxy" refers to a group of the formula -OR a wherein R a is alkyl as defined. Unless otherwise specifically stated in the specification, the alkoxy may be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkoxy is optionally substituted by halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or -NO 2 substitution. In some embodiments, the alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkoxy is optionally substituted by halogen.

[0060] "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 can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). The aryl includes but is not limited to aryls derived from hydrocarbon ring systems of anthracenylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, , fluoranthene, fluorene, asym-diphenyleneethane, sym-diphenyleneethane, indane, indene, naphthalene, phenalene, phenanthrene, picene, pyrene and triphenylene. Unless otherwise specifically stated in the specification, the aryl 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, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 or -NO 2Substituted. In some embodiments, the aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the aryl is optionally substituted by halogen.

[0061] "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 (C 3 -C 15 cycloalkyl or C 3 -C 15 cycloalkenyl), cycloalkyls having three to ten carbon atoms (C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl), cycloalkyls having three to eight carbon atoms (C 3 -C 8 cycloalkyl or C 3 -C 8 cycloalkenyl), cycloalkyls having three to six carbon atoms (C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl), cycloalkyls having three to five carbon atoms (C 3 -C 5 cycloalkyl or C 3 -C 5 cycloalkenyl) or cycloalkyls having three to four carbon atoms (C 3 -C 4 cycloalkyl or C 3 -C 4cycloalkenyl). In some embodiments, the cycloalkyl is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl. Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthalene, trans-decahydronaphthalene, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically stated otherwise in the specification, the cycloalkyl 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, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH 2 or -NO 2 substituted. In some embodiments, the cycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the cycloalkyl is optionally substituted by halogen.

[0062] "Halogen" or "halo" means bromine, chlorine, fluorine or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0063] "Haloalkyl" means an alkyl as defined above substituted by one or more of the above-defined halo groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0064] "Hydroxyalkyl" means an alkyl as defined above substituted by one or more hydroxy groups. In some embodiments, the alkyl is substituted by one hydroxy group. In some embodiments, the alkyl is substituted by one, two or three hydroxy groups. Hydroxyalkyls include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0065] "Aminoalkyl" means 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 includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0066] "Deuterated alkyl" means 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 includes, for example, CD 3 , CH 2 D, CHD 2 , CH 2 CD 3 , CD 2 CD 3 , CHDCD 3 , CH 2 CH 2 D, or CH 2 CHD 2 . In some embodiments, the deuterated alkyl is CD 3 .

[0067] "Heteroalkyl" means an alkyl group in which one or more of the skeletal atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof). The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is C 1 -C 6 heteroalkyl, where the heteroalkyl 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 combinations thereof), and where the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH(CH 3 )OCH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3) 2 、 -CH 2 CH 2 NHCH 3 or -CH 2 CH 2 N(CH 3 ) 2 . Unless otherwise specifically stated in the specification, the heteroalkyl group may be optionally substituted, for example, by oxo group, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the heteroalkyl group is optionally substituted by oxo group, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 or -NO 2 substituted. In some embodiments, the heteroalkyl group is optionally substituted by oxo group, halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the heteroalkyl group is optionally substituted by halogen.

[0068] "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, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl group contains one to three nitrogens. In some embodiments, the heterocycloalkyl group contains one or two nitrogens. In some embodiments, the heterocycloalkyl group contains one nitrogen. In some embodiments, the heterocycloalkyl group contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, the heterocycloalkyl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl group can be optionally oxidized; the nitrogen atoms can be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having two to fifteen carbon atoms (C 2 -C 15 heterocycloalkyl or C 2 -C 15 heterocycloalkenyl), heterocycloalkyl groups having two to ten carbon atoms (C 2 -C 10 heterocycloalkyl or C 2 -C 10 heterocycloalkenyl), heterocycloalkyl groups having two to eight carbon atoms (C 2 -C 8 heterocycloalkyl or C2 -C 8 heterocycloalkenyl), heterocycloalkyl having two to seven carbon atoms (C 2 -C 7 heterocycloalkyl or C 2 -C 7 heterocycloalkenyl), heterocycloalkyl having two to six carbon atoms (C 2 -C 6 heterocycloalkyl or C 2 -C 6 heterocycloalkenyl), heterocycloalkyl having two to five carbon atoms (C 2 -C 5 heterocycloalkyl or C 2 -C 5 heterocycloalkenyl) or heterocycloalkyl having two to four carbon atoms (C 2 -C 4 heterocycloalkyl or C 2 -C 4(heterocycloalkenyl). Examples of such heterocycloalkyls 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, pyrazolidinyl, 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. The term heterocycloalkyl also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, 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 make up heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless specifically stated otherwise 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, -CF 3 , -OH, -OMe, -NH 2 or -NO 2 . In some embodiments, heterocycloalkyl is optionally substituted by halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0069] "Heteroaryl" refers to a 5- to 14-membered 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 contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains one to three nitrogens. In some embodiments, the heteroaryl contains one or two nitrogens. In some embodiments, the heteroaryl contains one nitrogen. The heteroaryl 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 heteroaryl is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include but are not limited to azido group, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyroneyl, benzofuranyl, benzofuranoneyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanoneyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazido group, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and phenylthio (i.e., thienyl). Unless specifically stated otherwise in the specification, the heteroaryl can 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, the heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 , -OH, -OMe, -NH2 or -NO 2 substitution. In some embodiments, the heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF 3 , -OH or -OMe. In some embodiments, the heteroaryl is optionally substituted by halogen.

[0070] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes instances where the described event or circumstance occurs and instances where the described event or circumstance does not occur. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. In addition, an optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ), fully substituted (e.g., -CF 2 CF 3 ), monosubstituted (e.g., -CH 2 CH 2 F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc.). Those skilled in the art should understand that for any group containing one or more substituents, such groups are not intended to introduce any substitutions or substitution patterns that are spatially unrealistic and / or synthetically infeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which is in turn defined to include optionally substituted alkyl, potentially infinitely). Therefore, any substituent described should generally be understood to have a maximum molecular weight of about 1,000 daltons, and more typically, up to about 500 daltons.

[0071] 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.

[0072] "Effective amount" or "therapeutically effective amount" means the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses, which effectively produces the desired therapeutic effect.

[0073] As used herein, the terms "treatment", "treating" refer to therapeutic treatment, wherein the aim is to slow down (alleviate) an undesired physiological condition, disorder or disease, or to obtain a beneficial or desired clinical outcome. For the purposes described herein, beneficial or desired clinical outcomes include, but are not limited to, alleviation of symptoms; reduction in the degree of a condition, disorder or disease; stabilization (i.e., not worsening) of a condition, disorder or disease state; delay in the onset or slowdown in the progression of a condition, disorder or disease; improvement of a condition, disorder or disease state; and remission (whether partial or total) of a condition, disorder or disease, whether detectable or not detectable or enhanced or improved. Treatment includes eliciting a clinically significant response without excessive side effects. Treatment also includes prolonging survival as compared to the expected survival if treatment is not received. As used herein, the terms "treatment", "treating" and the words derived therefrom do not necessarily mean 100% or complete treatment. On the contrary, there are varying degrees of treatment that are considered by those of ordinary skill in the art to have potential benefit or therapeutic effect. In this regard, the disclosed methods can provide treatment of a disorder in a mammal at any amount or any level. For example, a disorder (including its symptoms or conditions) can be reduced, e.g., by about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10%. "Synergy" or "synergistic" means that the combined effect is greater than the sum of the effects of each component alone at the same dose.

[0074] As used herein, "PARP-related disease or disorder" or alternatively "PARP-mediated disease or disorder" means any disease or other adverse condition in which PARP or its mutants are known or suspected to play a role.

[0075] As used herein, "PARP1-related disease or disorder" or alternatively "PARP1-mediated disease or disorder" means any disease or other adverse condition in which PARP1 or its mutants are known or suspected to play a role.

[0076] Compound

[0077] Compounds or pharmaceutically acceptable salts, solvates or stereoisomers thereof useful for treating cancer are described herein.

[0078] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0079]

[0080] Wherein:

[0081] R 1 is hydrogen, deuterium, halogen, -CN, -ORa 、 -NR c R d 、 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0082] R 2 is hydrogen, deuterium, halogen, -CN, -OR a 、 -NR c R d 、 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;

[0083] X is N or CR 3 ;

[0084] Y is N or CR 4 ;

[0085] Z is N or CR 5 ;

[0086] R 3 is hydrogen, deuterium, halogen, -CN, -OR a 、 -NR c R d 、 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2-C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0087] R 4 is hydrogen, deuterium, halogen, -CN, -OR a -, -NR c R d alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0088] R 5 is hydrogen, deuterium, halogen, -CN, -OR a -, -NR c R d alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0089] Each R 6 is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1-C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0090] or two Rs 6 together form a cycloalkyl or heterocycloalkyl; each optionally being deuterium, halogen, -CN, -OH, -OR a , -NR c R d C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl substituted;

[0091] each R 7 independently is deuterium, halogen, -CN, -OH, -OR a , -NR c R d C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;

[0092] or two Rs on the same carbon 7 together form an oxo group;

[0093] or two Rs on the same carbon or different carbons 7Together form a cycloalkyl or heterocycloalkyl group; each is optionally substituted by one or more R;

[0094] n is from 0 to 4;

[0095] T is N or CR 8 ;

[0096] U is N or CR 9 ;

[0097] R 8 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are each optionally substituted by one or more R;

[0098] R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are each optionally substituted by one or more R;

[0099] R10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0100] R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0101] R 12 is cyano or halogen;

[0102] Each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0103] each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; and

[0104] each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1-C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0105] or R c and R d together with the atom to which they are attached form a heterocycloalkyl, optionally substituted by one or more R;

[0106] each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 、-NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 、-NHC(=O)OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 alkyl, -C(=O)NH 2 、-C(=O)N(C 1 -C 6 alkyl) 2 、-C(=O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0107] or two Rs together on the same atom form an oxo group;

[0108] provided that when X is CR 3 , Y is CR 4 and Z is CR 5 ; then one of R 3 , R 4 and R 5 is not hydrogen and R 4 is not -OMe; and

[0109] provided that when X is CH, Y is CH, and Z is CH; then R 2 is not hydrogen.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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 .

[0119] 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 .

[0120] 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 .

[0121] 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 5。In some embodiments of the compound of formula (I), X is CH; Y is N; and Z is CH. In some embodiments of the compound of formula (I), X is N; Y is CR 4 ; and Z is CR 5 。In some embodiments of the compound of formula (I), X is N; Y is CH; and Z is CH.

[0122] In some embodiments of the compound of formula (I), the compound has the formula (Ia):

[0123]

[0124] In some embodiments of the compound of formula (I), the compound has the formula (Ib):

[0125]

[0127] In some embodiments of the compound of formula (I), the compound has the formula (Ic):

[0128]

[0129] In some embodiments of the compound of formula (I), the compound has the formula (Id):

[0130]

[0131] wherein one of R 3 , R 4 and R 5 is not hydrogen and R 4 is not -OMe.

[0132] In some embodiments of the compound of formula (I), the compound has the formula (Ie):

[0133]

[0134] wherein R 2 is deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl.

[0135] In some embodiments of the compound of formula (I) or formula (Ia) to formula (Ie), R 1 is hydrogen, deuterium, halogen, -CN, -ORa 、 -NR c R d 、 C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R.

[0136] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl or cycloalkyl; wherein the alkyl, alkynyl and cycloalkyl are optionally substituted by one or more R. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6Halogenated alkyl, C 2 -C 6 alkynyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl, C 2 -C 6 alkynyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is C 1 -C 6 alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is methyl or ethyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is methyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is ethyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is cyclopropyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is heterocycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is C 1 -C 6 halogenated alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is difluoromethyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is halogen, C 1 -C 6 halogenated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is halogen or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1is fluorine or chlorine. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 1 is chlorine.

[0137] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is hydrogen, deuterium, halogen, -OR a , C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is hydrogen, halogen, -OR a or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is fluorine. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is methyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is -OR a . In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is -OCF 3 . In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 2 alkyl, C 1 -C 2 haloalkyl or C 1 -C 2 deuterated alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is hydrogen, halogen, -OR a or C 1 -C 2 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is halogen, -OR a or C 1-C 2 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 2 is halogen or C 1 -C 2 alkyl.

[0138] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 3 is hydrogen, deuterium, halogen, -OR a 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 3 is hydrogen, halogen, -OR a or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 3 is hydrogen, halogen or C 1 -C 6 alkyl.

[0139] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 3 is hydrogen or halogen.

[0140] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 3 is halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 3 is hydrogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 3 is not hydrogen.

[0141] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is hydrogen, deuterium, halogen, -CN, -NR c R d 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is hydrogen, deuterium, halogen, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is hydrogen, halogen, -OR a or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is hydrogen, halogen or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is hydrogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 4 is not hydrogen.

[0142] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 5 is hydrogen, deuterium, halogen, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 5 is hydrogen, halogen, -OR a or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R5 is hydrogen, a halogen, or C 1 -C 6 alkyl.

[0143] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 5 is hydrogen or a halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 5 is a halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 5 is hydrogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 5 is not hydrogen.

[0144] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), each R 6 is independently hydrogen, deuterium, a halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), each R 6 is independently hydrogen, deuterium, or C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), one R 6 is hydrogen and the other R 6 is C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), each R 6 is deuterium. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), each R 6 is independently C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), each R 6 is hydrogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), two Rs 6 together form a cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), two Rs 6 together form a cyclopropyl.

[0145] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), each R 7 is independently C 1-C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuterated alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), each R 7 is independently C 1 -C 6 alkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), two R 7 on the same carbon or different carbons together form cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), two R 7 on the same carbon or different carbons together form cyclopropyl.

[0146] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), n is 0 or 1. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), n is from 0 to 2. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), n is 1 or 2. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), n is 1. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), n is 2. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), n is 3. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), n is 4.

[0147] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), T is N. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), T is CR 8 .

[0148] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), U is N. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), U is CR 9 .

[0149] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), is In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), is

[0150] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 8 is hydrogen, deuterium, halogen, -CN, -OH, -ORa , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 8 is hydrogen, halogen, -CN, -OR a , C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 8 is hydrogen, halogen, -CN, -OR a or C 1 -C 6 haloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 8 is hydrogen, halogen or C 1 -C 6 haloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 8 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 8 is hydrogen.

[0151] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 9 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 9 is hydrogen, deuterium, halogen, -CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 9 is hydrogen, halogen, -C 1 -C 6 alkyl, C 1 -C6 is a haloalkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (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 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 9 is hydrogen.

[0152] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 10 is hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 10 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 10 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 10 is hydrogen.

[0153] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 11 is hydrogen, deuterium, halogen, C1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 11 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 11 is hydrogen or halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 11 is hydrogen.

[0154] In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 12 is cyano. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 12 is halogen. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 12 is fluorine or chlorine. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 12 is fluorine. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 12 is chlorine. In some embodiments of the compounds of formula (I) or formula (Ia) to formula (Ie), R 12 is fluorine or bromine.

[0155] In some embodiments of the compounds disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C6 Alkylene(heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted by one or more Rs. In some embodiments of the compounds disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl), or C 1 -C 6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a is independently C 1 -C 6 alkyl. In some embodiments of the compounds disclosed herein, each R a is independently C 1 -C 6 haloalkyl.

[0156] In some embodiments of the compounds disclosed herein, each R bIndependently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, 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, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently and optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C6 haloalkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl. In some embodiments of the compounds disclosed herein, each R b is independently hydrogen or C 1 -C 6 alkyl. In some embodiments of the compounds disclosed herein, each R b is hydrogen. In some embodiments of the compounds disclosed herein, each R b is independently C 1 -C 6 alkyl. In some embodiments of the compounds disclosed herein, each R b is independently C 1 -C 6 haloalkyl.

[0157] In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6Halogenated alkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more Rs. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 halogenated alkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 halogenated alkyl. In some embodiments of the compounds disclosed herein, each R c and R d are independently hydrogen or C 1 -C 6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d is hydrogen. In some embodiments of the compounds disclosed herein, each R c and R d are independently C 1 -C 6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d are independently C 1 -C 6 halogenated alkyl.

[0158] In some embodiments of the compounds disclosed herein, R c and R d together with the atoms to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0159] In some embodiments of the compounds disclosed herein, each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl; or two Rs 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, -OC 1 -C 6 alkyl, -NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl; or two Rs 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, -OC 1 -C 6 alkyl, -NH 2 , C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or two Rs on the same atom together form an oxo group.

[0160] This text contemplates any combination of groups of the various variables described above. Throughout the specification, those skilled in the art select the groups and their substituents to provide stable moieties and compounds.

[0161] In some embodiments, the compounds or their pharmaceutically acceptable salts, solvates or stereoisomers disclosed herein are selected from the compounds of Table 1.

[0162] Table 1

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173] The absolute label (abs) is added to the chiral center to indicate that it is explicitly a pure sample of the depicted stereoisomer.

[0174] The OR label (or) indicates a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with the isolated pure structure, multiple OR labels with the same value (OR indicating purity) will indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0175] The AND label (and) indicates the presence of both isomers at the depicted stereochemical center. Assigning different values to the AND labels indicates that they are independent of each other. The use of AND labels with the same value indicates that the two stereocenters are relative to each other and can only change simultaneously.

[0176] In some embodiments, the compounds or their pharmaceutically acceptable salts, solvates or stereoisomers disclosed herein are selected from:

[0177]

[0178] Other forms of the compounds disclosed herein

[0179] Isomers / Stereoisomers

[0180] 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, trans, syn, anti, entgegen (E) and 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 the R configuration or the S configuration. The compounds described herein include all diastereomers, enantiomers and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination or interconversion can be used in the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomer. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography or preferably by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomer and the resolving agent are then recovered by any practical means that does not result in racemization.

[0181] Labeled compound

[0182] In some embodiments, the compounds described herein exist in their isotopically labeled forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those described herein, but with one or more atoms replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, 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. The compounds described herein containing the above isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates or stereoisomers, are within the scope of the present invention. Certain isotopically labeled compounds, such as those incorporating radioactive isotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. In addition, substitution with heavy isotopes such as deuterium (i.e., 2 H) can confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements.

[0183] In some embodiments, the compounds described herein are labeled by other means, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels or chemiluminescent labels.

[0184] Pharmaceutically acceptable salts

[0185] In some embodiments, the compounds described herein exist in their pharmaceutically acceptable salt forms. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0186] In some embodiments, the compounds described herein have acidic or basic groups and thus 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 or their solvates or stereoisomers described herein, or by reacting the purified compound in its free form with a suitable acid or base separately and isolating the salt thus formed.

[0187] Examples of pharmaceutically acceptable salts include those salts prepared by reacting the compounds described herein with an inorganic, organic, or inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, mesylate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propynoate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0188] 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 or organic acid, said pharmaceutically acceptable inorganic or organic acid including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, etc.; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptanoic 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, hydroxy-naphthoic acid, salicylic acid, stearic acid, muconic acid. In some embodiments, other acids, such as oxalic acid, although not pharmaceutically acceptable per se, are used to prepare salts that are intermediates useful for obtaining the compounds, solvates, or stereoisomers thereof and their pharmaceutically acceptable acid addition salts disclosed herein.

[0189] In some embodiments, those compounds described herein that contain free acid groups react with suitable bases such as hydroxides, carbonates, bicarbonates, sulfates of pharmaceutically acceptable metal cations, with ammonia or with pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amines. 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, etc. Exemplary examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 etc.

[0190] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups contained therein. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0191] Solvates

[0192] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods for treating diseases by administering such solvates. The present invention also provides methods for treating diseases by administering such solvates as pharmaceutical compositions.

[0193] Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed, in some embodiments, during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the 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 form as well as solvated form. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0194] Tautomers

[0195] In some cases, compounds exist in tautomeric forms. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can interconvert by the migration of a hydrogen atom, accompanied by the conversion of a single bond and an adjacent double bond. In the bonding arrangements where tautomerism can 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.

[0196] Therapeutic method

[0197] The present disclosure provides methods of treating diseases in which inhibition of PARP is beneficial, the methods comprising administering a compound disclosed herein. The present disclosure also provides 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, gastric cancer, thyroid cancer, or uterine cancer.

[0198] In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer has metastasized to the brain.

[0199] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0200] In some embodiments, the cancer comprising a BRCA1 and / or BRCA2 mutation 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, gastric cancer, thyroid cancer, or uterine cancer.

[0201] In some embodiments, the cancer is a cancer lacking Flomologous recombination (FIR)-dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via a homologous mechanism 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 1A (NM_005590), and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulators such as EMSY. In some embodiments, a cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells having a reduced or eliminated ability to repair DNA DSBs via this pathway relative to normal cells, i.e., the activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in the one or more cancer cells.

[0202] In some embodiments, in one or more cancer cells of an individual having a cancer lacking FIR-dependent DNA DSB repair, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is eliminated.

[0203] In some embodiments, cancer cells have a BRCA1 and / or BRCA2-deficient phenotype, i.e., reduced or eliminated BRCA1 and / or BRCA2 activity in the cancer cells. Cancer cells with such a phenotype may lack BRCA1 and / or BRCA2, i.e., the expression and / or activity of BRCA1 and / or BRCA2 in the cancer cells can be reduced or eliminated, e.g., by mutations or polymorphisms in the coding nucleic acid, or by amplification, mutation or polymorphism of a gene encoding a regulatory factor (e.g., the EMSY gene encoding a BRCA2 regulatory factor). BRCA1 and BRCA2 are known tumor suppressor genes, and their wild-type alleles are often lost in tumors of heterozygous carriers. Amplification of the EMSY gene, which encodes a BRCA2-binding factor, is also associated with breast and ovarian cancers. 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 cancers, gastrointestinal cancers and lung cancer.

[0204] Also disclosed herein is a method of treating cancer in a subject in need thereof that comprises a mutation in a gene that results in homologous repair deficiency, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the mutation in the gene that results in homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L or any combination thereof.

[0205] Also disclosed herein is a method of treating cancer present in the brain, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0206] In some embodiments, the cancer present in the brain is caused by a primary peripheral tumor that has metastasized to the brain. In some embodiments, the cancer present in the brain is caused by primary brain tissue.

[0207] Also disclosed herein is a method of treating brain cancer, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0208] In some embodiments, the brain cancer is a primary brain tumor that originates in the brain and tends to remain in the brain.

[0209] In some embodiments, the brain cancer is a secondary brain tumor. These cancers originate 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.

[0210] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts, solvates or stereoisomers thereof are capable of penetrating the blood-brain barrier (BBB). In some embodiments, the rate of compound penetration of the BBB is >0.1, where 1 is complete BBB penetration and 0 is no penetration. In some embodiments, the rate of the compound that penetrates the BBB is >0.2. In some embodiments, the rate of the compound that penetrates the BBB is >0.3. In some embodiments, the rate of the compound that penetrates the BBB is measured using the rat kp,uu assay. In some embodiments, as determined in the rat kp,uu assay, the rate of the compound is >0.3 (i.e., 0.3 to 1).

[0211] Administration

[0212] In certain embodiments, a composition containing a compound described herein is administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient having a disease or condition in an amount sufficient to cure or at least partially inhibit at least one of the symptoms of the disease or condition. The amount effective for such use depends on the severity and course of the disease or condition, previous treatment, the health status, weight and response to the drug of the patient, 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.

[0213] In prophylactic applications, a composition containing a compound described herein is administered to a patient susceptible to a particular disease, disorder or condition or otherwise at risk of a particular disease, disorder or condition. Such amount is defined as a "prophylactically effective amount or dose". In such use, the exact amount also depends on the health status, weight, etc. of the patient. When used in a patient, the effective amount for such use will depend on the severity and course of the disease, disorder or condition, previous treatment, the health status and response to the drug of the patient, and the judgment of the treating physician. In one aspect, prophylactic treatment includes administering to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof to prevent recurrence of the symptoms of the disease or condition.

[0214] In certain embodiments where the patient's condition does not improve, the administration of the compound is a long-term administration, i.e., for a prolonged period of time, including the entire duration of the patient's life, to improve or otherwise control or limit the symptoms of the patient's disease or condition, at the discretion of the physician.

[0215] In certain embodiments where the patient's condition has indeed improved, 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 from 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%.

[0216] Once the patient's condition improves, a maintenance dose is administered as necessary. Subsequently, in specific embodiments, as the symptoms change, the dose or frequency or both of the administered drug are 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.

[0217] The amount of a given pharmaceutical agent corresponding to such a quantity varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., weight, gender), but is still determined according to the specific circumstances surrounding the case, including, for example, the specific pharmaceutical agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0218] However, generally speaking, the dose for adult treatment is usually in the range of 0.01 mg - 5000 mg per day. In one aspect, the dose for adult treatment is from about 1 mg to about 1000 mg per day. In one embodiment, the required dose is conveniently provided as a single dose or as divided doses administered simultaneously or at appropriate intervals, such as two, three, four, or more sub-doses per day.

[0219] In one embodiment, the daily dose suitable for the compounds or their pharmaceutically acceptable salts, solvates, or stereoisomers described herein is from about 0.01 mg / kg body weight to about 50 mg / kg body weight. In some embodiments, based on a plurality of variables related to an individual treatment regimen, the amount of the active substance in the daily dose or dosage form is lower or higher than the ranges 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 physician.

[0220] The toxicity and therapeutic efficacy of such treatment regimens are determined in cell cultures or experimental animals by standard pharmaceutical procedures, including but not limited to LD 10 and ED90 Determination. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, expressed as the ratio of LD 50 to ED 50 The data obtained from cell culture assays and animal studies are used in some embodiments to formulate a therapeutically effective daily dose range and / or a therapeutically effective unit dose for mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within the circulating concentration range including the ED 50 with the least toxicity. In certain embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form employed and the route of administration employed.

[0221] In a further embodiment in any of the foregoing aspects, 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 to a mammal non-systemically or topically.

[0222] In a further embodiment in any of the foregoing aspects, it includes a single administration of an effective amount of the compound, including further embodiments wherein (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times during the course of a day.

[0223] In a further embodiment in any of the foregoing aspects, it includes 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 the mammal every 8 hours; (iv) the compound is administered to the subject every 12 hours; (v) the compound is administered to the subject every 24 hours. In a further or alternative embodiment, the method includes a drug holiday, wherein the 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 restarted. In one embodiment, the length of the drug holiday ranges from 2 days to 1 year.

[0224] Route of administration

[0225] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, 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.

[0226] In certain embodiments, the compounds described herein are administered locally rather than systemically, e.g., by direct injection of the compound into an organ, typically in the form of a depot formulation or a sustained release formulation. In specific embodiments, the long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Additionally, in other embodiments, the drug is delivered in a targeted drug delivery system, e.g., in liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target the organ and are selectively taken up by the organ. In other embodiments, the compounds described herein are provided in the form of an immediate release formulation, an extended release formulation, or an intermediate release formulation. In other embodiments, the compounds described herein are administered locally.

[0227] Pharmaceutical composition / formulation

[0228] In accordance with 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 an animal. These compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0229] In another aspect, the present disclosure provides pharmaceutical compositions that comprise a compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof as described herein, and at least one pharmaceutically acceptable excipient. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically useful formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th 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, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 17th Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0230] In some embodiments, the pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, wetting agents, plasticizers, stabilizers, permeability enhancers, humectants, defoaming agents, antioxidants, preservatives, and any combination thereof.

[0231] 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. The pharmaceutical formulations described herein include but are not limited to aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, 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, multiparticulate formulations, and combinations of immediate-release and controlled-release formulations.

[0232] A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as described herein is prepared in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, sugar coating, grinding, emulsifying, encapsulating, entrapping or compression processes.

[0233] A pharmaceutical composition for oral use is obtained by mixing one or more solid excipients with one or more compounds as described herein, optionally grinding the resulting mixture, and processing the granule mixture, if desired, with the addition of suitable auxiliaries, 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, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added such as cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate. In some embodiments, colorants or pigments are added to the tablet or dragee coating to identify or characterize different combinations of the active compound dosage.

[0234] 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. The push-fit capsules contain the active ingredient admixed 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 the 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.

[0235] Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, a pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution, dispersion or sterile powder comprising a compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof as described herein. In some embodiments, the pharmaceutical composition contains a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides and any combination thereof. In some embodiments, the pharmaceutical composition further contains a preservative to prevent microbial growth.

[0236] Combination

[0237] The present disclosure relates to 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.

[0238] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0239] In some embodiments, the additional therapeutic agent is administered concurrently with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administering the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administering the compound disclosed herein.

[0240] Example

[0241] The compounds described herein are synthesized according to what is generally described in General Scheme 1 and General Scheme 2.

[0242] General Scheme 1

[0243]

[0244] General Scheme 2

[0245]

[0246] Example 1

[0247]

[0248] Step 1: Preparation of 3 - bromo - 2 - methoxy - 6 - methyl - 5 - nitropyridine :

[0249] At 0 °C under a nitrogen atmosphere, NaOMe (15.76 g, 87.49 mmol, 1.10 eq, 30 wt%) was added dropwise to a stirred mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g, 79.54 mmol, 1.00 eq) in MeOH (50 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether:EtOAc = 1:1, R f = 0.4). After completion, the reaction 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), dried over anhydrous Na 2 SO 4Dry, filter, and concentrate to obtain 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70 (s, 3H).

[0250] Step 2: Preparation of (E)-2-(5 - bromo - 6 - methoxy - 3 - nitropyridin - 2 - yl)-N,N - dimethylethen - 1 - amine Preparation :

[0251] 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 overnight at 100 °C under a nitrogen atmosphere. 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-dimethylethen-1-amine. The crude product was used directly in the next step without further purification.

[0252] Step 3: Preparation of 5 - bromo - 6 - methoxy - 3 - nitropyridinecarbaldehyde :

[0253] At 0 °C under a nitrogen atmosphere, NaIO 2 (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise 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 H 4 O (100 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC (petroleum ether:EtOAc = 5:1, R f = 0.2). The reaction was quenched at room temperature by the addition of saturated sodium thiosulfate (aqueous solution) (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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 HNMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H).

[0254] Step 4: Preparation of ethyl 7 - bromo - 6 - methoxy - 1,5 - naphthyridine - 3 - carboxylate :

[0255] At room temperature under a nitrogen atmosphere, SnCl was added portionwise to a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3,3-diethoxypropionate (20.40 g, 107.27 mmol, 4.00 eq) in EtOH (100 mL). 2 (26.25 g, 134.09 mmol, 5.00 eq). The resulting mixture was stirred at 90 °C under a 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 crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% over three steps). LC-MS: (ES + H, m / z): [M + H] + = 311.0

[0256] Step 5: Preparation of ethyl 7 - bromo - 6 - oxo - 5H - 1,5 - naphthyridine - 3 - carboxylate :

[0257] At room temperature, TMSI (13.8 mL, 96.42 mmol, 6.00 eq) was added dropwise to a solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 eq) in ACN (400 mL). The final reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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 ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (3.8 g, 80%). LC-MS: (ES + H, m / z): [M + H] + = 296.95.

[0258] Step 6: Preparation of ethyl 7 - [2 - (tert - butyldimethylsilyl)ethynyl]-6 - oxo - 5H - 1,5 - naphthyridine - 3 - carboxylate Preparation :

[0259] Ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.50 g, 5.05 mmol, 1.00 eq), tert-butyl(ethynyl)dimethylsilane (850 mg, 6.05 mmol, 1.20 eq), CuI (0.19 g, 1.01 mmol, 0.20 eq), Et 3 N (1.53 g, 15.15 mmol, 3 eq) and Pd(PPh 3 ) 2 Cl 2(0.35 g, 0.51 mmol, 0.10 equiv) in DMF (45 mL) was stirred at 50 °C under a nitrogen atmosphere for 2 h. 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 Na 2 SO 4 4. 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.

[0260] Step 7: Preparation of 3 - [2 - (tert - butyldimethylsilyl)ethynyl]-7 - (hydroxymethyl)-1H - 1,5 - naphthyridin - 2 - one Preparation :

[0261] At 0 °C under a nitrogen atmosphere, LiEt3BH (13.46 mL, 13.46 mmol, 4.00 equiv, 1 M solution in THF) was added dropwise 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). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of citric acid (5.05 mL, 5.05 mmol, 1.50 equiv, 1 M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (840 mg, 79%). LC-MS: (ES + H, m / z): [M + H] + = 315.0.

[0262] Step 8: Preparation of 3 - [2 - (tert - butyldimethylsilyl)ethynyl]-7 - (chloromethyl)-1H - 1,5 - naphthyridin - 2 - one Preparation :

[0263] At 0 °C under a nitrogen atmosphere, SOCl 2(0.06 mL, 0.88 mmol, 3.00 eq., 1.64 g / mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 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.

[0264] Step 9: Preparation of 5 - [4 - ({7 - [2 - (tert - butyldimethylsilyl)ethynyl]-6 - oxo - 5H - 1,5 - naphthyridin - 3 - yl}methyl)piperazin - 1 - yl]pyridine - 2 - carbonitrile :

[0265] At room temperature under a nitrogen atmosphere, KI (11 mg, 0.07 mmol, 0.20 eq.) was added portionwise to a stirred mixture of 5-(piperazin-1-yl)pyridine-2-carbonitrile hydrochloride (119 mg, 0.53 mmol, 1.48 eq.), DIEA (232 mg, 1.80 mmol, 5.00 eq.) and 3-[2-(tert-butyldimethylsilyl)ethynyl]-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (120 mg, 0.36 mmol, 1.00 eq.) in MeCN (5 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 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%).

[0266] Step 10: Preparation of 5 - {4 - [(7 - ethynyl - 6 - oxo - 5H - 1,5 - naphthyridin - 3 - yl)methyl]piperazin - 1 - yl}pyridine - 2 - carbonitrile :

[0267] At room temperature under a nitrogen atmosphere, TBAF (0.27 mL, 0.27 mmol, 1.10 eq.) was added dropwise 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 eq.) in THF (2.5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The 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), over anhydrous Na 2 SO 4Dry. 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): [M-H] - = 369.1; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.17 (s, 1H), 8.48 (d, 1H), 8.42 (d, 1H), 8.15 (s, 1H), 7.75 (d, 1H), 7.64 (d, 1H), 7.36 (dd, 1H), 4.51 (s, 1H), 3.67 (s, 2H), 3.47 - 3.38 (m, 4H), 2.60 - 2.52 (m, 4H).

[0268] Example 2

[0269]

[0270] Step 1: Preparation of methyl 5 - nitro - 6 - (prop - 1 - en - 2 - yl)pyridine - 3 - carboxylate :

[0271] 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), K 2 CO 3 (12.76 g, 92.34 mmol, 2.00 equiv) and Pd(dppf)Cl 2 (3.38 g, 4.62 mmol, 0.10 equiv) in a mixture of dioxane (150 mL) and water (15 mL) were stirred at 100 °C under a nitrogen atmosphere for 3 h. 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 (aqueous solution) (3 × 100 mL), dried over anhydrous Na 2 SO 4 and 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 as a pale yellow oil (5.00 g, 48.74%). LC-MS: (ES+H, m / z): [M+H] + = 222.95; 11H NMR (300 MHz, DMSO-d 6 ) δ 9.25 (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).

[0272] Step 2: Preparation of methyl 5 - nitro - 6 - (prop - 1 - en - 2 - yl)pyridine - 3 - carboxylate :

[0273] To a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL) was added NH 4 Cl (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 h. 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 CH 2 Cl 2 / 2-propanol (5:1, 200 mL) and washed with water (250 mL) and brine (250 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered and concentrated under reduced pressure. Methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90.17%) was obtained and used directly without further purification. LC-MS: (ES + H, m / z): [M + H] + = 193.15; 1 1H NMR (300 MHz, DMSO-d 6 ) δ 8.29 (d, 1H), 7.60 (d, 1H), 5.51 - 5.47 (m, 1H), 5.41 (s, 2H), 5.39–5.36 (m, 1H), 3.84 (s, 3H), 2.08 (t, 3H).

[0274] Step 3: Preparation of methyl 8 - methyl - 6 - oxo - 5H - 1,5 - naphthyridine - 3 - carboxylate :

[0275] At 0 °C under a nitrogen atmosphere, a solution of triphosgene (1.54 g, 5.20 mmol, 0.50 equiv) in toluene (20 mL) was added to methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et 3A solution of N (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 CH 2 Cl 2 / 2-propanol (5:1, 3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.80 g, 40.66%). LC-MS: (ES + H, m / z): [M + H] + = 219.1; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.92 (s, 1H), 8.92 (d, 1H), 8.15 (d, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.48 (s, 3H).

[0276] Step 4: Preparation of methyl 7 - chloro - 8 - methyl - 6 - oxo - 5H - 1,5 - naphthyridine - 3 - carboxylate :

[0277] At room temperature under a nitrogen atmosphere, 2,2-dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) was added dropwise to a solution of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH 3 COOH (7 mL). The resulting mixture was stirred overnight at 100 °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 methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 93.5%). LC-MS: (ES + H, m / z): [M + H] + = 253.0; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.90 (d, 1H), 8.13 (d, 1H), 3.93 (s, 3H), 2.60 (s, 3H).

[0278] Step 5: Preparation of 3 - chloro - 7 - (hydroxymethyl)-4 - methyl - 1H - 1,5 - naphthyridin - 2 - one :

[0279] At 0 °C under a nitrogen atmosphere, a solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL) was stirred and LiAlH 4 (2 mL, 2.5 M solution in THF, 4.75 mmol, 2.00 equiv) was added dropwise. 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 HCl (1 mL, 12 M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (230 mg, 43.1%). LC-MS: (ES + H, m / z): [M + H] + = 225.1; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.24 (br, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 5.69 (s, 1H), 4.63 (s, 2H), 2.63 (s, 3H).

[0280] Step 6: Preparation of 3 - chloro - 7 - (chloromethyl)-4 - methyl - 1H - 1,5 - naphthyridin - 2 - one :

[0281] At 0 °C under a nitrogen atmosphere, a 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 stirred and SOCl 2 (318 mg, 2.67 mmol, 3.00 equiv) was added dropwise. 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.

[0282] Step 7: Preparation of 4 - {4 - [(7 - chloro - 8 - methyl - 6 - oxo - 5H - 1,5 - naphthyridin - 3 - yl)methyl]piperazin - 1 - yl}benzonitrile Preparation :

[0283] 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 a nitrogen atmosphere for 2 h. 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): [M-H] - = 392.15; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.30 (s, 1H), 8.51 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.7 Hz, 2H), 7.02 (d, J = 8.7 Hz, 2H), 3.67 (s, 2H), 3.38–3.34 (m, 4H), 2.64 (s, 3H), 2.57 - 2.54 (m, 4H).

[0284] Example 3

[0285]

[0286] Step 1: Preparation of methyl 6 - methyl - 5 - nitropyridine - 3 - carboxylate :

[0287] At room temperature under a nitrogen atmosphere, Pd(dppf)Cl 2 (0.83 g, 1.15 mmol, 0.05 equiv) and CsF (7 g, 46.17 mmol, 2.00 equiv) were added 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 H 2 (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 a nitrogen atmosphere overnight. 500 mL of water was added to the resulting mixture and the mixture was extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate. 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) δ 9.29 (d, 1H), 8.84 (d, 1H), 4.01 (s, 3H), 2.94 (s, 3H).

[0288] Step 2: Preparation of methyl 6 - formyl - 5 - nitropyridine - 3 - carboxylate :

[0289] A mixture of methyl 6-methyl-5-nitropyridine-3-carboxylate (35 g, 178.42 mmol, 1.00 equiv) and SeO 2 (30 g, 267.64 mmol, 1.50 equiv) in dioxane (200 mL) was stirred overnight at 110 °C under a nitrogen atmosphere. 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 then the crude product was dissolved in THF (200 mL). The resulting mixture was filtered and the filter cake was washed with THF (3 × 100 mL). The filtrate was concentrated under reduced pressure to give the nitropyridine-3-carboxylate (40 g, crude). LC-MS: (ES + H, m / z): [M + H] + = 211.1.

[0290] Step 3: Preparation of methyl (Z)-6-(2-(ethoxycarbonyl)but - 1 - en - 1 - yl)-5 - nitronicotinate :

[0291] Under a nitrogen atmosphere at 0 °C, a solution of NaH (11.42 g, 285.52 mmol, 1.50 equiv, 60 wt%) in THF (500 mL) was added dropwise to a solution of ethyl 2-(diethoxyphosphoryl)butyrate (72 g, 285.52 mmol, 1.50 equiv) in THF (50 mL). The resulting mixture was stirred at 0 °C for 10 minutes, then warmed to 40 °C and stirred for 10 minutes under a nitrogen atmosphere. The resulting mixture was cooled to -78 °C, and then a solution of methyl 6-formyl-5-nitropyridine-3-carboxylate (40 g, 190.35 mmol, 1.00 equiv) in THF (50 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH 4 Cl (aqueous solution) (100 mL) at 0 °C. 400 mL of water was added to the resulting mixture and the mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 500 mL) and dried over anhydrous Na 2 SO 4Dry, filter and concentrate. Purify the residue by silica gel column chromatography to obtain methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinate (20 g in two steps, 36%) and methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinate (8.8 g). Data for methyl (Z)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinate: LC-MS: (ES + H, m / z): [M + H] + = 309.1; 1H NMR (300 MHz, chloroform-d) δ 9.27 (d, 1H), 8.88 (d, 1H), 7.10 (t, 1H), 4.22–4.16 (m, 2H), 4.03 (s, 3H), 2.59 (qd, 2H), 1.25 (t, 3H), 1.19 (t, 3H). Data for methyl (E)-6-(2-(ethoxycarbonyl)but-1-en-1-yl)-5-nicotinate: LC-MS: (ES + H, m / z): [M + H] + = 309.1; 1 1H 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).

[0292] Step 4: Preparation of ethyl 7 - ethyl - 6 - oxo - 5H - 1,5 - naphthyridine - 3 - carboxylate :

[0293] At room temperature under a nitrogen atmosphere, add CaCl 2 (19.44 g, 175.16 mmol, 6.00 equivalents) to a stirred mixture of methyl 6-[(1Z)-3-ethoxy-2-ethyl-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (9.00 g, 29.19 mmol, 1.00 equivalent) and Fe (16.30 g, 291.93 mmol, 10.00 equivalents) in EtOH (200 mL). Stir the resulting mixture at 90 °C under a nitrogen atmosphere overnight. Monitor the reaction by LCMS. Filter the resulting mixture, wash the filter cake with EtOAc (5 × 100 mL), and concentrate the combined filtrates. Add the resulting mixture to 250 mL of water and extract with EtOAc (3 × 250 mL). Wash the combined organic layers with brine (1 × 250 mL), dry over anhydrous Na 2 SO 4 2. After filtration, concentrate the filtrate 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 (400 MHz, DMSO-d 6 ) δ 12.06 (s, 1H), 8.90 (s, 1H), 8.16 (s, 1H), 7.83 (s, 1H), 4.38 (q, 2H), 2.58 (q, 2H), 1.36 (t, 3H), 1.20 (t, 3H).

[0294] Step 5: Preparation of 3 - ethyl - 7 - (hydroxymethyl)-1H - 1,5 - naphthyridin - 2 - one :

[0295] At 0 °C under a nitrogen atmosphere, a 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 stirred and LiAlH 4 (13 mL, 32.49 mmol, 2.00 equiv, 2.5 M THF solution) was added dropwise. 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-naphthyridin-2-one (2.00 g, 60%). LC-MS: (ES + H, m / z): [M + H] + = 204.8; 1H NMR (400 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 8.38 (d, 1H), 7.74 (s, 1H), 7.62 (d, 1H), 5.49 (t, 1H), 4.62 (d, 2H), 2.55 (dd, 2H), 1.18 (t, 3H).

[0296] Step 6: Preparation of 7 - (chloromethyl)-3 - ethyl - 1H - 1,5 - naphthyridin - 2 - one :

[0297] At 0 °C under a nitrogen atmosphere, a solution 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 stirred and SOCl 2 (1.05 g, 8.81 mmol, 6.00 equiv) was added dropwise. 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 (400 MHz, DMSO-d 6)δ 11.99 (s, 1H), 8.50 (d, 1H), 7.76 (s, 1H), 7.70 (d, 1H), 4.93 (s, 2H), 2.56 (td, 2H), 1.19 (t, 3H).

[0298] Step 7: Preparation of 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile Preparation :

[0299] At room temperature, DIEA (1.45 g, 11.25 mmol, 5.00 eq) and KI (75 mg, 0.45 mmol, 0.20 eq) were added portionwise to a stirred mixture of 5-(piperazin-1-yl)pyridine-2-carbonitrile, HCl salt (600 mg) and 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (500 mg, 2.25 mmol, 1.00 eq) in ACN (4 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction mixture was poured into water (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-{4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-2-carbonitrile (650 mg, 77%). LC-MS: (ES + H, m / z): [M + H] + = 375.2; 1 H NMR (300 MHz, DMSO-d 6 )δ 11.86 (s, 1H), 8.41 - 8.35 (m, 2H), 7.75 (t, 2H), 7.61 (s, 1H), 7.36 (dd, 1H), 3.64 (s, 2H), 3.52 - 3.42 (m, 4H), 2.61 - 2.54 (m, 6H), 1.18 (t, 3H).

[0300] Example 5

[0301]

[0302] Step 1: Preparation of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butyrate :

[0303] At room temperature, DIEA (27.15 g, 210.10 mmol, 5.00 eq) was added dropwise to a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.02 mmol, 1.00 eq) and methyl 2-aminobutyrate hydrochloride (6.43 g, 42.02 mmol, 1.00 eq) in NMP (200 mL). 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 Na 2 SO 4 . 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 (400 MHz, DMSO-d 6 ) δ 8.09 (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).

[0304] Step 2: Preparation of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one :

[0305] At 80 °C under a nitrogen atmosphere, AcOH (20 mL) containing methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]butyrate (6.00 g, 17.90 mmol, 1.00 eq) was added dropwise to a stirred mixture of Fe (5.00 g, 89.52 mmol, 5.00 eq) in AcOH (100 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC (CH 2 Cl 2 / 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 trituration 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%). 1 H NMR (400 MHz, DMSO-d 6)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).

[0306] Step 3: Preparation of 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one :

[0307] At room temperature under a nitrogen atmosphere, DDQ (4.39 g, 19.33 mmol, 1.20 equiv) was added portionwise to a stirred solution of 7-bromo-3-ethyl-5-fluoro-3,4-dihydro-1H-quinoxalin-2-one (4.40 g, 16.11 mmol, 1.00 equiv) in DCM (100 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NaHCO 3 (aqueous solution) (100 mL). The residue was purified by trituration with saturated NaHCO 3 (aqueous solution) (5 × 100 mL). The precipitated solid was collected by filtration and washed with water (3 × 100 mL) to give 7-bromo-3-ethyl-5-fluoro-1H-quinoxalin-2-one (3.50 g, 80%). LC-MS: (ES-H, m / z): [M-H] - = 269.0; 1 HNMR (400 MHz, DMSO-d 6 )δ12.51(s,1H),7.44(d,1H),7.24(s,1H),2.79(q,2H),1.21(t,3H).

[0308] Step 4: Preparation of 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde :

[0309] In a pressure vessel, 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-quinoxalin-2-one (2.90 g, 10.70 mmol, 1.00 equiv) in toluene (100 mL). The mixture was purged with nitrogen for 5 min and then with (CO:H 2= 1:1) Pressurize to 30 atm. Stir the mixture at 100 °C overnight. Monitor the reaction by LCMS. Cool the reaction mixture to room temperature and filter to remove insoluble solids. Concentrate the resulting mixture in vacuo. Purify the residue by silica gel column chromatography and concentrate the pure fractions in vacuo to give 2-ethyl-8-fluoro-3-oxo-4H-quinoxaline-6-carbaldehyde (1.40 g, 59%). LC-MS: (ES-H, m / z): [M-H] - = 219.0; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.74 (s, 1H), 10.01 (d, 1H), 7.65–7.47 (m, 2H), 2.86 (q, 2H), 1.24 (t, 3H).

[0310] Step 5: Preparation of 6-(4-((2-ethyl-8-fluoro-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl)piperazin-1-yl)nicotinonitrile Preparation :

[0311] At room temperature under a nitrogen atmosphere, add Ti(OiPr) 4 (453 mg, 1.60 mmol, 1.50 equiv) 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). After 2 h, add NaBH(AcO) 3 (901 mg, 4.25 mmol, 4.00 equiv) at 0 °C and warm the reaction mixture to room temperature. After 2 h, quench the reaction by adding water (10 mL) at 0 °C. Extract the aqueous layer with EtOAc (5 × 30 mL). Concentrate the combined organic phases under reduced pressure and purify the crude product 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 (300 MHz, DMSO-d 6 ) δ 12.43 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.16 - 7.04 (m, 2H), 6.93 (d, 1H), 3.77–3.52 (m, 6H), 2.87 - 2.75 (m, 2H), 2.50 - 2.43 (m, 4H), 1.22 (t, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -125.38.

[0312] Example 12

[0313]

[0314] Step 1: Preparation of methyl 2-fluoro-4-[(1-methoxy-1-oxobutan-2-yl)amino]-5-nitrobenzoate :

[0315] At room temperature under a nitrogen atmosphere, DIEA (48.1 mL, 276.34 mmol, 6.00 equivalents) was added dropwise to a stirred mixture of methyl 2,4-difluoro-5-nitrobenzoate (10.00 g, 46.06 mmol, 1.00 equivalent) and methyl 2-aminobutyrate, HCl salt (5.40 g, 46.06 mmol, 1.00 equivalent) in NMP (100 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of 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 Na 2 SO 4 dried, 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 (400 MHz, DMSO-d 6 ) δ 8.80 - 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).

[0316] Step 2: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate :

[0317] At room temperature under a nitrogen atmosphere, Pd(OH) 2 / C (2.40 g). The resulting mixture was stirred overnight at room temperature under a 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; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 7.25 - 7.20 (m, 1H), 7.19 - 7.14 (s, 1H), 4.00 - 3.91 (m, 1H), 3.75 (s, 3H), 1.76–1.60 (m, 2H), 0.94 - 0.86 (m, 3H).

[0318] Step 3: Preparation of methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate :

[0319] At room temperature, dichloromethane (70 mL) containing DDQ (7.56 g, 33.30 mmol, 1.20 equiv) was added to a stirred mixture of methyl 2-ethyl-7-fluoro-3-oxo-2,4-dihydro-1H-quinoxaline-6-carboxylate (7.00 g, 27.75 mmol, 1.00 equiv) in DCM (70 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The residue was then dissolved in saturated aqueous NaHCO 3 solution (200 mL). The precipitated solid was collected by filtration and washed with saturated aqueous NaHCO 3 solution (3 × 200 mL) and water (3 × 200 mL). The solid was purified by trituration with EtOAc (30 mL) / hexane (100 mL). The resulting mixture was filtered and the filter cake was washed with hexane (3 × 100 mL). The filter cake was dried under reduced pressure to give methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate (6 g, 86%). LC-MS: (ES + H, m / z): [M + H] + = 251.1; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.44 (s, 1H), 7.78 (d, 1H), 7.63 (d, 1H), 3.89 (s, 3H), 2.82 (q, 2H), 1.23 (t, 3H).

[0320] Step 4: Preparation of 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one :

[0321] At 0 °C under a nitrogen atmosphere, a solution of lithium aluminum hydride 4 (40 mL, 39.96 mmol, 2.00 equivalents, 1 mol / L solution in THF) was added dropwise to a stirred mixture of methyl 2-ethyl-7-fluoro-3-oxo-4H-quinoxaline-6-carboxylate (5.00 g, 19.98 mmol, 1.00 equivalent) in THF (100 mL). The reaction was monitored by LCMS. The reaction was quenched by adding water (1.5 mL), 15% NaOH (1.5 mL) and water (4.5 mL) at 0 °C. The precipitated solid was collected by filtration and washed with water (3 × 30 mL). The solid was dissolved in water (500 mL) and EtOAc (200 mL). The resulting mixture was extracted with EtOAc (8 × 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by trituration with MeOH (5 mL) and EtOAc (20 mL). The resulting mixture was filtered and the cake was washed with EtOAc (3 × 10 mL). The solid was dried under reduced pressure to give 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (1.2 g, 27%). LC-MS: (ES + H, m / z): [M + H] + = 223.2; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 7.48 (d, 1H), 7.41 (d, 1H), 5.52 (brs, 1H), 4.64 (s, 2H), 2.80 (q, 2H), 1.18 (t, 3H).

[0322] Step 5: Preparation of 7-(bromomethyl)-3-ethyl-6-fluoro-1H-quinoxalin-2-one :

[0323] At room temperature under a nitrogen atmosphere, to a stirred solution of 3-ethyl-6-fluoro-7-(hydroxymethyl)-1H-quinoxalin-2-one (150 mg, 0.68 mmol, 1.00 equivalent) in HBr (4 mL, 33 wt% solution in AcOH). 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 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.

[0324] Step 6: Preparation of 6-{4-[(2-ethyl-7-fluoro-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile Preparation :

[0325] 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 a nitrogen atmosphere for 1 h. The mixture was cooled to room temperature. The reaction mixture was poured into water (30 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product (200 mg) was purified by 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 (300 MHz, DMSO-d 6 ) δ 12.31 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.54 (d, 1H), 7.38 (d, 1H), 6.94 (d, 1H), 3.75 - 3.67 (m, 6H), 2.81 (q, 2H), 2.56 - 2.51 (m, 4H), 1.21 (t, 3H); 19 F NMR (282 MHz, DMSO-d6) δ -124.28.

[0326] Example 16

[0327]

[0328] Step 1: Preparation of ethyl 2-bromo-2-cyclopropaneacetate :

[0329] At -78 °C under a nitrogen atmosphere, LDA (42.9 mL, 85.82 mmol, 1.10 equiv, 2.0 M solution in THF) was added dropwise to a stirred solution of ethyl 2-cyclopropylacetate (10.00 g, 78.02 mmol, 1.00 equiv) in THF (100 mL). The reaction mixture was stirred for 1 h, then TMSCl (8.48 g, 78.02 mmol, 1.00 equiv) was added dropwise, and the reaction mixture was stirred for 3 h while warming to room temperature. The reaction was cooled to -78 °C, and NBS (15.28 g, 85.82 mmol, 1.10 equiv) was added dropwise in 50 mL of THF. Then the reaction mixture was stirred for 2 h and warmed to room temperature. The reaction was monitored by LCMS. The reaction was quenched by adding saturated NH 4 Cl (aqueous solution) (50 mL) at 0 °C. With Et2 The mixture obtained by extraction with O(3×200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase combinatorial flash chromatography to give ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 31%). 1 1H 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).

[0330] Step 2: Preparation of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate :

[0331] 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 h. The residue was purified by reversed-phase combinatorial flash chromatography to give ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (2.40 g, 38%). 1 1H NMR (300 MHz, chloroform-d) δ 4.26–4.07 (m, 6H), 2.19 (dd, 1H), 1.30 (dt, 10H), 0.71 (dddd, 1H), 0.60 (ddddd, 1H), 0.47–0.37 (m, 1H), 0.24 (ddtd, 1H).

[0332] Step 3: Preparation of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate Preparation :

[0333] Under a nitrogen atmosphere at 0 °C, a solution of ethyl 2-cyclopropyl-2-(diethoxyphosphoryl)acetate (1.89 g, 7.14 mmol, 1.50 equiv) was added dropwise to a stirred mixture of NaH (0.29 g, 7.14 mmol, 1.50 equiv, 60 wt%) in THF (20 mL). The resulting mixture was stirred at 0 °C for 10 min, then warmed to 40 °C and stirred for 10 min under a nitrogen atmosphere. The resulting mixture was cooled to -78 °C, and then a solution of methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g, 4.76 mmol, 1.00 equiv) in THF (20 mL) was added dropwise. The resulting mixture was stirred at -78 °C under a nitrogen atmosphere for 30 min. The reaction was monitored by LCMS. By adding saturated NH 4Quench the reaction with Cl (aqueous solution) (5 mL). Add 20 mL of water to the resulting mixture and extract with EtOAc (3 × 20 mL). Wash the combined organic layers with brine (1 × 50 mL) and dry over anhydrous Na 2 SO 4 4. Filter the solution, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to afford 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.

[0334] Step 4: Preparation of ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0335] At room temperature under a nitrogen atmosphere, add CaCl 2 2 (1.24 g, 11.24 mmol, 6.00 equiv) to a stirred mixture of methyl 6-[(1Z)-2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl]-5-nitropyridine-3-carboxylate (600 mg, 1.87 mmol, 1.00 equiv) and Fe (1.04 g, 18.73 mmol, 10.00 equiv) in EtOH (10 mL). Stir the resulting mixture at 90 °C under a nitrogen atmosphere overnight. Monitor the reaction by LCMS. Cool the mixture to room temperature. Filter the resulting mixture and wash the cake with EtOAc (2 × 50 mL). Concentrate the filtrate under reduced pressure. Add 50 mL of water to the resulting mixture and extract with EtOAc (2 × 50 mL). Wash the combined organic layers with brine (2 × 50 mL) and dry over anhydrous Na 2 SO 4 4. Filter the solution, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography to afford ethyl 7-cyclopropyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (200 mg, 41%). LC-MS: (ES + H, m / z): [M + H] + = 259.0.

[0336] Step 5: Preparation of 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0337] At 0 °C under a nitrogen atmosphere, add LiAlH 4(0.50 mL, 1.23 mmol, 2.00 equiv, 2.5 M solution in THF). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of 1 M aqueous HCl solution (1 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyclopropyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (100 mg, 75%). LC-MS: (ES + H, m / z): [M + H] + = 217.2.

[0338] Step 6: Preparation of 7-(chloromethyl)-3-cyclopropyl-1H-1,5-naphthyridin-2-one :

[0339] At 0 °C under a nitrogen atmosphere, SOCl 2 (264 mg, 2.22 mmol, 6.00 equiv) was added dropwise 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). The resulting mixture was stirred at room temperature under a nitrogen atmosphere overnight. 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.

[0340] Step 7: Preparation of 3-cyclopropyl-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one Preparation :

[0341] At room temperature, DIEA (357 mg, 2.76 mmol, 5.00 equiv) and KI (18 mg, 0.11 mmol, 0.20 equiv) were added 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). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature and then poured into H 2 O (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 (300 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 8.38 (d, 1H), 8.09 (d, 1H), 7.61 (d, 1H), 7.55 - 7.45 (m, 1H), 7.42 (s, 1H), 6.86 (dd, 1H), 3.62 (s, 2H), 3.49 - 2.38 (m, 4H), 2.50 - 2.45 (m, 4H), 2.20 - 2.08 (m, 1H), 1.02–0.92 (m, 2H), 0.86–0.78 (m, 2H); 19 F NMR (282 MHz, DMSO-d6) δ -143.41.

[0342] Examples 28 and 29

[0343]

[0344] Step 1: Preparation of 7-(1-ethoxyvinyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0345] At room temperature, 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(PPh 3 ) 2 Cl 2 (0.44 g, 0.62 mmol, 0.05 equiv). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature and the resulting solution was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 231.1

[0346] Step 2: Preparation of 7-acetyl-3-methyl-1,5-naphthyridin-2(1H)-one :

[0347] 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 h and then basified to pH 8 with saturated NaHCO 3 (aqueous solution). The resulting mixture was then diluted with water (100 mL) and extracted with CH 2 Cl 2 (3 × 200 mL). The combined organic layers were washed with brine (1 × 300 mL), over anhydrous Na2 SO 4 Dry, filter and concentrate. Purify the crude product by silica gel column chromatography to obtain 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

[0348] Step 3: Preparation of 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin- 1-yl]pyridine-3-carbonitrile :

[0349] Add 7-acetyl-3-methyl-1H-1,5-naphthyridin-2-one (350 mg, 1.73 mmol, 1.00 equiv) to a solution of 6-[(2R)-2-methylpiperazin-1-yl]pyridine-3-carbonitrile (455 mg, 2.25 mmol, 1.30 equiv) in CH 2 Cl 2 (8 mL). Then concentrate the resulting mixture under reduced pressure. At room temperature, add Ti(OiPr) 4 (4.6 mL, 15.58 mmol, 9.00 equiv) dropwise to the above mixture. Stir the resulting mixture at 80 °C for an additional 4 h, then cool to room temperature. At room temperature, add EtOH (5 mL) and NaBH 3 CN (217 mg, 3.46 mmol, 2.00 equiv) portionwise to the above mixture. Stir the resulting mixture at 80 °C for an additional 2 h, then cool to room temperature. Pour the reaction mixture into water (100 mL) and stir for 1 h, filter through a Celite plug and wash with DCM / MeOH (3 / 1; 300 mL). Extract the aqueous layer with DCM / i-PrOH (5 / 1; 2 × 100 mL), then wash the combined organic extracts with brine (2 × 50 mL), dry over Na 2 SO 4. Dry, filter and concentrate. Purify the residue by silica gel column chromatography to obtain 6-[(2R)-2-methyl-4-[1-(7-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)ethyl]piperazin-1-yl]pyridine-3-carbonitrile (280 mg, 41.6%). LC-MS: (ES-H, m / z): [M+H] += 389.1. The diastereomers were separated by chiral HPLC to 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; 1 1H NMR (300 MHz, DMSO-d 6 ) 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 1H NMR (300 MHz, DMSO-d 6 ) 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 Examples 28 and 29 was arbitrarily assigned.

[0350] Example 36

[0351]

[0352] Step 1: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate :

[0353] 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 a mixture of dioxane (150 mL) and water (15 mL) were stirred at 100 °C under a nitrogen atmosphere for 3 h. 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 (aqueous solution) (3 × 100 mL), dried over anhydrous Na 2 SO 4 and 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 as a pale yellow oil (5.00 g, 49%). LC-MS: (ES + H, m / z): [M + H] + = 222.95.

[0354] Step 2: Preparation of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate :

[0355] NH 4 Cl (25 mL, saturated aqueous solution) and Fe (5.03 g, 90.01 mmol, 4.00 equiv) were added to a stirred solution of methyl 5-nitro-6-(prop-1-en-2-yl)pyridine-3-carboxylate (5.00 g, 22.50 mmol, 1.00 equiv) in MeOH (100 mL). The reaction was stirred at 80 °C under a nitrogen atmosphere for 4 h. 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 CH 2 Cl 2 / 2-propanol (5:1, 200 mL) and washed with water (250 mL) and brine (250 mL). The organic layer was dried over anhydrous Na 2 SO 4 and filtered, and concentrated under reduced pressure. Methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 90%) was obtained and used directly without further purification. LC-MS: (ES + H, m / z): [M + H] + = 193.15. 1 H NMR (300 MHz, DMSO-d 6)δ 8.29 (d, 1H), 7.60 (d, 1H), 5.51 - 5.47 (m, 1H), 5.41 (s, 2H), 5.39–5.36 (m, 1H), 3.84 (s, 3H), 2.08 (t, 3H).

[0356] Step 3: Preparation of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0357] At 0 °C under a 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 methyl 5-amino-6-(prop-1-en-2-yl)pyridine-3-carboxylate (3.90 g, 20.29 mmol, 1.00 equiv) and Et 3 N (6.16 g, 60.87 mmol, 3.00 equiv) in toluene (40 mL). The resulting mixture was stirred at 60 °C under nitrogen overnight. 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 CH 2 Cl 2 / 2-propanol (5:1, 3 × 200 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (1.80 g, 41%). LC-MS: (ES + H, m / z): [M + H] + = 219.1; 1 H NMR (400 MHz, DMSO-d 6 )δ 11.92 (s, 1H), 8.92 (d, 1H), 8.15 (d, 1H), 6.79 (s, 1H), 3.93 (s, 3H), 2.48 (s, 3H).

[0358] Step 4: Preparation of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0359] At room temperature under a nitrogen atmosphere, to a solution of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.75 mmol, 1.00 equiv) and NCS (587 mg, 4.40 mmol, 1.60 equiv) in CH 32,2-Dichloroacetic acid (71 mg, 0.55 mmol, 0.20 equiv) was added dropwise to a solution in COOH (7 mL). The resulting mixture was stirred overnight at 100 °C and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 94%). LC-MS: (ES + H, m / z): [M + H] + = 253.0; 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.90 (d, 1H), 8.13 (d, 1H), 3.93 (s, 3H), 2.60 (s, 3H).

[0360] Step 5: Preparation of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0361] At 0 °C under a nitrogen atmosphere, LiAlH 4 (2 mL, 2.5 M solution in THF, 4.75 mmol, 2.00 equiv) was added dropwise to a stirred solution of methyl 7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (600 mg, 2.38 mmol, 1.00 equiv) in THF (5 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of HCl (1 mL, 12 M) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (230 mg, 43%). LC-MS: (ES + H, m / z): [M + H] + = 225.1; 1 H NMR (300 MHz, DMSO-d6) δ 12.24 (br, 1H), 8.48 (d, 1H), 7.77 (d, 1H), 5.69 (s, 1H), 4.63 (s, 2H), 2.63 (s, 3H).

[0362] Step 6: Preparation of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0363] At 0 °C under a nitrogen atmosphere, SOCl2 (318 mg, 2.67 mmol, 3.00 equivalents) was added dropwise to a stirred solution of 3-chloro-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (200 mg, 0.89 mmol, 1.00 equivalent) and DMF (7 mg, 0.09 mmol, 0.10 equivalent) in DCM (10 mL). 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.

[0364] Step 7: Preparation of 6-{4-[(7-chloro-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine- 3-carbonitrile :

[0365] At room temperature under a nitrogen atmosphere, DIEA (136 mg, 1.05 mmol, 3.00 equivalents) and KI (1 mg, 0.01 mmol, 0.10 equivalent) were added to a stirred mixture of 3-chloro-7-(chloromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (85 mg, 0.35 mmol, 1.00 equivalent) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 equivalent) in ACN (1 mL). 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 the 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 (300 MHz, DMSO-d 6 ) δ 12.30 (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).

[0366] Example 42

[0367]

[0368] Step 1: Preparation of methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0369] A mixture of methyl 8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (800 mg, 3.67 mmol, 1.00 equiv), sodium difluoromethylsulfinate (1012 mg, 7.33 mmol, 2.00 equiv), 2-methylpropan-2-yl hydroperoxide (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 CH 2 Cl 2 / 2-propanol (5:1, 3 × 100 mL). The combined organic layers were washed with water (3 × 50 mL) and 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 1H NMR (400 MHz, DMSO-d 6 ) δ 12.39 (s, 1H), 8.99 (d, 1H), 8.19 (m, 1H), 7.26 (t, 1H), 3.94 (s, 3H), 2.72 (s, 3H).

[0370] Step 2: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0371] At 0 °C under a nitrogen atmosphere, a solution of LiAlH 4 (2.5 M in THF, 3.9 mL, 9.75 mmol, 4.00 equiv) was added dropwise to a stirred solution of methyl 7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (650 mg, 2.42 mmol, 1.00 equiv) in THF (65 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of saturated NH 4 Cl aqueous solution (10 mL) at 0 °C and dried over anhydrous Na 2 SO 4 . The mixture was filtered and washed with CH 2 Cl 2Washed with / MeOH (10:1, 100 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(difluoromethyl)-7-(hydroxymethyl)-4-methyl-1H-1,5-naphthyridin-2-one (520 mg, 89%). LC-MS: (ES+H, m / z): [M+H] + = 241.1 1 H NMR (400 MHz, methanol-d4) δ 8.58 (d, 1H), 7.73 (d, 1H), 7.20 (t, 1H), 4.79 (s, 2H), 2.81 (t, 3H).

[0372] Step 3: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one :

[0373] At 0 °C under a nitrogen atmosphere, SOCl 2 Cl 2 (475 mg, 4.00 mmol, 3.00 equiv) was added dropwise 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 CH 2 (32 mL). The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 2 h. 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

[0374] Step 4: Preparation of 6-(4-{[7-(difluoromethyl)-8-methyl-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1- yl)pyridine-3-carbonitrile :

[0375] A mixture of 7-(chloromethyl)-3-(difluoromethyl)-4-methyl-1H-1,5-naphthyridin-2-one (380 mg, 1.47 mmol, 1.00 equiv), 6-(piperazin-1-yl)pyridine-3-carbonitrile (415 mg, 2.20 mmol, 1.50 equiv), KI (365 mg, 2.20 mmol, 1.50 equiv) and DIEA (569 mg, 4.40 mmol, 3.00 equiv) in MeCN (4 mL) was stirred at 80 °C under a nitrogen atmosphere for 1 h. 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), dried over anhydrous Na 2 SO 4Drying. 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; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.17 (br, 1H), 8.57 (d, 1H), 8.41 (d, 1H), 7.85 (dd, 1H), 7.68 (d, 1H), 7.24 (t, 1H), 6.94 (d, 1H), 3.80 - 3.60 (m, 6H), 2.72 (s, 3H), 2.60 - 2.40 (m, 4H); 19 F NMR (282 MHz, DMSO-d6) δ -115.51.

[0376] Example 47

[0377]

[0378] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine :

[0379] At 0 °C under a nitrogen atmosphere, NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30 wt%) was added dropwise 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). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by TLC (petroleum ether:EtOAc = 1:1, R f = 0.4). After completion, the reaction 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), dried over anhydrous Na 2 SO 4 and filtered and concentrated to give 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70 (s, 3H).

[0380] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine ene :

[0381] 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 overnight at 100 °C under a nitrogen atmosphere. 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-dimethyleth Step 3: Preparation of 5-bromo-6-methoxy-3-nitrobenzaldehyde -1-amine. The crude product was used directly in the next step without further purification.

[0382] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0383] At 0 °C under a nitrogen atmosphere, NaIO 2 was added portionwise 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 H 4 O (100 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC (petroleum ether:EtOAc = 5:1, R f = 0.2). The reaction was quenched at room temperature by the addition of saturated sodium thiosulfate (aqueous solution) (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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H).

[0384] Step 5: Preparation of ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0385] At room temperature under a nitrogen atmosphere, SnCl 2(26.25 g, 134.09 mmol, 5.00 equiv). 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, and the residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% over three steps). LC-MS: (ES + H, m / z): [M + H] + = 311.0

[0386] Step 6: Preparation of ethyl 7-chloro-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0387] At room temperature under a nitrogen atmosphere, CuCl (0.57 g, 5.78 mmol, 1.50 equiv) was added 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). 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% NH 3 ×H 2 O). 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 (300 MHz, DMSO-d 6 ) δ 9.27 (d, 1H), 8.63 (d, 1H), 8.57 (s, 1H), 4.41 (q, 2H), 4.12 (s, 3H), 1.37 (t, 3H).

[0388] Step 7: Preparation of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0389] At room temperature under a nitrogen atmosphere, to ethyl 7-chloro-6-methoxy-1,5-naphthyridine-3-carboxylate (800 mg, 3.00 mmol, 1.00 equiv) in CH 3TMSI (1.80 g, 9.00 mmol, 3.00 equiv) was added to the stirred mixture in CN (8 mL). The resulting mixture was stirred at 50 °C for 2 h. 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% Et 3 N). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography to afford 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 (300 MHz, DMSO-d 6 ) δ 12.61 (s, 1H), 8.94 (d, 1H), 8.37 (d, 1H), 8.20 (s, 1H), 4.39 (q, 2H), 1.36 (t, 3H).

[0390] Step 4: Preparation of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one :

[0391] Under a nitrogen atmosphere at 0 °C, LiAlH 4 (2.5 mL, 5.85 mmol, 2.00 equiv) was added dropwise 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). The resulting mixture was stirred at 0 °C for an additional 2 h. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1 M HCl. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 40.53%). LC-MS: (ES + H, m / z): [M + H] + = 211.0; 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.45 (d, 1H), 8.28 (s, 1H), 7.69 (d, 1H), 5.53 (t, 1H), 4.64 (d, 2H).

[0392] Step 9: Preparation of 3-chloro-7-{[4-(5-fluoropyridin-2-yl)piperazin-1-yl]methyl}-1H-1,5-naphthyridin-2-one :

[0393] Under a nitrogen atmosphere at room temperature, to a stirred mixture of 3-chloro-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (250 mg, 1.18 mmol, 1.00 equiv) in CH 2 Cl2 SOCl was added dropwise to the stirred mixture in (5 mL). 2 (423 mg, 3.56 mmol, 3.00 equivalents) and DMF (8 mg, 0.11 mmol, 0.10 equivalents). 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. Thus, 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (280 mg, crude) was obtained. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 228.95.

[0394] Example 48 Step 1: Preparation of ethyl 7-(difluoromethyl)-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0395] At room temperature, DIEA (564 mg, 4.36 mmol, 5 equivalents) and KI (14 mg, 0.08 mmol, 0.10 equivalents) were added to the stirred mixture of 3-chloro-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (200 mg, 0.87 mmol, 1.00 equivalent) and 1-(5-fluoropyridin-2-yl)piperazine (126 mg, 0.69 mmol, 0.80 equivalent) in CH 3 CN (5 mL). 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 Na 2 SO 4 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 1H NMR (300 MHz, DMSO-d 6 ) δ 12.48 (s, 1H), 8.48 (d, 1H), 8.29 (s, 1H), 8.09 (d, 1H), 7.70 (d, 1H), 7.55–7.47 (m, 1H), 6.87 (dd, 1H), 3.66 (s, 2H), 3.46–3.42 (m, 4H), 2.53–2.50 (m, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -143.39.

[0396] Step 2: Preparation of ethyl 7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridine-3-carboxylate

[0397]

[0398] Step 3: Preparation of 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0399] 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]difluoromethyl silver(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 a nitrogen atmosphere for 1.5 h. 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 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 (300 MHz, DMSO-d 6 ) δ 9.25 (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 (282 MHz, DMSO-d 6 ) δ -117.83.

[0400] Step 4: Preparation of 7-(chloromethyl)-3-(difluoromethyl)-1H-1,5-naphthyridin-2-one :

[0401] At room temperature, TMSI (680 mg, 3.40 mmol, 4.00 equiv) was added dropwise 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). The reaction mixture was then stirred at 50 °C under a nitrogen atmosphere for 5 h, 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.

[0402] Step 5: Preparation of 6-(4-{[7-(difluoromethyl)-6-oxo-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyr :

[0403] At 0 °C under a nitrogen atmosphere, LiAlH 4 (0.69 mL, 2.5 mol / L solution in THF, 2.00 equiv) was added dropwise 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). The resulting mixture was stirred at room temperature for 1 h. The reaction was monitored by LCMS. The resulting mixture was quenched with MeOH (10 mL), and then DCM (50 mL) was added. The solution was filtered and the filter cake was washed with DCM / MeOH (5:1) (3 × 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH) to give 3-(difluoromethyl)-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (50 mg, 26%). LC-MS: (ES + H, m / z): [M + H] + = 227.0; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.36 (s, 1H), 8.50 (d, 1H), 8.16 (d, 1H), 7.70 (s, 1H), 6.98 (t, 1H), 5.57 (t, 1H), 4.67 (d, 2H).

[0404] idine-3-carbonitrile :

[0405] At room temperature under a nitrogen atmosphere, SOCl 2(126 mg, 1.06 mmol, 3.00 eq). The resulting mixture was stirred at room temperature for 5 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES + H, m / z): [M + H] + = 245.0.

[0406] Example 49 Step 1: Preparation of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propionate :

[0407] At room temperature, DIEA (227 mg, 1.76 mmol, 5.00 eq) was added dropwise 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 eq), 6-(piperazin-1-yl)pyridine-3-carbonitrile (66 mg, 0.35 mmol, 1.00 eq), and KI (11 mg, 0.07 mmol, 0.20 eq) in ACN (5 mL). The resulting mixture was stirred at 80 °C for 1 h. 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 the 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 (300 MHz, DMSO-d 6 ) δ 12.33 (s, 1H), 8.54 (d, 1H), 8.48 (d, 1H), 8.16 (s, 1H), 7.85 (dd, 1H), 7.71 (d, 1H), 7.20–6.73 (m, 2H), 3.72–3.68 (m, 4H), 3.67 (s, 2H), 2.51–2.49 (m, 4H); 19 F NMR (282 MHz, DMSO-d 6 ) δ -119.30.

[0408] Step 2: Preparation of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one

[0409]

[0410] ​ :

[0411] At room temperature under a nitrogen atmosphere, DIEA (27.15 g, 210.09 mmol, 5.00 equivalents) was added dropwise to a stirred mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (10.00 g, 42.01 mmol, 1.00 equivalent) and methyl 2-aminopropionate hydrochloride (2.93 g, 21.00 mmol, 1.00 equivalent) in NMP (200 mL). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 hours. 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 Na 2 SO 4 . 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]propionate as a red oil (7.5 g, 56%). 1 1H NMR (400 MHz, DMSO-d 6 6) δ 8.08 (t, 1H), 7.87 (dd, 1H), 7.77 (dd, 1H), 4.67 - 4.55 (m, 1H), 3.68 (s, 3H), 1.48 (dd, 3H); 19 19F NMR (377 MHz, DMSO-d6) δ -122.19.

[0412] ​ :

[0413] At room temperature under a nitrogen atmosphere, Fe (5.22 g, 93.43 mmol, 5.00 equivalents) was added to a stirred solution of methyl 2-[(4-bromo-2-fluoro-6-nitrophenyl)amino]propionate (6.00 g, 18.68 mmol, 1.00 equivalent) in HOAc (200 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere 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 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 3 (aqueous solution). Then the resulting mixture was extracted with CH 2 Cl 2 3 (3 × 300 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous Na 2 SO 4Dry. After filtration, the filtrate was concentrated under reduced pressure to give 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.2 g, 87%). LC-MS: (ES-H, m / z): [M-H] - = 257.1; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.54 (s, 1H), 7.01 (dd, 1H), 6.76 (t, 1H), 6.20 (s, 1H), 3.90 - 3.80 (m, 1H), 1.28 (d, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -132.99.

[0414] Step 3: Preparation of 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one :

[0415] At room temperature, DDQ (4.34 g, 19.10 mmol, 1.10 eq) was added to a stirred solution of 7-bromo-5-fluoro-3-methyl-3,4-dihydro-1H-quinoxalin-2-one (4.50 g, 17.36 mmol, 1.00 eq) in DCM (500 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with saturated NaHCO 3 (aqueous solution) (500 mL). The resulting mixture was stirred at room temperature for 30 min. The resulting mixture was filtered and the cake was washed with saturated NaHCO 3 (aqueous solution) (3 × 100 mL). The cake was dried under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one (3 g, 67%). LC-MS: (ES-H, m / z): [M-H] - = 255.0; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 7.49 - 7.40 (m, 1H), 7.24 (q, 1H), 2.40 (q, 3H).

[0416] Step 4: Preparation of 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde :

[0417] In a pressure vessel, to a solution of 7-bromo-5-fluoro-3-methyl-1H-quinoxalin-2-one (500 mg, 1.94 mmol, 1.00 equiv) in toluene (100 mL) was added 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). The mixture was purged with nitrogen for 5 minutes and then pressurized to 30 Mpa with CO2:H2 = 1:1 at room temperature. The resulting mixture was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 8-fluoro-2-methyl-3-oxo-4H-quinoxaline-6-carbaldehyde (300 mg, 74.8%). LC-MS: (ES-H, m / z): [M-H] - = 205.2; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.75 (s, 1H), 10.02 (q, 1H), 7.67–7.52 (m, 2H), 2.49–2.44 (m, 3H).

[0418] Step 5: 6-{4-[(8-Fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3- Preparation of carbonitrile :

[0419] At room temperature under a nitrogen atmosphere, 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-(piperazin-1-yl)pyridine-3-carbonitrile (274 mg, 1.45 mmol, 1.50 equiv) in THF (20 mL) was added tetra(propan-2-yloxy)titanium (551 mg, 1.94 mmol, 2.00 equiv). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. At room temperature, NaBH(OAc) 3 (822 mg, 3.88 mmol, 4.00 equiv) was added to the above mixture. The resulting mixture was stirred at room temperature for an additional 4 hours. 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 Na 2 SO 4Dry. 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 afford 6-{4-[(8-fluoro-2-methyl-3-oxo-4H-quinoxalin-6-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (51.1 mg, 14%). LC-MS: (ES + H, m / z): [M + H] + = 379.2; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.44 (s, 1H), 8.48 (d, 1H), 7.85 (dd, 1H), 7.09 (d, 2H), 6.93 (d, 1H), 3.68 (t, 4H), 3.60 - 3.55 (m, 2H), 2.47 (d, 4H), 2.41 (s, 3H); 19 F NMR (377 MHz, DMSO-d 6 ) δ -125.51.

[0420] Example 60

[0421]

[0422] Step 1: Preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine :

[0423] At 0 °C under a nitrogen atmosphere, NaOMe (15.76 g, 87.49 mmol, 1.10 equiv, 30 wt%) was added dropwise 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). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by TLC (PE:EA = 1:1, R f = 0.4). 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), dried over anhydrous Na 2 SO 4 and filtered. After filtration, the filtrate was concentrated under reduced pressure to afford 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, 99%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 4.04 (s, 3H), 2.70 (s, 3H).

[0424] Step 2: Preparation of (E)-2-(5-bromo-6-methoxy-3-nitropyridin-2-yl)-N,N-dimethylethen-1-amine Preparation :

[0425] At 100 °C under a nitrogen atmosphere, 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 overnight. The reaction was monitored by TLC (PE:EA = 1:1, R f = 0.5). 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.

[0426] Step 3: Preparation of 5-bromo-6-methoxy-3-nitropyridinecarbaldehyde :

[0427] At 0 °C under a nitrogen atmosphere, NaIO 2 (28.00 g, 131.07 mmol, 2.20 equiv) was added portionwise 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 H 4 O (100 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was monitored by TLC (PE:EA = 5:1, R f = 0.2). The reaction was quenched at room temperature by the addition of saturated sodium thiosulfate (aqueous solution) (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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.87 (s, 1H), 4.10 (s, 3H).

[0428] Step 4: Preparation of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate :

[0429] At room temperature under a nitrogen atmosphere, SnCl 2(26.25 g, 134.09 mmol, 5.00 equivalents). 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 give the crude product. The crude product was purified by trituration with hexane (50 mL) to give ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (3.50 g, 18.5% yield over three steps). LC-MS: (ES + H, m / z): [M + H] + = 311.0 / 313.0; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.22 (s, 1H), 8.78 (s, 1H), 8.58 (s, 1H), 4.42 (q, 2H), 4.12 (s, 3H), 1.39 (t 3H).

[0430] Step 5: Preparation of ethyl 7-bromo-6-oxo-5H-1,5-naphthyridine-3-carboxylate :

[0431] At room temperature, TMSI (13.8 mL, 96.42 mmol, 6.00 equivalents) was added dropwise to a solution of ethyl 7-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (5.00 g, 16.07 mmol, 1.00 equivalent) in ACN (400 mL). The final reaction mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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 under the following conditions: column, silica gel; mobile phase, DCM containing EA, 45% to 60% gradient in 20 min; 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

[0432] Step 6: Preparation of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one :

[0433] At 0 °C under a nitrogen atmosphere, LiAlH 4(1.21 mL, 3.03 mmol, 2.00 eq., 2.5 M solution in THF). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The reaction was quenched by the addition of HCl (3.03 mL, 3.03 mmol, 2.00 eq.) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (220 mg, 56.9%). LC-MS: (ES + H, m / z): [M + H] + = 255.0 / 257.0.

[0434] Step 7: Preparation of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one :

[0435] At 0 °C under a nitrogen atmosphere, SOCl 2 (321 mg, 2.70 mmol, 3.00 eq.) was added dropwise to a stirred mixture of 3-bromo-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (230 mg, 0.90 mmol, 1.00 eq.) and DMF (6 mg, 0.09 mmol, 0.10 eq.) in DCM (7 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 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.

[0436] Step 8: Preparation of 6-{4-[(7-bromo-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile Preparation :

[0437] At room temperature under a nitrogen atmosphere, KI (18 mg, 0.11 mmol, 0.20 eq.) was added portionwise to a stirred mixture of 3-bromo-7-(chloromethyl)-1H-1,5-naphthyridin-2-one (150 mg, 0.54 mmol, 1.00 eq.), DIEA (354 mg, 2.74 mmol, 5.00 eq.) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (113 mg, 0.60 mmol, 1.10 eq.) in MeCN (7 mL). The resulting mixture was stirred at 80 °C under a 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 crude product (120 mg) was purified by preparative HPLC, the pure fractions were concentrated and then lyophilized to afford 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 (400 MHz, DMSO-d 6 ) δ 12.41 (s, 1H), 8.47 (s, 3H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.68 (s, 1H), 6.93 (d, J = 9.1 Hz, 1H), 3.78–3.59 (m, 6H), 2.48 (d, J = 4.7 Hz, 4H).

[0438] Examples 68 and 69

[0439]

[0440] Step 1: Preparation of ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-naphthyridine-3-carboxylate :

[0441] At room temperature under a nitrogen atmosphere, 5,5'-dimethyl-2,2'-bipyridine (0.74 g, 4.01 mmol, 0.25 equiv), nickel(II) acetylacetonate (1.03 g, 4.01 mmol, 0.25 equiv) and Na 2 CO 3 (1.70 g, 16.07 mmol, 1.00 equiv) were added 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. The resulting mixture was placed approximately ~3 cm away from two 40 W blue LEDs and stirred for 7 days at room temperature under a nitrogen atmosphere. 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 Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 6-methoxy-7-(oxolan-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 (400 MHz, DMSO-d 6)δ 9.20 (d, J = 2.0 Hz, 1H), 8.57 (dd, J = 2.1, 0.8 Hz, 1H), 8.27–8.10 (m, 1H), 5.13–5.04 (m, 1H), 4.41 (q, J = 7.1 Hz, 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 = 7.1 Hz, 3H).

[0442] Step 2: Preparation of ethyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate :

[0443] At 0 °C under a nitrogen atmosphere, AcOH containing HBr (0.25 mL, 33 wt%, 2.00 equivalents) was added to a stirred solution of ethyl 6-methoxy-7-(oxolan-2-yl)-1,5-naphthyridine-3-carboxylate (1.30 g, 4.30 mmol, 1.00 equivalent) in MeCN. 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 Et 3 N. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridine-3-carboxylate (730 mg, 58.89%). LC-MS: (ES + H, m / z): [M + H] + = 289.10; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.14 (s, 1H), 8.91 (d, J = 1.9 Hz, 1H), 8.18 (d, J = 1.9 Hz, 1H), 7.84 (d, J = 1.1 Hz, 1H), 4.96–4.87 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.12–4.04 (m, 1H), 3.91–3.79 (m, 1H), 2.48–2.32 (m, 1H), 1.99–1.81 (m, 2H), 1.74–1.63 (m, 1H), 1.36 (t, J = 7.1 Hz, 3H).

[0444] Step 3: Preparation of 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one :

[0445] At 0 °C under a nitrogen atmosphere, LiAlH was added dropwise 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). 4 (192 mg, 5.06 mmol, 2.00 equiv). The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of 1 M HCl (1 mL) at 0 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-(hydroxymethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (280 mg, 44.90%). LC-MS: (ES + H, m / z): [M + H] + = 247.00; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.97 (s, 1H), 8.40 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 5.48 (t, J = 5.6 Hz, 1H), 4.98–4.84 (m, 1H), 4.63 (d, J = 5.3 Hz, 2H), 4.18–4.01 (m, 1H), 3.91–3.75 (m, 1H), 2.45–2.31 (m, 1H), 2.02–1.78 (m, 2H), 1.74–1.58 (m, 1H).

[0446] Step 4: Preparation of 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one :

[0447] At 0 °C under a nitrogen atmosphere, SOCl was added dropwise 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. 2 (0.25 mL, 3.41 mmol, 3.00 equiv). The resulting mixture was stirred at room temperature under a 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.

[0448] Step 5: Preparation of 6-(4-{[6-oxo-7-(oxolan-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1- yl)pyridine-3-carbonitrile :

[0449] At room temperature under a nitrogen atmosphere, DIEA (292 mg, 2.26 mmol, 4.00 eq) and KI (18 mg, 0.11 mmol, 0.20 eq) were added to a stirred mixture of 7-(chloromethyl)-3-(oxolan-2-yl)-1H-1,5-naphthyridin-2-one (150 mg, 0.56 mmol, 1.00 eq) and 6-(piperazin-1-yl)pyridine-3-carbonitrile (106 mg, 0.56 mmol, 1.00 eq in MeCN (10 mL)). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na 2 SO 4 4. 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-(oxolan-2-yl)-5H-1,5-naphthyridin-3-yl]methyl}piperazin-1-yl)pyridine-3-carbonitrile (88 mg, 37.29%). LC-MS: (ES+ H, m / z): [M + H] + = 417.10. The racemate (88 mg) was separated by preparative chiral HPLC under the following conditions: column: CHIRALPAK IH, 2 * 25 cm, 5 μm; mobile phase A: Hex (10 mM NH 3 4 - MeOH), mobile phase B: EtOH:ACN = 5:1; flow rate: 20 mL / min; gradient: 50% B to 50% B in 12 min; wavelength: 218 / 282 nm; RT1 (min): 4.62; RT2 (min): 6.76; sample solvent: MeOH:DCM = 1:1 - HPLC; injection volume: 0.75 mL; number of runs: 6. The pure fractions were concentrated 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; 1 1H NMR (300 MHz, DMSO-d 6)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 H NMR (300 MHz, DMSO-d 6 )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

[0450] –2.31 (m, 1H), 2.02–1.78 (m, 2H), 1.74–1.57 (m, 1H).

[0451] Example 71

[0452]

[0453] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-2-methyl-3-phenylprop-2-enamide :

[0454] At room temperature under a nitrogen atmosphere, a solution of α-methylcinnamic acid (2.56 g, 15.78 mmol, 1.00 equivalent) in DCM (30 mL) was treated with DIEA (8.16 g, 63.15 mmol, 4.00 equivalents), T 3P (15.07 g, 23.68 mmol, 1.50 equiv, 50 wt% solution in DCM) was treated for 5 minutes, and then 3-bromo-2-fluoroaniline (3.00 g, 15.78 mmol, 1.00 equiv) was added at room temperature. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na 2 SO 4 . 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 (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 7.62–7.41 (m, 7H), 7.21 - 7.13 (m, 1H), 6.85–6.69 (m, 1H), 2.12 (d, J = 1.4 Hz, 3H).

[0455] Step 2: Preparation of 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one :

[0456] At 0 °C under a nitrogen atmosphere, AlCl 3 (2.39 g, 17.95 mmol, 3.00 equiv) was added 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). The resulting mixture was stirred at 120 °C under a 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 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 (400 MHz, DMSO-d 6 ) δ 11.94 (s, 1H), 7.82 (s, 1H), 7.44 - 7.34 (m, 2H), 2.09 (s, 3H).

[0457] Step 3: Preparation of 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one :

[0458] A solution of 7-bromo-8-fluoro-3-methyl-1H-quinolin-2-one (800 mg, 3.12 mmol, 1.00 equiv), (tributylstannyl)methanol (1.10 g, 3.43 mmol, 1.10 equiv), and a second-generation XPhos precatalyst (123 mg, 0.15 mmol, 0.05 equiv) in 1,4-dioxane (10 mL) was stirred 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 afford 8-fluoro-7-(hydroxymethyl)-3-methyl-1H-quinolin-2-one (400 mg, 61.7%). LC-MS: (ES + H, m / z): [M + H] + = 208.15

[0459] Step 4: Preparation of 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one :

[0460] At 0 °C under a nitrogen atmosphere, SOCl 2 (2.30 g, 19.30 mmol, 10.00 equiv) was added dropwise 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). The resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (400 mg, 91.8%). LC-MS: (ES + H, m / z): [M + H] + = 226.3

[0461] Step 5: Preparation of 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carboxylic acid Preparation of nitrile :

[0462] At room temperature under a nitrogen atmosphere, a solution of 6-(piperazin-1-yl)pyridine-3-carbonitrile hydrochloride (229 mg, assuming 100% yield, 0.88 mmol, 1.00 equivalent) in MeCN (10 mL) was treated with DIEA (573 mg, 4.43 mmol, 5.00 equivalents) for 5 minutes, followed by the addition of KI (17 mg, 0.10 mmol, 0.10 equivalent) and 7-(chloromethyl)-8-fluoro-3-methyl-1H-quinolin-2-one (200 mg, 0.88 mmol, 1.00 equivalent). The resulting mixture was stirred at 100 °C under a 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 6-{4-[(8-fluoro-3-methyl-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile (92.1 mg, 23.8%). LC-MS: (ES + H, m / z): [M + H] + = 378.10; 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.77 (s, 1H), 8.47 (d, J = 4.0 Hz, 1H), 7.87–7.76 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.1, 6.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 3.66–3.65 (m, 6H), 2.51 - 2.48 (m, 4H), 2.10 (d, J = 1.3 Hz, 3H). 19 F NMR (377 MHz, DMSO-d 6 ) δ -135.84.

[0463] Example 82

[0464]

[0465] Step 1: Preparation of 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate :

[0466] At room temperature under a nitrogen atmosphere, ethyl 1-tert-butyl 3-ethylmalonate (35.67 g, 189.52 mmol, 1.50 equiv) was added dropwise to a stirred solution of potassium tert-butoxide (21.27 g, 189.52 mmol, 1.50 equiv) in THF (500 mL). To the above mixture, a solution of 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 an additional 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 aqueous solution) (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 Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give ethyl 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (45 g, 91.5%). LC-MS: (ES-H, m / z): [M-H] - = 387.1

[0467] Step 2: Preparation of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate :

[0468] At room temperature under a nitrogen atmosphere, TFA (200 mL) was added to a stirred solution of ethyl 1-(tert-butyl) 3-ethyl 2-(5-bromo-3-nitropyridin-2-yl)malonate (45.00 g, 115.62 mmol, 1.00 equiv) in CH 2 Cl 2 (300 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was diluted with saturated aqueous NaHCO3 (100 mL). The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were washed with brine (1 × 200 mL) and dried over anhydrous Na 2 SO 4 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

[0469] Step 3: Preparation of ethyl 2-(3-amin-5-bromopyridin-2-yl)acetate :

[0470] At room temperature under a nitrogen atmosphere, saturated NH 4 Cl aqueous solution (250 mL) was added to a stirred solution of ethyl 2-(5-bromo-3-nitropyridin-2-yl)acetate (35.00 g, 121.07 mmol, 1.00 equivalent) and Fe (79.72 g, 1219.36 mmol, 7.50 equivalents) in EtOH (250 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. 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 min. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 × 70 mL). The resulting mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with brine (2 × 200 mL) and then dried over anhydrous Na 2 SO 4 4. 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 as a pale yellow oil (9.3 g, 29.7%). LC-MS: (ES + H, m / z): [M + H] + = 259.1

[0471] Step 4: Preparation of ethyl 2-(5-bromo-3-(2,2-dimethoxypropanamido)pyridin-2-yl)acetate :

[0472] At room temperature under a nitrogen atmosphere, an aqueous solution of NaOH (9.72 g, 242.98 mmol, 3.00 equivalents) in H 2 2O (120 mL) was added dropwise to a stirred solution of methyl 2,2-dimethoxypropionate (12.00 g, 80.99 mmol, 1.00 equivalent) in MeOH (120 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The reaction was monitored by TLC. The mixture was acidified to pH 8 with HCl (2 M aqueous solution). The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with EtOH (500 mL). The resulting mixture was stirred at room temperature for 2 h. The resulting mixture was filtered and the filter cake was washed with EtOH (3 × 100 mL). The filtrate was concentrated under reduced pressure to give sodium 2,2-dimethoxypropionate (8.5 g, 78.2%). 1 1H NMR (300 MHz, D 2 2O) δ 3.12 (d, J = 1.7 Hz, 6H), 1.33 (s, 3H).

[0473] At room temperature under a nitrogen atmosphere, DIEA (12.57 g, 97.26 mmol, 3.00 equivalents) and T3 P (30.95 g, 97.26 mmol, 3.00 eq., 50 wt% solution in EtOAc). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. At room temperature, ethyl 2-(3-amino-5-bromopyridin-2-yl)acetate (8.40 g, 32.42 mmol, 1.00 eq.) was added to the above mixture. 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), dried over anhydrous Na 2 SO 4 and filtered. 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-dimethoxypropanamido)pyridin-2-yl)acetate (9.3 g, 79.4%). LC-MS: (ES+H, m / z): [M+H] + = 375.1

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

[0475] At room temperature under a nitrogen atmosphere, H 2 O (7 mL) was added to a stirred solution of ethyl 2-(5-bromo-3-(2,2-dimethoxypropanamido)pyridin-2-yl)acetate (7.00 g, 18.65 mmol, 1.00 eq.) in TFA (100 ml), followed by the addition of 2 drops of a fresh solution of I2 (30 mg of I2 was suspended in TFA (10 mL)). The resulting mixture was stirred at 50 °C under a 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 1H NMR (400 MHz, DMSO-d 6 ) δ 12.20 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 7.86 (d, J = 2.1 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 2.06 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0476] Step 6: Preparation of 7-Bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0477] At 0 °C under a nitrogen atmosphere, a 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 stirred and LiEt 3 BH (30 ml, 1 M solution in THF) was added dropwise. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 2 h. 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 CH 2 Cl 2 / MeOH (0 to 10:1 gradient over 30 min) to give 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (1.8 g, 69.4%). LC-MS: (ES-H, m / z): [M-H] - = 267.0 / 269.0; 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 8.57 (d, J = 2.1 Hz, 1H), 7.83 (d, J = 2.1 Hz, 1H), 5.04 (t, J = 5.5 Hz, 1H), 4.90 (d, J = 5.2 Hz, 2H), 2.21 (s, 3H).

[0478] Step 7: Preparation of 7-Bromo-3-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbaldehyde :

[0479] At room temperature under a nitrogen atmosphere, 1,1-bis(acetoxy)-3-oxo-3H-1λ[5],2-benziodoxol-1-yl acetate (3.40 g, 8.02 mmol, 1.20 equiv) was added to a stirred mixture of 7-bromo-4-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (1.80 g, 6.68 mmol, 1.00 equiv) in THF (20 ml). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. 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 combinatorial 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): [M-H] - = 264.9; 1 H NMR (300 MHz, DMSO-d 6) δ 12.28 (s, 1H), 10.88 (s, 1H), 8.62 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 2.1 Hz, 1H), 2.25 (s, 3H).

[0480] Step 8: Preparation of 7-Bromo-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0481] At 0 °C under a nitrogen atmosphere, BAST (2.49 g, 11.23 mmol, 4 equivalents) was added dropwise 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 equivalent) in THF (5 ml). The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reaction was quenched with saturated NH 4 Cl (aqueous solution) (3 ml) at 0 °C. The resulting mixture was extracted with EtOAc (3 × 20 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-bromo-4-(difluoromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (320 mg, 39.4%). LC-MS: (ES-H, m / z): [M-H] - = 287.0

[0482] Step 9: Preparation of 4-(Difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0483] At room temperature under a nitrogen atmosphere, (tributylstannyl)methanol (959 mg, 2.98 mmol, 2.40 equivalents) was added to a stirred solution of 7-bromo-4-(difluoromethyl)-3-methyl-1H-1,5-naphthyridin-2-one (360 mg, 1.24 mmol, 1.00 equivalent) and the second-generation XPhos precatalyst (195 mg, 0.24 mmol, 0.20 equivalent) in dioxane (5 ml). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 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.

[0484] Step 10: Preparation of 7-(Chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one :

[0485] At 0 °C under a nitrogen atmosphere, to a stirred solution of 4-(difluoromethyl)-7-(hydroxymethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (185 mg, 0.25 mmol, 1.00 equivalent) and DMF (2 mg, 0.02 mmol, 0.10 equivalent) in CH 2 Cl 2 (3 ml) was added dropwise SOCl 2 (183 mg, 1.54 mmol, 6.00 equivalents). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo 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

[0486] Step 11: 6-(4-((8-(Difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl) Piperazin-1-yl)nicotinonitrile Preparation :

[0487] At room temperature under a nitrogen atmosphere, to a stirred solution of 7-(chloromethyl)-4-(difluoromethyl)-3-methyl-1,5-naphthyridin-2(1H)-one (104 mg, 0.40 mmol, 1.00 equivalent) and 6-(piperazin-1-yl)nicotinonitrile (91 mg, 0.48 mmol, 1.20 equivalents) in MeCN (5 ml) were added DIEA (260 mg, 2.01 mmol, 5.00 equivalents) and KI (13 mg, 0.08 mmol, 0.20 equivalent). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 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-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (crude). The crude product was further purified by trituration with MeOH (6 mL) to give 6-(4-((8-(difluoromethyl)-7-methyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl)piperazin-1-yl)nicotinonitrile (28.3 mg, 16.6%). LC-MS: (ES + H, m / z): [M + H] + = 411.10; 1 H NMR (300 MHz, DMSO-d 6)δ 12.25 (s, 1H), 8.48 (t, J = 1.8 Hz, 2H), 8.14–7.74 (m, 2H), 7.70 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 3.39 - 3.67 (m, 6H), 2.50 - 2.48 (m, 4H), 2.33 (t, J = 2.8 Hz, 3H). 19 F NMR (282 MHz, DMSO-d 6 )δ -117.71.

[0488] Example 83

[0489]

[0490] Step 1: Preparation of (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyacrylamide-2 :

[0491] At room temperature under a nitrogen atmosphere, pyridine (14.99 g, 189.45 mmol, 1.80 eq) was added dropwise to a stirred mixture of 3-bromo-2-fluoroaniline (20.00 g, 105.25 mmol, 1.00 eq) in DCM (300 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 5 h. At room temperature, (2E)-3-ethoxyprop-2-enoyl chloride (21.24 g, 157.88 mmol, 1.50 eq) was added dropwise to the above mixture within 5 min. The resulting mixture was stirred at room temperature for another 2 h. 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.

[0492] Step 2: Preparation of 7-Bromo-8-fluoro-1H-quinolin-2-one :

[0493] At room temperature under a nitrogen atmosphere, (2E)-N-(3-bromo-2-fluorophenyl)-3-ethoxyprop-2-enamide (17.00 g, 59.00 mmol, 1.00 eq) in H 2 SO 4The mixture in (85 mL) was stirred 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.

[0494] Step 3: Preparation of 7-Bromo-3-chloro-8-fluoro-1H-quinolin-2-one :

[0495] At room temperature under a nitrogen atmosphere, 2,2-dichloroacetic acid (0.32 g, 2.47 mmol, 0.20 equivalent) was added dropwise to a stirred mixture of 7-bromo-8-fluoro-1H-quinolin-2-one (3.00 g, 12.39 mmol, 1.00 equivalent) and NCS (2.65 g, 19.83 mmol, 1.60 equivalents) in CH 3 COOH (50 mL). The resulting mixture was stirred overnight at 100 °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 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, crude). LC-MS: (ES + H, m / z): [M + H] + = 275.9 / 277.9; 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.52–7.42 (m, 2H).

[0496] Step 4: Preparation of 3-Chloro-7-vinyl-8-fluoro-1H-quinolin-2-one :

[0497] At room temperature under a nitrogen atmosphere, H 2 was added dropwise to a stirred mixture of 7-bromo-3-chloro-8-fluoro-1H-quinolin-2-one (2.48 g, 8.97 mmol, 1.00 equivalent), CsF (4.09 g, 26.91 mmol, 3.00 equivalents), Pd(dppf)Cl 2O (5 mL). The resulting mixture was stirred at 100 °C under a 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 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 37.3%). LC-MS: (ES + H, m / z): [M + H] + = 224.0; 1 HNMR (300 MHz, DMSO-d 6 ) δ 12.38 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.53 - 7.46 (m, 2H), 6.95 (dd, J = 17.7, 11.2 Hz, 1H), 6.07 (dd, J = 17.7, 1.0 Hz, 1H), 5.57 (dd, J = 11.2, 1.0 Hz, 1H).

[0498] Step 5: Preparation of 3-Chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde :

[0499] At room temperature under a nitrogen atmosphere, to a stirred mixture of 3-chloro-7-vinyl-8-fluoro-1H-quinolin-2-one (750 mg, 3.35 mmol, 1.00 equiv), K 2 OsO 2 (OH) 4 (123 mg, 0.33 mmol, 0.10 equiv), NaIO 4 (2.87 g, 13.41 mmol, 4.00 equiv) and 2,6-dimethylpyridine (718 mg, 6.70 mmol, 2.00 equiv) in THF (15 mL) was added dropwise H 2 O (1.5 mL). The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (630 mg, 83.2%). LC-MS: (ES - H, m / z): [M - H] - = 224.1.

[0500] Step 6: 6-{4-[(3-Chloro-8-fluoro-2-oxo-1H-quinolin-7-yl)methyl]piperazin-1-yl}pyridine-3-carbonitrile Preparation :

[0501] A mixture of 3-chloro-8-fluoro-2-oxo-1H-quinoline-7-carbaldehyde (150 mg, 0.66 mmol, 1.00 equiv) and 6-(piperazin-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. To the resulting mixture was added EtOH (3 mL) containing HOAc (19 mg, 0.33 mmol, 0.50 equiv), and the mixture was stirred at 50 °C under a nitrogen atmosphere for 4 hours. The mixture was cooled to room temperature. Under a nitrogen atmosphere at 0 °C, NaBH 3 CN (83 mg, 1.33 mmol, 2.00 equiv) was added portionwise to the stirred mixture. 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 (400 MHz, DMSO-d 6 ) δ 12.46 (s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 1.5 Hz, 1H), 7.85 (dd, J = 9.1, 2.4 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.28 (dd, J = 8.1, 6.3 Hz, 1H), 6.97–6.87 (m, 1H), 3.71–3.63 (m, 6H), 2.50–2.44 (m, 4H); 19 F NMR (282 MHz, DMSO-d6) δ -134.50.

[0502] The following compounds were synthesized as described above.

[0503] Table 2. Characterization Data

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512]

[0513] Example A: Cell Growth Inhibition Assay

[0514] Cell proliferation was measured by cell viability assay using DLD-1 BRCA2(- / -) and parental isogenic pairs and the MDA-MB-436 (mutated BRCA1) cell line. The CellTiter-Glo (CTG)-based cell viability assay was designed to determine the number of viable cells in the culture affected by the compound by quantifying ATP, which indicates the presence of metabolically active cells.

[0515] DLD-1 BRCA2(- / -) and parental isogenic pairs were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both were cultured at 37 °C with 5% CO 2 cultivation. The compounds of the present invention were dispensed into 384-well plates (Corning, 3764) using an Echo acoustic liquid handler to form a 1:3 serial dilution with a final concentration with a maximum dose of 10 μM or 30 μM. Cells were seeded into the plates at a density of 50 cells / well (DLD-1 parental), 200 cells / well (DLD-1 BRCA2- / -), or 500 cells / well (MDA-MB-436). After a short centrifugation, the cells were cultured undisturbed in a fully humidified incubator at 37 °C and 5% CO 2 for 7 days. Cell viability was measured using the CellTiterGlo 2.0 assay kit (Promega, G9243), and the growth inhibition rate was calculated and plotted against the final compound concentration, and the data were fitted in Xfit to generate the IC 50 value.

[0516] Example B: Biochemical (FP) Assay

[0517] Fluorescence polarization (FP)-based assays have been widely used in drug discovery due to the homogeneous format, robust performance, and lack of interference observed in other assays. Compounds were characterized using an assay that measures displacement of a commercially available fluorescently labeled PARP 1 / 2 inhibitor (PARPi-FL, Tocris Biosciences, #6461), as exemplified in the assays performed in WO2014 / 064149 and WO2021 / 013735A1. The assay was carried out using the following method:

[0518] Compounds were dissolved in DMSO and serially diluted in an Optiplate-384F plate using an Echo550 liquid handler within the desired concentration range. 100% DMSO was used for high (protein-containing) and low (protein-free) control samples. 20 nL of compound or DMSO alone was added to individual assay plate wells.

[0519] 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 MgCl 2 , 150 mM NaCl. PARPi-FL was then added at a final concentration of 3 nM.

[0520] The assay plates were centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 4 hours.

[0521] Fluorescence polarization was read using an Envision microplate reader using the following settings:

[0522] Excitation filter - FITC FP 480 - excitation slot 3

[0523] Emission filter - FITC FP P-pol 535 - emission slot 4

[0524] Second emission filter - FITC FP S-pol 535 - emission slot 3

[0525] Mirror module - FITC FP Dual Enh - slot 1

[0526] The inhibition rate was calculated using the percentage of the Mahalanobis distance (mP value) greater than that of the control samples according to the following equation:

[0527] <![CDATA[mP c : mP value of the compound]]> <![CDATA[mP L : mP value with low control]]> <![CDATA[mP H : High control mP value]]>

[0528]

[0529] The reported IC of each compound was calculated using XLFit (Equation 201)50 .

[0530] Data for Example A and Example B are provided in Table 3.

[0531] Table 3

[0532]

[0533]

[0534] Example C: In Vitro Human Transporter Efflux

[0535] Madin-Darby canine kidney (MDCKII) cells expressing MDR1 and BCRP were seeded onto a Corning HTS 96-well polycarbonate permeable (0.4 μm pore) support at a density of 545,000 cells / cm2. The cells were incubated for 4 to 8 days prior to the assay, and monolayer integrity was evaluated by measuring the trans-epithelial electrical resistance (TEER). The test compound and reference compound were diluted to concentrations 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). The bidirectional (apical to basolateral and basolateral to apical) fluxes of the test compound and reference compound were determined within 2 hours of incubation at 37 °C, 5% CO2, and 95% relative humidity. At the end of incubation, samples were taken from the apical side and the basolateral side 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 via HPLC-MS / MS. Integrity

[0536] The apparent permeability (Papp, in units of ×10-6 cm / s) was calculated using the following equation:

[0537] Papp = (dQ / dt) / (AxD0)

[0538] where dQ / dt is the drug transport rate (pmol / s), A is the membrane surface area (0.143 cm 2 2), and D0 is the initial donor concentration (nM or pmol / cm3).

[0539] Efflux ratio = Papp(B→A) / Papp(A→B)

[0540] 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.

[0541] Example D: In Vivo Determination of Kp,uu in Rats

[0542] Determination of Unbound Fraction (Pu) in Plasma

[0543] Equilibrium dialysis was used to study the in vitro binding of the test article and the reference compound to plasma proteins. Plasma samples containing 5 μM of the test article or blank dialysis buffer (PBS, pH 7.4) were added to separate chambers of the dialysis wells of a high-throughput equilibrium dialysis (HTD) device. The dialysis plate was sealed and placed in an incubator at 37 °C containing 5% CO 2 and shaken at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Ketoconazole (5 μM) was used as the reference compound. After incubation, the seal was removed and 50 μL of the post-dialysis samples were pipetted from the buffer chamber and the plasma chamber into fresh 96-well plates. The samples were equimatrixed by adding blank plasma to the buffer samples or blank buffer to the plasma samples. Subsequently, 400 μL (4 volumes) of acetonitrile containing an internal standard was added to all samples to precipitate the proteins before analysis by UPLC-MS / MS to determine the relative concentration of the test article. The unbound fraction in plasma was calculated using the concentrations of the test article in the buffer samples and the plasma samples according to the following equation:

[0544]

[0545] Determination of Unbound Fraction (Bu) in Brain Homogenate

[0546] Equilibrium dialysis was used to study the in vitro binding of the test article and the reference compound to rodent brain homogenate. Brains collected from the donor animals were weighed and homogenized in 4 volumes of PBS (pH 7.4). Brain homogenate samples containing 1 μM of the test article or blank dialysis buffer (PBS, pH 7.4) were added to separate chambers of the dialysis wells of a high-throughput equilibrium dialysis (HTD) device. The dialysis plate was sealed and placed in an incubator at 37 °C containing 5% CO 2 and shaken at approximately 100 rpm for 6 hours. All experiments were performed in duplicate. Telmisartan (5 μM) was used as the reference compound. After incubation, the seal was removed and 50 μL of the post-dialysis samples were pipetted from the buffer chamber and the brain homogenate chamber into fresh 96-well plates. The samples were equimatrixed by adding blank homogenate to the buffer samples or blank buffer to the homogenate samples. Subsequently, 400 μL (4 volumes) of acetonitrile containing an internal standard was added to all samples to precipitate the proteins before 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 concentrations of the test article in the buffer samples and the homogenate samples according to the following equation:

[0547]

[0548] The correction for the unbound percentage in the undiluted brain was achieved by the following equation:

[0549]

[0550] Determination of Drug Brain-Plasma Partition Coefficient (Kp) and Unbound Kp (Kp,uu) of Drug in Rats

[0551] The compounds were individually formulated in sterile water containing 0.5% (w / v) methylcellulose 400 cP at a concentration of 0.1 mg / mL / compound or formulated in a cassette (as a mixture) and administered to male Sprague-Dawley rats via gavage at a dose volume of 10 mL / kg. One animal was sacrificed at each of the following time points: 0.5 hour, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after dosing, and brain samples and blood samples were collected. Plasma was prepared from the blood by freezing and centrifugation, and the plasma samples were stored frozen at -80 °C until bioanalysis. The brain samples were rinsed with saline to remove residual blood and blotted dry with tissue paper. The brain samples were then weighed, homogenized with 3 volumes (v / w) of water, and stored frozen at -80 °C until bioanalysis.

[0552] Prior to bioanalysis, plasma samples and brain samples were extracted with 4 volumes of acetonitrile containing an internal standard and centrifuged for 15 minutes. The supernatant was diluted with 2 volumes of water and injected for analysis via HPLC-MS / MS. The controls were determined by calibration curves generated by spiking the drug into blank rat plasma or brain homogenate over the appropriate concentration range. The brain homogenate concentration was corrected according to the homogenization buffer dilution factor to obtain the total brain drug concentration.

[0553] 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-time curve in one matrix dropped below the lower limit of quantification at an earlier time point than in the other matrix, the brain Kp was calculated as the average of the ratios of the total brain drug concentration to the total plasma drug concentration measured at each time point where the drug concentration could be quantified in both matrices.

[0554] Then, Kp,uu was calculated using the following formula: Kp,uu = Kp * (unbound fraction in brain homogenate / unbound fraction in plasma).

[0555] The data from Example C and Example D are provided in Table 4.

[0556] Table 4

[0557]

[0558] In summary, the present invention relates to the following aspects:

[0559] 1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0561]

[0562] Wherein:

[0563] R 1 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0564] R 2 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl;

[0565] X is N or CR 3 ;

[0566] Y is N or CR 4 ;

[0567] Z is N or CR 5 ;

[0568] R 3 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d , C1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R;

[0569] R 4 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R;

[0570] R 5 is hydrogen, deuterium, halogen, -CN, -OR a , -NR c R d 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R;

[0571] Each R 6 is independently hydrogen, deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R;

[0572] Or two Rs 6 together form a cycloalkyl or heterocycloalkyl; each optionally being substituted by deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl substituted;

[0573] Each R 7 is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl or C 2 -C 6 Alkynyl;

[0574] Or two Rs on the same carbon 7 Together form an oxo group;

[0575] Or two Rs on the same or different carbons 7 Together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more Rs;

[0576] n is 0 to 4;

[0577] T is N or CR 8 ;

[0578] U is N or CR 9 ;

[0579] R 8 Is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Halogenated alkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are each optionally substituted by one or more Rs;

[0580] R 9 Is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 Alkyl, C 1 -C 6 Halogenated alkyl, C 1-C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R;

[0581] R 10 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R;

[0582] R 11 is hydrogen, deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C2 -C 6 an alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one or more R;

[0583] R 12 is a cyano group or a halogen;

[0584] each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R;

[0585] each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C6 Alkylene(cycloalkyl), C 1 -C 6 Alkylene(heterocycloalkyl), C 1 -C 6 Alkylene(aryl) or C 1 -C 6 Alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R; and

[0586] each R c and R d is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently and optionally substituted by one or more R;

[0587] or R c and R d together with the atom to which they are attached form a heterocycloalkyl, optionally substituted by one or more R;

[0588] each R is independently deuterium, halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 、-NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2, -NHC(=O)OC 1 -C 6 alkyl, -C(=O)C 1 -C 6 alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 alkyl, -C(=O)NH 2 , -C(=O)N(C 1 -C 6 alkyl) 2 , -C(=O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl;

[0589] Or two Rs on the same atom together form an oxo group;

[0590] Provided that when X is CR 3 , Y is CR 4 and Z is CR 5 ; then one of R 3 , R 4 and R 5 is not hydrogen and R 4 is not -OMe; and

[0591] Provided that when X is CH, Y is CH, and Z is CH; then R 2 is not hydrogen.

[0592] 2. The compound according to item 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein X is N.

[0593] 3. The compound according to item 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein X is CR 3 .

[0594] 4. The compound according to any one of items 1 to 3 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Y is N.

[0595] 5. The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Y is CR 4 .

[0596] 6. The compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is N.

[0597] 7. The compound according to any one of items 1 to 5, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is CR 5 .

[0598] 8. The compound according to item 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has the formula (Ia):

[0599]

[0600] 9. The compound according to item 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has the formula (Ib):

[0601]

[0602] 10. The compound according to item 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has the formula (Ic):

[0603]

[0604] 11. The compound according to item 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has the formula (Id):

[0605]

[0606] wherein R 3 , R 4 and R 5 in which one is not hydrogen and R 4 is not -OMe.

[0607] 12. The compound according to item 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has the formula (Ie):

[0608]

[0609] wherein R 2 is deuterium, halogen, -CN, -OR a , -NR c R d , C1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 deuterated alkyl.

[0610] 13. A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl or cycloalkyl.

[0611] 14. A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is C 1 -C 6 alkyl or cycloalkyl.

[0612] 15. A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is C 1 -C 6 alkyl.

[0613] 16. A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is cycloalkyl.

[0614] 17. A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 1 is halogen.

[0615] 18. A compound according to any one of items 1 to 17 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 is hydrogen or halogen.

[0616] 19. A compound according to any one of items 1 to 18 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 is halogen.

[0617] 20. A compound according to any one of items 1 to 19 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 is hydrogen or halogen or C 1 -C 6Alkyl.

[0618] 21. The compound according to any one of items 1 to 20, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 is hydrogen or halogen.

[0619] 22. The compound according to any one of items 1 to 21, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 is hydrogen.

[0620] 23. The compound according to any one of items 1 to 22, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4 is hydrogen or halogen or C 1 -C 6 alkyl.

[0621] 24. The compound according to any one of items 1 to 23, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4 is hydrogen or halogen.

[0622] 25. The compound according to any one of items 1 to 24, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 4 is hydrogen.

[0623] 26. The compound according to any one of items 1 to 25, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 5 is hydrogen or halogen or C 1 -C 6 alkyl.

[0624] 27. The compound according to any one of items 1 to 26, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 5 is hydrogen or halogen.

[0625] 28. The compound according to any one of items 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 5 is hydrogen.

[0626] 29. The compound according to any one of items 1 to 28, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 6 is independently hydrogen, deuterium or C 1 -C 6 alkyl.

[0627] 30. The compound according to any one of items 1 to 29, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein one R 6 is hydrogen and the other R6 is C 1 -C 6 alkyl group.

[0628] 31. The compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 6 is deuterium.

[0629] 32. The compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 6 is independently C 1 -C 6 alkyl group.

[0630] 33. The compound according to any one of items 1 to 29 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 6 is hydrogen.

[0631] 34. The compound according to any one of items 1 to 33 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 7 is independently C 1 -C 6 alkyl group.

[0632] 35. The compound according to any one of items 1 to 33 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein two Rs on the same carbon or different carbons 7 together form a cycloalkyl group.

[0633] 36. The compound according to any one of items 1 to 35 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 0 or 1.

[0634] 37. The compound according to any one of items 1 to 35 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein n is 1 or 2.

[0635] 38. The compound according to any one of items 1 to 37 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein is

[0636] 39. The compound according to any one of items 1 to 37 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein is

[0637] 40. The compound according to any one of items 1 to 39 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8is hydrogen, halogen, -CN, -OR a , C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0638] 41. A compound according to any one of items 1 to 40 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 9 is hydrogen, halogen, -C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or cycloalkyl.

[0639] 42. A compound according to any one of items 1 to 41 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 10 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0640] 43. A compound according to any one of items 1 to 42 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 11 is hydrogen, halogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.

[0641] 44. A compound according to any one of items 1 to 43 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 12 is cyano.

[0642] 45. A compound according to any one of items 1 to 43 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 12 is halogen.

[0643] 46. A compound according to any one of items 1 to 43 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 12 is fluorine or chlorine.

[0644] 47. A compound according to item 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, selected from the compounds in Table 1.

[0645] 48. A pharmaceutical composition comprising a compound according to any one of items 1 to 47 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0646] 49. A method for treating cancer in a subject in need thereof, the method comprising administering a compound according to any one of items 1 to 47 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0647] 50. The method according to item 49, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer or lung cancer.

[0648] 51. A method for treating cancer in a subject in need thereof that comprises a BRCA1 and / or BRCA2 mutation, the method comprising administering a compound according to any one of items 1 to 47 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0649] 52. A method for treating cancer in a subject in need thereof that comprises a mutation in a gene that results in homologous repair deficiency, the method comprising administering a compound according to any one of items 1 to 47 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0650] 53. The method according to item 52, wherein the mutation in the gene that results in homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D or RAD54L or any combination thereof.

[0651] 54. The method according to any one of items 49 to 53, wherein 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, gastric cancer, thyroid cancer or uterine cancer.

[0652] 55. The method according to any one of items 49 to 54, wherein the cancer is metastatic cancer.

[0653] 56. The method according to any one of items 49 to 55, wherein the cancer has metastasized to the brain.

[0654] 57. A method for treating cancer present in the brain of a subject in need thereof, the method comprising administering a compound according to any one of items 1 to 47 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0655] 58. A method of treating brain cancer in a subject in need thereof, the method comprising administering a compound according to any one of items 1 to 47 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: Wherein: R 1 is hydrogen, deuterium, a halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R; R 2 is hydrogen, deuterium, a halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or C 1 -C 6 deuterated alkyl; X is N or CR 3 ; Y is N or CR 4 ; Z is N or CR 5 ; R 3 is hydrogen, deuterium, a halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R; R 4 is hydrogen, deuterium, a halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R; R 5 is hydrogen, deuterium, a halogen, -CN, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R; Each R 6 is independently hydrogen, deuterium, a halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterioalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 -heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more Rs; or two Rs 6 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted with deuterium, halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl substituted; Each R 7 is independently deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; or two Rs on the same carbon 7 together form an oxo group; or two Rs on the same carbon or different carbons 7 together form a cycloalkyl or heterocycloalkyl; each is optionally substituted by one or more Rs; n is from 0 to 4; T is N or CR 8 ; U is N or CR 9 ; R 8 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R; R 9 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R; R 10 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R; R 11 is hydrogen, deuterium, a halogen, -CN, -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted by one or more R; R 12 is cyano or halogen; Each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 alkylene(cycloalkyl), C 1 -C 6 alkylene(heterocycloalkyl), C 1 -C 6 alkylene(aryl) or C 1 -C 6 alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; Each R b is independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterated alkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 -heteroalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 -alkylene(cycloalkyl), C 1 -C 6 -alkylene(heterocycloalkyl), C 1 -C 6 -alkylene(aryl) or C 1 -C 6 -alkylene(heteroaryl); where each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; and Each R c and R d are independently hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -deuterioalkyl, C 1 -C 6 -hydroxyalkyl, C 1 -C 6 -aminoalkyl, C 1 -C 6 -heteroalkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 -alkylene(cycloalkyl), C 1 -C 6 -alkylene(heterocycloalkyl), C 1 -C 6 -alkylene(aryl) or C 1 -C 6 -alkylene(heteroaryl); wherein each alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is independently and optionally substituted by one or more R; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl group, optionally substituted by one or more R; Each R is independently deuterium, a halogen, -CN, -OH, -OC 1 -C 6 alkyl, -NH 2 , -NHC 1 -C 6 alkyl, -N(C 1 -C 6 alkyl) 2 , -NHC(=O)OC 1 -C 6 alkyl, - C(=O)C 1 -C 6 alkyl, -C(=O)OH, -C(=O)OC 1 -C 6 alkyl, -C(=O)NH 2 、- C(=O)N(C 1 -C 6 alkyl) 2 , -C(=O)NHC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuterated alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl or C 1 -C 6 heteroalkyl; or two Rs on the same atom together form an oxo group; The prerequisite is that when X is CR 3 , Y is CR 4 and Z is CR 5 ; then one of R 3 , R 4 and R 5 is not hydrogen and R 4 is not -OMe; and The prerequisite is that when X is CH, Y is CH, and Z is CH; then R 2 is not hydrogen.

2. The compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to claim 1, wherein X is N.

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein X is CR 3 .

4. The compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 3, wherein Y is N.

5. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 3, wherein Y is CR 4 .

6. The compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 5, wherein Z is N.

7. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1 to 5, wherein Z is CR 5 .

8. The compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to claim 1, wherein the compound has formula (Ia):

9. The compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to claim 1, wherein the compound has formula (Ib):

10. The compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof according to claim 1, wherein the compound has formula (Ic):

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