Tricyclic PARP1 inhibitors and uses thereof

Abstract

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

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 336,078, filed on April 28, 2022, and U.S. Provisional Application Serial No. 63 / 381,482, filed on October 28, 2022, both of which are hereby incorporated by reference in their entirety. Background Art

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

[0004] PARP1 and PARP2 are the most extensively studied PARPs due to their roles in DNA damage repair. PARP1 is activated by DNA damage breaks and functions to catalyze the addition of poly(ADP-ribose) (PAR) chains to target proteins. This post-translational modification, known as PARylation, mediates the recruitment of additional DNA repair factors to DNA lesions.

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

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

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

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

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

[0010]

[0011] in:

[0012] Ring A together with X and Y is a 5-membered heterocycloalkyl or a 5-membered heteroaryl;

[0013] X is C, CH or N;

[0014] Y is C, CH or N;

[0015] Each R 1 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0016] Or two R on the same carbon 1 Together they form an oxo group;

[0017] n is 0-6;

[0018] Z is N or CR Z ;

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

[0020] R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0021] R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0022] or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0023] Each R 4 are independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0024] Or two R on the same carbon 4 Together they form an oxo group;

[0025] or two R on the same carbon or on different carbons 4 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0026] m is 0-4;

[0027] R 5 Hydrogen, deuterium, halogen, -CN, -OH, -ORa 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0028] R 6 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0029] R 7 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0030] R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0031] Each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R;

[0032] Each R c and R dis independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R;

[0033] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0034] Each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl) -C(═O)C1-C3 alkyl, -C(═O)OH, -C(═O)OC1-C3 alkyl, -C(═O)NH2, -C(═O)NHC1-C3 alkyl, -C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0035] Alternatively, two R on the same atom may together form an oxo group.

[0036] 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.

[0037] Also disclosed herein is a method for treating a cancer comprising a BRCA1 and / or BRCA2 mutation in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. Also disclosed herein is a method for treating a cancer comprising a gene mutation that confers homologous repair defects in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the gene mutation that confers homologous repair defects comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof. In some embodiments, the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer has metastasized in the brain.

[0038] Also disclosed herein is a method of treating cancer present in the brain of a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0039] Also disclosed herein is a method of treating brain cancer in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the compound or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is a brain penetrant.

[0040] Incorporated by Reference

[0041] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION

[0042] definition

[0043] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, those skilled in the art will appreciate that the present invention can be practiced without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, throughout the specification and the subsequent claims, the word "include" and its variations such as "comprises" and "containing" should be interpreted in an open, inclusive sense, i.e., interpreted as "including but not limited to". In addition, the titles provided herein are for convenience only and do not explain the scope or meaning of the claimed invention.

[0044] References throughout this specification to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in conjunction with the embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in multiple places throughout this specification do not necessarily all refer to the same embodiment. In addition, in one or more embodiments, the particular features, structures, or characteristics may be combined in any suitable manner. In addition, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the term "or" is generally used in its sense including "and / or" unless clearly specified otherwise.

[0045] As used herein, unless otherwise indicated, the following terms have the following meanings:

[0046] "Oxo" refers to =0.

[0047] "Carboxyl" refers to -COOH.

[0048] "Cyano" refers to -CN.

[0049] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monovalent radical having one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever it appears in this document, a numerical range such as "C1-C6 alkyl" or "C 1-6The term "alkyl" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the definition also covers the occurrence of the term "alkyl" in which no numerical range is specified. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise specifically stated in the specification, alkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkyl is optionally substituted by halogen.

[0050] "Alkenyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon double bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. The group can be in a cis or trans conformation about the double bond, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, etc. Whenever it appears in this article, a numerical range such as "C2-C6 alkenyl" or "C 2-6 "Alkenyl" means that the alkenyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkenyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkenyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0051] "Alkynyl" refers to a straight or branched hydrocarbon monovalent group having one or more carbon-carbon triple bonds and having two to about ten carbon atoms, more preferably two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Whenever a numerical range such as "C2-C6 alkynyl" or "C 2-6 "Alkynyl" means that the alkynyl group may be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkynyl" in which no numerical range is specified. Unless otherwise specifically stated in the specification, the alkynyl group may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0052] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically stated in the specification, alkylene may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0053] "Alkoxy" refers to a group of the formula -OR a A group in which R a It is an alkyl group as defined. Unless specifically stated otherwise in the specification, alkoxy may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0054] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl group is bonded through an aromatic ring atom) or a bridged ring system. In some embodiments, the aryl group is a 6-10 membered aryl group. In some embodiments, the aryl group is a 6-membered aryl group (phenyl). Aryl groups include, but are not limited to, aryl groups derived from anthracene, naphthylene, phenanthrenyl, anthracene, azulene, benzene, The aryl group of the hydrocarbon ring system of fluoranthene, fluorene, asymmetric indene, symmetric indene, indane, indene, naphthalene, phenanthene, phenanthrenes, pyrenes, pyrene and triphenylene. Unless otherwise specifically stated in the specification, the aryl group may be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the aryl group is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, the aryl group is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, the aryl group is optionally substituted by halogen.

[0055] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include a fused ring system (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having three to fifteen carbon atoms (C3-C 15 Cycloalkyl or C3-C 15 cycloalkenyl), cycloalkyl (C3-C 10 Cycloalkyl or C3-C 10In some embodiments, the cycloalkyl group is a 3- to 10-membered cycloalkyl or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered cycloalkyl or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptane. Partially saturated cycloalkyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically stated in the specification, cycloalkyls may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0056] "Halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, halogen is fluorine or chlorine. In some embodiments, halogen is fluorine.

[0057] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0058] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0059] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0060] "Deuterated alkyl" refers to an alkyl group as defined above that is substituted with one or more deuteriums. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuteriums. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuteriums. Deuterated alkyl groups include, for example, CD3, CH2D, CHD2, CH2CD3, CD2CD3, CHDCD3, CH2CH2D, or CH2CHD2. In some embodiments, the deuterated alkyl group is CD3.

[0061] "Assorted alkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof). Assorted alkyl groups are connected to the rest of the molecule at the carbon atom of the assorted alkyl group. In one aspect, assorted alkyl groups are C1-C6 assorted alkyl groups, wherein the assorted alkyl group is composed of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or a combination thereof), wherein the assorted alkyl group is connected to the rest of the molecule at the carbon atom of the assorted alkyl group. The example of such assorted alkyl groups is, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless otherwise specifically stated in the specification, heteroalkyl can be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0062] "Heterocycloalkyl" refers to a 3 to 24-membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, heterocycloalkyl is fully saturated. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, heterocycloalkyl contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heterocycloalkyl contains one to three nitrogens. In some embodiments, heterocycloalkyl contains one or two nitrogens. In some embodiments, heterocycloalkyl contains one nitrogen. In some embodiments, heterocycloalkyl contains one nitrogen and one oxygen. Unless otherwise specifically stated in the specification, heterocycloalkyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is bonded by a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl can be optionally oxidized; the nitrogen atom can be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having two to fifteen carbon atoms (C2-C 15 Heterocycloalkyl or C2-C 15 heterocycloalkenyl), heterocycloalkyl (C2-C10 Heterocycloalkyl or C2-C 10C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C8 heterocycloalkyl or C2-C8 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C6 heterocycloalkyl or C2-C6 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl), C2-C7 heterocycloalkyl or C2-C7 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrrolid ... Oxazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl -2-oxo-1,3-dioxol-4-yl and 2-oxo-1,3-dioxol-4-yl.Term heterocycloalkyl also includes all ring forms of carbohydrate, including but not limited to monosaccharide, disaccharide and oligosaccharide.Unless otherwise indicated, heterocycloalkyl has 2 to 10 carbons in the ring.It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) (that is, the skeleton atoms of heterocycloalkyl ring) constituting heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is 3 to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 3 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 4 to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is 5 to 6-membered heterocycloalkenyl. Unless otherwise specifically stated in the specification, heterocycloalkyl may be optionally substituted as described below, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc.In some embodiments, heterocycloalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heterocycloalkyl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted by halogen.

[0063] "Heteroaryl" refers to a 5 to 14 ring system group containing one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl group contains one to three nitrogens. In some embodiments, the heteroaryl group contains one or two nitrogens. In some embodiments, the heteroaryl group contains one nitrogen. The heteroaryl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused ring system (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded by an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl group is a 5 to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5 to 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, aza benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxinyl, benzopyranyl, benzopyrone, benzofuranyl, benzofuranone , benzothiophenyl (benzophenylthio), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzophenylthio, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolyl, isoindolyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine The heteroaryl group may be optionally substituted, for example, by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroaryl is optionally substituted by halogen.

[0064] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes instances in which the event or situation occurs and instances in which the event or situation does not occur. For example, "optionally substituted alkyl" refers to "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted at any level between fully substituted and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). It should be understood by those skilled in the art that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically unfeasible (e.g., substituted alkyl includes optionally substituted cycloalkyl, which is in turn defined to include optionally substituted alkyl, possibly infinite). Therefore, any substituent described is generally understood to have a maximum molecular weight of about 1,000 Daltons, and more typically, up to about 500 Daltons.

[0065] When referring to optional substituents, the term "one or more" means that the subject group is optionally substituted by one, two, three, four or more substituents. In some embodiments, 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 a substituent. In some embodiments, the subject group is optionally substituted by two substituents.

[0066] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.

[0067] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used to attempt to alter the natural course of an individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after a pathological event has been initiated or contact with a pathogen, and includes stabilizing the condition (e.g., the condition does not worsen) or alleviating the condition.

[0068] "Synergy" or "acting synergistically" means that the effect of the combination is greater than the sum of the effects of each component alone at the same dose.

[0069] As used herein, a "disease or disorder associated with PARP" or alternatively a "PARP-mediated disease or disorder" means any disease or other deleterious condition in which PARP or a mutant thereof is known or suspected to play a role.

[0070] As used herein, a "disease or disorder associated with PARP1" or alternatively a "PARPl-mediated disease or disorder" means any disease or other deleterious condition in which PARP1 or a mutant thereof is known or suspected to play a role.

[0071] Compound

[0072] Described herein are compounds useful for treating cancer, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.

[0073] Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:

[0074]

[0075] in:

[0076] Ring A together with X and Y is a 5-membered heterocycloalkyl or a 5-membered heteroaryl;

[0077] X is C, CH or N;

[0078] Y is C, CH or N;

[0079] Each R 1 is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0080] Or two R on the same carbon 1 Together they form an oxo group;

[0081] n is 0-6;

[0082] Z is N or CR Z ;

[0083] R Z is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0084] R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0085] R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0086] or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0087] Each R 4 are independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl or C2-C6 alkynyl;

[0088] Or two R on the same carbon4 Together they form an oxo group;

[0089] or two R on the same carbon or on different carbons 4 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R;

[0090] m is 0-4;

[0091] R 5 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0092] R 6 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0093] R 7 Hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl and the heterocycloalkyl are optionally substituted with one or more R;

[0094] R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R;

[0095] Each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted by one or more R;

[0096] Each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R;

[0097] or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and

[0098] Each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -SC1-C3 alkyl, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl) -C(═O)C1-C3 alkyl, -C(═O)OH, -C(═O)OC1-C3 alkyl, -C(═O)NH2, -C(═O)NHC1-C3 alkyl, -C(═O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl;

[0099] Alternatively, two R on the same atom may together form an oxo group.

[0100] In some embodiments of compounds of formula (I), Ring A together with X and Y is a 5-membered heterocycloalkyl. In some embodiments of compounds of formula (I), Ring A together with X and Y is a pyrrolidinyl or furanyl. In some embodiments of compounds of formula (I), Ring A together with X and Y is a 5-membered heteroaryl. In some embodiments of compounds of formula (I), Ring A together with X and Y is a pyrrolyl, pyrazolyl, imidazolyl, or triazolyl. In some embodiments of compounds of formula (I), Ring A together with X and Y is a pyrazolyl or imidazolyl. In some embodiments of compounds of formula (I), Ring A together with X and Y is a furanyl.

[0101] In some embodiments of compounds of formula (I), X is C. In some embodiments of compounds of formula (I), X is CH. In some embodiments of compounds of formula (I), X is N.

[0102] In some embodiments of compounds of formula (I), Y is C. In some embodiments of compounds of formula (I), Y is CH. In some embodiments of compounds of formula (I), Y is N.

[0103] In some embodiments of the compound of Formula (I), the compound has Formula (Ia):

[0104]

[0105] Formula (Ia);

[0106] Where R 1 ' is hydrogen or R 1 .

[0107] In some embodiments of the compound of Formula (I), the compound has Formula (Ib):

[0108]

[0109] Where R 1 ' is hydrogen or R 1 .

[0110] In some embodiments of the compound of Formula (I), the compound has Formula (Ic):

[0111]

[0112] Where R 1 ' is hydrogen or R 1 .

[0113] In some embodiments of the compound of Formula (I), the compound has Formula (Id):

[0114]

[0115] Where R 1 ' is hydrogen or R 1 .

[0116] In some embodiments of the compound of Formula (I), the compound has Formula (Ie):

[0117]

[0118] Where R 1 ' is hydrogen or R 1 .

[0119] In some embodiments of the compound of Formula (I), the compound has Formula (If):

[0120]

[0121] Where R 1 ' is hydrogen or R 1 .

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

[0123]

[0124] Where R 1 ' is hydrogen or R 1 .

[0125] In some embodiments of the compound of Formula (I), the compound has Formula (Ih):

[0126]

[0127] Where R 1 ' is hydrogen or R 1 .

[0128] In some embodiments of the compound of Formula (I), the compound has Formula (Ii):

[0129]

[0130] Where R 1 ' is hydrogen or R 1 .

[0131] In some embodiments of the compound of Formula (I), the compound has Formula (Ij):

[0132]

[0133] Where R 1 ' is hydrogen or R 1 .

[0134] In some embodiments of the compound of Formula (I), the compound has Formula (Ik):

[0135]

[0136] Where R 1 ' is hydrogen or R 1 .

[0137] In some embodiments of the compound of formula (I), the compound has formula (II):

[0138]

[0139] Where R 1 ' is hydrogen or R 1 .

[0140] In some embodiments of the compound of Formula (I), the compound has Formula (Im):

[0141]

[0142] Where R 1 ' is hydrogen or R 1 .

[0143] In some embodiments of the compound of Formula (I), the compound has Formula (In):

[0144]

[0145] Where R 1 ' is hydrogen or R 1 .

[0146] In some embodiments of the compound of Formula (I), the compound has Formula (Io):

[0147]

[0148] Where R 1 ' is hydrogen or R 1 .

[0149] In some embodiments of the compound of Formula (I), the compound has Formula (Ip):

[0150]

[0151] Where R 1 ' is hydrogen or R 1 .

[0152] In some embodiments of the compound of Formula (I), the compound has Formula (Iq):

[0153]

[0154] Where R 1 ' is hydrogen or R 1 .

[0155] In some embodiments of the compound of formula (I), the compound has formula (Ir):

[0156]

[0157] Where R 1 ' is hydrogen or R 1 .

[0158] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Ia) to Formula (Il):

[0159]

[0160] Where R 1 ' is hydrogen or R 1 .

[0161] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Ia) to Formula (Ih):

[0162]

[0163] Where R 1 ' is hydrogen or R 1 .

[0164] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Ii) to Formula (Il):

[0165]

[0166] Where R 1 ' is hydrogen or R 1 .

[0167] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound has Formula (Im) or Formula (In):

[0168]

[0169] Where R 1 ' is hydrogen or R 1 .

[0170] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Io) to Formula (Ir):

[0171]

[0172]

[0173] Where R 1 ' is hydrogen or R 1 .

[0174] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, the compound has Formula (Io) or Formula (Ip):

[0175]

[0176] Where R 1 ' is hydrogen or R 1 .

[0177] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, the compound has Formula (Iq) or Formula (Ir):

[0178]

[0179] Where R 1 ' is hydrogen or R 1 .

[0180] In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), each R 1 is independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ir), each R 1 is independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ir), each R 1 is independently deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ir), each R 1is independently deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl; wherein the alkyl is optionally substituted with one or more R. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ir), each R 1 is independently deuterium, halogen or C1-C6 alkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ir), each R 1 is independently halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), each R 1 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), each R 1 are independently C1-C6 alkyl.

[0181] In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), each R 1 ' is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 1 ' is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 1 ' is independently hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of compounds of Formula (Ia) to (Ir), each R 1 ' is independently hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl; wherein the alkyl is optionally substituted with one or more R. In some embodiments of the compounds of Formula (Ia) to Formula (Ir), each R 1 ' is independently hydrogen, deuterium, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (Ia) to Formula (Ir), each R 1 ' is independently hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (Ia) to Formula (Ir), each R 1 ' is independently hydrogen or halogen. In some embodiments of compounds of Formula (Ia) to (Ir), each R 1' is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of Formula (Ia) to (Ir), each R 1 ' is hydrogen. In some embodiments of compounds of Formula (Ia) to (Ir), each R 1 ' is independently C1-C6 alkyl.

[0182] In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 0-4. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 0-3. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 0-2. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 0 or 1. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 0. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 1. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 2. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 3. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), n is 4.

[0183] In some embodiments of the compound of Formula (I) or Formula (Ia)-Formula (Ir), Z is N. In some embodiments of the compound of Formula (I) or Formula (Ia)-Formula (Ir), Z is CR Z .

[0184] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R Z is hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl; wherein alkylheterocycloalkyl is optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R Z is hydrogen, deuterium, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R Z In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R Z In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R Z It is a C1-C6 alkyl group.

[0185] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 2is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 2 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 2 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 2 is hydrogen, deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 2 is hydrogen, deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 2 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 2 is deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 2 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 2 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 2 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 2 It is a C1-C6 alkyl group.

[0186] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 3 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 3is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 3 is hydrogen, deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 3 is hydrogen, deuterium, halogen, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 3 is hydrogen, deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 3 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 3 is deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 3 is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 3 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 3 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 3 It is a C1-C6 alkyl group.

[0187] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 2 is hydrogen and R 3 For hydrogen.

[0188] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 2 and R 3 Together they form a cycloalkyl group.

[0189] In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), each R 4 is independently deuterium, C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ir), each R 4 are independently C1-C6 alkyl.

[0190] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), two R 4In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), two R on the same carbon 4 In some embodiments of compounds of Formula (I) or (Ia) to (Ir), two R on different carbons are 4 Together they form a cycloalkyl group.

[0191] In some embodiments of compounds of Formula (I) or (Ia)-(Ir), m is 0-2. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), m is 0 or 1. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), m is 0. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), m is 1. In some embodiments of compounds of Formula (I) or (Ia)-(Ir), m is 2.

[0192] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 5 is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 5 is hydrogen, deuterium, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 5 It is hydrogen, halogen or C1-C6 alkyl.

[0193] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 5 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 5 It is a halogen.

[0194] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 6 is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 6 is hydrogen, deuterium, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 6 is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 6 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 6 It is a halogen.

[0195] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 7 is hydrogen, deuterium, halogen, -CN, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 7 is hydrogen, deuterium, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 7 is hydrogen, halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 7 In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 7 It is a halogen.

[0196] In some embodiments of the compounds of Formula (I) or Formula (Ia) to Formula (Ir), R 8 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R. In some embodiments of the compound of formula (I) or formula (Ia) to formula (Ir), R 8 is C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl; wherein alkyl and cycloalkyl are optionally substituted with one or more R. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 8 is C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 8 is C1-C6 alkyl or cycloalkyl; wherein alkyl and cycloalkyl are optionally substituted by one or more R. In some embodiments of the compound of Formula (I) or Formula (Ia) to Formula (Ir), R 8 is C1-C6 alkyl or cycloalkyl. In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 8 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 8 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 8 In some embodiments of the compounds of Formula (I) or (Ia) to (Ir), R 8 It is cyclopropyl.

[0197] In some embodiments of the compounds disclosed herein, each R ais independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. In some embodiments of the compounds disclosed herein, each R a is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R a are independently C1-C6 alkyl.

[0198] In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl; wherein each alkyl is independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, each R c and R d R is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 deuterated alkyl. c and R dR is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl. c and R d is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each R c and R d In some embodiments of the compounds disclosed herein, each R c and R d are independently C1-C6 alkyl.

[0199] In some embodiments of the compounds disclosed herein, R c and R d Together with the atoms to which they are attached they form a heterocycloalkyl group optionally substituted with one or more R.

[0200] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl or C3-C6 cycloalkyl; or two R on the same atom together form an oxo group. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -OC1-C3 haloalkyl, -NH2, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 deuterated alkyl, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, or C3-C6 cycloalkyl; or two R on the same atom together form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -NH2, C1-C3 alkyl, or C1-C3 haloalkyl; or two R on the same atom together form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C3 alkyl, -NH2, C1-C3 alkyl; or two R on the same atom together form an oxo. In some embodiments of the compounds disclosed herein, each R is independently halogen or C1-C3 alkyl.

[0201] Any combination of the various groups of variables described above is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0202] In some embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are selected from the compounds found in Table 1.

[0203] Table 1

[0204]

[0205]

[0206]

[0207]

[0208]

[0209] The absolute designation (abs) is added to the chiral center to indicate that it is unequivocally a pure sample of the drawn stereoisomer.

[0210] The OR notation (or) indicates a pure substance, but the absolute configuration of the stereochemical center is unknown. After chiral separation with an isolated pure structure, multiple OR notations with the same value (OR stands for purity) will indicate that the sample is one of a pair of pure enantiomers (but the absolute configuration of the stereochemical center is unknown).

[0211] The AND symbol (and) indicates that both isomers are present at the depicted stereochemical center. Assigning different values ​​to the AND symbol indicates that they are independent of each other. Using the AND symbol with the same value indicates that the two stereocenters are relative to each other and can only change in unison.

[0212] In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from:

[0213]

[0214]

[0215]

[0216] Other forms of the compounds disclosed herein

[0217] Isomers / stereoisomers

[0218] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in R configuration or S configuration. The compounds described herein include all diastereomers, enantiomers and diastereomeric forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or diastereoisomer mixtures produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, a pair of diastereomeric compounds are formed by reacting the racemic mixture of the compound with an optically active resolving agent, separating the diastereomers and recovering the optically pure enantiomers, and the compounds described herein are prepared as their individual stereoisomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.), and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography, or preferably by separation / resolution techniques based on solubility differences. In some embodiments, optically pure enantiomers and resolving agents are then recovered by any practical means that do not result in racemization.

[0219] Labeled compounds

[0220] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, but one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H. 3 H. 13 C. 14 C. l5 N. 18 O. 17 O. 31 P.32 P. 35 S. 18 F and 36 Cl. Compounds described herein and pharmaceutically acceptable salts, solvates or stereoisomers thereof containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes such as 3 H and 14 C, can be used in drug and / or substrate tissue distribution assays. Particularly preferred are tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes because of their ease of preparation and detectability. In addition, heavy isotopes such as deuterium (i.e., 2 H) Substitutions may confer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0221] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0222] Pharmaceutically acceptable salts

[0223] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0224] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified compound in its free form with a suitable acid or base separately and isolating the salt thus formed.

[0225] Examples of pharmaceutically acceptable salts include those prepared by reacting a compound described herein with a mineral, organic acid, or inorganic base, such salts include acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate salt, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0226] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, Acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable in themselves, are used to prepare salts that can be used as intermediates to obtain the compounds disclosed herein, their solvates or stereoisomers, and pharmaceutically acceptable acid addition salts thereof.

[0227] In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (such as a pharmaceutically acceptable metal cation hydroxide, carbonate, bicarbonate, sulfate), with ammonia or with a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts, such as lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0228] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0229] Solvate

[0230] In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The present invention also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0231] Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein can be conveniently prepared or formed during the process of the methods described herein. By way of example only, hydrates of compounds described herein can be conveniently prepared from aqueous / organic solvent mixtures, using organic solvents including but not limited to dioxane, tetrahydrofuran, or methanol. In addition, compounds provided herein can exist in non-solvated forms as well as solvated forms. Generally, for the purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to non-solvated forms.

[0232] Tautomer

[0233] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. Tautomers are compounds that can be interconverted by the migration of hydrogen atoms, with the conversion of single bonds and adjacent double bonds. In the bonding arrangements where tautomerism may occur, there will be a chemical equilibrium of tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0234] Treatment

[0235] Disclosed herein are methods of treating diseases in which inhibition of PARP is beneficial, the methods comprising administering a compound disclosed herein. Also disclosed herein are methods of treating diseases in which inhibition of PARP1 is beneficial, the methods comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer (such as gastric cancer and colorectal cancer), or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer. In some embodiments, the cancer is bladder cancer, brain cancer and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, kidney cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.

[0236] In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer has metastasized in the brain.

[0237] In some embodiments, the cancer comprises a BRCA1 and / or BRCA2 mutation.

[0238] 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, stomach cancer, thyroid cancer, or uterine cancer.

[0239] In some embodiments, the cancer is a cancer that lacks Flomologous Recombination (FIR)-dependent DNA DSB repair activity.The FIR-dependent DNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA via homologous mechanisms to reform a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_000051), RAD51 (NM_002875), RAD51 L1 (NM_002877), RAD51 C (NM_002876), RAD51 L3 (NM_002878), DMC1 (NM_007068), XRCC2 (NM_005431), XRCC3 (NM_005432), RAD52 (NM_002879), RAD54L (NM_003579), RAD54B (NM_012415), BRCA1 (NM_007295), BRCA2 (NM_000059), RAD50 (NM_005732), MRE1 (NM_007068). 1A (NM_005590) and NBS1 (NM_002485). Other proteins involved in the FIR-dependent DNA DSB repair pathway include regulatory factors such as EMSY. In some embodiments, the cancer lacking FIR-dependent DNA DSB repair comprises one or more cancer cells whose ability to repair DNA DSB by this pathway is reduced or eliminated relative to normal cells, that is, the activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in the one or more cancer cells.

[0240] In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is abolished in one or more cancer cells of an individual suffering from a cancer deficient in FIR-dependent DNA DSB repair.

[0241] In some embodiments, the cancer cells have a BRCA1 and / or BRCA2 defective phenotype, i.e., the activity of BRCA1 and / or BRCA2 is reduced or eliminated in the cancer cells. Cancer cells with this phenotype may lack BRCA1 and / or BRCA2, i.e., the expression and / or activity of BRCA1 and / or BRCA2 in the cancer cells may be reduced or eliminated, for example, by mutations or polymorphisms in the encoding nucleic acid, or by amplification, mutation or polymorphism of genes encoding regulatory factors (e.g., the EMSY gene encoding BRCA2 regulatory factors). BRCA1 and BRCA2 are known tumor suppressor genes, and their wild-type alleles are often lost in tumors of heterozygous carriers. It is also known that the amplification of the EMSY gene encoding BRCA2 binding factors is associated with breast cancer and ovarian cancer. Carriers of BRCA1 and / or BRCA2 mutations are also at high risk for certain cancers, including breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer and lung cancer.

[0242] Also disclosed herein is a method for treating a cancer comprising a gene mutation that confers homologous repair deficiency in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the gene mutation that confers homologous repair deficiency comprises ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, or RAD54L, or any combination thereof.

[0243] 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.

[0244] In some embodiments, the cancer present in the brain originates from a primary peripheral tumor that has metastasized to the brain. In some embodiments, the cancer present in the brain originates from native brain tissue.

[0245] Also disclosed herein is a method of treating brain cancer, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0246] In some embodiments, the brain cancer is a primary brain tumor that starts in the brain and tends to stay there.

[0247] In some embodiments, the brain cancer is a secondary brain tumor. These cancers start elsewhere in the body and travel to the brain. Lung cancer, breast cancer, kidney cancer, colon cancer, and skin cancer are the most common cancers that spread to the brain.

[0248] 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 ratio of the compound that penetrates the BBB is>0.1, where 1 is complete BBB penetration and 0 is no penetration. In some embodiments, the ratio of the compound that penetrates the BBB is>0.2. In some embodiments, the ratio of the compound that penetrates the BBB is>0.3. In some embodiments, the ratio of the compound that penetrates the BBB is measured using a rat kp,uu assay. In some embodiments, as determined in a rat kp,uu assay, the ratio of the compound is>0.3 (i.e., 0.3 to 1).

[0249] Drug administration

[0250] In certain embodiments, compositions containing compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially suppress at least one of the symptoms of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, previous treatment, the patient's health, body weight, and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0251] In preventive applications, compositions containing the compounds described herein are administered to patients who are susceptible to or otherwise at risk for a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the exact amount also depends on the patient's health, weight, etc. When used for a patient, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatment, the patient's health and response to the drug, and the judgment of the treating physician. In one aspect, preventive treatment includes administering a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom or risk factor for the disease being treated and is currently in a state of remission to prevent the recurrence of symptoms of the disease or condition.

[0252] In certain embodiments where the patient's condition does not improve, administration of the compound is administered chronically, i.e., for an extended period of time, including the entire duration of the patient's life, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition, at the discretion of the physician.

[0253] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, as symptoms change, the dose or frequency of administration, or both, is reduced to a level that maintains the improved disease, disorder, or condition. However, in certain embodiments, after any recurrence of symptoms, the patient requires long-term intermittent or daily treatment.

[0254] The amount of a given agent that corresponds to such an amount varies depending on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., weight, sex), but will still be determined according to the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the subject or host being treated.

[0255] However, in general, dosages for adult treatment are generally in the range of 0.01 mg to 5000 mg per day. In one aspect, dosages for adult treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., two, three, four or more sub-doses per day.

[0256] In one embodiment, the daily dose suitable for the compound described herein or its pharmaceutically acceptable salt is about 0.01 mg / kg body weight to about 50 mg / kg body weight. In some embodiments, based on multiple variables related to individual treatment regimens, the amount of active substance in the daily dose or dosage form is lower or higher than the range indicated herein. In various embodiments, the daily dose and unit dose vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the doctor.

[0257] Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to LD 10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index, expressed as LD 50 With ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals (including humans). In some embodiments, the daily dose of the compounds described herein is within the range that includes the ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or the unit dosage varies within this range, depending on the dosage form employed and the route of administration employed.

[0258] Route of administration

[0259] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, ear, nasal and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic and intranasal injection.

[0260] In certain embodiments, the compound as described herein is applied in a local rather than systemic manner, for example, via direct injection of the compound into an organ, typically in the form of a reservoir formulation or a sustained release formulation. In a specific embodiment, the long-acting preparation is applied by implantation (for example, subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such an embodiment, the liposome is targeted to an organ and selectively absorbed by the organ. In other embodiments, the compound as described herein is provided in the form of a rapid release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation. In other embodiments, the compound as described herein is applied locally.

[0261] Pharmaceutical compositions / preparations

[0262] According to standard pharmaceutical practice, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient or diluent in the form of a pharmaceutical composition to a subject in need thereof. In one embodiment, the compounds of the invention can be administered to animals. These compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.

[0263] In another aspect, provided herein is a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compound into a pharmaceutically usable formulation. Appropriate formulations depend on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventeenth Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0264] In some embodiments, the pharmaceutically acceptable excipient is selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, humectants, defoamers, antioxidants, preservatives, and any combination thereof.

[0265] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal or transdermal routes of administration. Pharmaceutical formulations described herein include but are not limited to aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multi-particulate formulations, and mixed immediate release formulations and controlled release formulations.

[0266] Pharmaceutical compositions containing a compound described herein, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0267] The pharmaceutical composition for oral use is obtained in such a way that one or more solid excipients are mixed with one or more compounds described herein, the resulting mixture is optionally ground, and if necessary, the granular mixture is processed after adding suitable auxiliary agents to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others, such as polyvinyl pyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinyl pyrrolidone, agar or alginic acid or its salts such as sodium alginate are added. In some embodiments, colorants or pigments are added to tablets or dragee coatings to identify or characterize different combinations of active compound dosages.

[0268] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules contain the active ingredient mixed with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0269] The pharmaceutical composition for parenteral use is formulated as an infusion or injection. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution, dispersion or sterile powder comprising a compound as described herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or a liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides and any combination thereof. In some embodiments, the pharmaceutical composition also includes a preservative to prevent microbial growth.

[0270] combination

[0271] Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0272] In some embodiments, the additional therapeutic agent is an anti-cancer agent.

[0273] In some embodiments, the additional therapeutic agent is administered simultaneously with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compounds disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered before the compounds disclosed herein are administered. In some embodiments, the additional therapeutic agent is administered after the compounds disclosed herein are administered.

[0274] Example

[0275] Example 1

[0276]

[0277] Step 1 and Step 2: Preparation of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide:

[0278] A solution of 2H-pyrazole-3-carboxylic acid (3.00 g, 26.76 mmol, 1.00 equiv) in SOCl2 (30 mL) was stirred overnight at 90 ° C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with toluene (3×50 mL). The resulting mixture was concentrated under reduced pressure. The crude product 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]twelve-3,5,9,11-tetraene-2,8-dione (2.3 g) was used directly in the next step without further purification.

[0279] To a stirred solution of 1,6,7,12-tetraazatricyclo[7.3.0.0^{3,7}]twelve-3,5,9,11-tetraene-2,8-dione (2.30 g, 12.22 mmol, 1.00 equiv) and 3-bromo-2,6-difluoroaniline (5.09 g, 24.45 mmol, 2.00 equiv) in THF (100 mL) was added NaHMDS (2M, 30.56 mL, 61.12 mmol, 5.00 equiv) dropwise at -10 °C. The resulting mixture was stirred at -10 °C for another 2 hours. The reaction was monitored by LCMS. The mixture was neutralized to pH 7 with CH3CO2H. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in H2O (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography, eluting with PE / EA (0% to 30% gradient in 30 minutes) to give N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (6 g, 74.4%). LC-MS: (ES+H, m / z): [M+H] + =301.9; 1 H NMR (300MHz, DMSO-d6) δ13.49(s,1H),10.01(s,1H),7.92(d,J=2.4Hz,1H),7.78-7.66(m,1H),7.25(td,J=9.1,1.9Hz,1H),6.77(d,J=2.2Hz,1H).

[0280] Step 3: Preparation of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one:

[0281] To a stirred solution of N-(3-bromo-2,6-difluorophenyl)-2H-pyrazole-3-carboxamide (5.80 g, 19.20 mmol, 1.00 equiv) in DMA (2 mL) was added NaH (1.15 g, 28.80 mmol, 1.50 equiv, 60% in mineral oil) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 120 ° C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The reactants were quenched with water (50 mL) at 0 ° C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was dissolved in DMSO (20 mL) and purified by reverse phase flash chromatography (column: C18; mobile phase: aqueous MeOH (0.1% TFA), 50% to 70% gradient in 40 minutes; detector, UV 254 nm) to provide 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (1.5 g, 26.3%). LC-MS: (ES+H, m / z): [M+H] + =281.9; 1 H NMR (400MHz, DMSO-d6) δ12.14(s,1H),8.13(s,1H),7.89(d,J=8.9Hz,1H),7.58(t,J=7.7Hz,1H),7.21(s,1H).

[0282] Step 4: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one:

[0283] To a stirred solution of 7-bromo-6-fluoro-5H-pyrazolo[1,5-a]quinoxaline-4-one (1.00 g, 3.54 mmol, 1.00 equiv) and (tributylstannyl)methanol (1366 mg, 4.25 mmol, 1.20 equiv) in dioxane (16 mL) was added the second generation XPhos precatalyst (279 mg, 0.35 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with DCM / MeOH=(1:5) (3×150 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (0% to 7% gradient in 30 minutes) to give 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (400 mg, 45.9%). LC-MS: (ES+H, m / z): [M+H] + =234.0; 1H NMR (300MHz, DMSO-d6) δ11.95(s,1H),8.10(d,J=2.1Hz,1H),7.93(dd,J=8.5,1.4Hz,1H),7.38( dd,J=8.5,7.0Hz,1H),7.19(d,J=2.1Hz,1H),5.42(t,J=5.8Hz,1H),4.63(dd,J=5.8,1.5Hz,2H).

[0284] Step 5: Preparation of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one:

[0285] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (300 mg, 1.28 mmol, 1.00 equiv) in DCM (8 mL) was added dropwise SOCl2 (765 mg, 6.43 mmol, 5.00 equiv) and DMF (5 mg, 0.07 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with DCM (3×30 mL). The crude product (7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one) was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =252.0.

[0286] Step 6: 6-Fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazine- Preparation of 1-methyl]-N-methylpyridine-2-carboxamide:

[0287] To a stirred mixture of 7-(chloromethyl)-6-fluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (180 mg, 0.71 mmol, 1.00 equiv) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (204 mg, 0.86 mmol, 1.20 equiv) in MeCN (10 ml) was added KI (24 mg, 0.14 mmol, 0.20 equiv) and DIEA (462 mg, 3.57 mmol, 5.00 equiv) at room temperature. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 10% gradient in 30 min)) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide. The crude product was further purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 50*250 mm, 10 μm; mobile phase A: water (0.05% NH3H2O), mobile phase B: MeCN; flow rate: 25 ml / min; gradient: 5% B to 40% B, 40% B in 35 minutes; wavelength: 254 / 220 nm; RT1 (min): 30.5) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (204.4 mg, 62.4%). LC-MS: (ES+H, m / z): [M+H] + =454.1; 1 H NMR (300MHz, DMSO-d6) δ11.98(s,1H),8.40(q,J=4.7Hz,1H),8.10(d,J=2.1Hz,1H),7.94(dd,J=8.5,1.2Hz,1H),7.84(dd,J=8.1,1.4Hz,1H),7.55(d d,J=10.6,8.1Hz,1H),7.34(dd,J=8.5,6.8Hz,1H),7.19(d,J=2.1Hz,1H), 3.69(s,2H),3.17-3.14(m,4H),2.77(d,J=4.7Hz,3H),2.65-2.57(m,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.57,-131.02.

[0288] The following examples were carried out using similar procedures as described for Example 1.

[0289]

[0290]

[0291]

[0292] Example 6

[0293]

[0294] Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate:

[0295] A solution of methyl 3-amino-2-fluorobenzoate (20.00 g, 118.23 mmol, 1.00 equiv) and NIS (23.94 g, 106.41 mmol, 0.90 equiv) in AcOH (250 mL) was stirred at room temperature under nitrogen for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase combi-flash chromatography (column: C18 gel; mobile phase, aqueous MeOH (0.1% FA), 10% to 50% gradient in 10 minutes; detector, UV 254 nm) to give methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 11.4%). LC-MS: (ES+H, m / z): [M+H] + =295.80; 1 H NMR (300MHz, DMSO-d6) δ7.52 (dd, J=8.4, 1.5Hz, 1H), 6.81 (dd, J=8.3, 6.7Hz, 1H), 5.43 (s, 2H), 3.83 (s, 3H).

[0296] Step 2: Preparation of methyl 2-fluoro-3-(furan-3-amide)-4-iodobenzoate:

[0297] To a 250 mL round-bottom flask was added methyl 3-amino-2-fluoro-4-iodobenzoate (4.00 g, 13.55 mmol, 1.00 equiv), 3-furancarboxylic acid (1.52 g, 13.55 mmol, 1.00 equiv), T3P (43.14 g, 67.78 mmol, 5.00 equiv, 50% EA solution) and DIEA (2.08 g, 16.10 mmol, 5.00 equiv) at room temperature. 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 diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA (0% to 20% gradient in 30 minutes)) to give methyl 2-fluoro-3-(furan-3-amido)-4-iodobenzoate (4.50 g, 85.3%). LC-MS: (ES+H, m / z): [M+H] + =389.85; 1 H NMR (300MHz, DMSO-d6) δ9.99 (s, 1H), 8.40 (s, 1H), 7.91 (dd, J = 8.4, 1.2Hz, 1H), 7. 83(t,J=1.7Hz,1H),7.61(dd,J=8.4,7.0Hz,1H),7.02–6.96(m,1H),3.86(s,3H).

[0298] Step 3: Preparation of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amide]-2-fluoro-4-iodobenzoate:

[0299] To a stirred mixture of 2-fluoro-3-(furan-3-amide)-4-iodobenzoic acid methyl ester (2.60 g, 6.68 mmol, 1.00 equiv) and (Boc)2O (2.92 g, 13.36 mmol, 2.00 equiv) in DCE (50 mL) was added DMAP (0.82 g, 6.68 mmol, 1.00 equiv) in batches at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by TLC (PE:EA=5:1, r=0.5). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, which was eluted with PE / EA (0% to 20% gradient in 30 minutes) to give 3-[N-(tert-butoxycarbonyl)furan-3-amide]-2-fluoro-4-iodobenzoic acid methyl ester (3.00 g, 91.7%).

[0300] Step 4: Preparation of 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester:

[0301] PCy3 (344 mg, 1.22 mmol, 0.20 equiv), Pd(OAc)2 (275 mg, 1.22 mmol, 0.20 equiv) and K2CO3 (1.69 g, 12.26 mmol, 2.00 equiv) were added to a stirred solution of methyl 3-[N-(tert-butoxycarbonyl)furan-3-amide]-2-fluoro-4-iodobenzoate (3.00 g, 6.13 mmol, 1.00 equiv) in DMF (30 mL) at room temperature under nitrogen atmosphere. The reaction mixture was irradiated with microwave radiation at 120°C for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 30 minutes)) to give methyl 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (310 mg, 19.3%). LC-MS: (ES+H, m / z): [M+H+MeCN] + =302.95.

[0302] Step 5: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one:

[0303] To a stirred solution of 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (150 mg, 0.57 mmol, 1.00 equiv) in THF (10 mL) was added dropwise LiAlH4 (0.46 mL, 1.14 mmol, 2.00 equiv, 2.5 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched at 0°C by adding HCl (aqueous solution) (1 M, 1.2 mL). The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes)) to give 6-fluoro-7-(hydroxymethyl)-5H-furo[3,2-c]quinoline-4-one (100 mg, 74.6%). LC-MS: (ES+H, m / z): [M+H] + =233.95.

[0304] Step 6: Preparation of 7-(chloromethyl)-6-fluoro-5H-furo[3,2-c]quinolin-4-one:

[0305] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-furo[3,2-c]quinolin-4-one (100 mg, 0.42 mmol, 1.00 equiv) and DMF (2 mg, 0.03 mmol, 0.10 equiv) in DCM (10 mL) was added dropwise SOCl2 (0.24 mL, 3.30 mmol, 10.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-6-fluoro-5H-furo[3,2-c]quinolin-4-one (100 mg, 92.6%). LC-MS: (ES+H, m / z): [M+H] + =252.00.

[0306] Step 7: 6-Fluoro-5-[4-({6-fluoro-4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazine-1-yl] Preparation of 1-methyl-2-pyridine-2-carboxamide:

[0307] A solution of 6-fluoro-N-methyl-5-(piperazine-1-yl)pyridine-2-carboxamide (95 mg, 0.39 mmol, 1.00 equiv) in MeCN (5 mL) was treated with DIEA (205 mg, 1.58 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere for 5 minutes, followed by the addition of KI (7 mg, 0.04 mmol, 0.10 equiv), 7-(chloromethyl)-6-fluoro-5H-furo[3,2-c]quinolin-4-one (100 mg, 0.39 mmol, 1.00 equiv). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 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 reverse phase flash chromatography (C18 gel; mobile phase, aqueous MeOH (0.1% NH3.H2O), 10% to 50% gradient in 10 minutes; detector, UV 254nm) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (43.2 mg, 23.8%). LC-MS: (ES+H, m / z): [M+H] + =454.10; 1HNMR (400MHz, DMSO-d6) δ11.84–11.57(m,1H),8.39(q,J=4.7Hz,1H),8.13(d,J=2.1Hz,1H),7.84(dd,J=8.1,1.4Hz,1H),7.73(d,J=8.1Hz,1H),7.55( dd,J=10.6,8.1Hz,1H),7.33(dd,J=8.2,6.2Hz,1H),7.11(d,J=2.1Hz,1H) ,3.72(s,2H),3.19–3.16(m,4H),2.77(d,J=4.7Hz,3H),2.62–2.60(m,4H). 19 F NMR (377MHz, DMSO-d6) δ-72.56, δ-132.19.

[0308] The following examples were carried out using a similar procedure as shown for Example 6.

[0309]

[0310] Example 7

[0311]

[0312] Step 1: Preparation of methyl 3-amino-2-fluoro-4-iodobenzoate:

[0313] A solution of methyl 3-amino-2-fluorobenzoate (10 g, 59.12 mmol, 1.00 equiv) and NIS (12 g, 53.21 mmol, 0.90 equiv) in AcOH (120 mL) was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (10 mL) and poured into NaHCO3 (100 mL) (aqueous solution). The aqueous layer was extracted with EtOAc (3×100 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (C18; mobile phase: MeOH aqueous solution (0.1% FA), 10% to 50% gradient in 10 minutes; detector, UV 254 nm) to give methyl 3-amino-2-fluoro-4-iodobenzoate (2.1 g, 11.98%). LC-MS: (ES+H, m / z): [M+H] + =295.80; 1 H NMR (400MHz, DMSO-d6) δ7.52 (d, J=8.4, 1.3Hz, 1H), 6.83-6.78 (m, J=8.3, 6.7Hz, 1H), 5.44 (s, 2H), 3.82 (s, 3H).

[0314] Step 2: Preparation of tert-butyl 2-[2-amino-3-fluoro-4-(methoxycarbonyl)phenyl]pyrrole-1-carboxylate:

[0315] To a stirred solution of methyl 3-amino-2-fluoro-4-iodobenzoate (1 g, 3.39 mmol, 1.00 equiv) and 1-(tert-butyloxycarbonyl)pyrrol-2-ylboronic acid (1 g, 6.78 mmol, 2.00 equiv) in 1,4-dioxane (120 mL) was added Pd(dppf)Cl2.CH2Cl2 (276 mg, 0.34 mmol, 0.10 equiv) and CsF (1 g, 6.78 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was heated and stirred at 100 °C under nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography (C18; mobile phase: aqueous MeCN (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 minutes; detector, UV 254 nm) to provide tert-butyl 2-[2-amino-3-fluoro-4-(methoxycarbonyl)phenyl]pyrrole-1-carboxylate (420 mg, 29.84%). LC-MS: (ES+H, m / z): [M+H] + =335.10.

[0316] Step 3 to Step 4: Preparation of 7-fluoro-8-(hydroxymethyl)-6H-pyrrolo[1,2-c]quinazolin-5-one:

[0317] A solution of tert-butyl 2-[2-amino-3-fluoro-4-(methoxycarbonyl)phenyl]pyrrole-1-carboxylate (380 mg, 1.14 mmol, 1.00 equiv) in HCl in 1,4-dioxane (5 mL) was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to provide methyl 7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazoline-8-carboxylate (370 mg, crude).

[0318] To a solution of methyl 7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazoline-8-carboxylate (crude product) in THF (10 mL) was added LiAlH4 (0.9 mL, 2.28 mmol, 2.00 equiv., 2.5 M in THF) at 0°C under nitrogen atmosphere. The mixture was stirred at 0°C for 2 hours. The reaction was monitored by LCMS. The mixture was poured into water (50 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×50 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA (3:1-1:1)) to give 7-fluoro-8-(hydroxymethyl)-6H-pyrrolo[1,2-c]quinazoline-5-one (160 mg, 40.98%). LC-MS: (ES+H, m / z): [M+H]+ =233.1; 1 H NMR (300MHz, DMSO-d6) δ11.54(s,1H),7.74(d,J=8.1Hz,1H),7.64(dd,J=3.1,1.5Hz,1H),7.30-7.23( m,1H),7.04(dd,J=3.6,1.5Hz,1H),6.72-6.68(m,1H),5.37-5.32(m,1H),4.60(dd,J=5.7,1.5Hz,2H).

[0319] Step 5 to Step 6: 6-fluoro-5-[4-({7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazolin-8-yl}methyl Preparation of [1-yl)piperazine-1-yl]-N-methylpyridine-2-carboxamide:

[0320] To a stirred solution of 7-fluoro-8-(hydroxymethyl)-6H-pyrrolo[1,2-c]quinazolin-5-one (130 mg, 0.560 mmol, 1.00 equiv) and 2 drops of DMF in DCM (15 mL) was added SOCl2 (333 mg, 2.8 mmol, 5.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product mixture was used directly in the next step without further purification.

[0321] To a stirred solution of 8-(chloromethyl)-7-fluoro-6H-pyrrolo[1,2-c]quinazolin-5-one (130 mg, crude) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (124 mg, 0.52 mmol, 1.00 equiv, HCl salt) in MeCN (15 mL) was added KI (9 mg, 0.1 mmol, 0.10 equiv) and DIEA (201 mg, 1.56 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was poured into water (35 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (3×100 mL) and concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC (column: Xselect CSH C18 OBD column, 50*250 mm, 10 μm; mobile phase A: water (0.1% NH4HCO3), mobile phase B: MeCN-preparative; flow rate: 100 ml / min; gradient: 35% B to 55% B, 52% B in 30 minutes; wavelength: 254 / 220 nm; RT1 (min): 27) to give 6-fluoro-5-[4-({7-fluoro-5-oxo-6H-pyrrolo[1,2-c]quinazolin-8-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (50.2 mg, 21.2%). LC-MS: (ES+H, m / z): [M+H] + =453.15; 1 H NMR (300MHz, DMSO-d6) δ11.57(s,1H),8.40(q,J=4.9Hz,1H),7.84(dd,J=8.1,1.5Hz,1H),7.74(d,J=8.1Hz,1H),7.65(dd,J=3.1,1.5Hz,1H),7.61-7.5 2(m,1H),7.28-7.18(m,1H),7.06(dd,J=3.6,1.5Hz,1H),6.75-6.67(m,1H) ,3.67(s,2H),3.25-3.11(m,4H),2.76(d,J=4.7Hz,3H),2.66-2.56(m,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.56,-133.82.

[0322] Example 9

[0323]

[0324] Step 1: Preparation of 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester:

[0325] Pd / C (163 mg, 10%) was added to a stirred solution of 6-fluoro-4-oxo-5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (200 mg, 0.76 mmol, 1.00 equiv) in CF3CH2OH (50 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. Upon completion, the resulting mixture was filtered and the filter cake was washed with CH2Cl2 / MeOH (10:1, 3×50 mL). The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes) to give 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (70 mg, 34.7%). LC-MS: (ES+H, m / z): [M+H] + =263.95; 1 H NMR (300MHz, DMSO-d6) δ11.68(s,1H),7.58(dd,J=8.4,6.1Hz,1H),7.49(d,J=8.5Hz,1H),4.85(t,J=9.4Hz,2H),3.89(s,3H),3.10(t,J=9.4Hz,2H). 19 F NMR(377MHz,DMSO-d6)δ-124.45.

[0326] Step 2: Preparation of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[0327] To a stirred solution of methyl 6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate (60 mg, 0.22 mmol, 1.00 equiv) in THF (5 mL) was added dropwise LiAlH4 (0.18 mL, 0.45 mmol, 2.00 equiv, 2.5 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of HCl(aq) (1 M, 0.5 mL) at 0°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes) to give 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 93.2%). LC-MS: (ES+H, m / z): [M+H] + =236.0.

[0328] Step 3: Preparation of 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[0329] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 0.21 mmol, 1.00 equiv) and DMF (2 mg, 0.02 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl (253 mg, 2.13 mmol, 4.6 equiv) dropwise at room temperature under nitrogen atmosphere.

[0330] 10.00 equivalents). The resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 92.7%). LC-MS: (ES+H, m / z): [M+H] + =254.0.

[0331] Step 4: 6-Fluoro-5-[4-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperidin Preparation of [1-oxazine-1-yl]-N-methylpyridine-2-carboxamide:

[0332] A solution of 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (47 mg, 0.19 mmol, 1.00 equiv) in MeCN (3 mL) was treated with DIEA (102 mg, 0.78 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere for 5 min, followed by the addition of KI (3 mg, 0.02 mmol, 0.10 equiv) and 7-(chloromethyl)-6-fluoro-2H,3H,5H-furo[3,2-c]quinolin-4-one (50 mg, 0.19 mmol, 1.00 equiv). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 h. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes)) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (44.0 mg, 47.7%). LC-MS: (ES+H, m / z): [M+H] + =456.05; 1H NMR (300MHz, DMSO-d6) δ11.42(s,1H),8.40(d,J=5.0Hz,1H),7.84(dd,J=8.1,1.4Hz,1H),7.55(dd,J=10.6,8.1Hz,1H),7.41(d,J=8.2Hz,1H ),7.27–7.19(m,1H),4.82(t,J=9.3Hz,2H),3.69(s,2H),3.18–3.15(m,4H),3.07(t,J=9.3Hz,2H),2.76(d,J=4.8Hz,3H),2.60–2.57(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-72.57,-132.99.

[0333] The following examples were carried out using similar procedures as shown for Example 9.

[0334]

[0335]

[0336] Example 10

[0337]

[0338] Step 1: Preparation of 1-(4-bromo-3-fluoro-2-nitrophenyl)pyrrole-2-carboxylic acid methyl ester:

[0339] To a stirred solution of methyl pyrrole-2-carboxylate (1.1 g, 8.791 mmol, 1 eq.) and K2CO3 (2.4 g, 17.58 mmol, 2 eq.) in DMF (10 mL) was added 1-bromo-2,4-difluoro-3-nitrobenzene (3.1 g, 13.19 mmol, 1.50 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×150 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 30%)) to give a crude product. The crude product (2.5 g) was further purified by preparative HPLC (column: YMC-Triart PrepC18-S, 100*250 mm, S-100 μm, 120A; mobile phase A: water (0.05% NH3.H2O+12.5 mmol / L NH4HCO3), mobile phase B: MeOH; flow rate: 120 ml / min; gradient: 45% B to 85% B, 74% B in 40 minutes; wavelength: 254 / 220 nm; RT1 (min): 27;) to give 1-(4-bromo-3-fluoro-2-nitrophenyl)pyrrole-2-carboxylic acid methyl ester (1.2 g, 38.8%). LC-MS: (ES+H, m / z): [M+H] + =342.95; 1 H NMR(300MHz,DMSO-d6)δ8.19(dd,J=8.7,7.3Hz,1H),7.53(dd,J=8.7,1.8Hz,1H),7.32(dd ,J=2.8,1.7Hz,1H),7.07(dd,J=3.9,1.7Hz,1H),6.42(dd,J=3.9,2.8Hz,1H),3.64(s,3H).

[0340] Step 2: Preparation of 7-bromo-6-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one:

[0341] To a stirred solution of methyl 1-(4-bromo-3-fluoro-2-nitrophenyl)pyrrole-2-carboxylate (1.1 g, 3.206 mmol, 1 eq.) and Fe (895 mg, 16.030 mmol, 5 eq.) in AcOH (10 mL) was added at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 75 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (2×10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (1:0 to 10:1) to give 7-bromo-6-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (800 mg, 88.7%). LC-MS: (ES+H, m / z): [M+H] + =281.0; 1 HNMR(300MHz,DMSO-d6)δ11.47(s,1H),8.22(dd,J=2.9,1.5Hz,1H),7.89(dd,J=9.0,1.7Hz ,1H),7.50(dd,J=8.9,6.8Hz,1H),7.11(dd,J=3.9,1.4Hz,1H),6.74(dd,J=3.9,2.8Hz,1H).

[0342] Step 3: Preparation of 6-fluoro-7-(hydroxymethyl)-5H-pyrrolo[1,2-a]quinoxalin-4-one:

[0343] XPhos Pd G2 (53 mg, 0.068 mmol, 0.05 eq) was added to a stirred solution of 7-bromo-6-fluoro-5H-pyrrolo[1,2-a]quinoxaline-4-one (380 mg, 1.352 mmol, 1.00 eq) and (tributylstannyl)methanol (521 mg, 1.622 mmol, 1.2 eq) in 1,4-dioxane (10 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 20%)) to give 6-fluoro-7-(hydroxymethyl)-5H-pyrrolo[1,2-a]quinoxaline-4-one (250 mg, 79.6%). LC-MS: (ES+H, m / z): [M+H] + =233.3; 1H NMR(300MHz,DMSO-d6)δ11.28(s,1H),8.18(dd,J=2.9,1.5Hz,1H),7.88(dd,J=8.6,1.4Hz,1H),7.26(dd,J=8.5,7.2Hz,1H),7.08(dd,J=3.9,1.4Hz,1H),6.71(dd,J=3.9,2.8Hz,1H),5.36(t,J=5.8Hz,1H),4.61-4.59(m,2H).

[0344] Step 4 to Step 5: 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrrolo[1,2-a]quinoxalin-7-yl}methyl Preparation of [1-yl)piperazine-1-yl]-N-methylpyridine-2-carboxamide:

[0345] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-5H-pyrrolo[1,2-a]quinoxaline-4-one (150 mg, 0.646 mmol, 1 eq) and SOCl2 (384 mg, 3.230 mmol, 5 eq) in DCM (5 mL) was added DMF (9 mg, 0.129 mmol, 0.2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting crude mixture was used directly in the next step without further purification. To a stirred solution of 7-(chloromethyl)-6-fluoro-5H-pyrrolo[1,2-a]quinoxalin-4-one (crude) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide (142 mg, 0.598 mmol, 1 eq, 1 eq HCl salt) in MeCN (5 mL) was added KI (10 mg, 0.060 mmol, 0.1 eq) and DIEA (232 mg, 1.794 mmol, 3 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 5 hours. The reaction was monitored by LCMS. The resulting mixture was poured into water (20 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product (300 mg) was purified by preparative HPLC (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% formic acid), mobile phase B: MeOH-preparative; flow rate: 60 ml / min; gradient: 21% B to 36% B, 36% B in 9 minutes; wavelength: 254 / 220 nm; RT1 (min): 8.12;) to give 6-fluoro-5-[4-({6-fluoro-4-oxo-5H-pyrrolo[1,2-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (54 mg, 19.3%). LC-MS: (ES+H, m / z): [M+H] + =453.15; 1H NMR (300MHz, DMSO-d6) δ11.30(s,1H),8.40(q,J=4.9Hz,1H),8.20(dd,J=2.9,1.5Hz,1H),7.96-7.77(m,2H),7.56(dd,J=10.6,8.1Hz,1H),7.23(t, J=8.1Hz,1H),7.09(dd,J=3.9,1.4Hz,1H),6.72(t,J=3.6Hz,1H),3.66(s,2H),3.17(t,J=4.6Hz,4H),2.76(d,J=4.8Hz,3H),2.60(t,J=4.8Hz,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.56,-131.51.

[0346] Example 19 and Example 20

[0347]

[0348] Step 1: Preparation of methyl 2-amino-4-bromo-3-fluorobenzoate:

[0349] At room temperature under nitrogen atmosphere, a solution of 2-amino-4-bromo-3-fluorobenzoic acid (15.00 g, 64.09 mmol, 1.00 equivalent) in DMF (200 mL) was treated with DIEA (33.14 g, 256.38 mmol, 4.00 equivalent) for 5 minutes, followed by dropwise addition of CH3I (16.38 g, 115.37 mmol, 1.80 equivalent) at room temperature. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (1000 mL). The resulting mixture was washed with brine (3 × 500 mL), and the combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 30 minutes)) to give methyl 2-amino-4-bromo-3-fluorobenzoate (12.30 g, 73.4%). LC-MS: (ES+H, m / z): [M+H] + =247.8 / 249.8; 1 H NMR (300MHz, DMSO-d6) δ7.48 (dd, J=8.8, 1.7Hz, 1H), 6.93-6.22 (m, 3H), 3.82 (s, 3H).

[0350] Step 2: Preparation of methyl 4-bromo-2-acetylamino-3-fluorobenzoate:

[0351] To a stirred solution of methyl 2-amino-4-bromo-3-fluorobenzoate (12.30 g, 49.58 mmol, 1.00 equiv) in MeCN (100 mL) was added acetyl chloride (5.84 g, 74.38 mmol, 1.50 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (50 mL) to give methyl 4-bromo-2-acetamido-3-fluorobenzoate (9.00 g, 73.4%). LC-MS: (ES+H, m / z): [M+H] + =290.2 / 290.2.

[0352] Step 3: Preparation of 7-bromo-8-fluoro-4-hydroxy-1H-quinolin-2-one:

[0353] To a stirred solution of methyl 4-bromo-2-acetamido-3-fluorobenzoate (9.50 g, 32.74 mmol, 1.00 equiv) in THF (80 mL) was added LiHMDS (81 mL, 1.0 mol / L, 2.50 equiv) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reactants were quenched with water at 0 °C. The resulting mixture was diluted with water (100 mL) and acidified to pH 5 with HCl (aqueous solution). The precipitated solid was collected by filtration and washed with water (2×50 mL) to provide 7-bromo-8-fluoro-4-hydroxy-1H-quinolin-2-one (6.40 g, 76.9%). LC-MS: (ES+H, m / z): [M+H] + =257.8 / 259.8.

[0354] Step 4: Preparation of (3Z)-7-bromo-3-[(dimethylamino)methylene]-8-fluoro-1H-quinoline-2,4-dione:

[0355] A solution of 7-bromo-8-fluoro-4-hydroxy-1H-quinolin-2-one (6.50 g, 25.18 mmol, 1.00 equiv) and DMF-DMA (4.50 g, 37.78 mmol, 1.50 equiv) in toluene (70 mL) was stirred at 80 °C under nitrogen atmosphere for 24 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The precipitated solid was collected by filtration, washed with toluene (3×30 mL) and dried in vacuo to give (3Z)-7-bromo-3-[(dimethylamino)methylene]-8-fluoro-1H-quinoline-2,4-dione (2.50 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =313.2 / 315.2.

[0356] Step 5: Preparation of 7-bromo-4-chloro-8-fluoro-2-oxo-1H-quinoline-3-carbaldehyde:

[0357] A solution of (3Z)-7-bromo-3-[(dimethylamino)methylene]-8-fluoro-1H-quinoline-2,4-dione (2.50 g, 7.98 mmol, 1.00 equiv) and POCl3 (1.46 g, 9.58 mmol, 1.20 equiv) in DMF (40 mL) was stirred at 0°C under nitrogen atmosphere for 10 min. The resulting mixture was stirred at 60°C under nitrogen atmosphere for 24 h. The reaction was monitored by LCMS. The resulting mixture was diluted with water (50 mL) at 0°C. The precipitated solid was collected by filtration and washed with water (3×20 mL) to give 7-bromo-4-chloro-8-fluoro-2-oxo-1H-quinoline-3-carbaldehyde (2.25 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =303.8 / 305.8.

[0358] Step 6: 7-bromo-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-6-fluoro-2-methyl- Preparation of 5H-pyrazolo[4,3-c]quinolin-4-one:

[0359] A solution of 7-bromo-4-chloro-8-fluoro-2-oxo-1H-quinoline-3-carbaldehyde (2.25 g, 7.38 mmol, 1.00 equiv), K2CO3 (2.04 g, 14.77 mmol, 2.00 equiv) and methylhydrazine (1.28 g, 8.86 mmol, 1.20 equiv) in DMF (25 mL) was stirred at 80 ° C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with water (3×50 mL). The resulting solid was dried in vacuo to give a mixture of 7-bromo-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (3.50 g, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =295.9 / 297.9. 1 H NMR (300MHz, DMSO-d6) δ11.38(s,1H),8.15(s,1H),7.97(dd,J=8.8,1.5Hz,1H),7.55(dd,J=8.8,6.5Hz,1H),4.35(s,3H).

[0360] Step 7: 6-Fluoro-7-(hydroxymethyl)-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 6-fluoro-7-(hydroxymethyl)-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one Preparation of 2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one:

[0361] A solution of 7-bromo-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-bromo-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (3.5 g, 11.82 mmol, 1.00 equiv) and 2nd generation XPhos precatalyst (930 mg, 1.18 mmol, 0.10 equiv) and (tributylstannyl)methanol (4.55 g, 14.18 mmol, 1.20 equiv) in dioxane (20 mL) was stirred overnight at 80° C. under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo, and the crude residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 10% gradient in 20 minutes)) to give 6-fluoro-7-(hydroxymethyl)-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 6-fluoro-7-(hydroxymethyl)-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (mixture, 700 mg, 23.9%). LC-MS: (ES+H, m / z): [M+H] + =247.9.

[0362] Step 8: 7-(Chloromethyl)-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-(chloromethyl)-6- Preparation of fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one:

[0363] To a stirred solution of 6-fluoro-7-(hydroxymethyl)-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 6-fluoro-7-(hydroxymethyl)-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (700 mg, 2.83 mmol, 1.00 equiv) and DMF (20 mg, 0.28 mmol, 0.10 equiv) in DCM (10 mL) was added SOCl2 (3368 mg, 28.31 mmol, 10.00 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to give 7-(chloromethyl)-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-(chloromethyl)-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (700 mg, crude). The crude product was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =265.95.

[0364] Step 9: 6-Fluoro-5-[4-({6-fluoro-1-methyl-4-oxo-5H-pyrazolo[4,3-c]quinolin-7-yl}methyl) Piperazine-1-yl]-N-methylpyridine-2-carboxamide and 6-fluoro-5-[4-({6-fluoro-2-methyl-4-oxo-5H-pyrazolo[4,3- Preparation of [C]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide:

[0365] A solution of 7-(chloromethyl)-6-fluoro-1-methyl-5H-pyrazolo[4,3-c]quinolin-4-one and 7-(chloromethyl)-6-fluoro-2-methyl-5H-pyrazolo[4,3-c]quinolin-4-one (700 mg, 2.63 mmol, 1.00 equiv), KI (43 mg, 0.26 mmol, 0.10 equiv), DIEA (1702 mg, 13.17 mmol, 5.00 equiv) and 6-fluoro-N-methyl-5-(piperazine-1-yl)pyridine-2-carboxamide (627 mg, 2.63 mmol, 1.00 equiv) in MeCN (20 mL) was stirred at 80 ° C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with CH3CN (3×10 mL) to give the crude product. The crude product was purified by HPLC (column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MeOH-preparative; flow rate: 60 ml / min; gradient: 45% B to 56% B, in 13 minutes, 56% B; wavelength: 254 / 220nm) to give 6-fluoro-5-[4-({6-fluoro-1-methyl-4-oxo-5H-pyrazolo[4,3-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (Example 19, 54mg, 4.35%) and 6-fluoro-5-[4-({6-fluoro-2-methyl-4-oxo-5H-pyrazolo[4,3-c]quinolin-7-yl}methyl)piperazin-1-yl]-N-methylpyridine-2-carboxamide (Example 20, 1.8mg, 0.14%).

[0366] Example 19: LC-MS: (ES+H, m / z): [M+H] + =468.05; 1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.40(d,J=5.1Hz,1H),8.13(s,1H),8.02(d,J=8.4Hz,1H),7.84(dd,J=8.0,1.4Hz,1H),7.56(d d,J=10.6,8.1Hz,1H),7.34(t,J=7.5Hz,1H),4.36(s,3H),3.74(s,2H),3.23–3.11(m,4H),2.76(d,J=4.8Hz,3H),2.66–2.56(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-72.56,-131.30.

[0367] Example 20: LC-MS: (ES+H, m / z): [M+H] + =468.0; 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),8.59(s,1H),8.40(d,J=5.5Hz,1H),7.82(dd,J=16.8,8.0Hz,2H),7.55(t,J=9.4 Hz,1H),7.24(t,J=7.4Hz,1H),4.10(s,3H),3.69(s,2H),3.24–3.08(m,4H),2.76(d,J=4.7Hz,3H),2.66–2.56(m,4H). 19 F NMR(377MHz,DMSO-d6)δ-72.54,-132.86.

[0368] Embodiment 25

[0369]

[0370] Step 1: Preparation of 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylic acid ethyl ester:

[0371] To a stirred solution of ethyl 3-fluoro-1H-pyrazole-5-carboxylate (1.00 g, 2.10 mmol, 1.00 equiv) and K2CO3 (1.75 g, 12.64 mmol, 2.00 equiv) in DMF (10 mL) was added BnBr (2.16 g, 12.64 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (120 mL). The resulting mixture was extracted with EtOAc (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 30% gradient in 30 minutes)) to give ethyl 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylate (1.3 g, 82.8%). LC-MS: (ES+H, m / z): [M+H] + =249.1; 1 H NMR (300MHz, DMSO-d6) δ7.41–7.24(m,3H),7.23–7.12(m,2H),6.68(d,J=6.1Hz,1H),5.61(s,2H),4.29(q,J=7.1Hz,2H),1.26(t,J=7.1Hz,3H).

[0372] Step 2: Preparation of 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylic acid:

[0373] To a stirred solution of ethyl 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylate (1.30 g, 8.22 mmol, 1.00 equiv) in THF (10 mL) at room temperature was added LiOH (984 mg, 41.10 mmol, 5.00 equiv, 2M aqueous solution). The resulting solution was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The mixture was acidified to pH 3 with 2N HCl (aq), and the resulting mixture was extracted with EtOAc (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylic acid (1.10 g, 95.6%). LC-MS: (ES-H, m / z): [MH] - =219.0.

[0374] Step 3: Preparation of 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-3-fluoro-1H-pyrazole-5-carboxamide:

[0375] To a stirred solution of 1-benzyl-5-fluoro-1H-pyrazole-3-carboxylic acid (1.00 g, 4.54 mmol, 1.00 equiv) and 3-bromo-2,6-difluoroaniline (1.13 g, 5.44 mmol, 1.20 equiv) in T3P (2 mL, 50% EA solution) was added DIEA (1.76 g, 13.62 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ° C. under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (0% to 20% gradient in 30 minutes) to give 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-3-fluoro-1H-pyrazole-5-carboxamide (1.40 g, 96.3%). LC-MS: (ES+H, m / z): [M+H] + =409.9; 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),7.80-7.78(m,1H),7.39-7.26(m,4H),7.26-7.14(m,2H),6.85(d,J=5.8Hz,1H),5.61(s,2H).

[0376] Step 4: Preparation of ethyl 3-(2-benzyl-5-fluoropyrazole-3-amido)-2,4-difluorobenzoate:

[0377] To a stirred solution of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide (800 mg, 1.95 mmol, 1.00 equiv) and Pd(dppf)Cl2 (142 mg, 0.19 mmol, 0.10 equiv) in EtOH (6 mL) was added TEA (592 mg, 5.85 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C under carbon monoxide atmosphere for 2 days. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 30 minutes)) to give ethyl 3-(2-benzyl-5-fluoropyrazole-3-amido)-2,4-difluorobenzoate (300 mg, 38.1%). LC-MS:(ES-H,m / z):[MH] - =402.1; 1 H NMR(300MHz,DMSO-d6)δ10.52(s,1H),7.99-7.91(m,1H),7.45-7.24(m,4H),7.23-7.17( m,2H),6.85(d,J=5.9Hz,1H),5.62(s,2H),4.34(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0378] Step 5: Preparation of ethyl 2,4-difluoro-3-(3-fluoro-1H-pyrazole-5-carboxamido)benzoate:

[0379] To a stirred solution of ethyl 3-(1-benzyl-3-fluoro-1H-pyrazole-5-carboxamido)-2,4-difluorobenzoate (200 mg, 0.51 mmol, 1.00 equiv) in MeOH (3 mL) and 2M HCl (aqueous solution) (0.2 mL) was added Pd(OH)2 / C (72 mg, 0.10 mmol, 0.20 equiv, 20%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3×3 mL). The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (PE / EtOAc (0% to 20% gradient in 30 minutes)) to give ethyl 2,4-difluoro-3-(3-fluoro-1H-pyrazole-5-carboxamido)benzoate (240 mg, 39.0%). LC-MS:(ES-H,m / z):[MH] - =311.9; 1HNMR(300MHz,DMSO-d6)δ13.57(d,J=2.2Hz,1H),10.46(s,1H),8.07-7.80(m,1H),7.44 -7.37(m,1H),6.76(dd,J=6.2,2.3Hz,1H),4.34(q,J=7.1Hz,2H),1.32(t,J=7.1Hz,3H).

[0380] Step 6: Preparation of ethyl 2,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate:

[0381] To a stirred solution of ethyl 2,4-difluoro-3-(5-fluoro-2H-pyrazole-3-amide)benzoate (300 mg, 0.95 mmol, 1.00 equiv) in DMA (4 mL) was added NaH (76 mg, 1.91 mmol, 2.00 equiv, 60% in mineral oil) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred overnight at 120 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc (0% to 30% gradient in 30 minutes) to give ethyl 2,6-difluoro-4-oxo-4,5-dihydropyrazolo[1,5-a]quinoxaline-7-carboxylate (160 mg, 56.9%). LC-MS: (ES-H, m / z): [MH] - =292.0; 1 HNMR (300MHz, DMSO-d6) δ12.32(s,1H),7.88-7.83(m,1H),7.80-7.75(m,1H),7.08(d,J=5.6Hz,1H),4.36(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0382] Step 7: Preparation of 2,6-difluoro-7-(hydroxymethyl)-pyrazolo[1,5-a]quinoxaline-4(5H)-one:

[0383] To a stirred solution of ethyl 2,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate (150 mg, 0.10 mmol, 1.00 equiv) in THF (4 mL) was added dropwise LiEt3BH (1.5 mL, 1.53 mmol, 3.00 equiv, 1 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched at 0°C by adding water (1 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (40% to 70% gradient in 30 minutes) to give 2,6-difluoro-7-(hydroxymethyl)-pyrazolo[1,5-a]quinoxaline-4(5H)-one (102 mg, crude). LC-MS: (ES-H, m / z): [MH] - =250.0.

[0384] Step 8: Preparation of 7-(chloromethyl)-2,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one:

[0385] To a stirred solution of 2,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (90 mg, 0.35 mmol, 1.00 equiv) and DMF (2 mg, 0.03 mmol, 0.10 equiv) in CH2Cl2 (3 mL) was added dropwise SOCl2 (255 mg, 2.14 mmol, 6.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The filtrate was concentrated under reduced pressure to give 7-(chloromethyl)-2,6-difluoropyrazolo[1,5-a]quinoxalin-4(5H)-one (90 mg, crude). LC-MS: (ES-H, m / z): [MH] - =268.0.

[0386] Step 9: 5-[4-({2,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazine-1-yl Preparation of 6-fluoro-N-methylpyridine-2-carboxamide:

[0387] To a stirred solution of 7-(chloromethyl)-2,6-difluoro-5H-pyrazolo[1,5-a]quinoxaline-4-one (90 mg, 0.33 mmol, 1.00 equiv) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (79 mg, 0.33 mmol, 1.00 equiv) in MeCN (5 mL) was added DIEA (215 mg, 1.67 mmol, 5.00 equiv) and KI (5 mg, 0.03 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The precipitated solid was collected by filtration and washed with MeOH (3×5 mL). The precipitated solid was purified by trituration with MeOH (6 mL). The precipitated solid was filtered and washed with MeOH (3×5 mL) to give 5-[4-({2,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazin-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide (82.3 mg, 50.4%). LC-MS: (ES+H, m / z): [M+H] + =472.2; 1 H NMR (300MHz, DMSO-d6) δ12.17(s,1H),8.41(d,J=4.9Hz,1H),7.87–7.72(m,2H),7.56(dd,J=10.7,8.1Hz,1H),7. 40–7.30(m,1H),6.98(d,J=5.7Hz,1H),3.69(s,2H),3.18-3.15(m,4H),2.76(d,J=4.8Hz,3H),2.63-2.60(m,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.59,-126.66,-131.30.

[0388] Embodiment 28

[0389]

[0390] Step 1: Preparation of ethyl 4-fluoro-2H-pyrazole-3-carboxylate:

[0391] To a stirred solution of 4-fluoro-2H-pyrazole-3-carboxylic acid (850 mg, 6.53 mmol, 1.00 equiv) in EtOH (15 mL) was added SOCl2 (4.66 g, 39.21 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70 °C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, 96.7%). LC-MS: (ES-H, m / z): [MH] - =157.1; 1 H NMR (300MHz, DMSO-d6) δ7.60 (d, J = 4.5Hz, 1H), 4.38 (q, J = 7.1Hz, 2H), 1.35 (t, J = 7.1Hz, 3H).

[0392] Step 2: 1-Benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid ethyl ester and 1-Benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid ethyl ester Preparation of ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate:

[0393] To a stirred solution of ethyl 4-fluoro-2H-pyrazole-3-carboxylate (1.00 g, 6.32 mmol, 1.00 equiv) and KCO (2.62 g, 18.97 mmol, 3.00 equiv) in DMF (30 mL) was added (bromomethyl)benzene (2.16 g, 12.64 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (150 mL), washed with water (2×100 mL), dried over anhydrous NaSO, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 30% gradient in 30 minutes)) to give a mixture of ethyl 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylate and ethyl 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylate (1.30 g, 82.8%). LC-MS: (ES+H, m / z): [M+H] + =249.0; 1 H NMR(300MHz,DMSO-d6)δ7.50–7.29(m,6H),7.28–7.20(m,4H),5.69(s,1H),5.32(s,2H),4 .46(q,J=7.2Hz,2H), 4.36(q,J=7.1Hz,1H), 1.43(t,J=7.1Hz,3H), 1.36(t,J=7.1Hz,2H).

[0394] Step 3: Preparation of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid:

[0395] To a stirred solution of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid ethyl ester and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid ethyl ester (1.30 g, 5.23 mmol, 1.00 equiv) in THF (15 mL) was added LiOH (15 mL, 30.00 mmol, 5.73 equiv, 2 M aqueous solution) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL) and washed with EtOAc (1 × 80 mL). The aqueous layer was acidified to pH 6 with citric acid. The aqueous layer was extracted with EtOAc (3×100 mL), and the combined organic layers were dried over Na2SO4, filtered and concentrated to give 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid (1.10 g, 95.4%). LC-MS: (ES-H, m / z): [MH] - =219.1.

[0396] Step 4: 2-Benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide and 1-benzyl-N-(3-bromo- Preparation of 2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide:

[0397] To a stirred solution of 1-benzyl-4-fluoro-1H-pyrazole-3-carboxylic acid and 1-benzyl-4-fluoro-1H-pyrazole-5-carboxylic acid (1.10 g, 4.99 mmol, 1.00 equiv) in T3P (40 mL, 50% EA solution) was added DIEA (1.94 g, 14.98 mmol, 3.00 equiv) and 3-bromo-2,6-difluoroaniline (1.25 g, 5.99 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 ° C. under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (120 mL). The resulting mixture was washed with 2×100 mL of water, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (PE / EtOAc (0% to 30% gradient in 30 minutes)) to give a mixture of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide and 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide (1.60 g, 78.0%). LC-MS: (ES+H, m / z): [M+H] + =410.0 / 412.0; 1HNMR(300MHz,DMSO-d6)δ10.25(s,1H),10.06(s,1H),8.22(d,J=4.4Hz,1H),7.8 4–7.67(m,2H),7.45–7.28(m,7H),7.28–7.15(m,3H),5.56(s,1H),5.40(s,2H).

[0398] Step 5: 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoic acid ethyl ester and 3-(1-benzyl-4- Preparation of ethyl 2-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzoate:

[0399] To a solution of 2-benzyl-N-(3-bromo-2,6-difluorophenyl)-5-fluoropyrazole-3-carboxamide and 1-benzyl-N-(3-bromo-2,6-difluorophenyl)-4-fluoro-1H-pyrazole-3-carboxamide (1.20 g, 2.92 mmol, 1.00 equiv) in EtOH (8 mL) in a pressure vessel was added Pd(dppf)Cl2 (214 mg, 0.29 mmol, 0.10 equiv). The mixture was purged with nitrogen for 10 minutes and then pressurized to 50 atm with carbon monoxide at 120°C overnight. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EtOAc (0% to 40% gradient in 40 minutes)) to give a mixture of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoate and ethyl 3-(1-benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzoate (1.10 g, Y=93.2%). LC-MS: (ES+H, m / z): [M+H] + =404.1; 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),10.00(s,2H),8.21(d,J=4.4Hz,2H),7.99–7.86(m,3H),7.78(d,J=4.3H z,1H),7.46–7.25(m,16H),7.23–7.16(m,2H),5.56(s,2H),5.40(s,4H),4.38-4.3(m,6H),1.35-1.28(m,9H).

[0400] Step 6: Preparation of ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amide)benzoate:

[0401] To a solution of ethyl 3-(2-benzyl-4-fluoropyrazole-3-amido)-2,4-difluorobenzoate and ethyl 3-(1-benzyl-4-fluoro-1H-pyrazole-3-carboxamido)-2,4-difluorobenzoate (500 mg, 1.24 mmol, 1.00 equiv) in 20 mL MeOH / HCl=10:1 in a pressure vessel was added Pd(OH)2 / C (1.04 g, 1.49 mmol, 1.20 equiv, 20%). The mixture was hydrogenated at room temperature under 30 psi hydrogen pressure overnight and then filtered by Filter the pad and The pad was further washed with DCM:MeOH=10:1 (3×50 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc (30% to 60% gradient in 30 minutes)) to give ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amide)benzoate (150 mg, 38.6%). LC-MS: (ES+H, m / z): [M+H] + =314.1.

[0402] Step 7: Preparation of ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate:

[0403] To a stirred solution of ethyl 2,4-difluoro-3-(4-fluoro-2H-pyrazole-3-amide)benzoate (160 mg, 0.51 mmol, 1.00 equiv) in DMF (10 mL) was added Cs2CO3 (499 mg, 1.53 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ° C for 2 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (40 mL). The resulting mixture was extracted with CH2Cl2:IPA=10:1 (3×30 mL). The combined organic layers were washed with water (2×40 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (0% to 40% gradient in 40 minutes) to give ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate (60 mg, 40.0%). LC-MS: (ES-H, m / z): [MH] - =292.0; 1 H NMR (300MHz, DMSO-d6) δ12.11(s,1H),8.32(d,J=3.8Hz,1H),7.99(dd,J=8.8,1.3 Hz,1H),7.77(dd,J=8.8,6.9Hz,1H),4.37(q,J=7.1Hz,2H),1.34(t,J=7.1Hz,3H).

[0404] Step 8: Preparation of 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxaline-4-one:

[0405] To a stirred solution of ethyl 3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxaline-7-carboxylate (60 mg, 0.20 mmol, 1.00 equiv) in THF (4 mL) was added dropwise LiEt3BH (0.61 mL, 0.61 mmol, 3.00 equiv, 1 M in THF) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched at 0°C by adding water (0.2 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes)) to give 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxaline-4-one (50 mg, 97.2%). LC-MS:(ES-H,m / z):[MH] - =249.9.

[0406] Step 9: Preparation of 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one:

[0407] To a stirred solution of 3,6-difluoro-7-(hydroxymethyl)-5H-pyrazolo[1,5-a]quinoxalin-4-one (50 mg, 0.19 mmol, 1.00 equiv) and DMF (1 mg, 0.02 mmol, 0.10 equiv) in DCM (1 mL) was added dropwise SOCl2 (118 mg, 0.99 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxalin-4-one (50 mg, crude). LC-MS: (ES-H, m / z): [MH] - =268.0.

[0408] Step 10: 5-[4-({3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazine- Preparation of 1-methyl]-6-fluoro-N-methylpyridine-2-carboxamide:

[0409] To a stirred solution of 7-(chloromethyl)-3,6-difluoro-5H-pyrazolo[1,5-a]quinoxaline-4-one (50 mg, 0.18 mmol, 1.00 equiv) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (50 mg, 0.18 mmol, 1.00 equiv) in MeCN (3 mL) was added KI (3 mg, 0.01 mmol, 0.10 equiv) and DIEA (95 mg, 0.74 mmol, 4.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with MeCN (5 mL), and the precipitated solid was collected by filtration and washed with MeOH (3×3 mL). The precipitated solid was then purified by trituration with MeOH (4 mL), filtered and washed with MeOH (3×2 mL). The precipitated solid was then further purified by trituration with hexanes (4 mL). The precipitated solid was collected by filtration and washed with MeOH (3×2 mL) to give 5-[4-({3,6-difluoro-4-oxo-5H-pyrazolo[1,5-a]quinoxalin-7-yl}methyl)piperazine-1-yl]-6-fluoro-N-methylpyridine-2-carboxamide (42 mg, 46.9%). LC-MS: (ES+H, m / z): [M+H] + =472.1; 1 H NMR (300MHz, DMSO-d6) δ11.95(s,1H),8.40(q,J=4.6Hz,1H),8.22(d,J=3.8Hz,1H),7.91(dd,J=8.5,1.3Hz,1H),7.84(dd,J=8.0,1.5Hz, 1H),7.56(dd,J=10.6,8.1Hz,1H),7.35(dd,J=8.6,6.8Hz,1H),3.69(s,2H),3.19-3.16(m,4H),2.76(d,J=4.8Hz,3H),2.63-2.59(m,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.59,-130.76,-168.39.

[0410] The following examples were carried out using similar procedures as shown for Example 28.

[0411]

[0412] Embodiment 31

[0413]

[0414] Step 1: Preparation of 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione:

[0415] At 0 ℃ under nitrogen atmosphere, to the stirring mixture of 2-amino-4-bromo-3-fluorobenzoic acid (50.00g, 213.65mmol, 1.00 equivalent) in THF (500mL), a solution of ditrichloromethyl carbonate (31.70g, 106.82mmol, 0.50 equivalent) in THF (200mL) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in THF (100mL), stirred for 30 minutes, and then concentrated. The residue was then dissolved in hexane (100mL). The resulting mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The precipitated solid was collected by filtration and washed with hexane (3×100mL). The resulting mixture was concentrated under reduced pressure to give 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione (54 g, 97.2%). LC-MS: (ES-H, m / z): [MH] - =257.8 / 259.8; 1 HNMR (400MHz, DMSO-d6) δ12.15(s,1H),7.68(dt,J=8.6,1.6Hz,1H),7.53(ddd,J=8.4,6.0,1.9Hz,1H). 19 F NMR(377MHz,DMSO-d6)δ-122.54.

[0416] Step 2: Preparation of 3-(2-amino-4-bromo-3-fluorobenzoyl)dihydrofuran-2(3H)-one-5,5-d2:

[0417] Preparation of dihydrofuran-2(3H)-one-5,5-d2: To a stirred solution of succinic anhydride (10.00 g, 100.02 mmol, 1.00 equiv) in THF (200 mL) was added dropwise LiAlD4 (60 mL, 60.01 mmol, 0.60 equiv, 1 M in THF) at -55 °C under nitrogen atmosphere. The mixture was warmed to 0 °C and stirred for 1.5 hours. The reaction was monitored by TLC (PE:EA=1:1). The reaction was quenched at -15 °C by adding HCl (aqueous solution, 6 M) (35 mL). The resulting mixture was extracted with CH2Cl2 (3×500 mL). The combined organic layers were washed with brine (2×300 mL), dried over anhydrous MgSO4, filtered and concentrated to give dihydrofuran-2(3H)-one-5,5-d2 (4.5 g, 51.0%). 1 HNMR (400MHz, CDCl3) δ2.56–2.47(m,2H),2.31–2.20(m,2H).

[0418] To a stirred mixture of 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione (4.50 g, 17.30 mmol, 1.00 equiv) and dihydrofuran-2(3H)-one-5,5-d2 (2.29 g, 25.95 mmol, 1.50 equiv) in THF (90 mL) was added LDA (30.29 mL, 60.57 mmol, 3.50 equiv, 2 M in THF) dropwise at -70 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by adding MeOH (30 mL) at -15 °C. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS: (ES-H, m / z): [MH] - =301.9 / 303.9.

[0419] Step 3: Preparation of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-2,2-d2)quinolin-2(1H)-one:

[0420] To a stirred solution of 3-(2-amino-4-bromo-3-fluorobenzoyl)dihydrofuran-2(3H)-one-5,5-d2 (5.3 g, assuming 100% yield, 17.42 mmol, 1.00 equiv) in DMF (100 mL) was added K2CO3 (4.82 g, 34.85 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The mixture was diluted with ice water (800 mL) and then acidified to pH 4 with citric acid. The resulting mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water (3×100 mL) and dried to give 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-2,2-d2)quinolin-2(1H)-one (3.5 g, 66.0%). LC-MS: (ES+H, m / z): [M+H] + =304.0 / 306.0; 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),7.60(dd,J=8.7,1.4Hz,1H),7.39(dd,J=8.7,6.2Hz,1H),2.79(s,2H).

[0421] Step 4: Preparation of 7-bromo-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2:

[0422] To a stirred mixture of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-2,2-d2)quinolin-2(1H)-one (3.00 g, 9.86 mmol, 1.00 equiv) in DMA (30 mL) was added H2SO4 (3 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 140 °C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with ice water (500 mL) and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration and washed with water (3×100 mL). MeOH (30 mL) was added, and the precipitated solid was collected by filtration and washed with MeOH (3×5 mL). The resulting solid was dried to give 7-bromo-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2 (1.34 g, 47.4%). LC-MS: (ES+H, m / z): [M+H] + 285.9 / 287.9. 1 H NMR (400MHz, DMSO-d6) δ11.63(s,1H),7.43(dd,J=8.6,6.0Hz,1H),7.36(dd,J=8.6,1.2Hz,1H),3.05(s,2H).

[0423] Step 5: Preparation of 6-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2:

[0424] To a stirred mixture of 7-bromo-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2 (1.34 g, 4.68 mmol, 1.00 equiv) and (tributylstannyl)methanol (3.01 g, 9.36 mmol, 2.00 equiv) in dioxane (10 mL) was added 2nd Generation XPhos precatalyst (737 mg, 0.93 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 5% gradient in 30 minutes)) to give 6-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2 (730 mg, 65.7%). LC-MS: (ES-H, m / z): [MH] - =238.0; 1 H NMR (300MHz, DMSO-d6) δ11.38(s,1H),7.40(d,J=8.1Hz,1H),7.26(dd,J=8.2,6.3Hz,1H),5.44(s,1H),4.64(s,2H),3.05(s,2H).19 F NMR(282MHz,DMSO-d6)δ-134.69.

[0425] Step 6: Preparation of 7-(chloromethyl)-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2:

[0426] To a stirred mixture of 6-fluoro-7-(hydroxymethyl)(2,2-2H2)-3H,5H-furo[3,2-c]quinolin-4-one (711 mg, 2.99 mmol, 1.00 equiv) in DCM (10 mL) was added SOCl2 (2139 mg, 17.98 mmol, 6.00 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2 (779 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =256.0.

[0427] Step 7: 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl-2,2- d2) Preparation of methyl)piperazine-1-yl)-N-methylpicolinamide:

[0428] To a stirred mixture of 7-(chloromethyl)-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-2,2-d2 (779 mg, assuming 100% yield, 3.04 mmol, 1.00 equiv) and 6-fluoro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (837 mg, 3.04 mmol, 1.00 equiv) in MeCN (30 mL) was added DIEA (1.58 g, 12.18 mmol, 4.00 equiv) and KI (51 mg, 0.30 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with MeCN (3×20 mL). The residue was triturated with DMSO (15 mL) and the precipitated solid was collected by filtration and washed with MeOH (3 x 20 mL). The crude product (400 mg) was purified by preparative HPLC (column: XBridge Shield C18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3H2O), mobile phase B: MeCN; flow rate: 100 ml / min; gradient: 10% B to 40% B in 30 minutes; wavelength: 254 / 220 nm; RT1 (min): 10) to give 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl-2,2-d2)methyl)piperazin-1-yl)-N-methylpicolinamide (239.5 mg, 17.1% over two steps). LC-MS: (ES+H, m / z): [M+H] + =458.15; 1 H NMR (400MHz, DMSO-d6) δ11.42(s,1H),8.41(d,J=4.9Hz,1H),7.84(dd,J=8.2,1.4Hz,1H),7.55(dd,J=10.6,8.1Hz,1H),7.41(d, J=8.1Hz,1H),7.23(dd,J=8.2,6.1Hz,1H),3.69(s,2H),3.17(d,J=5.1Hz,4H),3.06(s,2H),2.76(d,J=4.8Hz,3H),2.58(s,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.56,-132.97.

[0429] Embodiment 32

[0430]

[0431] Step 1: Preparation of dihydrofuran-2(3H)-one-4,4-d2:

[0432] Sodium (1.2g, 51.76mmol, 1.54 equivalents) is dissolved in methane-d3-alcohol-d (128mL). Once sodium is consumed, add succinic acid, monomethyl ester (4.4g, 33.61mmol, 1.00 equivalents), then add methane-d3-alcohol-d (68mL). The solution is heated to reflux for 24 hours, then cooled in ice, and acetic acid-d3 acid-d (1.2g, 18.15mmol, 0.54 equivalents) is added. The solution is stirred for 20 minutes, and the solvent is removed in vacuo. The white solid is dissolved in water (50mL) and cooled in a water bath, while slowly adding NaBH4 (10.9g, 289.02mmol, 8.60 equivalents), then more water (15mL) is added. The reactant is stirred at room temperature for 12.5 hours, then cooled in ice. Concentrated HCl (29 mL) was added, followed by more concentrated HCl (5.9 mL), and the solution was heated to 110°C for 1 hour. It was then cooled to room temperature, saturated with NaCl, and extracted with DCM (4×150 mL). The combined organic extracts were dried over anhydrous MgSO4 and concentrated to give dihydrofuran-2(3H)-one-4,4-d2 (1.8 g, 60.8%). 1 H NMR (300MHz, CDCl3) δ4.35 (s, 2H), 2.49 (s, 2H).

[0433] Step 2 and Step 3: Preparation of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-1,1-d2)quinolin-2(1H)-one:

[0434] To a stirred mixture of 7-bromo-8-fluoro-1H-3,1-benzoxazine-2,4-dione (3.00 g, 11.54 mmol, 1.00 equiv) in THF (20 mL) was added dihydrofuran-2(3H)-one-4,4-d2 (1.20 g, 13.85 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The mixture was cooled to -70°C. To the above mixture was added LDA (20 mL, 40.38 mmol, 3.50 equiv, 2M in THF) dropwise at -70°C over 1 hour. The resulting mixture was stirred at 0°C for another 3 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (20 mL) at 0°C and then concentrated. DMF (50 mL) was added to the residue at room temperature under nitrogen atmosphere, followed by K2CO3 (3.20 g, 23.15 mmol, 2.00 equiv). The resulting mixture was stirred at 80°C under nitrogen atmosphere for another 3 hours and then cooled to room temperature. The mixture was diluted with ice water (500 mL), acidified to pH 4 with citric acid, and stirred at room temperature for 1 hour. The precipitated solid was collected by filtration, washed with water (3×50 mL) and dried at 45°C to give 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-1,1-d2)quinolin-2(1H)-one (1.9 g, 54.3% over two steps). LC-MS: (ES+H, m / z): [M+H] + =303.9.

[0435] Step 4: Preparation of 7-bromo-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2:

[0436] To a stirred mixture of 7-bromo-8-fluoro-4-hydroxy-3-(2-hydroxyethyl-1,1-d2)quinolin-2(1H)-one (1.90 g, 6.25 mmol, 1.00 equiv) in DMA (30 mL) was added dropwise concentrated H2SO4 (3 mL) at room temperature under nitrogen atmosphere (note: exothermic). The resulting mixture was stirred at 140°C under nitrogen atmosphere for 3 hours, cooled to room temperature, and then poured into ice water. The resulting mixture was stirred at room temperature for another 30 minutes. The precipitated solid was collected by filtration, washed with water (3×20 mL) and dried at 45°C to give 7-bromo-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2 (1.1 g, 61.5%). LC-MS: (ES+H, m / z): [M+H] + =285.9 / 287.9; 1 H NMR (300MHz, DMSO-d6) δ11.61(s,1H),7.53–7.26(m,2H),4.82(s,2H). 19F NMR(282MHz,DMSO-d6)δ-121.96.

[0437] Step 5: Preparation of 6-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2:

[0438] To a stirred mixture of 7-bromo-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2 (1.10 g, 3.85 mmol, 1.00 equiv) and 2nd generation XPhos precatalyst (303 mg, 0.39 mmol, 0.10 equiv) in dioxane (15 mL) was added (tributylstannyl)methanol (1.50 g, 4.61 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 3 hours. The mixture was allowed to cool to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (CH2Cl2 / MeOH (0% to 10% in 30 minutes)) to give 6-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2 (470 mg, 51.5%). LC-MS: (ES+H, m / z): [M+H] + =238.0; 1 HNMR (300MHz, DMSO-d6) δ11.37 (s, 1H), 7.41 (dd, J=8.2, 1.0Hz, 1H), 7.26 (dd, J= 8.2, 6.3Hz, 1H), 5.43 (t, J=5.8Hz, 1H), 4.81 (s, 2H), 4.64 (dd, J=5.8, 1.6Hz, 2H). 19 F NMR(282MHz,DMSO-d6)δ-135.04.

[0439] Step 6: Preparation of 7-(chloromethyl)-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2:

[0440] To a stirred mixture of 6-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2 (470 mg, 1.98 mmol, 1.00 equiv) in DCM (15 mL) at 0°C under nitrogen atmosphere was added SOCl2 (0.9 mL, 11.89 mmol, 6.00 equiv) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 5 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with CH2Cl2 (10 mL) and then concentrated under reduced pressure. The crude product was diluted with THF (40 mL) and then concentrated under reduced pressure. The product was further purified by trituration with MeCN (10 mL) to give 7-(chloromethyl)-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2 (560 mg, crude). LC-MS: (ES+H, m / z): [M+H] + =256.1

[0441] Step 7: 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuro[3,2-c]quinolin-7-yl-3,3- d2) Preparation of methyl)piperazine-1-yl)-N-methylpicolinamide:

[0442] To a stirred mixture of 7-(chloromethyl)-6-fluoro-3,5-dihydro[3,2-c]quinolin-4(2H)-one-3,3-d2 (540 mg, 2.11 mmol, 1.00 equiv) and 6-fluoro-N-methyl-5-(piperazine-1-yl)pyridine-2-carboxamide hydrochloride (580 mg, 2.11 mmol, 1.00 equiv) in MeCN (15 mL) was added DIEA (1.10 g, 8.45 mmol, 4.00 equiv) and KI (175 mg, 1.06 mmol, 0.50 equiv) at room temperature. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with MeCN (10 mL), and the precipitated solid was collected by filtration and washed with MeCN (3×5 mL). The residue was purified by trituration with MeOH (10 mL). The precipitated solid was collected by filtration and washed with MeOH (3 x 10 mL). The residue was purified by trituration with DMSO (5 mL). The precipitated solid was collected by filtration and washed with MeOH (3 x 10 mL). The obtained solid was concentrated under reduced pressure, and the crude product (550 mg) was purified by preparative HPLC (column: XBridge Shield C18 OBD column, 19*250 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3+0.1% NH3H2O), mobile phase B: MeCN; flow rate: 100 ml / min; gradient: 10% B to 40% B in 30 minutes; wavelength: 254 / 220 nm) to give 6-fluoro-5-(4-((6-fluoro-4-oxo-2,3,4,5-tetrahydrofuran[3,2-c]quinolin-7-yl-3,3-d2)methyl)piperazin-1-yl)-N-methylpicolinamide (409.8 mg, 42.0%). LC-MS: (ES+H, m / z): [M+H] + =458.15; 1 H NMR (300MHz, DMSO-d6) δ11.42(s,1H),8.40(d,J=5.0Hz,1H),7.84(dd,J=8.0,1.5Hz,1H),7.55(dd,J=10.6,8.1Hz,1H),7.40(d,J=8. 1Hz, 1H), 7.22 (dd, J = 8.2, 6.1Hz, 1H), 4.81 (s, 2H), 3.69 (s, 2H), 3.16 (d, J = 5.4Hz, 4H), 2.76 (d, J = 4.8Hz, 3H), 2.59 (d, J = 4.8Hz, 4H). 19 F NMR(282MHz,DMSO-d6)δ-72.56,-133.00.

[0443] Comparative Example:

[0444] Comparative Example 1 (Example 19 in WO2023025307)

[0445]

[0446] Step 1: Preparation of tert-butyl 4-[2-methyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate:

[0447] A mixture of 5-bromo-N,6-dimethylpyridine-2-carboxamide (1.00 g, 4.37 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (975 mg, 5.23 mmol, 1.20 equiv), BINAP (272 mg, 0.44 mmol, 0.10 equiv), Pd(OAc)2 (98 mg, 0.44 mmol, 0.10 equiv) and Cs2CO3 (3.56 g, 10.91 mmol, 2.50 equiv) in toluene (20.00 mL) was stirred at 80° C. under nitrogen atmosphere for several hours. The reaction system was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse combi-flash using the following conditions (70% aqueous MeOH with 0.1% NH3H2O) to give tert-butyl 4-[2-methyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (1.17 g, 79.9%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =335.3. 1 H NMR (300MHz, CD4OD) δ7.89(d,J=8.2Hz,1H),7.51(d,J=8.3Hz,1H),3.63(t,J=5.0Hz,4H),2.97(d,J=4.4Hz,7H),2.59(s,3H),1.51(s,9H).

[0448] Step 2: Preparation of N,6-dimethyl-5-(piperazin-1-yl)picolinamide hydrochloride:

[0449] To a stirred solution of tert-butyl 4-[2-methyl-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (200 mg, 0.60 mmol, 1 eq.) in DCM (4 mL) was added HCl (gas) (4 mL, 16.00 mmol, 26.75 eq., 4 M) in 1,4-dioxane at room temperature. The resulting solution was stirred at room temperature for 1 hour. LCMS was normal. The resulting mixture was concentrated under reduced pressure to give N,6-dimethyl-5-(piperazine-1-yl)pyridineamide hydrochloride (160 mg, crude) as a white solid, which was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =235.2

[0450] Step 3: Preparation of methyl 3-(furan-3-amide)-4-iodobenzoate:

[0451] A mixture of methyl 3-amino-4-iodobenzoate (10.00 g, 36.09 mmol, 1.00 equiv), 3-furoic acid (8.09 g, 72.18 mmol, 2.00 equiv), T3P (114.84 g, 180.46 mmol, 5.00 equiv, 50 wt% solution in EA) and DIEA (23.32 g, 180.46 mmol, 5.00 equiv) in DCM (100 mL) was stirred overnight at 60° C. under nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (PE 5:1) to give methyl 3-(furan-3-amide)-4-iodobenzoate (6.80 g, 50.76%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =372.0.

[0452] Step 4: Preparation of methyl 3-[N-(tert-butyloxycarbonyl)furan-3-amide]-4-iodobenzoate:

[0453] A solution of methyl 3-(furan-3-amido)-4-iodobenzoate (6.00 g, 16.167 mmol, 1.00 equiv), (Boc)2O (7.06 g, 32.34 mmol, 2.00 equiv) and DMAP (1.98 g, 16.17 mmol, 1.00 equiv) in DCE (100 mL) was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with EtOAc (250 mL) and washed with water (2×200 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (PE 3:1) to give methyl 3-[N-(tert-butoxycarbonyl)furan-3-amido]-4-iodobenzoate (5.00 g, 65.63%) as a white solid. 1 H NMR (300MHz, DMSO-d6) δ8.31(dd,1H),8.13(d,1H),7.90(d,1H),7.79(t,1H),7.69(dd,1H),6.79(dd,1H),3.87(s,3H),1.34(s,9H).

[0454] Step 5: Preparation of methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate:

[0455] To a mixture of methyl 3-[N-(tert-butyloxycarbonyl)furan-3-amido]-4-iodobenzoate (400 mg, 0.85 mmol, 1.00 equiv) and PCy3 (48 mg, 0.17 mmol, 0.20 equiv) in DMF (12 mL) at room temperature under nitrogen atmosphere was added Pd(OAc)2 (38 mg, 0.17 mmol, 0.20 equiv) and K2CO3 (235 mg, 1.70 mmol, 2.00 equiv). The final reaction mixture was irradiated with microwave radiation at 100°C for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (2×25 mL). The combined organic layers were washed with brine (2×25 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (100:1 to 1:2) to give methyl 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylate (120 mg, 58.13%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =244.0.

[0456] Step 6: Preparation of methyl 4-oxo-2H,3H,5H-furo[3,2-c]quinoline-7-carboxylate:

[0457] Under nitrogen atmosphere, Pd / C (200 mg, 10 wt %) was added to a solution of 4-oxo-5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (480 mg, 1.97 mmol, 1.00 equiv) in MeOH / DCM (80 mL / 20 mL). The mixture was hydrogenated under a hydrogen atmosphere at room temperature for 2 days. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography under the following conditions: column, C18; mobile phase, aqueous MeCN, 20% to 50% gradient, within 10 minutes; detector, UV 220 nm, to give 4-oxo-2H, 3H, 5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (170 mg, 35%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =246.2.

[0458] Step 7: Preparation of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[0459] To a stirred solution of 4-oxo-2H, 3H, 5H-furo[3,2-c]quinoline-7-carboxylic acid methyl ester (170 mg, 0.69 mmol, 1.00 equiv) in THF (8 mL) was added dropwise LiAlH4 (0.55 mL, 1.39 mmol, 2.00 equiv, 2.5 M in THF) at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred at 0 ° C for 2 hours under a nitrogen atmosphere. The reaction was quenched by adding 1M HCl aqueous solution (10 mL) at 0 ° C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2Cl2 / MeOH (10: 1 to 2: 1) to give 7-(hydroxymethyl)-2H, 3H, 5H-furo[3,2-c]quinoline-4-one (150 mg, 100%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =218.0. 1 H NMR (400MHz, DMSO-d6) δ11.38(s,1H),7.53(d,1H),7.34(s,1H),7.09(dd,1H),5.40-5.36(m,1H),4.79(t,2H),4.56(s,2H),3.03(t,2H).

[0460] Step 8: Preparation of 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one:

[0461] To a stirred solution of 7-(hydroxymethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (170 mg, 0.78 mmol, 1.00 equiv) and DMF (29 mg, 0.39 mmol, 0.50 equiv) in DCM (6 mL) was added thionyl chloride (744 mg, 6.26 mmol, 8.00 equiv) dropwise at 0 ° C under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography, which was eluted with CH2Cl2 / MeOH (30: 1 to 10: 1) to give 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (160 mg, 87%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =236.0.

[0462] Step 9: N,6-dimethyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl) Preparation of [piperazine-1-yl]pyridine-2-carboxamide:

[0463] A mixture of 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (200 mg, 0.849 mmol, 1.00 equiv), N,6-dimethyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (299 mg, assuming 100% yield, 1.10 mmol, 1.30 equiv), DIEA (438.74 mg, 3.396 mmol, 4 equiv) and KI (14.09 mg, 0.085 mmol, 0.10 equiv) in MeCN (5 mL) was stirred at 80° C. under nitrogen atmosphere for 2 hours. The resulting mixture was diluted with water (15 mL) and extracted with CH2Cl2:MeOH=10:1 (3×20 mL). The combined organic layers were washed with CH2Cl2 (3×5 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes) to give N,6-dimethyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazine-1-yl]pyridine-2-carboxamide (100 mg) as a yellow solid. The residue was purified by trituration with MeCN (5 mL). The precipitated solid was collected by filtration and washed with MeCN (1×1 mL) to give N,6-dimethyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazine-1-yl]pyridine-2-carboxamide (72 mg, 19.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =434.15.1 H NMR (400MHz, DMSO-d6) δ11.34(s,1H),8.41(q,J=4.8Hz,1H),7.79(d,J=8.2Hz ,1H),7.56(d,J=8.1Hz,1H),7.48(d,J=8.3Hz,1H),7.35(d,J=1.5Hz,1H),7.1 7(dd,J=8.2,1.5Hz,1H),4.79(t,J=9.2Hz,2H),3.62(s,2H),3.04(t,J=9.2Hz ,2H),2.95(t,J=4.7Hz,4H),2.80(d,J=4.8Hz,3H),2.58(s,4H),2.49(s,3H).

[0464] Comparative Example 2 (Example 18 in WO2023025307)

[0465]

[0466] Step 1: Preparation of tert-butyl 4-[6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate:

[0467] To a stirred mixture of methyl 5-bromopyridine-2-carboxylate (10.00 g, 46.28 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (12.93 g, 69.43 mmol, 1.50 equiv) in 1,4-dioxane (100 mL) was added Cs2CO3 (30.16 g, 92.57 mmol, 2.00 equiv) and RuPhos Palladacycle Gen.3 (1.94 g, 2.31 mmol, 0.05 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 5 hours. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EA (300 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (20% to 50% gradient in 25 minutes), and the pure fractions were concentrated in vacuo to give tert-butyl 4-[6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (11 g, Y=67.2%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =322.2.

[0468] Step 2: Preparation of tert-butyl 4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate:

[0469] A solution of tert-butyl 4-[6-(methoxycarbonyl)pyridin-3-yl]piperazine-1-carboxylate (5.00 g, 15.55 mmol, 1.00 equiv) in MeOH (50 mL) was treated with CH3NH2 (15 mL, 25 wt% to 30 wt% in water) at room temperature under nitrogen atmosphere for 10 minutes. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated in vacuo to give tert-butyl 4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (5 g, Y=96.8%) as a yellow solid. The resulting mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =321.3.

[0470] Step 3: Preparation of tert-butyl 4-[2-chloro-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate:

[0471] At room temperature under nitrogen atmosphere, a solution of tert-butyl 4-[6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (5 g, 15.60 mmol, 1.00 equiv) in MeCN (30 mL) was treated with a solution of NCS (2.71 g, 20.28 mmol, 1.30 equiv) in MeCN (20 mL) for 10 minutes. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20% to 50% gradient in 25 minutes), and the pure fractions were concentrated in vacuo to give tert-butyl 4-[2-chloro-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (3.5 g, Y=63.2%) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =355.1. 1 H NMR (400MHz, DMSO-d6) δ8.45(q,J=4.7Hz,1H),7.95(d,J=8.1Hz,1H),7.68(d,J=8. 2Hz, 1H), 3.60–3.44 (m, 4H), 3.13–3.01 (m, 4H), 2.79 (d, J = 4.8Hz, 3H), 1.43 (s, 9H).

[0472] Step 4: Preparation of 6-chloro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride:

[0473] A solution of tert-butyl 4-[2-chloro-6-(methylcarbamoyl)pyridin-3-yl]piperazine-1-carboxylate (300 mg, 0.84 mmol, 1.00 equiv) in DCM (3 mL) was treated with HCl in 1,4-dioxane (2 mL) for 1 minute at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated in vacuo to give 6-chloro-N-methyl-5-(piperazine-1-yl)pyridine-2-carboxamide hydrochloride (251 mg, crude) as a yellow solid. The resulting mixture was used directly in the next step without further purification. LC-MS: (ES+H, m / z): [M+H] + =255.1.

[0474] Step 5: 6-chloro-N-methyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl) Preparation of [piperazine-1-yl]pyridine-2-carboxamide:

[0475] To a stirred mixture of 6-chloro-N-methyl-5-(piperazin-1-yl)pyridine-2-carboxamide hydrochloride (203 mg, 0.70 mmol, 1.50 equiv) and 7-(chloromethyl)-2H,3H,5H-furo[3,2-c]quinolin-4-one (110 mg, 0.46 mmol, 1.00 equiv) in MeCN (5 mL) was added KI (15 mg, 0.09 mmol, 0.20 equiv) and DIEA (301 mg, 2.33 mmol, 5.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with CH2Cl2 / MeOH (10:1, 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 10 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.05% NH3H2O), mobile phase B: MeOH; flow rate: 60 ml / min; gradient: 53% B to 68% B in 8 minutes; wavelength: 254 nm / 220 nm; RT1 (min): 9.27). The pure fractions were concentrated in vacuo and lyophilized to give 6-chloro-N-methyl-5-[4-({4-oxo-2H,3H,5H-furo[3,2-c]quinolin-7-yl}methyl)piperazin-1-yl]pyridine-2-carboxamide (77.8 mg, Y=36.4%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =454.20. 1H NMR (400MHz, DMSO-d6) δ11.36(s,1H),8.43(q,J=4.7Hz,1H),7.94(d,J=8.1Hz,1H),7.70–7.63(m,1H),7.56(d,J=8.0Hz,1H),7.34(d ,J=1.4Hz,1H),7.16(d,J=8.1,1.7Hz,1H),4.79(t,J=9.2Hz,2H),3.61(s,2H),3.16–2.99(m,6H),2.79(d,J=4.7Hz,3H),2.58(s,4H).

[0476] Comparative Example 3 (Example 64 in WO2023025307)

[0477]

[0478] Step 1: Preparation of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate:

[0479] At -78 ° C under nitrogen atmosphere, DIEA (7 mL, 41.63 mmol, 1.20 equivalents) was added dropwise to a stirred mixture of 4-oxotetrahydrofuran-3-formic acid methyl ester (5.00 g, 34.69 mmol, 1.00 equivalents) in CH2Cl2 (50 mL) at -78 ° C. The resulting mixture was stirred at -78 ° C for 10 minutes under a nitrogen atmosphere. Tf2O (7 mL, 41.63 mmol, 1.20 equivalents) was added dropwise to the above mixture at -78 ° C. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, which was eluted with PE / EtOAc (0% to 20% gradient in 30 minutes) to give 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-formic acid methyl ester (8.40 g, 87.6%) as a red liquid. 1 H NMR (400MHz, CDCl3) δ4.91 (dd, J=5.8, 4.5Hz, 2H), 4.79 (dd, J=5.9, 4.5Hz, 2H), 3.83 (s, 3H). 19 F NMR (377MHz,CDCl3)δ-73.79.

[0480] Step 2: 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydrofuran-3-carboxylate Preparation of methyl ester:

[0481] To a stirred mixture of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydrofuran-3-carboxylate (8.20 g, 29.69 mmol, 1.00 equiv) and bis(pinacol)diboron (9.05 g, 35.63 mmol, 1.20 equiv) in dioxane (300 mL) at room temperature under nitrogen atmosphere was added Pd(dppf)Cl2 (1.09 g, 1.49 mmol, 0.05 equiv) and KOAc (8.74 g, 89.07 mmol, 3.00 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by gel column chromatography, eluting with PE / EtOAc (10% to 40% gradient in 30 minutes) to give methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydrofuran-3-carboxylate (4.20 g, 55.6%) as a light yellow oil. LC-MS: (ES+H, m / z): [M+H] + =255.1. 1 H NMR (300MHz, CDCl3) δ4.93 (td, J=5.2, 4.8, 1.0Hz, 2H), 4.83 (td, J=5.2, 1.0Hz, 2H), 3.78 (s, 3H), 1.36 (s, 12H).

[0482] Step 3: Preparation of 4-chloro-2-fluoro-6-nitroaniline:

[0483] A solution of 2-fluoro-6-nitroaniline (2.00 g, 12.81 mmol, 1.00 equiv) and NCS (1.80 g, 13.45 mmol, 1.05 equiv) in DMF (20 mL) was stirred overnight at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc (300 mL). The organic layer was washed with water (3 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, which was eluted with PE / EtOAc (0% to 20% gradient in 30 minutes) to give 4-chloro-2-fluoro-6-nitroaniline (1.80 g, 73.7%) as a yellow solid. LC-MS: (ES-H, m / z): [MH] - =189.1. 1 HNMR (400MHz, DMSO-d6) δ7.85 (t, J=2.2Hz, 1H), 7.68 (dd, J=11.0, 2.5Hz, 1H), 7.45 (s, 2H).

[0484] Step 4: Preparation of 2-bromo-5-chloro-1-fluoro-3-nitrobenzene:

[0485] A mixture of CuBr2 (3.99 g, 17.84 mmol, 2.00 equiv) and tert-butyl nitrite (5.35 mL, 44.61 mmol, 5.00 equiv) in MeCN (15 mL) was stirred at 60 ° C under a nitrogen atmosphere for 10 minutes. A solution of 4-chloro-2-fluoro-6-nitroaniline (1.70 g, 8.92 mmol, 1.00 equiv) in MeCN (10 mL) was added dropwise to the above mixture at 60 ° C. The resulting mixture was stirred at 60 ° C for another 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (0% to 5% gradient over 30 min) to give 2-bromo-5-chloro-1-fluoro-3-nitrobenzene (1.70 g, 74.8%) as a white solid. 1 HNMR(400MHz, DMSO-d6)δ8.19–8.13(m,1H),8.05(ddt,J=8.5,2.3,0.9Hz,1H).

[0486] Step 5: Preparation of methyl 4-(4-chloro-2-fluoro-6-nitrophenyl)-2,5-dihydrofuran-3-carboxylate:

[0487] To a stirred mixture of 2-bromo-5-chloro-1-fluoro-3-nitrobenzene (700 mg, 2.75 mmol, 1.00 equiv) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydrofuran-3-carboxylate (699 mg, 2.75 mmol, 1.00 equiv) in dioxane (20 mL) and H2O (1 mL) was added Pd(dppf)Cl2.CH2Cl2 (112 mg, 0.14 mmol, 0.05 equiv) and K2CO3 (1141 mg, 8.25 mmol, 3.00 equiv). The resulting mixture was stirred at 80°C under nitrogen atmosphere overnight. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (0% to 20% gradient in 30 minutes) to give methyl 4-(4-chloro-2-fluoro-6-nitrophenyl)-2,5-dihydrofuran-3-carboxylate (300 mg, 36.1%) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ8.22(t,J=1.8Hz,1H),8.13(dd,J=9.2,2.0Hz,1H),4.91(s,4H),3.55(s,3H).

[0488] Step 6: Preparation of 7-chloro-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one:

[0489] To a stirred mixture of methyl 4-(4-chloro-2-fluoro-6-nitrophenyl)-2,5-dihydrofuran-3-carboxylate (300 mg, 1.00 mmol, 1.00 equiv) and Fe (245 mg, 4.31 mmol, 10.00 equiv) in EtOH (10 mL) was added CaCl2 (662 mg, 5.97 mmol, 6.00 equiv). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with MeCN (3 mL) to give 7-chloro-9-fluoro-3,5-dihydrofuro[3,4-c]quinolin-4(1H)-one (170 mg, 71.3%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =240.1. 1 H NMR (400MHz, DMSO-d6) δ12.15(s,1H),7.28(dd,J=10.4,1.9Hz,1H),7.24(dd,J=2.0,0.9Hz,1H),5.30(td,J=4.3,2.2Hz,2H),4.92(t,J=4.2Hz,2H).

[0490] Step 7: Preparation of 9-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,4-c]quinolin-4(1H)-one:

[0491] To a stirred mixture of 7-bromo-9-chloro-3,5-dihydro[3,4-c]quinolin-4(1H)-one (190 mg, 0.79 mmol, 1.00 equiv) and 2nd generation XPhos precatalyst (62 mg, 0.08 mmol, 0.10 equiv) in dioxane (6 mL) was added (tributylstannyl)methanol (509 mg, 1.59 mmol, 2.00 equiv). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH2Cl2 / MeOH (10:1) (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes) to give 9-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,4-c]quinolin-4(1H)-one (80 mg, 42.9%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =236.1. 1 H NMR (400MHz, DMSO-d6) δ12.06(s,1H),7.22(s,1H),6.95(d,J=11.3Hz,1H),5.51(t,J= 5.7Hz, 1H), 5.32 (tt, J = 3.9, 1.8Hz, 2H), 4.93 (t, J = 4.2Hz, 2H), 4.57 (d, J = 5.7Hz, 2H).

[0492] Step 8: Preparation of 7-(chloromethyl)-9-fluoro-3,5-dihydro[3,4-c]quinolin-4(1H)-one:

[0493] To a stirred mixture of 9-fluoro-7-(hydroxymethyl)-3,5-dihydro[3,4-c]quinolin-4(1H)-one (60 mg, 0.26 mmol, 1.00 equiv) and DMF (2 mg, 0.03 mmol, 0.10 equiv) in CH2Cl2 (4 mL) was added dropwise SOCl2 (0.06 mg, 0.77 mmol, 3.00 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 7-(chloromethyl)-9-fluoro-3,5-dihydro[3,4-c]quinolin-4(1H)-one (50 mg, crude) as a yellow solid. LC-MS: (ES+H, m / z): [M+H] + =253.9.

[0494] Step 9: 6-Fluoro-5-(4-((9-fluoro-4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinolin-7-yl)methane Preparation of 1-methylpiperazine-1-yl)-N-methylpicolinamide:

[0495] To a stirred mixture of 7-(chloromethyl)-9-fluoro-3,5-dihydro[3,4-c]quinolin-4(1H)-one (45 mg, 0.18 mmol, 1.00 equiv) and 6-fluoro-N-methyl-5-(piperazin-1-yl)picolinamide hydrochloride (73 mg, 0.27 mmol, 1.50 equiv) in MeCN (3 mL) was added KI (6 mg, 0.04 mmol, 0.20 equiv) and DIEA (115 mg, 0.89 mmol, 5.00 equiv). The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 2 hours. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / MeOH (0% to 10% gradient in 30 minutes) to give the crude product (70 mg). The crude product (70 mg) was purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (0.1% HCOOH), mobile phase B: MeCN; flow rate: 60 milliliters per minute (mL / min); gradient: 4% B to 15% B in 8 minutes; wavelength: 254 nm / 220 nm nm; RT1 (minute): 12.82). The pure fractions were concentrated under reduced pressure and lyophilized to give 6-fluoro-5-(4-((9-fluoro-4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]quinolin-7-yl)methyl)piperazin-1-yl)-N-methylpicolinamide (28.0 mg, 34.2%) as a white solid. LC-MS: (ES+H, m / z): [M+H] + =456.10. 1 H NMR (300MHz, DMSO-d6) δ12.03(s,1H),8.41(q,J=4.7Hz,1H),7.85(dd,J=8.0,1.5Hz,1H),7.57(dd,J=10.6,8.1Hz,1H),7.22(s,1H),7.03(d ,J=11.2Hz,1H),5.32(d,J=5.1Hz,2H),4.93(t,J=4.2Hz,2H),3.62(s,2H),3.26–3.11(m,4H),2.77(d,J=4.7Hz,3H),2.57(t,J=4.6Hz,4H). 19 F NMR(282MHz,DMSO-d6)δ-72.508,-118.241.

[0496] Comparative Example 4 (Example 4 in CN115232129A)

[0497]

[0498] Example A: Cell Growth Inhibition Assay

[0499] The purpose of this study is to evaluate the effects of compounds disclosed herein on cell proliferation by cell viability assay in DLD-1BRCA2(- / -) and parental isogenic pairs and MDA-MB-436 (mutated BRCA1) cell lines. The CellTiter-Glo (CTG) based cell viability assay is designed to determine the number of viable cells in culture due to the effects of the compound by quantifying ATP (which indicates the presence of metabolically active cells).

[0500] DLD-1BRCA2 (- / -) and parent isogenic pairs were cultured in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both were cultured at 37 ° C and 5% CO2. The compounds of the present invention were distributed into 384-well plates (Corning, 3764) using an Echo sonic liquid handler to form a final concentration of 1:3 serial dilutions, with a maximum dose of 10 μM or 30 μM. Cells were seeded into plates at a density of 50 cells / well (DLD-1 parent), 200 cells / well (DLD-1BRCA2- / -) or 500 cells / well (MDA-MB-436). After a short period of centrifugation, cells were cultured undisturbed at 37 ° C and 5% CO2 in a fully humidified incubator for 7 days. Cell viability was measured by CellTiterGlo 2.0 assay kit (Promega, G9243), and growth inhibition was calculated and plotted against final compound concentration, and the data were fitted in Xfit to generate IC 50 .

[0501] Example B: Biochemical (FP) assay

[0502] Fluorescence polarization (FP) based assays have been widely used in drug discovery due to homogeneous format, robust performance and lack of interference observed in other assays. To characterize our compounds, we utilized an assay that measures displacement of a commercially available fluorescently labeled PARP1 / 2 inhibitor (PARPi-FL, Tocris Biosciences, #6461), as exemplified in assays performed in WO2014 / 064149 and WO2021 / 013735A1. The assay was performed using the following method:

[0503] Compounds were dissolved in DMSO and serially expanded over the desired concentration range in Optiplate-384F plates using an Echo 550 liquid handler. 100% DMSO was used for high (with protein) and low (without protein) control samples. 20 nL of compound or DMSO alone was added to each assay plate well.

[0504] PARP1 and PARP2 proteins were expressed, purified and diluted to a final concentration of 20 nM in assay buffer containing 50 mM Tris pH 8.0, 0.001% Triton X-100, 10 mM MgCl2, 150 mM NaCl. PARPi-FL was then added at a final concentration of 3 nM.

[0505] The assay plate was centrifuged at 1000 rpm for 1 minute and incubated at room temperature for 4 hours.

[0506] Fluorescence polarization was read using an Envision microplate reader using the following settings:

[0507] Excitation filter - FITC FP 480 - Excitation slot 3

[0508] Emission filter - FITC FP P-pol 535 - emission slot 4

[0509] 2nd emission filter - FITC FP S-pol 535 - emission slot 3

[0510] Mirror Module - FITC FP Dual Enh - Slot 1

[0511] The inhibition rate was calculated using the percentage of aligned Mahalanobis distances greater than the control sample (mP value) according to the following equation:

[0512] <![CDATA[mP c :mP value of the compound]]> <![CDATA[mP L : mP value of low control<!-- 70 --> ]]> <![CDATA[mP H : mP value of high control]]>

[0513]

[0514] The reported IC for each compound was calculated using XLFit (Eq. 201). 50 .

[0515] The data for Example A and Example B are provided in Table 2.

[0516] Table 2

[0517]

[0518] Example C: In vitro human transporter efflux Example C1: MDR1 and BCRP

[0519] Madin-Darby canine kidney (MDCKII) cells expressing MDR1 or BCRP were cultured at 545,000 cells / cm 2 Corning 96-well polycarbonate permeability (0.4 μm pore) support. Cells were cultured for 4 to 8 days before the assay, and monolayer integrity was assessed by measuring transepithelial electrical resistance (TEER). Test compounds and reference compounds were diluted to concentrations of 10 μM and 1 μM, respectively, with transport buffer (HBSS HEPES pH7.4). The final organic solvent concentration was 0.5% (v / v). The bidirectional (top to basolateral and basolateral to top) fluxes of test compounds and reference compounds were determined within 2 hours of incubation at 37°C and 5% CO2 and 95% relative humidity. At the end of the incubation, samples were taken from the top and basolateral sides and then precipitated with an internal standard containing acetonitrile. After centrifugation at 3200 × g, the supernatant was diluted with water 1: 1 (v / v) and analyzed via HPLC-MS / MS. The integrity of the cell monolayer during the assay was confirmed by using a marker fluorescent yellow at a final concentration of 100 μM.

[0520] Example C2: Caco-2

[0521] After a 1-hour equilibration period in cell culture medium at 37°C in an incubator containing 5% CO2 and 95% relative humidity, Corning 96-well HTS Permeable support plates were seeded with 34,300 Caco-2 cells (ATCC) per well. After seeding, plates were cultured for 14 to 18 days, with cell culture medium replaced every other day, starting at the latest 24 hours after plate seeding. During the culture period, monolayer barrier integrity was monitored using transepithelial electrical resistance (TEER) measurements performed with the Millicell Epithelial Volt-Ohm system. When TEER values ​​were >230 ohm·cm 2, it is considered that the Caco-2 monolayer is ready for use. The working stock solution of each test product with a concentration of 5 μM is prepared by diluting the 1mM stock solution prepared in DMSO into 10mM HEPES. Before measuring, the Caco-2 plate is washed twice with preheated 10mM HEPES, and then balanced in 10mM HEPES at 37°C for 30 minutes. After balance, the test product flux (in both directions from the top to the basolateral side and the basolateral side to the top) is tested bidirectionally by adding the test product working stock solution to the top chamber or the basolateral chamber. Blank 10mM HEPES is added to the opposite sides. The plate is then incubated for 2 hours at 37°C. At the end of the incubation, the aliquots from both sides of each monolayer are quenched with 4 volumes of ACN containing internal standards. After the centrifugation step, the supernatant is diluted with pure water and then analyzed via LC-MS / MS.

[0522] The apparent permeability (P) for all transport assays was calculated using the following formula: app , ×10 -6 cm / s):

[0523]

[0524] Where: P app is the apparent permeability (×10 -6 cm / s).

[0525] dQ / dt is the drug transport rate (pmol / s).

[0526] A is the surface area of ​​the membrane (cm 2 ).

[0527] D0 is the initial donor concentration (nM; pmol / cm 3 ).

[0528] P in the basolateral to apical direction was calculated by using the following formula app P in the apical to basolateral direction app The outflow rate is determined by the ratio of:

[0529]

[0530] Where: P app(B-to-A) is the apparent permeability in the basolateral to apical direction.

[0531] P app(A-to-B) is the apparent permeability in the apical to basolateral direction.

[0532] The data for Example C1 and Example C2 are provided in Table 3.

[0533] Table 3: MDR1, BCRP and Caco-2

[0534]

[0535] Example D: In vivo determination of rat Kp,uu

[0536] Determination of unbound fraction (Pu) in plasma

[0537] Use equilibrium dialysis to study the in vitro binding of test article and reference compound to plasma protein. Plasma samples containing 5 μM test article or blank dialysis buffer solution (PBS, pH 7.4) are added to the separate chamber of the dialysis well of high-throughput equilibrium dialysis (HTD) device. The dialysis plate is sealed and placed in an incubator at 37 ° C and 5% CO2, and shaken at about 100 rpm for 6 hours. All experiments are performed in duplicate. Ketoconazole (5 μM) is used as a reference compound. After cultivation, the seal is removed, and 50 μL of the post-dialysis sample is pipetted from the buffer chamber and the plasma chamber to a fresh 96-well plate. By adding blank plasma to the buffer sample or adding blank buffer to the plasma sample, matrixization (equimatrilyzed) samples are carried out. Subsequently, 400 μL (4 volumes) of the internals containing acetonitrile are added to all samples to precipitate protein, and then UPLC-MS / MS analysis is performed to determine the relative concentration of the test article. The unbound fraction in plasma was calculated using the test article concentrations in the buffer and plasma samples according to the following equation:

[0538]

[0539] Determination of the unbound fraction (Bu) in brain homogenates

[0540] Use equilibrium dialysis to study the in vitro binding of test article and reference compound to rodent brain homogenate. The brain collected from protozoa is weighed and homogenized in 4 volumes of pH 7.4PBS. The brain homogenate sample containing 1 μM test article or blank dialysis buffer solution (PBS, pH 7.4) is added to the separate chamber of the dialysis well of high-throughput equilibrium dialysis (HTD) device. The dialysis plate is sealed and placed in an incubator at 37 ° C and 5% CO2, and shaken at about 100 rpm for 6 hours. All experiments are performed in duplicate. Telmisartan (5 μM) is used as a reference compound. After cultivation, the seal is removed, and 50 μL of the post-dialysis sample is pipetted into a fresh 96-well plate from the buffer chamber and the brain homogenate chamber. Matrixed samples are prepared by adding blank homogenate to the buffer sample or adding blank buffer to the homogenate sample. Subsequently, 400 μL (4 volumes) of acetonitrile-containing internals were added to all samples to precipitate proteins before UPLC-MS / MS analysis to determine the relative concentration of the test article. The unbound fraction in the diluted brain homogenate was calculated using the test article concentration in the buffer sample and the homogenate sample according to the following equation:

[0541]

[0542] Correction for percent unbound in undiluted brain was achieved using the following equation:

[0543]

[0544] Determination of drug brain-plasma partition coefficient (Kp) and drug unbound Kp (Kp,uu) in rats

[0545] Compounds are prepared individually or in boxes (as a mixture) at a concentration of 0.1 mg / mL / compound in sterile water containing 0.5% (w / v) methylcellulose 400 cP, and administered to male Sprague-Dawley rats via oral gavage at a dose volume of 10 mL / kg. One animal is killed at each time point in the following time points: 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration, and brain samples and blood samples are collected. Plasma is prepared from blood via refrigerated centrifugation, and plasma samples are stored frozen at -80°C until bioanalysis. Brain samples are rinsed with saline to remove residual blood and blotted with paper towels. Then, brain samples are weighed and homogenized with 3 volumes (v / w) of water, and stored frozen at -80°C until bioanalysis.

[0546] Prior to bioanalysis, plasma and brain samples were extracted with 4 volumes of internal standard containing acetonitrile and centrifuged for 15 minutes. The supernatant was diluted with 2 volumes of water and injected for analysis via HPLC-MS / MS. Plasma and brain homogenate drug concentrations were determined relative to calibration curves generated by spiking blank rat plasma or brain homogenate with drug across an appropriate concentration range. Brain homogenate concentrations were corrected for the homogenization buffer dilution factor to obtain total brain drug concentrations.

[0547] The brain to plasma partition coefficient (Kp) was determined for each compound and calculated as: AUC brain: AUC plasma, provided that t last was the same in each matrix. If the drug concentration versus time curve for one matrix was below the lower limit of quantification at an earlier time point than the other matrix, then the brain Kp was calculated as the average of the ratios of the total brain drug concentration to the total plasma drug concentration measured at each time point at which the drug concentration in both matrices was quantifiable.

[0548] Subsequently, Kp,uu was calculated from Kp using the following equation: Kp,uu = Kp x (unbound fraction in brain homogenate / unbound fraction in plasma).

[0549] The data for Example D is provided in Table 4.

[0550] Table 4: Kp,uu data

[0551] Example Rat Kpuu 1 1.0 9 0.65 24 0.81

[0552] Example E: HLM and hHEP assays

[0553] HLM

[0554] The working stock solution of each test article with a concentration of 100 μM is prepared by diluting the 10mM stock solution prepared in DMSO 100 times (v:v) into ACN. The thawed liver microsomes are suspended in 100mM potassium phosphate buffer (pH 7.4) to a microsomal protein concentration of 0.562 mg / mL. The diluted microsomes are mixed with 10mM NADPH solution, and the mixture is preheated to 37°C for 8 minutes. The reaction is initiated by adding the test article working stock solution to reach a final test article concentration of 1 μM. The final microsomal protein and NADPH concentrations are 0.5 mg / mL and 1 mM, respectively. Incubations containing NADPH are carried out in duplicate. In the absence of NADPH, the test article loss mediated by non-CYP mechanisms is assessed in the incubation runs of parallel groups. The incubation lacking NADPH consists of 1 replicate for each test article. After incubation in a 37°C water bath, aliquots of each reaction were quenched with cold ACN containing internal standard at 0.5 min, 15 min, 30 min, 60 min, 90 min, and 120 min. The precipitated protein was precipitated via refrigerated centrifugation. The supernatant was diluted into an equal volume of pure water and mixed thoroughly before analysis via LC-MS / MS. The in vitro intrinsic clearance (CL) was calculated in μL / min / mg for each incubation. int ) was determined from the calculated in vitro half-life determined using standard log-linear regression methods. int The values ​​were scaled using the following physiological scaling factors: 40 mg liver microsomal protein / g human liver and 25.7 g human liver / kg body weight. To calculate the predicted human hepatic clearance (CL) in mL / min / kg hep,pred ), assuming a human liver blood flow of 21 mL / min / kg and without correction for test article binding to erythrocytes, plasma proteins, or components of the incubation system, ultimately introducing scaled intrinsic clearance values ​​to a well-stirred liver model.

[0555] HkD

[0556] Working stocks of each test article at a concentration of 100 μM were prepared by diluting a 10 mM stock solution prepared in DMSO 100-fold (v:v) into ACN / H2O (50 / 50, v:v). Human cryopreserved hepatocytes were thawed in a 37°C water bath for <2 min, suspended in thawing medium, and then centrifuged at 100×g for 10 min. The thawing medium was aspirated and the pelleted hepatocytes were centrifuged at 1.5×10 6 Cell viability was determined using acridine orange / propidium iodide stain, and hepatocytes were further diluted to 0.5 × 10 cells / mL in incubation medium. 6Live cells / mL. 198 μL of hepatocyte aliquots were added to the wells of a 96-well plate, and incubation of the test article was initiated by adding 2 μL of a 100 μM working stock solution. The plates were incubated at 37°C, 5% CO2 atmosphere, 95% relative humidity on an orbital shaker at 300 rpm. Incubations were performed in duplicate. After incubation, aliquots of each reaction were terminated by adding ACN containing an internal standard at 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, and 240 minutes. The precipitated protein was precipitated via frozen centrifugation. The supernatant was diluted into an equal volume of pure water and mixed thoroughly, then analyzed by LC-MS / MS. Each incubation was performed at μL / min / 10 6 Intrinsic clearance (CL) of cells int ) was determined from the calculated in vitro half-life determined using standard log-linear regression methods. int Values ​​are scaled using the following physiological scaling factor: 99×10 6 cells / g human liver and 25.7 g human liver / kg body weight. To calculate the predicted human liver clearance (CL) in mL / min / kg hep,pred ), assuming a human liver blood flow of 21 mL / min / kg and without correction for test article binding to erythrocytes, plasma proteins, or components of the incubation system, ultimately introducing scaled intrinsic clearance values ​​to a well-stirred liver model.

[0557] The data for Example E is provided in Table 5.

[0558] Table 5: HLM and HHEP data

[0559] Example HLM Clh (mL / min / kg) HHEP Clh (mL / min / kg) 9 <4 <3.3 Comparative Example 1 <4 <3.3 Comparative Example 2 4.2 6.6 Comparative Example 3 7.2 7.1 Comparative Example 4 11.5 14.5

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof: in: Ring A together with X and Y is a 5-membered heterocycloalkyl or a 5-membered heteroaryl; X is C, CH or N; Y is C, CH or N; Each R 1 are independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 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 with one or more R; Or two R on the same carbon 1 Together they form an oxo group; n is 0-6; Z is N or CR Z ; R Z For 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 with one or more R; R 2 For 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 with one or more R; R 3 For 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 with one or more R; or R 2 and R 3 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R; Each R 4 Independently for deuterium, 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 R on the same carbon 4 Together they form an oxo group; or two R on the same carbon or on different carbons 4 together form a cycloalkyl or heterocycloalkyl; each optionally substituted by one or more R; m is 0-4; R 5 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 with one or more R; R 6 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 with one or more R; R 7 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 with one or more R; R 8 For 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 or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more R; Each R a Independently for 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 each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R; Each R c and R d are independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 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 each alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more R; or R c and R d together with the atoms to which they are attached form heterocycloalkyl optionally substituted with one or more R; and Each R is independently halogen, -CN, -OH, -OC 1 -C 3 Alkyl, -OC 1 -C 3 Halogenated alkyl, -SC 1 -C 3 Alkyl, -S(=O)C 1 -C 3 Alkyl, -S(=O) 2 C 1 -C 3 alkyl,- S(=O) 2 NH 2 、-S(=O) 2 NHC 1 -C 3 Alkyl, -S(=O) 2 N(C 1 -C 3 alkyl) 2 、-NH 2 、- NHC 1 -C 3 Alkyl, -N(C 1 -C 3 alkyl) 2 、-C(=O)C 1 -C 3 Alkyl, -C(=O)OH, - C(=O)OC 1 -C 3 Alkyl, -C(=O)NH 2 、-C(=O)NHC 1 -C 3 Alkyl, -C(=O)N(C 1 - C 3 alkyl) 2 , C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Deuterated alkyl, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Aminoalkyl, C 1 -C 3 Heteroalkyl or C 3 -C 6 Cycloalkyl; Alternatively, two R on the same atom may together form an oxo group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ia): Where R 1 ' is hydrogen or R 1 .

3. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ib): Where R 1 ' is hydrogen or R 1 .

4. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ic): Where R 1 ' is hydrogen or R 1 .

5. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Id): Where R 1 ' is hydrogen or R 1 .

6. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ie): Where R 1 ' is hydrogen or R 1 .

7. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (If): Where R 1 ' is hydrogen or R 1 .

8. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ig): Where R 1 ' is hydrogen or R 1 .

9. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ih): Where R 1 ' is hydrogen or R 1 .

10. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ii): Where R 1 ' is hydrogen or R 1 .

11. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ij): Where R 1 ' is hydrogen or R 1 .

12. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ik): Where R 1 ' is hydrogen or R 1 .

13. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (I1): Where R 1 ' is hydrogen or R 1 .

14. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Im): Where R 1 ' is hydrogen or R 1 .

15. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (In): Where R 1 ' is hydrogen or R 1 .

16. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Io): Where R 1 ' is hydrogen or R 1 .

17. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ip): Where R 1 ' is hydrogen or R 1 .

18. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Iq): Where R 1 ' is hydrogen or R 1 .

19. The compound according to claim 1 or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound has formula (Ir): Where R 1 ' is hydrogen or R 1 .

20. A compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 are independently halogen or C 1 -C 6 alkyl.

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

22. A compound according to any one of claims 2 to 19, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 1 ' is hydrogen.

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

24. A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein Z is CR Z .

25. A compound according to any one of claims 1 to 22 or 24, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R Z is hydrogen, deuterium, halogen or C 1 -C 6 alkyl.

26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 is hydrogen, deuterium or C 1 -C 6 alkyl.

27. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 3 is hydrogen, deuterium or C 1 -C 6 alkyl.

28. A compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 2 and R 3 Together they form a cycloalkyl group.

29. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 Independently for deuterium, C 1 -C 6 Alkyl or C 1 -C 6 Halogenated alkyl.

30. A compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein each R 4 Independently for C 1 -C 6 alkyl.

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

32. A compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 5 is hydrogen, halogen or C 1 -C 6 alkyl.

33. A compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 5 It is a halogen.

34. A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 6 is hydrogen, halogen or C 1 -C 6 alkyl.

35. A compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 6 For hydrogen.

36. A compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7 is hydrogen, halogen or C 1 -C 6 alkyl.

37. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 7 For hydrogen.

38. A compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8 C 1 -C 6 Alkyl or cycloalkyl; wherein The alkyl and cycloalkyl groups are optionally substituted with one or more R groups.

39. A compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R 8 C 1 -C 6 alkyl.

40. A compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein the compound or a pharmaceutically acceptable salt, solvate or stereoisomer thereof is selected from the compounds disclosed in the present specification.

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

42. A method of treating cancer in a subject in need thereof, the method comprising administering a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

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

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

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

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

47. The method of any one of claims 42 to 46, 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, stomach cancer, thyroid cancer, or uterine cancer.

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

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

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

51. A method of treating brain cancer in a subject in need thereof, the method comprising administering a compound according to any one of claims 1 to 40, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

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

Images