BCL6 inhibitor

Abstract

To provide compounds that function as inhibitors of BCL6 (B-cell lymphoma 6) activity, processes for preparation of these compounds, pharmaceutical compositions comprising them, and use thereof in treatment of proliferative disorders, such as cancer, and other diseases or conditions in which BCL6 activity is implicated.SOLUTION: The invention presents compounds represented by the formula in the figure, and specifically, e.g., (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinolin-6(7H)-one.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention relates to certain compounds that function as inhibitors of BCL6 (B-cell lymphoma 6) activity. The invention also relates to processes for preparing these compounds, pharmaceutical compositions containing them, and their use in the treatment of proliferative disorders such as cancer, and other diseases or conditions associated with BCL6 activity. [Background technology]

[0002] BCL6 is a zinc finger transcriptional repressor that plays a crucial role in germinal center formation and development, where somatic mutations and rearrangements of immunoglobulin genes occur in B cells, resulting in antibody diversity against various foreign antibodies (Dent et al., Science, 1997, 276, 589-592). BCL6 promotes the proliferation of antibody-producing B cells by repressing genes involved in DNA damage response, cell cycle arrest, and apoptosis. BCL6 mediates this repression by recruiting corepressor proteins SMRT, NCoR, and BCoR to an expanded groove motif formed along the dimer interface of the BCL6 BTB (BR-C, Ttk, and Bab) domain (Ahmad et al., Mol Cell, 2003, 12, 1551-1564; Ghetu et al., Mol Cell, 2008, 29, 384-391). Genetic upregulation of the BCL6 gene, observed in many lymphomas, leads to the proliferation of malignant B cells (Hatzi & Melnick, Trends Mol Med, 2014, 20, 343-352). Therefore, there is a need to develop drugs that inhibit the oncogenic effects of BCL6 by selectively binding to the BTB domain and preventing corepressor recruitment, or by binding to the BTB domain and inducing proteolysis (Kerres et al. Cell Rep., 2017, 20, 2860-2875). [Overview of the project]

[0003] According to a first aspect of the present invention, the compounds defined above herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided.

[0004] A further aspect of the present invention provides a pharmaceutical composition comprising a compound as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate (in a mixture thereof), and a pharmaceutically acceptable diluent or carrier.

[0005] A further aspect of the present invention provides a method for inhibiting BCL6 kinase enzyme activity in vitro or in vivo, the method comprising the step of contacting cells with an effective amount of a compound defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0006] A further aspect of the present invention provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising the step of contacting cells with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0007] A further aspect of the present invention provides a method for treating a disease or disorder related to BCL6 activity, which is to be performed in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0008] A further aspect of the present invention provides a method for treating a proliferative disorder, which is to be performed in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0009] A further aspect of the present invention provides a method for treating cancer, which is to be performed in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0010] Further aspects of the present invention provide compounds, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in therapeutic purposes.

[0011] Further aspects of the present invention provide compounds as defined herein, or pharmaceutically acceptable salts, hydrates or solvates thereof, or pharmaceutical compositions as defined herein, for use in treating proliferative conditions.

[0012] Further embodiments of the present invention provide compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, for use in the treatment of cancer. In certain embodiments, cancer is human cancer.

[0013] Further aspects of the present invention provide compounds as defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, which are used to inhibit BCL6 activity.

[0014] Further aspects of the present invention provide compounds as defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in treating diseases or disorders associated with BCL6 activity.

[0015] A further aspect of the present invention provides the use of the compounds defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for treating proliferative conditions.

[0016] Preferably, the proliferative disorder is cancer, and preferably human cancer (e.g., lymphoma (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), and multiple myeloma, as well as hematological cancers such as solid tumors (including glial cell tumors, breast cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinoma (SCC) (including SCC of the head and neck, esophagus, lung, and ovary))).

[0017] A further aspect of the present invention provides the use of the compounds defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for the treatment of cancer.

[0018] A further aspect of the present invention provides the use of the compounds defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for inhibiting BCL6 activity.

[0019] A further aspect of the present invention provides the use of the compounds defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for the treatment of diseases or disorders related to BCL6 activity.

[0020] Further aspects of the present invention provide processes for preparing the compounds defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0021] Further aspects of the present invention provide compounds that can be obtained by, or are obtained directly by, a compound preparation process defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof.

[0022] A further aspect of the present invention provides a novel intermediate, as defined herein, which is suitable for use in any one of the synthesis methods described herein.

[0023] Any optional feature comprising preferred and desirable features relating to one aspect of the present invention may also be any optional feature comprising preferred and desirable features relating to any other aspect of the present invention. [Modes for carrying out the invention]

[0024] definition Unless otherwise specified, the following terms used in the specification and claims shall have the meanings set forth below.

[0025] It should be recognized that references to “treating” or “treatment” include the prevention and mitigation of established symptoms of a condition. Therefore, “treating” or “treatment” of a condition, disorder, or state includes: (1) prevention or delay of the onset of clinical symptoms of a condition, disorder, or state in a person who is suffering from or susceptible to a condition, disorder, or state but has not yet experienced or may not have shown any clinical or quasi-clinical symptoms of the condition, disorder, or state; (2) inhibition of the condition, disorder, or state, i.e., prevention, reduction, or delay of the onset or recurrence of the disease (in the case of maintenance therapy) or at least one clinical or quasi-clinical symptom thereof; or (3) reduction or attenuation of the disease, i.e., regression of at least one clinical or quasi-clinical symptom thereof.

[0026] The "therapeutic effective dose" refers to the amount of a compound sufficient to treat a disease effectively when administered to a mammal. The therapeutic effective dose will vary depending on the compound, the disease and its severity, and the age and weight of the mammal being treated.

[0027] In this specification, the term “alkyl” includes both linear and branched alkyl groups. References to individual alkyl groups, such as “propyl,” are specific only to linear ones, and references to individual branched alkyl groups, such as “isopropyl,” are specific only to branched ones. For example, “(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and t-butyl.

[0028] The term "(m~nC)" or "(m~nC) group" is used alone or as a prefix to refer to any group having m to n carbon atoms.

[0029] The "alkylene" group is an alkyl group that is located and bonded between two other chemical groups. Therefore, "(1-6C)alkylene" refers to a linear saturated divalent hydrocarbon radical having 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon radical having 3 to 6 carbon atoms, such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), 2-methylpropylene (-CH2CH(CH3)CH2-), pentylene (-CH2CH2CH2CH2CH2-), etc.

[0030] The term "alkenyl" refers to linear and branched alkyl groups containing two or more carbon atoms, with at least one carbon-carbon double bond present in the group. Examples of alkenyl groups include ethenyl, propenyl, and buta-2,3-enyl, as well as all possible geometric (E / Z) isomers.

[0031] The term "alkynyl" refers to linear and branched alkyl groups containing two or more carbon atoms, with at least one carbon-carbon triple bond present in the group. Examples of alkynyl groups include acetylenyl and propynyl.

[0032] "(3-10C)cycloalkyl" means a hydrocarbon ring containing 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and bicyclo[2.2.1]heptyl.

[0033] "(3-10C) cycloalkenyl" refers to a hydrocarbon ring containing 3 to 10 carbon atoms and at least one double bond, such as cyclobutenyl, cyclopentenyl, 3-cyclohexen-1-yl, or cyclohexenyl or cycloheptenyl.

[0034] The term "alkoxy" refers to O-bonded linear and branched alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and t-butoxy.

[0035] The terms "haloalkyl" and "haloalkoxy" are used herein to refer to alkyl or alkoxy groups, respectively, in which one or more hydrogen atoms are replaced by halogen (e.g., fluorine) atoms. Examples of haloalkyl groups include -CH2F, -CHF2, and -CF3. Examples of haloalkoxy groups include -OCH2F and -OCF3.

[0036] The term "aminoalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by an amino group (NH2). Examples of aminoalkyl groups include -CH2NH2 and -C2H4NH2.

[0037] The terms "halo" or "halogeno" refer to fluoro, chloro, bromo, and iodine, preferably fluoro, chloro, and bromo, and more preferably fluoro and chloro.

[0038] The terms "carbocyclyl," "carbocyclic," or "carbocycle" refer to non-aromatic saturated or partially saturated monocyclic, condensed, bridged, or spiro-dicyclic carbon-containing ring systems. Monocyclic carbocycles contain about 3 to 12 (preferably 3 to 7) ring atoms. Bicyclic carbocycles contain 6 to 17, preferably 7 to 12, ring-member atoms in the ring. Bicyclic carbocycles can be condensed, spiro, or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexenyl, and spiro[3.3]heptanyl.

[0039] The terms "heterocyclyl," "heterocyclic," or "heterocyclic" refer to non-aromatic saturated or partially saturated monocyclic, condensed, bridging, or spiro-dicyclic heterocyclic systems. Monocyclic heterocyclics contain approximately 3 to 12 (preferably 3 to 7) ring atoms, with 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. Bicyclic heterocyclics contain 7 to 17 ring-member atoms, preferably 7 to 12. Bicyclic heterocyclics can be condensed, spiro, or bridging cyclic systems. Examples of heterocyclic groups include oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and cyclic ethers such as substituted cyclic ethers. Examples of nitrogen-containing heterocyclics include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, and tetrahydropyrazolyl. Typical sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. Regarding sulfur-containing heterocycles, oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl 1,1-dioxide and thiomorpholinyl 1,1-dioxide. The heterocycle may contain one or two oxo (=O) or thioxo (=S) substituents. Preferred values ​​for the heterocyclyl group having one or two oxo (=O) or thioxo (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl, or 2,6-dioxopiperidinyl.Certain heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyls containing 1, 2, or 3 heteroatoms selected from nitrogen, oxygen, or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl, or homopiperazinyl. As will be recognized by those skilled in the art, any heterocycle may be bonded to another group via any preferred atom such as carbon or nitrogen. However, references to piperidino or morpholino herein refer to piperidino-1-yl or morpholin-4-yl rings bonded via ring nitrogen.

[0040] A "bridged ring system" refers to a ring system in which two rings share three or more atoms (see, for example, Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992). Examples of bridged heterocyclyl ring systems include azabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane, azabicyclo[3.2.1]octane, and quinuclidine.

[0041] The inventors define a "spiro-bicyclic ring system" as a bicyclic system sharing one common spirocarbon atom, i.e., a heterocycle bonded to a further carbocyclic or heterocycle via a single common spirocarbon atom. Examples of spiro-ring systems include 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7-azaspiro[3.5]nonane, and 2-oxa-6-azaspiro[3.5]nonane.

[0042] The terms “heteroaryl” or “aromatic heterocyclic” refer to monocyclic, bicyclic, or polycyclic aromatic rings incorporating one or more heteroatoms (e.g., 1 to 4, particularly 1, 2, or 3) selected from nitrogen, oxygen, or sulfur. The term heteroaryl includes both monovalent and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more commonly 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings or 9- or 10-membered bicyclic rings, and can be, for example, fused 5- and 6-membered rings or bicyclic structures formed from two fused 6-membered rings. Each ring may typically contain about 4 or fewer heteroatoms selected from nitrogen, sulfur, and oxygen. Typically, a heteroaryl ring will contain 3 or fewer heteroatoms, more commonly 2 or fewer, for example, a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. Nitrogen atoms in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group containing any amino group substituent in the ring will be less than five.

[0043] Examples of heteroaryls include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazeninyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, prinyl, benzoflazanil, quinolyl, isoxyl Examples include noryl, quinazolinil, quinoxalinil, cinolinil, pteridinil, naphthilidinil, carbazolyl, phenadinil, benzisoquinolinil, pyridopyradinil, thieno[2,3-b]furanil, 2H-flof[3,2-b]-pyranil, 5H-pyrido[2,3-d]-o-oxazinil, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinil, imidazo[2,1-b]thiazolyl, and imidazo[1,2-b][1,2,4]triazinil. "Heteroaryl" also includes a partially aromatic bicyclic or polycyclic ring system, where at least one ring is aromatic and one or more of the other rings are non-aromatic, saturated, or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Examples of partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxynyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indlinyl, 1,2,3,4-tetrahydro-1,8-naphthilidinyl, 1,2,3,4-tetrahydropyrrolid[2,3-b]pyrazinyl, and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0044] Examples of five-membered heteroaryl groups, though not limited to these, include pyrrolyl, furanil, thienyl, imidazolyl, furazanil, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0045] Examples of six-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridadinyl, pyrimidinyl, and triazinyl.

[0046] Bicyclic heteroaryl groups are, for example: A benzene ring fused to a five-membered or six-membered ring containing one, two, or three ring heteroatoms; A pyridine ring fused to a five-membered or six-membered ring containing one, two, or three ring heteroatoms; A pyrimidine ring condensed to a five-membered or six-membered ring containing one or two ring heteroatoms; A pyrrole ring fused to a five-membered or six-membered ring containing one, two, or three ring heteroatoms; A pyrazole ring fused to a five-membered or six-membered ring containing one or two ring heteroatoms; A pyrazine ring fused to a five-membered or six-membered ring containing one or two ring heteroatoms; An imidazole ring fused to a five-membered or six-membered ring containing one or two ring heteroatoms; An oxazole ring fused to a five-membered or six-membered ring containing one or two ring heteroatoms; An isoxazole ring fused to a five-membered or six-membered ring containing one or two ring heteroatoms; A thiazole ring fused to a five-membered or six-membered ring containing one or two ring heteroatoms; An isothiazole ring fused to a five-membered or six-membered ring containing one or two ring heteroatoms; A thiophene ring fused to a five-membered or six-membered ring containing one, two, or three ring heteroatoms; A furan ring fused to a five-membered or six-membered ring containing one, two, or three ring heteroatoms; A cyclohexyl ring fused to a 5-membered or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms; and A cyclopentyl ring fused to a 5-membered or 6-membered aromatic heterocycle containing 1, 2, or 3 ring heteroatoms. It can be a base selected from among them.

[0047] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzfuranil, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl, isobenzofuranil, indolyl, isoindolyl, indolidinyl, indolinyl, isoindolinyl, prinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0048] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiadinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, phthalazinyl, naphthilidinyl, and pteridinyl groups.

[0049] The term "aryl" refers to a cyclic or polycyclic aromatic ring having 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups, but not limited to, include phenyl, biphenyl, and naphthyl. In certain embodiments, the aryl is phenyl.

[0050] The term "optionally substituted" refers to either a substituted or unsubstituted group, structure, or molecule. The term "in the formula, one / any (a / any) of the CH, CH2, CH3 group or heteroatom (i.e., NH) in the R1 group is optionally substituted" preferably means that one of the hydrogen radicals of the R1 group is substituted by the relevant specified group.

[0051] When an optional substituent is selected from "one or more" groups, this definition should be understood to include all substituents selected from one of a particular group, or substituents selected from two or more of a particular group.

[0052] The phrase "compounds of the present invention" means the compounds disclosed herein in general and specifically.

[0053] The compound of the present invention In one embodiment, the present invention relates to the following structural formula (I): [ka] (In the formula: X1 is N or CR a Selected from, here, R a This includes hydrogen, (1-2C)alkyl, halogen, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, or NR. b R c Selected from, here, R b and R c Each is independently selected from hydrogen or (1-2C) alkyl; X2 is selected from N, CH, CF, CCl, or C-CH3; R 1 is hydrogen or a group of the following formula: -LYZ (In the formula: L is either absent or (1-3C)alkylene; Y is absent, or O, C(O), C(O)O, or C(O)N(R)e ) and wherein R e is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclyl; wherein Z is optionally oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g and is further substituted by one or more substituents independently selected from; wherein R g and R h are each independently selected from hydrogen or (1-4C) alkyl) selected from; R 2 is a group of formula A shown below:

Chemical formula

Chemical formula

[0054] The specific compounds of the present invention include, for example, the compounds of formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein X1, X2, R unless otherwise specified. 1 , R 2 , R 7 , R 30 , R 31 Ring A and any associated substituent each have the meanings defined above in this specification, or the meanings defined in any of the following paragraphs (1) to (64) in this specification. (1) X1 is N or CR a Selected from, here, R ais selected from hydrogen, (1-2C)alkyl, fluoro, chloro, (1-2C)alkoxy, CH2F, CHF2, CF3, OCF3, cyano or NR b R c (wherein R b and R c are independently selected from hydrogen or (1-2C)alkyl); (2) X1 is selected from N or CR a wherein R a is selected from hydrogen, methyl, fluoro, chloro, hydroxy, OCH3, CH2F, CHF2, CF3, OCF3, acetylenyl, cyano or NH2; (3) X1 is selected from N or CR a wherein R a is selected from hydrogen, methyl, fluoro, chloro, hydroxy, OCH3, CH2F, CHF2, acetylenyl or cyano; (4) X1 is selected from N or CR a wherein R a is selected from hydrogen, methyl, fluoro, chloro, OCH3, acetylenyl or cyano; (5) X1 is selected from N or CR a wherein R a is selected from hydrogen, (1-2C)alkyl or (1-2C)alkoxy; (6) X1 is selected from N or CR a wherein R a is selected from hydrogen, methyl, OCH3, fluoro or chloro; (7) X1 is selected from N or CH; (8) X1 is N; (9) X1 is CH; (10) X2 is selected from CH, CF or C-CH3; (11) X2 is selected from CH or CF; (12) X2 is CH; (13) R 1 is hydrogen or a group of the following formula: -L-Y-Z (wherein: L is absent or is (1-3C) alkylene; Y is absent or is C(O), C(O)O or C(O)N(R e )(where R e is selected from hydrogen or methyl); and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclyl; where Z is optionally further substituted by one or more substituents independently selected from oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g ; where R g and R h are each independently selected from hydrogen or (1-4C) alkyl) is selected from;

[0055] (14)R 1 is hydrogen or a group of the formula: -L-Z (wherein: L is absent or is (1-3C) alkylene; and Z is (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5- or 6-membered heteroaryl or 4-7-membered heterocyclyl; where Z is optionally further substituted by one or more substituents independently selected from oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR g R h or OR g ; where R g and R h are each independently selected from hydrogen or (1-2C) alkyl) is selected from; (15)R 1 is hydrogen or a group of the formula: -LZ (In the formula: L is either absent or (1-2C)alkylene; and Z is (1-6C)alkyl, (3-6C)cycloalkyl, or 4-7 membered heterocyclyl; where Z is optionally oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, cyano, or NR. g R h OR g Further substituted by one or more substituents independently selected from; where R g and R h (Each element is independently selected from hydrogen or (1-2C) alkyl.) Selected from; (16)R 1 is hydrogen, or the group of the following formula: -LZ (In the formula: L is either absent or (1-2C)alkylene; and Z is a (1-6C) alkyl, (3-6C) cycloalkyl, or 4-7 member heterocycline; where Z is optionally oxo, methyl, fluoro, or NR. g R h OR g It is further substituted by one or more substituents independently selected from, where R g and R h (Each element is independently selected from hydrogen or (1-2C) alkyl.) Selected from; (17)R 1 This is hydrogen, (1-6C) alkyl, or a group of the following formula: -LZ (In the formula: L is (1-2C)alkylene; and Z is a (3-6C)cycloalkyl or a 4-7 membered heterocycline; where Z is optionally oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, cyano, or NR.g R h OR g Further substituted by one or more substituents independently selected from; where R g R h (Each is independently selected from hydrogen or methyl.) Selected from; (18)R 1 is hydrogen, or the group of the following formula: -LZ (In the formula: L is either absent or (1-2C)alkylene; and Z is a (3-6C)cycloalkyl or 4-6 member heterocycline; where Z is optionally oxo, methyl, fluoro, or NR. g R h OR g It is further substituted by one or more substituents independently selected from, where R g and R h (Each element is independently selected from hydrogen or (1-2C) alkyl.) Selected from; (19)R 1 The element is selected from hydrogen, (1-6C) alkyl, or (3-6C) cycloalkyl, where the (1-6C) alkyl or (3-6C) cycloalkyl is optionally methyl, fluoro, or NR. g R h OR g It is further substituted by one or more substituents independently selected from, where R g and R h Each is independently selected from hydrogen or (1-2C) alkyl; (20)R 1 Fluoro, NR (Optional Selection) g R h OR g A (1-6C) alkyl group further substituted by one or more substituents independently selected from R, where R g and R h Each is independently selected from hydrogen or (1-2C) alkyl; (21)R 1NR is an optional choice. g R h or an alkyl group (1-3C) further substituted with one or more substituents independently selected from OH, where R g and R h Each is independently selected from hydrogen or (1-2C) alkyl; (22)R 1 is (1-6C) alkyl (e.g., methyl); (23)R 1 The basis of the following formula: -LZ (In the formula: L is (1-2C)alkylene; and Z is a (3-6C)cycloalkyl group; where Z is optionally oxo, methyl, fluoro, or NR. g R h OR g It is further substituted by one or more substituents independently selected from, where R g and R h (Each element is independently selected from hydrogen or (1-2C) alkyl.) and;

[0056] (24)R 1 The basis of the following formula: -LZ (In the formula: L is CH2; and Z is a (3-4C)cycloalkyl group; where Z is optionally further substituted by one or more substituents independently selected from methyl, fluoro, and OH groups. and; (25)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N, CH, or CF; X b is N or CR x1 Selected from, here, R x1 This is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, acetylenyl, CH2F, CF2H, or CF3; R 6 This is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, acetylenyl, CH2F, CF2H, or CF3; R 7 This includes hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, or a group of the following formula: -Y3-Z3 (In the formula: Y3 is either absent or O, S, N(R) j )(CR j R k ) q1 (Here, q1 is 0, 1, or 2), C(O), C(O)O, OC(O), C(O)N(R) j ) or N(R j )C(O), where R j and R k Each is independently selected from hydrogen or (1-4C) alkyl; and Z3 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, 5 or 6-membered heteroaryl, or 4-12-membered heterocyclyl; where Z3 is optionally (1-4C)alkyl, cyclopropyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, C(O)NR l R m , NR l R m OR l It is further substituted by one or more substituents independently selected from, where R l and R mEach is independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; or Z 3 The following formula is used as the basis by any choice: -L Z -W Z (In the formula: L Z is a (1-5C) alkylene substituted with one or more substituents optionally selected from (1-2C) alkyl or oxo; and W Z These are halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, and C(O)R. xa COOR xa , C(O)NR xa R xb or NR xa R xb And here, R xa and R xb (Each element is independently selected from hydrogen or (1-4C) alkyl.) (Further replaced by) (Selected from) and;

[0057] (26)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N, CH, or CF; X b is N or CR x1 Selected from, here, R x1 This is selected from hydrogen, fluoro, chloro, bromo, (1-2C) alkyl, cyano, acetylenyl, CH2F, CF2H, or CF3; R 6This is selected from hydrogen, fluoro, chloro, bromo, (1-2C)alkyl, (1-2C)alkoxy, cyano, acetylenyl, CH2F, CF2H, or CF3; R 7 This includes hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, or a group of the following formula: -Y3-Z3 (In the formula: Y3 is either absent or O, S, C(O), C(O)O, OC(O), C(O)N(R j ) or N(R j )C(O), where R j is selected from hydrogen or (1-4C) alkyl; and Z3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-12-membered heterocyclyl; where Z3 is optionally (1-4C)alkyl, cyclopropyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NR l R m , NR l R m OR l It is further substituted by one or more substituents independently selected from, where R l and R m (Each element is independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl.) (Selected from) and; (27)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N, CH, or CF; Xb is N or CR x1 Selected from, here, R x1 is selected from hydrogen, fluoro, chloro, bromo, or methyl; R 6 This is selected from fluoro, chloro, bromo, methyl, cyano, or acetylenyl; R 7 This includes hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, or a group of the following formula: -Y3-Z3 (In the formula: Y3 is either absent, or O, C(O), C(O)O, or C(O)N(R) j ) and here, R j is selected from hydrogen or (1-4C) alkyl; and Z3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-11-membered heterocyclyl; where Z3 is optionally (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NR l R m , NR l R m OR l It is further substituted by one or more substituents independently selected from, where R l and R m (Each element is independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl.) (Selected from) and; (28)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X ais selected from N or CH; X b is N or CR x1 Selected from, here, R x1 is selected from hydrogen, fluoro, chloro, bromo, or methyl; R 6 This is selected from fluoro, chloro, bromo, methyl, cyano, or acetylenyl; R 7 This includes hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, or the following formula: -Y3-Z3 (In the formula: Y3 is either absent, or O, C(O), C(O)O, or C(O)N(R) j ) and here, R j is selected from hydrogen or (1-4C) alkyl; and Z3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-8-membered heterocyclyl; where Z3 is optionally (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NR l R m , NR l R m OR l It is further substituted by one or more substituents independently selected from, where R l and R m (Each element is independently selected from hydrogen or (1-4C) alkyl.) (Selected from) and;

[0058] (29)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N or CH; X b It is selected from CH, CCl, CF, CBr, or CCH3; R 6 It is selected from chloro, fluoro, or cyano; R 7 The (1-6C) alkyl, (3-6C) cycloalkyl, 5 or 6-membered heteroaryl, or 4-8-membered heterocyclil is selected from; where each (1-6C) alkyl, (3-6C) cycloalkyl, 5 or 6-membered heteroaryl, or 4-8-membered heterocyclil is optionally selected from (1-4C) alkyl, halo, oxo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxyalkyl, cyano, C(O)NR l R m , NR l R m OR l It is further substituted by one or more substituents independently selected from, where R l and R m (Each element is independently selected from hydrogen or (1-4C) alkyl.) and; (30)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N or CH; X b It is selected from CH, CCl, CF, CBr, or CCH3; R 6 It is selected from chloro, fluoro, or cyano; R 7This is selected from a 5 or 6-membered heteroaryl or a 4- to 8-membered heterocycline; where the 5 or 6-membered heteroaryl or 4- to 8-membered heterocycline is optionally selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NR l R m , NR l R m OR l It is further substituted by one or more substituents independently selected from, where R l and R m (Each element is independently selected from hydrogen or (1-4C) alkyl.) and;

[0059] (31)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N or CH; X b It is selected from CH, CCl, or CCH3; R 6 It is selected from chloro, fluoro, or cyano; R 7 (The 5- or 6-membered heteroaryl or 4- to 8-membered heterocycline is selected from a 5- or 6-membered heteroaryl or a 4- to 8-membered heterocycline, which is optionally further substituted with one or more substituents independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, or OH.) and; (32)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N or CH; X b It is selected from CH, CCl, or CCH3; R 6 It is selected from chloro, fluoro, or cyano; R 7 (I) is a 4-8 membered heterocyclyl (e.g., piperidinyl); where the 4-8 membered heterocyclyl is further optionally substituted with one or more substituents independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, or OH. and;

[0060] (33)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is selected from N or CH; X b It is selected from CH, CCl, or CCH3; R 6 It is selected from chloro, fluoro, or cyano; R 7 (This is piperidinyl or piperazinyl, each optionally substituted with one or more substituents independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, or OH.) and; (34)R 2This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is CH; X b It is selected from CH or CCl; R 6 It is selected from chloro, fluoro, or cyano; R 7 is hydrogen, or the group of the following formula: -Y3-Z3 (In the formula: Y3 is O, C(O), C(O)O, or C(O)N(R j ) and here, R j is hydrogen or (1-4C) alkyl; and Z3 is hydrogen, (1-6C) alkyl, (3-6C) cycloalkyl, or 4-11 member heterocycline; where Z3 is optionally further substituted with one or more substituents independently selected from (1-4C) alkyl, halo, oxo, (1-4C) haloalkyl, (1-4C) haloalkoxy, (1-4C) alkoxyalkyl, cyano, or OH. (Selected from) and; (35)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is CH; X b It is selected from CH or CCl; R 6 It is selected from chloro, fluoro, or cyano; R 7 is hydrogen, or the group of the following formula: -Y3-Z3 (In the formula: Y3 is C(O) or C(O)N(R) j ) and here, R j is hydrogen or (1-4C) alkyl; and Z3 is hydrogen, (1-6C)alkyl, or 4-11 member heterocycline; where Z3 is optionally further substituted with one or more substituents independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, or OH. (Selected from) and; (36)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is CH; X b is CCl; R 6 is cyano; R 7 is hydrogen, or the group of the following formula: -Y3-Z3 (In the formula: Y3 is C(O); and Z3 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; where Z3 is optionally further substituted with one or more substituents independently selected from (1-4C)alkyl, fluoro, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, or OH. (Selected from) and;

[0061] (37)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is N; X b It is selected from CH or CCl; R 6 It is selected from chloro, fluoro, or cyano; R 7 R is selected from (3-6C)cycloalkyl, 5 or 6-membered heteroaryl, or 4-10-membered heterocyclyl; where R 7 The following can be optionally selected: (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NR l R m , NR l R m OR l It is further substituted by one or more substituents independently selected from, where R l and R m Each is independently selected from hydrogen or (1-4C) alkyl; or R 7 The following formula is used as the basis by any choice: -L Z -W Z (In the formula: L Z is (1-3C)alkylene; and W Z These are halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, and C(O)R. xa COOR xa , C(O)NR xa R xb or NR xa R xb And here, R xa and Rxb (Each element is independently selected from hydrogen or (1-4C) alkyl.) (Further replaced by) and; (38)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is N; X b It is selected from CH or CCl; R 6 is chloro or fluoro; R 7 The R is selected from a 5 or 6-membered heteroaryl or a 4- to 10-membered heterocycline; each R 7 The following can be optionally selected: (1-4C) alkyl, halo, oxo, (1-4C) haloalkyl, OH, or C(O)NR l R m It is further substituted by one or more substituents independently selected from, where R l and R m Each is independently selected from hydrogen or (1-4C) alkyl; or R 7 The following formula is used as the basis by any choice: -L Z -W Z (In the formula: L Z is (1-2C)alkylene; and W Z (These are fluoro, (1-4C)haloalkyl, cyano, hydroxy, or (1-2C)alkoxy.) (Further replaced by) and;

[0062] (39)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is N; X b is CH; R 6 is chloro or fluoro; R 7 The following can be optionally selected: (1-4C) alkyl, halo, oxo, (1-4C) haloalkyl, OH, or C(O)NR l R m (Here, R l and R m Each is a 4- to 10-membered heterocycline substituted with one or more substituents independently selected from (each independently selected from hydrogen or methyl); or R 7 The following formula is used as the basis by any choice: -L Z -W Z (In the formula: L Z is CH2; and W Z (These are cyano, hydroxy, or methoxy compounds.) (Further replaced by) and; (40)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is N; X b is CH; R 6 is chloro or fluoro; R 7These include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, 7,8-dihydropyrido[4,3-d]pyrimidine-(5H)-yl, 3-oxa-8-azabicyclo[3.2.1]-octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-6-azadamantanyl, 8-azabicyclo[3.2.1]octanyl, 3- Selected from azabicyclo[3.2.1]octanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 3,8-diazabicyclo[3.2.1]octanyl, 2,6-diazaspiro[3.3]heptanyl, and 3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octanyl, each of which can be optionally selected as (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, OH, or C(O)NR l R m (Here, R l and R m Each is substituted with one or more substituents independently selected from (each independently selected from hydrogen or methyl); or R 7 The following formula is used as the basis by any choice: -L Z -W Z (In the formula: L Z is CH2; and W Z (These are cyano, hydroxy, or methoxy compounds.) (Further replaced by) and; (41)R 2 This is the basis of equation A shown below: [ka] (In the formula: [ka] indicates a connection point; X a is N; X b is CH; R 6is chloro or fluoro; R 7 (These are selected from piperidinyl, piperazinyl, 3-oxa-8-azabicyclo[3.2.1]-octanyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, 2-oxa-6-azadamantanyl, 8-azabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, and 3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octanyl, each of which is optionally substituted with one or more substituents independently selected from methyl, fluoro, oxo, OH, and CH2OH.) and; (42)R 7 is hydrogen; (43)R 7 This is a 4-10 member nitrogen-containing heterocyclyl ring bonded to the remainder of the compound of formula (I) via a ring nitrogen, and optionally containing a second heteroatom selected from nitrogen, oxygen, and sulfur, where the heterocyclyl ring is optionally (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NR l R m , NR l R m OR l It is substituted with one or more substituents independently selected from, where R l and R m Each is independently selected from hydrogen, (1-4C) alkyl, or (3-6C) cycloalkyl; or Z 3 The following formula is used as the basis by any choice: -L Z -W Z (In the formula: L Z is a (1-5C) alkylene substituted with one or more substituents optionally selected from (1-2C) alkyl or oxo; and W Z These are halo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, and C(O)R.xa COOR xa , C(O)NR xa R xb or NR xa R xb And here, R xa and R xb (Each element is independently selected from hydrogen or (1-4C) alkyl.) Further replaced by; (44)R 7 This is a 7-10 member nitrogen-containing bicyclic heterocyclyl group that is bonded to the remainder of the compound of formula (I) via a cyclic nitrogen and optionally contains a second heteroatom selected from nitrogen, oxygen, and sulfur, where the heterocyclyl group can optionally be (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, hydroxy, or C(O)NR l R m , NR l R m OR l It is substituted with one or more substituents independently selected from, where R l and R m Each is independently selected from hydrogen and (1-4C) alkyl; (45)R 7 This is one of the following heterocyclyl groups: [ka] (In the formula, the heterocyclyl ring can be optionally represented as (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, hydroxy, or C(O)NR) l R m , NR l R m OR l It is substituted with one or more substituents independently selected from, where R l and R m Each of these is independently selected from hydrogen and (1-4C) alkyl; and here, the heterocyclyl ring is further optionally substituted with CH2CN, CH2OH, or CH2OMe. Selected from;

[0063] (46)R 7 This is one of the following heterocyclyl rings: [ka] (In the formula, the heterocyclyl ring is optionally substituted with one or more substituents independently selected from methyl, fluoro, oxo, OH, and CH2OH.) Selected from. (47)R 30 The substituent is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl, or cyano, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally selected from (1-4C)alkyl, cyclopropyl, hydroxy, (1-2C)alkoxy, or NR. u R v Or it is further substituted with one or more substituents selected from halo, where R u and R v is independently selected from hydrogen or (1-2C) alkyl; (48)R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano substituents, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from (1-4C)alkyl, cyclopropyl, hydroxy, (1-2C)alkoxy or halo substituents; (49)R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano substituents, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from (1-4C)alkyl, hydroxy, (1-2C)alkoxy or halo substituents; (50)R 30The substituent is selected from (1-4C)alkyl, (3-6C)cycloalkyl, or (1-4C)fluoroalkyl, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted with one or more substituents selected from hydroxy, (1-2C)alkoxy, or fluoro; (51)R 30 The substituent is selected from (1-4C)alkyl or (3-4C)cycloalkyl, where each (1-4C)alkyl and / or (3-4C)cycloalkyl substituent is optionally further substituted with one or more fluoro groups; (52)R 30 is (1-4C) alkyl (e.g., methyl or ethyl) or cyclopropyl; (53)R 30 It is cyclopropyl; (54)R 31 This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y5-L5-Z5 (In the formula: Y5 is absent, or C(O)O or C(O)N(R) w ) is selected, where R w is selected from hydrogen or (1-2C) alkyl; L5 is either absent or (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or a 5- or 6-membered heteroaryl; where Z5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, nitro, or hydroxy. Selected from; (55)R 31 This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y5-L5-Z5 (In the formula: Y5 is either absent or C(O)N(R w) and here, R w is selected from hydrogen or methyl; L5 is either absent or (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or a 5- or 6-membered heteroaryl; where Z5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, nitro, or hydroxy. Selected from;

[0064] (56)R 31 This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y5-L5-Z5 (In the formula: Y5 is either absent or C(O)N(R w ) and here, R w is selected from hydrogen or methyl; L5 is either absent or (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, cyclopropyl, or a 5- or 6-membered heteroaryl; where Z5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, nitro, or hydroxy. Selected from; (57)R 31 This refers to hydrogen (1-4C) alkyl, (1-4C) haloalkyl, or a group of the following formula: Y5-L5-Z5 (In the formula: Y5 is either absent or C(O)N(R w ) and here, R w is selected from hydrogen or methyl; L5 is either absent or (1-2C)alkylene; and Z5 is (1-6C)alkyl or cyclopropyl; where Z5 is optionally substituted with one or more substituents selected from halo, (1-2C)haloalkyl, (1-2C)alkoxy, or cyano. Selected from; (58)R 31 This is selected from hydrogen, methyl, CF3, CH2OCH3, or C(O)NHCH3; (59)R 31 is hydrogen; (60)R 30 and R 31 These are bonded together with the carbon atoms to which they are bonded, forming a 4-6 membered carbon ring; (61)R 30 and R 31 These are bonded together with the carbon atoms to which they are bonded, forming a 4- to 6-membered heterocycle; (62) Ring A is a 7-membered heterocycle, and it has substituent R 30 and R 31 In addition, they are optionally further substituted with one or more substituents selected from oxo, (1-2C)alkyl, cyclopropyl, spiro-cyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, amino, cyano, or hydroxy; (63) Ring A is a 7-membered heterocycle, and it has substituent R 30 and R 31 In addition, they are optionally further substituted with one or more substituents selected from oxo, (1-2C)alkyl, cyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, amino, cyano, nitro, or hydroxy; (64) Ring A is a 7-membered heterocycle, and it has substituent R 30 and R 31 In addition, they are optionally further substituted with one or more substituents selected from oxo, (1-2C)alkyl, cyclopropyl, fluoro, (1-2C)fluoroalkyl, (1-2C)alkoxy, or cyano. Preferably, the heteroaryl is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 heteroatoms selected from N, O, or S. Preferably, the aryl group is phenyl. Preferably, X1 is as described in any one of paragraphs (1) to (9) above. Most preferably, X1 is as described in paragraph (9) above. Preferably, X2 is as described in any one of paragraphs (10) to (12) above. Most preferably, X2 is as described in paragraph (12) above. Preferably, R 1 This is as described in any one of the above paragraphs (13) to (24). Most preferably, R 1 This is as stated in any one of the paragraphs (20) to (24) above.

[0065] Preferably, R 2 This is as described in any one of the above paragraphs (25) to (41). More preferably, R 2 This is as described in any one of the above paragraphs (29) to (41). Most preferably, R 2 This is as stated in either paragraphs (35)-(36) or paragraphs (40)-(41) above. Preferably, R 7 This is as described in any one of the above paragraphs (42) to (46). Most preferably, R 30 This is as stated in paragraph (46) above. Preferably, R 30 This is as described in either paragraphs (47) to (53) or (60) to (61) above. Most preferably, R 30 This is as stated in paragraph (53) above. Preferably, R 31 This is as described in any one of the above paragraphs (54) to (61). Most preferably, R 31This is as stated in paragraph (59) above. Preferably, ring A is as described in any one of paragraphs (62) to (64) above. Most preferably, ring A is as described in paragraph (64) above.

[0066] In a specific group of compounds according to the present invention, X2 is CH, that is, the compound has the following structural formula Ia (subordinate definition of formula (I)), or is a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] In the formula, X1, R 1 , R 2 , R 30 , R 31 And ring A are defined as described above.

[0067] In one embodiment of the compound of formula Ia: X1 is defined in any one of the above paragraphs (1) to (9); R 1 This is defined in any one of the above paragraphs (13) to (24); R 2 This is defined in any one of the above paragraphs (25) to (41); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); and Ring A is defined in any one of paragraphs (62) to (64) above.

[0068] In other embodiments of the compound of formula Ia: X1 is defined in paragraph (9) above; R 1This is defined in paragraphs (20) to (24) above; R 2 This is defined in paragraphs (35)-(36) or (40)-(41) above; R 30 This is defined in paragraph (53) above; R 31 This is defined in paragraph (59) above; and Ring A is defined in paragraph (64) above.

[0069] In a specific group of compounds according to the present invention, X1 and X2 are CH, that is, the compound has the following structural formula Ib (subordinate definition of formula (I)), or is a pharmaceutically acceptable salt, hydrate and / or solvate thereof: [ka] In the formula, R 1 , R 2 , R 30 , R 31 And ring A are defined as described above.

[0070] In one embodiment of the compound of formula Ib: R 1 This is defined in any one of the above paragraphs (13) to (24); R 2 This is defined in any one of the above paragraphs (25) to (41); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); and Ring A is defined in any one of paragraphs (62) to (64) above.

[0071] In other embodiments of the compound of formula Ib: R 1 This is defined in paragraphs (20) to (24) above; R 2 This is defined in paragraphs (35)-(36) or (40)-(41) above; R 30 This is defined in paragraph (53) above; R 31 This is defined in paragraph (59) above; and Ring A is defined in paragraph (64) above.

[0072] In a specific group of compounds according to the present invention, X1, X2 and X a CH is CH, and also R 2 This is as follows: the compound has the following structural formula Ic1 (subordinate definition of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, R 1 , R 6 , R 7 , X b , R 30 , R 31 And ring A are defined as described above.

[0073] In one embodiment of the compound of formula Ic1: R 1 This is defined in any one of the above paragraphs (13) to (24); R 6 This is defined in any one of the above paragraphs (25) to (36); R 7 This is defined in any one of the above paragraphs (25) to (36); X bThis is defined in any one of the above paragraphs (25) to (36); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); and Ring A is defined in any one of paragraphs (62) to (64) above.

[0074] In other embodiments of the compound of formula Ic1: R 1 This is defined in paragraphs (20) to (24) above; R 6 This is defined in paragraph (36) above; R 7 This is defined in paragraph (36) above; X b This is defined in paragraph (36) above; R 30 This is defined in paragraph (53) above; R 31 This is defined in paragraph (59) above; and Ring A is defined in paragraph (64) above.

[0075] In a specific group of compounds according to the present invention, X1 and X2 are CH, and X a is N, and also R 2 The following is the case: the compound has the following structural formula Ic2 (subordinate definition of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, R 1 , R 6 , R 7, X b , R 30 , R 31 And ring A are defined as described above.

[0076] In one embodiment of the compound of formula Ic2: R 1 This is defined in any one of the above paragraphs (13) to (24); R 6 This is defined in any one of the above paragraphs (25)-(33) and (37)-(41); R 7 This is defined in any one of the above paragraphs (25)-(33) and (37)-(46); X b This is defined in any one of the above paragraphs (25)-(33) and (37)-(41); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); and Ring A is defined in any one of paragraphs (61) to (64) above.

[0077] In other embodiments of the compound of formula Ic2: R 1 This is defined in paragraphs (20) to (24) above; R 6 This is defined in paragraph (41) above; R 7 This is defined in paragraph (46) above; X b This is defined in paragraph (41) above; R 30 This is defined in paragraph (53) above; R31 This is defined in paragraph (59) above; and Ring A is defined in paragraph (64) above.

[0078] In a specific group of compounds according to the present invention, this compound has the following structural formula Id, Ie, If, or Ig (sub-definitions of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, X1, X2, R 1 , R 2 , R 30 and R 31 Each of these is as defined above, where X3 is CH2, O, S, SO2 or NH, and R 40 , R 41 , R 50 and R 51 These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)OR z1 , C(O)N(R z2 )R z1 NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring or heterocycle.

[0079] In one embodiment of the compounds of formula Id, formula Ie, formula If and / or formula Ig: X1 is defined in any one of the above paragraphs (1) to (9); X2 is defined in any one of the above paragraphs (10) to (12); X3 is either O or S; R 1 This is defined in any one of the above paragraphs (13) to (24); R 2 This is defined in any one of the above paragraphs (25) to (41); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); and R 40 , R 41 , R 50 and R 51 These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)OR z1 , C(O)N(R z2 )R z1 , NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring.

[0080] In other embodiments of compounds of formula Id, formula Ie, formula If and / or formula Ig: X1 is defined in paragraph (9) above; X2 is defined in paragraph (12) above; X3 is either O or S; R 1 This is defined in paragraph (22) above; R 2 This is defined in paragraph (41) above; R 30 This is defined in paragraph (53) above; R 31 This is defined in paragraph (59) above; R 40 , R 41 and R 50 is independently selected from hydrogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (3-6C)cycloalkyl, halo or cyano; and R 51 is hydrogen; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a cyclopropyl ring.

[0081] In a specific group of compounds according to the present invention, this compound has the following structural formulas Ih, Ij, Ik, or Im (subordinate definitions of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, R 1 , R 2 , R 30 and R 31 Each of the above is defined, X3 is selected from CH2, O, S, SO2 or NH, and R 40 , R 41 , R 50 and R 51These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)OR z1 , C(O)N(R z2 )R z1 , NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring or heterocycle.

[0082] In one embodiment of the compounds of formula Ih, Ij, Ik and / or Im: R 1 This is defined in any one of the above paragraphs (13) to (24); R 2 This is defined in any one of the above paragraphs (25) to (41); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); X3 is either O or S; and R 40 , R 41 , R 50 and R 51 These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)ORz1 , C(O)N(R z2 )R z1 , NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring.

[0083] In other embodiments of compounds of formulas Ih, Ij, Ik and / or Im: R 1 This is defined in paragraph (22) above; R 2 This is defined in paragraph (41) above; R 30 This is defined in paragraph (53) above; R 31 This is defined in paragraph (59) above; X3 is either O or S; R 40 , R 41 and R 50 is independently selected from hydrogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (3-6C)cycloalkyl, halo or cyano; and R 51 is hydrogen; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a cyclopropyl ring.

[0084] In a specific group of compounds according to the present invention, this compound has the following structural formula In, Io, Ip, or Iq (sub-definitions of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, R 1 , R 6 , R 7 , X b , R 30 and R 31 Each of the above is as defined above, X3 is selected from CH2, O, S, SO2 or NH, and R 40 , R 41 , R 50 and R 51 These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)OR z1 , C(O)N(R z2 )R z1 , NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring or heterocycle.

[0085] In one embodiment of a compound of formula In, Io, Ip and / or Iq: R 1 This is defined in any one of the above paragraphs (13) to (24); R 6 This is defined in any one of the above paragraphs (25) to (36); R 7 This is defined in either paragraph (25)-(36) or (42)-(46) above; X b This is defined in any one of the above paragraphs (25) to (36); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); X3 is selected from O or S; and R 40 , R 41 , R 50 and R 51 These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)OR z1 , C(O)N(R z2 )R z1 , NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring.

[0086] In other embodiments of compounds of formulas In, Io, Ip and / or Iq: R 1 This is defined in paragraph (22) above; R 6 This is defined in paragraph (36) above; R7 This is defined in paragraph (36) above; X b This is defined in paragraph (36) above; R 30 This is defined in paragraph (53) above; R 31 This is defined in paragraph (59) above; X3 is either O or S; R 40 , R 41 and R 50 is independently selected from hydrogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (3-6C)cycloalkyl, halo or cyano; and R 51 is hydrogen; or R 40 and R 41 , and / or, R 50 and R 51 These are bonded together with the carbon atoms to which they are attached, forming a cyclopropyl ring.

[0087] In a specific group of compounds according to the present invention, this compound has the following structural formula Is or It (a sub-definition of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, R 1 , R 6 , R 7 , R 30 and R 31 Each of the above is as defined above, X3 is selected from CH2, O, S, SO2 or NH, and R 40 , R 41 and R 50These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)OR z1 , C(O)N(R z2 )R z1 NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring or heterocycle.

[0088] In one embodiment of a compound of formula Is or It: R 1 This is defined in any one of the above paragraphs (13) to (24); R 6 It is selected from chloro, fluoro, or cyano; R 7 This is defined in any one of the above paragraphs (25)-(33) and (37)-(46); R 30 This is defined in either paragraph (47)-(53) or (60)-(61) above; R 31 This is defined in any one of the above paragraphs (54) to (61); X3 is selected from O or S; and R 40 , R 41 and R 50 These are hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, (1-4C)alkoxyalkyl, (1-2C)aminoalkyl, NH2, cyano, nitro, OH, C(O)ORz1 , C(O)N(R z2 )R z1 , NR z2 C(O)R z1 Selected independently from, where R z1 and R z2 Each is independently selected from hydrogen or (1-2C) alkyl; or R 40 and R 41 These are bonded together with the carbon atoms to which they are attached, forming a 3- to 6-membered carbon ring.

[0089] In other embodiments of compounds of formula Is or It: R 1 This is defined in paragraph (24) above; R 6 It is selected from chloro, fluoro, or cyano; R 7 This is defined in paragraph (46) above; R 30 This is defined in paragraph (53) above; R 31 This is defined in paragraph (59) above; X3 is selected from O or S; and R 40 , R 41 and R 50 is independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, or hydroxyl; or R 40 and R 41 These are bonded together with the carbon atoms to which they are attached, forming a cyclopropyl ring.

[0090] In a specific group of compounds according to the present invention, this compound has any of the structural formulas Id to It shown above, or is a pharmaceutically acceptable salt, hydrate and / or solvate thereof, where R 40 and R 41 The element is selected independently from hydrogen and fluorocarbon.

[0091] In further embodiments, the compound has any of the structural formulas Id to It shown above, or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, where R 40 and R 41 Both are fluoro.

[0092] In further embodiments, the compound has any of the structural formulas Id to It shown above, or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, where R 40 and R 41 R is independently selected from hydrogen and fluoro, and 30 It is cyclopropyl.

[0093] In further embodiments, the compound has any of the structural formulas Id to It shown above, or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, where R 40 and R 41 R is independently selected from hydrogen and fluoro, and 30 It is cyclopropyl, and also, R 31 It is hydrogen.

[0094] In further embodiments, the compound has any of the structural formulas Id to It shown above, or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, where R 40 and R 41 Both are fluoro, and also, R 30 It is cyclopropyl.

[0095] In further embodiments, the compound has any of the structural formulas Id to It shown above, or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof, where R 40 and R 41 Both are fluoro, and also, R 30 It is cyclopropyl, and also, R 31 It is hydrogen.

[0096] In a specific group of compounds according to the present invention, this compound has the following structural formula Iu or Iv (subordinate definition of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, X 1 , R 1 , R 2 and R 30 and R 50 These are defined as described above.

[0097] In one embodiment of a compound of formula Iu or formula Iv: X 1 This is defined in any one of the above paragraphs (1) to (9); R 1 This is defined in any one of the above paragraphs (13) to (24); R 2 This is defined in any one of the above paragraphs (25) to (41); R 30 This is defined in any one of the above paragraphs (47) to (53); and R 50 These are hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, or halo.

[0098] In other embodiments of compounds of formula Iu or Iv: X 1 This is defined in paragraph (7) above; R 1 This is defined in paragraph (22) above; R 2 This is defined in paragraph (41) above; R 30 This is defined in paragraph (53) above; and R 50 It is hydrogen.

[0099] In a specific group of compounds according to the present invention, this compound has the following structural formula Iw or Ix (a sub-definition of formula (I)), or is a pharmaceutically acceptable salt, hydrate, and / or solvate thereof: [ka] In the formula, X 1 , R 1 , R 6 , R 7 and R 30 Each of these is as defined above, and X3 is selected from CH2, O, S, SO2, or NH.

[0100] In one embodiment of a compound of formula Iw or Ix: X 1 This is defined in any one of the above paragraphs (1) to (9); R 1 This is defined in any one of the above paragraphs (13) to (24); R 6 It is selected from chloro, fluoro, or cyano; R 7 This is defined in any one of the above paragraphs (25)-(33) and (37)-(46); R 30 This is defined in any one of the above paragraphs (47) to (53); and X3 is selected from either O or S.

[0101] In other embodiments of compounds of formula Iw or Ix: X 1 This is defined in paragraph (7) above; R 1 This is defined in paragraph (22) above; R 6 is chloro; R 7 This is defined in paragraph (46) above; R 30 This is defined in paragraph (53) above; and X3 is O.

[0102] The specific compounds of the present invention include any of the compounds exemplified in this application, or pharmaceutically acceptable salts or solvates thereof, and in particular include any of the following: (S)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2-ethyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (S)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2,2,7-trimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2-(methoxymethyl)-2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2,3,3,7-tetramethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2',7'-dimethyl-6'-oxo-1',2',6',7'-tetrahydro-4'H-spiro[cyclopropane-1,3'-[1,4]oxazepino[2,3-c]quinoline]-10'-yl)amino)nicotinonitrile; 2-Chloro-4-(((2S,4S)-2,4,7-trimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2,6-dimethyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinoline-9-yl)amino)nicotinonitrile; 2-Chloro-4-((2-ethyl-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinoline-9-yl)amino)nicotinonitrile; 2-Chloro-4-((2-cyclopropyl-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinoline-9-yl)amino)nicotinonitrile; 2-Chloro-4-((2-cyclobutyl-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinoline-9-yl)amino)nicotinonitrile; 2-Chloro-4-((7'-methyl-6'-oxo-3',4,4',5,6',7'-hexahydro-1'H,2H-spiro[furan-3,2'-[1,4]oxazepino[2,3-c]quinoline]-10'-yl)amino)nicotinonitrile; 2-Chloro-4-((2-(difluoromethyl)-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-2-cyclopropyl-10-((5,6-dichloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (S)-6-chloro-5-cyano-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)picolinic acid; (R)-6-chloro-5-cyano-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)picolinic acid; (S)-6-(azetidine-1-carbonyl)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)-6-(3-(trifluoromethyl)azetidine-1-carbonyl)nicotinonitrile; (S)-10-((2,3-dichloropyridine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-2-(methoxymethyl)pyrrolinidine-1-carbonyl)pyridine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-2-Cyclopropyl-10-((2,3-Dichloropyridine-4-yl)amino)-7-methyl-1,2,3,4-Tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)pyrimidine-4-yl)amino)-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-1-(5-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethylpiperidine-4-carboxamide; (S)-10-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-morpholinopyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)pyrimidine-4-yl)amino)-7'-methyl-3',4,4',5-tetrahydro-1'H,2H-spiro[furan-3,2'-[1,4]oxazepino[2,3-c]quinoline]-6'(7'H)-one; (R)-10-((5-chloro-2-(2,2,6,6-tetramethylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(2-oxa-6-azaadamantan-6-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-2-chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; (S)-2-chloro-4-((2-cyclopropyl-7-methyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2-cyclopropyl-7-methyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2,3,7-trimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; (S)-10-((5-chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (2S)-10-((2-(8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-1-(5-chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethylpiperidine-4-carboxamide; (S)-10-((5-chloro-2-(2-methyl-1-oxo-2,9-diazaspiro[5.5]undecane-9-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (2S)-10-((5-chloro-2-(3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-10-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (2S)-10-((2-(3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-10-((5-chloro-2-(2-oxopyrrolidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (2S)-10-((2-(8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-10-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-1-(5-chloro-4-((2-cyclopropyl-7-methyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethylpiperidine-4-carboxamide; (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; 10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; rac-(2S,3R)-10-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,3,7-trimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; rac-(2S,3S)-10-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,3,7-trimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; (S)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; (S)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2,6-dimethyl-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthyridine-9-yl)amino)nicotinonitrile; 2-Chloro-4-((2,6-dimethyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]thiadino[2,3-c]quinoline-9-yl)amino)nicotinonitrile; (S)-2-chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-(2-(methylamino)ethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,4R,5R)-4-fluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((R)-4,4-difluoro-3-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((S)-4,4-difluoro-3-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((R)-4,4-difluoro-3-hydroxypiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((S)-4,4-difluoro-3-hydroxypiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-5,5-dioxide-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-7-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-morpholinopyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((R)-2-methylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-2-methylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-Chloro-2-((R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 2-Chloro-4-((2,7-dimethyl-5,6-dioxo-2,3,4,5,6,7-hexahydro-1H-[1,4]diazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; (S)-10-((5-chloro-2-(4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((1S,5R)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((1R,5S)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (1R,5S,7S)-9-(5-chloro-4-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide; (1R,5S,7R)-9-(5-chloro-4-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide; (S)-10-((3-chloropyridine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-3-(4-(5-Chloro-4-((2-Cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)piperazine-1-yl)propanenitrile; (S)-2-Cyclopropyl-3,3-Difluoro-10-((5-Fluoro-2-(4-Methyl-3-Oxopiperazin-1-yl)Pyrimidine-4-yl)amino)-7-Methyl-1,2,3,4-Tetrahydro-[1,4]Oxazepino[2,3-c]Quinoline-6(7H)-one; (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (2S)-10-((5-chloro-2-(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; or (S)-10-((5-chloro-2-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.

[0103] Further compounds of the present invention include any of the compounds exemplified herein, or pharmaceutically acceptable salts or solvates thereof, and in particular include any of the following: (R)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-5,5-dioxide-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (S)-2-chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (S)-6-chloro-5-cyano-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)picolinic acid; (R)-6-chloro-5-cyano-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)picolinic acid; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)-6-(3-(trifluoromethyl)azetidine-1-carbonyl)nicotinonitrile; (S)-10-((3-chloropyridine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-morpholinopyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(2,2,6,6-tetramethylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(2-oxa-6-azaadamantan-6-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-2-chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one; (S)-10-((5-chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-7-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-(3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (S)-10-((5-chloro-2-morpholinopyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((R)-2-methylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-2-methylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-Chloro-2-((R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((R)-4,4-difluoro-3-hydroxypiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((S)-4,4-difluoro-3-hydroxypiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((1S,5R)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((1R,5S)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (1R,5S,7S)-9-(5-chloro-4-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide; (1R,5S,7R)-9-(5-chloro-4-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide; (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-3-(4-(5-Chloro-4-((2-Cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)piperazine-1-yl)propanenitrile; (S)-10-((5-chloro-2-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (2S)-10-((5-chloro-2-(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-2-Cyclopropyl-3,3-Difluoro-10-((5-Fluoro-2-(4-Methyl-3-Oxopiperazin-1-yl)Pyrimidine-4-yl)amino)-7-Methyl-1,2,3,4-Tetrahydro-[1,4]Oxazepino[2,3-c]Quinoline-6(7H)-one; (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; or (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-(2-(methylamino)ethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.

[0104] Further compounds of the present invention include any of the compounds exemplified herein, or pharmaceutically acceptable salts or solvates thereof, and in particular include any of the following: 2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-2-chloro-4-((2-cyclopropyl-7-methyl-5,5-dioxide-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (S)-2-chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-6-chloro-5-cyano-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)picolinic acid; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonane-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one; (S)-10-((5-chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (S)-10-((5-chloro-2-morpholinopyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((R)-2-methylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-2-methylmorpholino)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-Chloro-2-((R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((1S,5R)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((1R,5S)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (1R,5S,7S)-9-(5-chloro-4-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide; (1R,5S,7R)-9-(5-chloro-4-(((S)-2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide; (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-3-(4-(5-Chloro-4-((2-Cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)pyrimidine-2-yl)piperazine-1-yl)propanenitrile; (S)-10-((5-chloro-2-(6-methyl-2,6-diazaspiro[3,3]heptan-2-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (2S)-10-((5-chloro-2-(3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-2-Cyclopropyl-3,3-Difluoro-10-((5-Fluoro-2-(4-Methyl-3-Oxopiperazin-1-yl)Pyrimidine-4-yl)amino)-7-Methyl-1,2,3,4-Tetrahydro-[1,4]Oxazepino[2,3-c]Quinoline-6(7H)-one; (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; or (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one.

[0105] Further compounds of the present invention include any of the compounds exemplified herein, or pharmaceutically acceptable salts or solvates thereof, and in particular include any of the following: (S)-2-chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; (R)-10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one; (S)-10-((5-chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(4,4-difluoropiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-(3,3-dioxide-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; or (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.

[0106] The various functional groups and substituents that form compounds of formula (I) or subformulas Ia to Ix are typically selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More generally, the molecular weight of the compound will be less than 900, for example less than 800 or less than 750 or less than 700 or less than 650. More preferably, the molecular weight will be less than 600, for example 550 or less.

[0107] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, acid addition salts with the compounds of the present invention that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic are salts with alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or organic bases that yield pharmaceutically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0108] Compounds having the same molecular formula but differing in the nature or arrangement of their atomic bonds, or in the arrangement of their atoms in space, are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while those that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if four different groups are bonded together, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by the Kahn-Prelog R- and S- arrangement rules, or by the dextrorotatory or levorotatory nature of the molecule, which rotates the plane of polarization (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0109] The compounds of the present invention may have one or more chiral centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers, or as mixtures thereof. Unless otherwise stated, the description or naming of specific compounds in the specification and claims is intended to include both individual enantiomers and their racemic or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by separation of racemic forms. Some of the compounds of the present invention may have geometric isomeric centers (E- and Z-isomers). The present invention should be understood to include all optical isomers, diastereoisomers and geometric isomers, and mixtures thereof, that have antiproliferative activity.

[0110] The present invention also includes compounds of the present invention as defined herein, which involve one or more isotopic substitutions. For example, H may be in any isotopic form including 1H, 2H(D), and 3H(T); C may be in any isotopic form including 12C, 13C, and 14C; and O may be in any isotopic form including 16O and 18O, and so on.

[0111] It should be understood that certain compounds of formula I or subformulas Ia to Ix may exist in solvated and non-solvated forms, such as hydrates. The present invention should be understood to encompass all such solvated forms having antiproliferative activity.

[0112] Certain compounds of formula I or subformulas Ia to Ix may exhibit pleomorphism, and it should also be understood that the present invention includes all such forms having antiproliferative activity.

[0113] Compounds of formula I or subformulas Ia-Ix may exist in numerous different tautomerized forms, and references to compounds of formula I or subformulas Ia-Ix include all such forms. To avoid ambiguity, even if a compound can exist in one of several tautomerized forms and only one is specifically described or indicated, all other forms are nevertheless encompassed by formula I or subformulas Ia-Ix. Examples of tautomerized forms include, for example, the keto-, enol-, and enolate- forms found in the following tautomerized pairs: keto / enol (described below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acy-nitro. [ka]

[0114] Compounds of formula I or subformulas Ia-Ix containing amine functional groups may also form N-oxides. References herein to compounds of formula I or subformulas Ia-Ix containing amine functional groups also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid); see, for example, Advanced Organic Chemistry, Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be formed by the method of LWDeady (Syn.Comm. 1977, 7, 509-514), in which the amine compound is reacted with an inert solvent such as m-chloroperoxybenzoic acid (mCPBA), e.g., dichloromethane.

[0115] Compounds of formula (I) or subformulas Ia-Ix may be administered in the form of prodrugs that degrade in the body of a human or animal to release the compounds of the present invention. Prodrugs may be used to modify the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain suitable groups or substituents to which character-modifying groups can be bound. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed by carboxyl or hydroxyl groups in compounds of formula (I) or subformulas Ia-Ix, and in vivo cleavable amide derivatives that can be formed by carboxyl or amino groups in compounds of formula (I) or subformulas Ia-Ix.

[0116] Accordingly, the present invention includes compounds of formula (I) or subformulas Ia-Ix as defined herein, when made available by organic synthesis and when made available in the human or animal body by cleavage of its prodrug. Accordingly, the present invention includes compounds of formula I or subformulas Ia-Ix produced by organic synthesis means, and also includes compounds produced in the human or animal body by the metabolism of precursor compounds; that is, compounds of formula (I) or subformulas Ia-Ix may be synthetically produced compounds or metabolically produced compounds.

[0117] A suitable pharmaceutically acceptable prodrug of a compound of formula (I) or subformulas Ia-Ix is one that is deemed suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity, based on reasonable medical judgment.

[0118] Various forms of prodrugs are described, for example, in the following document. a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5“Design and Application of Pro-drugs”,by H.Bundgaard p.113-191(1991); d)H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992); e)H.Bundgaard,et al.,Journal of Pharmaceutical Sciences,77,285(1988); f)N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g)T.Higuchi and V.Stella,“Pro-Drugs as Novel Delivery Systems”,A.C.S.Symposium Series,Volume 14;and h)E.Roche(editor),“Bioreversible Carriers in Drug Design”,Pergamon Press,1987。

[0119] A suitable pharmaceutically acceptable prodrug of a compound of formula I or partial formulas Ia-Ix having a carboxyl group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of formula I or partial formulas Ia-Ix containing a carboxyl group is, for example, a pharmaceutically acceptable ester that cleaves in the body of a human or animal to produce a hydrophilic acid. Suitable pharmaceutically acceptable esters of carboxyl include (1-6C) alkyl esters such as methyl, ethyl, and tert-butyl; (1-6C) alkoxymethyl esters such as methoxymethyl; (1-6C) alkanoyloxymethyl esters such as pivaloyloxymethyl; (3-8C) cycloalkylcarbonyloxy-(1-6C) alkyl esters such as 3-phthalidyl esters, cyclopentylcarbonyloxymethyl, and 1-cyclohexylcarbonyloxyethyl; 2-oxo-1,3-dioxolennylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolennylmethyl; and (1-6C) alkoxycarbonyloxy-(1-6C) alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl.

[0120] A suitable pharmaceutically acceptable prodrug for a compound of formula (I) or partial formulas Ia-Ix having a hydroxyl group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether for a compound of formula I or partial formulas Ia-Ix containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that cleaves in the body of a human or animal to produce a parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups related to the hydroxyl group include inorganic esters such as phosphate esters (including phosphoramidoic acid cyclic esters). Further suitable pharmaceutically acceptable ester-forming sources related to the hydroxyl group include (1-10C) alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl; phenylacetyl; (1-10C) alkoxycarbonyl groups such as ethoxycarbonyl; N,N-(1-6C)2-carbamoyl; 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(1-4C alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups related to the hydroxyl group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0121] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or subformulas Ia-Ix having a carboxyl group are, for example, in vivo cleavable amides, which are amines such as ammonia; (1-4C) alkylamines such as methylamine; (1-4C alkyl) 2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine; (1-4C) alkoxy-(2-4C) alkylamines such as 2-methoxyethylamine; phenyl-(1-4C) alkylamines such as benzylamine; and amides formed with amino acids such as glycine or their esters.

[0122] A suitable pharmaceutically acceptable prodrug for compounds of formula I or partial formulas Ia-Ix having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, (1-10C) alkanoyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl, as well as amides formed with a phenylacetyl group. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(1-4C)alkyl)piperazine-1-ylmethyl.

[0123] The in vivo effect of the compound of formula (I) or partial formulas Ia-Ix may be partially exerted by one or more metabolites formed in the human or animal body after administration of the compound of formula (I) or partial formulas Ia-Ix. As described herein above, the in vivo effect of the compound of formula (I) or partial formulas Ia-Ix may also be exerted by the metabolism of a precursor compound (prodrug).

[0124] The present invention may relate to any compound or a particular group of compounds defined herein by any optional, preferred or suitable properties, or otherwise by a particular embodiment; however, the present invention may also relate to any compound or a particular group of compounds that specifically exclude the optional, preferred or suitable properties or the particular embodiment.

[0125] Preferably, any individual compounds that do not possess biological activity as defined herein are excluded from the present invention. The following compounds were tested in the HTRF assay described in the Examples section, but showed IC50 greater than 2.50 μM. 50 Because it had a certain value, it did not exhibit the desired activity. (R)-2-Cyclopropyl-10-((2-((3S,5R)-4,4-Difluoro-3,5-Dimethylpiperidine-1-yl)-5-Methoxypyrimidine-4-yl)amino)-7-Methyl-1,2,3,4-Tetrahydro-[1,4]Oxazepino[2,3-c]Quinoline-6(7H)-one; 2-Chloro-4-((2,4,4,7-tetramethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2,2,7-trimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile; (2S)-10-((2-(7-acetyl-3,7-diazabicyclo[3.3.1]nonane-3-yl)-5-chloropyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione; 2-Chloro-4-((2-isopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile; 2-Chloro-4-((2-(cyclopropylmethyl)-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinoline-9-yl)amino)nicotinonitrile; and 2-Chloro-4-((2-cyclobutyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)nicotinonitrile.

[0126] In one embodiment, the compound of the present invention is a compound of formula I as defined above, but this compound is not one of the compounds listed in the preceding paragraph.

[0127] synthesis The compounds of the present invention can be prepared by any preferred technique known in the art. The preparation processes for specific compounds are further described in the attached examples.

[0128] In the descriptions of the synthesis methods described herein, and in any of the synthesis methods mentioned for the preparation of the starting materials, it should be understood that all of the presented reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental time, and workup method, are selectable by those skilled in the art.

[0129] Those skilled in organic synthesis understand that the functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0130] It will be recognized that during the synthesis of the compounds of the present invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent undesirable reactions. Experienced chemists will understand when such protection is necessary and how to attach and subsequently remove such protecting groups.

[0131] For examples of protecting groups, see, for example, one of the many general texts on this subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by either a simple method described in the literature as suitable for removal of the protecting group, or a method known to experienced chemists, and such a method should be chosen to minimize the impact on other groups in the molecule during removal.

[0132] Therefore, if the reactants contain groups such as amino, carboxy, or hydroxy, it may be desirable to protect the groups in some of the reactions described herein.

[0133] As an example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups like acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl groups; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; or aroyl groups, such as benzoyl. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or alkoxycarbonyl groups, or aroyl groups, can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, such as lithium or sodium hydroxide. Alternatively, acyl groups such as t-butoxycarbonyl groups can be removed by treatment with suitable acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups can be removed by hydrogenation with a catalyst such as palladium carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). Suitable alternative protecting groups for primary amino groups are phthaloyl groups, which can be removed by treatment with alkylamines such as dimethylaminopropylamine or hydrazine.

[0134] Suitable protecting groups for hydroxyl groups include, for example, acyl groups, alkanoyl groups such as acetyl, alloyl groups such as benzoyl, or arylmethyl groups such as benzyl. The deprotection conditions for the above protecting groups will inevitably vary depending on the choice of protecting group. For example, acyl groups such as alkanoyl or alloyl groups can be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl can be removed by hydrogenation with a catalyst such as palladium carbon.

[0135] Suitable protecting groups for the carboxyl group are, for example, esterifying groups that can be removed by hydrolysis with a base such as sodium hydroxide, such as methyl or ethyl groups; or, for example, t-butyl groups that can be removed by treatment with an acid such as an organic acid such as trifluoroacetic acid; or, for example, benzyl groups that can be removed by hydrogenation with a catalyst such as palladium carbon.

[0136] Resins can also be used as protecting groups.

[0137] The methodology employed for the synthesis of compounds of formula (I) or subformulas Ia-Ix is X1, X2, R 1 , R 2 , R 30 , R 31 The properties of ring A and any of the substituents associated therewith will vary. Preferred processes for these preparations are further described in the attached examples.

[0138] Once a compound of formula (I) or subformulas Ia-Ix has been synthesized by any one of the processes defined herein, these processes then further include the following additional steps: (i) step of removing any existing protecting group; (ii) A step of converting a compound of formula (I) to another compound of formula (I); (iii) the step of forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or (iv) the step of forming the prodrug This may further include:

[0139] An example of (ii) above is the synthesis of a compound of formula I, followed by the addition of groups X1, X2, and R 1 , R 2 , R 30 , R 31 This is the case when one or more of ring A may react further to change the properties of this group, resulting in a compound of alternative formula (I).

[0140] The resulting compounds of formula (I) or subformulas Ia to Ix can be isolated and purified using techniques well known in the art.

[0141] The compound of formula (I) can be synthesized by the following general synthetic routes (schemes 1 to 10b), specific examples of which are described in more detail in the examples. [ka] In the formula, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTf, SOMe, or SO2Me, and R 3 is H or formyl, and R 1 , R 2 , R 30 , R 31 X1, X2, and ring A are preferred groups selected from those already defined.

[0142] The compound of formula (I) is formed by an aromatic amine (II) shown in scheme 1 and an aryl halide or equivalent R 2 The reaction with -Y may be carried out at high temperatures (e.g., 60-180°C) using conventional heating or microwave heating in a suitable solvent or solvent mixture such as NMP, DMA, DMF, or acetonitrile. This reaction may be carried out in the presence or absence of a base (e.g., triethylamine or DIPEA). Alternative reaction conditions include the use of a transition metal catalyst such as Pd2(dba)3 combined with a suitable ligand such as xanthophos, at high temperatures in the presence of a base such as cesium carbonate, using a suitable solvent or solvent mixture such as toluene, or a mixture of toluene and DMF or NMP. If Y is SOMe or SO2Me, alternative reaction conditions include the use of an acid such as TFA, at high temperatures (e.g., 70°C), using a suitable solvent such as trifluoroethanol. 3 If is formyl and Y is SO2Me, alternative reaction conditions include using a base such as NaH and a suitable solvent such as THF at a high temperature (e.g., 60°C).

[0143] Compound (II) can be prepared using methods such as those described in Schemes 2 and 3.

[0144] The compound of formula (I) can be converted to other compounds of formula (I) by methods generally known to those skilled in the art.

[0145] [ka] In the formula, W is NO2, or a halogen such as Cl, Br, I, or a suitable substitute such as OTf, and R 1 , R 30 , R 31 , X 1 , X 2 Ring A is a preferred group selected from those already defined.

[0146] The reduction of nitro compounds (III, W=NO2) to amino compounds (II) can be carried out by numerous methods well known in the art. Hydrogenation can be carried out in a suitable solvent or solvent mixture such as ethanol, methanol, ethyl acetate, or ethanol / NMP, in the presence of a metal catalyst such as palladium (often in the form of palladium carbon), at ambient temperature or high temperature (e.g., 40-80°C), using conventional heating or microwave heating. These reactions are carried out in a hydrogen atmosphere, or alternatively, by "mobile hydrogenation" using reagents such as ammonium formate or triethylsilane. Alternatively, tin(II) chloride is used in a suitable solvent or solvent mixture such as ethanol and trifluoroethanol, at high temperature such as 120°C, using conventional heating or microwave heating. Other approaches, such as iron or zinc metal-mediated reduction, are well known in the art.

[0147] The amination of halo compounds (e.g., W=Cl) to aromatic amines(II) can be carried out by methods well known in the art. For example, metal-catalyzed amination can be employed using a metal source and ligand. Conditions for this type of reaction are publicly known in the literature and include the use of palladium acetate and benzophenone imine, as described in Shen et al., Angew. Chem. Int. Ed. 2005, 44, 1371. The reaction is typically carried out at high temperature with a base such as sodium tert-butoxide in a suitable solvent or solvent mixture such as 1,2-dimethoxyethane. Hydrolysis of the imine intermediate can be carried out in a one-pot method at room temperature with the addition of an acid such as HCl. Aromatic amines(II) can also be formed from aryl halides (e.g., W=Br) by reaction with ammonia (e.g., derived from ammonium hydroxide solution) at high temperature (e.g., 140°C) in a suitable solvent such as NMP, using conventional heating or microwave heating. These reactions are typically catalyzed using a metal catalyst such as copper(I) oxide.

[0148] Compound (III) can be prepared by methods including those shown in schemes 4a-c, 7a-7b, 8 and 9.

[0149] [ka] In the formula, R 1 , R 30 , R 31 , X 1 , X 2 Ring A is a preferred group selected from those already defined.

[0150] Methods for preparing formamide compounds (II-d) are known in the art. For example, this can be carried out at ambient temperature in a suitable solvent such as dichloromethane in the presence of phenyl formate.

[0151] Compound (II) can be prepared by a method including those shown in schemes 2a and 3.

[0152] [ka] In the formula, R 1 , R 30 , R 31 X1 and X2 are preferred groups selected from those already defined. Z is a appropriately substituted methylene group (-CR). 40 R 41 -), for example, (-CH2-) or (-CH(Me)-).

[0153] The aniline compound (II-c) can be prepared by reduction of compound (II-b). This reaction can be carried out at low temperatures (e.g., 0°C) in a suitable solvent such as THF, with various reducing agents known in the art, such as sodium borohydride. Various additives such as Lewis acids (e.g., diethyl boron trifluoride etherate) may be used.

[0154] Compound (II-b) can be prepared as described in Scheme 2.

[0155] [ka] In the formula, W is as already defined, Y is a halogen such as Br or I, and R 1 , R 30 , R 31 , X 1 , X 2 And Z are appropriately substituted (1-2C) alkylene groups such as (-CH2-), (-CH2CH2-), (-CF2CH2), or (-CH(Me)CH2-).

[0156] The cyclized compound (III-a) can be prepared by intramolecular cyclization of the halogenated compound (IV). This reaction can be carried out at high temperatures (e.g., 60°C) in a suitable solvent such as DMSO, DMF, 1,2-dichloroethane (DCE), 1,2-dimethoxyethane (DME), or THF (preferably in THF) in the presence of a base (e.g., potassium tert-butoxide or lithium tert-butoxide (preferably lithium tert-butoxide)). Alternative reaction conditions include the use of a transition metal catalyst (e.g., copper(I) iodide) in combination with a suitable ligand (e.g., 1,10-phenanthroline) at high temperatures in the presence of a base (e.g., cesium carbonate), using a suitable solvent (e.g., NMP).

[0157] The halogenated compound (IV) can be prepared as shown in Scheme 5.

[0158] [ka] In the formula, V is a halogen such as Cl, Br, I, or a suitable substitute such as OTs, and R 2 is a suitable protecting group such as acetate, Y is a halogen such as Br or I, and R 1 , R 30 , R 31 X1 and X2 are preferred bases selected from those already defined, and Z is a linker appropriately substituted as already defined.

[0159] The oxidation of sulfide compounds (III-e) to sulfone compounds (III-i) can be carried out by numerous methods well known in the art. For example, oxidation can be carried out in a suitable solvent or mixture of solvents such as dichloromethane / acetonitrile at low temperatures (e.g., 0°C) or ambient temperature using a suitable oxidizing agent such as mCPBA. Compound (III-e) can be formed by thiol deprotection of IX-a, followed by substitution of Y at the 3-position of quinolinone (X) with insights. Preferred conditions for this conversion include the use of an additive (e.g., sodium hydroxide) at ambient temperature in a suitable solvent (e.g., methanol). Protected thiol (IX-a) can be formed by substitution of the leaving group V. Preferred conditions for this conversion include the use of high temperatures (e.g., 50°C) in a suitable solvent (e.g., DMF). Various additives (e.g., sodium iodide) can also be used. Alkylating agents (VIII-a) can be formed from the corresponding alcohol (IV). Various conditions for the activation of this alcohol are known in the art; a preferred method includes tosylation with tosylloride in pyridine at ambient temperature. Compound (IV) can be prepared as described in Scheme 5.

[0160] [ka] In the formula, W is as already defined, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTs, and R 1 , R 30 , R 31 X1 and X2 are preferred bases selected from those already defined, R 4 is a (1-2C)alkyl, cyclopropyl, or (1-2C)haloalkyl, and Z is a linker that is appropriately substituted as already defined.

[0161] The reduction of nitro compounds (VIII-b) to the intermediate aromatic amine (XI) can be carried out by numerous methods well known in the art. Hydrogenation can be carried out in a suitable solvent or solvent mixture such as ethanol, methanol, ethyl acetate, or ethanol / NMP, in the presence of a metal catalyst such as palladium (often in the form of palladium carbon), at ambient temperature or high temperature (e.g., 60-75°C), using conventional heating or microwave heating. These reactions are carried out under a hydrogen atmosphere, or instead by "mobile hydrogenation" using reagents such as ammonium formate or triethylsilane. Alternatively, tin(II) chloride is used in a suitable solvent or solvent mixture such as ethanol and trifluoroethanol, at high temperature such as 120°C, using conventional heating or microwave heating. Other approaches, such as iron or zinc metal-mediated reduction, are well known in the art. Incites cyclization to compound (III-f) can occur spontaneously during the reduction step or upon addition of additives (such as DIPEA) at ambient temperature. Nitro compounds (VIII-b) can be formed from the corresponding alcohol (Vb). Various conditions for the activation of this alcohol are known in the art; a preferred method involves tosylation with a tosyl chloride in DCM at ambient temperature, using a suitable base (such as triethylamine). Various additives (such as DMAP) may also be used. Further functionalization of the C3 nitrogen can be carried out by numerous methods known in the art for preparing compound (III-g).

[0162] Compound (Vb) can be prepared as described in scheme 6b.

[0163] [ka] In the formula, W is as already defined, Y is a halogen such as Br or I, and R 1 , R 30 , R 31 , X 1 , X 2is a preferred base selected from those already defined, and Z is a linker appropriately substituted as already defined.

[0164] The preparation of compound (IV) can be carried out by halogenation of compound (Va). This reaction can be carried out at various temperatures (0°C, room temperature, or 60°C, etc.) in a suitable solvent or solvent mixture such as DCM, methanol / water, with a suitable halogenating reagent such as N-bromosuccinimide or iodine. Various additives such as acids (e.g., TFA) may be used.

[0165] Compound (Va) can be prepared as shown in scheme 6a.

[0166] [ka] In the formula, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTf, and R 3 R is a small alkyl such as methyl or ethyl, and 1 , R 30 , R 31 X1 and X2 are preferred bases selected from those already defined, and Z is a linker appropriately substituted as already defined.

[0167] Nitro compounds (V) can be prepared by the reaction of an amino alcohol (VII) with a halo-aromatic or equivalent compound (VI-a). This reaction can be carried out at high temperatures (e.g., 80-200°C) in a suitable solvent or solvent mixture such as NMP, NMP / THF, or using an amine as the solvent. Various additives such as bases (e.g., DIPEA, triethylamine) and nucleophilic catalysts (e.g., DMAP) may be used. For amines that are low in nucleophilicity and also sterically hindered, alternative conditions may be required. For example, metal-catalyzed amination can be employed using a metal source and ligand. Conditions for this type of reaction are publicly known in the literature and include the use of palladium acetate and BINAP, as described in Naik et al., J.Med.Chem. 2014, 57, 5419. The reaction is typically carried out at high temperatures in a suitable solvent or solvent mixture such as toluene, and again using a base such as cesium carbonate. Alternatively, the use of an ester functional group (VI-b) can be used to assist in the substitution of halogens. The substitution of Y by (VII) is carried out at high temperatures (e.g., 90-160°C) in a suitable solvent such as NMP, MeCN, or THF, typically using a base such as DIPEA. The removal of the ester group can be carried out by known methods such as adding lithium chloride or sodium hydroxide to the reaction mixture and further heating (e.g., at 90-160°C). Microwave or conventional heating may be used for the above reaction.

[0168] The amino alcohol (VII) was obtained from a commercial supplier or prepared by a method known in the art. Compounds (VI-a) and (VI-b) can be prepared as shown in schemes 10a and 10b.

[0169] [ka] In the formula, W is as already defined, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTf, and R 1 , R 30 , R 31X1 and X2 are preferred bases selected from those already defined, and Z is a linker appropriately substituted as already defined.

[0170] Compound (Vb) can be prepared by the reaction of an amino alcohol (VII) with a halo-aromatic or equivalent compound (VI-c). This reaction can be carried out at a high temperature (e.g., 140°C) in a suitable solvent (e.g., NMP) and using a suitable base (e.g., DIPEA). The amino alcohol (VII) was obtained from a commercial supplier or prepared by a method known in the art. Compound (VI-c) can be prepared as shown in scheme 10b.

[0171] [ka] In the formula, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTf, and R 3 R is a small alkyl such as methyl or ethyl, and 1 , R 30 , R 31 X1 and X2 are preferred bases selected from those already defined, and Z is a linker appropriately substituted as already defined.

[0172] The nitro compound (III-b) can be prepared by the reaction of the amino alcohol (VII) with compound (VI-b). The substitution of Y with (VII) is carried out at high temperatures (e.g., 160°C) in a suitable solvent such as NMP, typically using a base such as DIPEA. Cyclation to lactone (III-b) can be carried out by adding an additive such as lithium chloride to the reaction mixture and further heating (e.g., at 160°C). Microwave or conventional heating can be used for the above reaction. This method can produce a mixture of compounds (III-b) and (Va), which can be separated by standard methods.

[0173] The amino alcohol (VII) was obtained from a commercial supplier or prepared by a method known in the art. Compound (VI-b) can be prepared as shown in Scheme 10b.

[0174] [ka] In the formula, W is as already defined, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTf, and R 2 Boc is a suitable protecting group, and R 3 R is a small alkyl such as methyl or ethyl. 4 is H, (1-2C)alkyl, cyclopropyl or (2C)haloalkyl, and R 1 , R 30 , R 31 X1 and X2 are preferred groups selected from those already defined, and Z is a well-defined, appropriately substituted methylene linker.

[0175] The cyclic lactam compound (III-h) can be prepared from compound (VI-b) by a one-pot method. Compound (Vd) can be prepared by the reaction of a suitably protected diamine (XII) with a halo-aromatic (or equivalent) ester functional group (VI-b). Substitution of Y with diamine (XII) is carried out at high temperature (e.g., 100°C) in a suitable solvent such as acetonitrile, typically using a base such as DIPEA. Insight amine deprotection can be achieved by adding an acid (e.g., HCl in dioxane) at high temperature (e.g., 75°C). Cyclization can then be achieved by adding an excess amount of base (e.g., DIPEA) at high temperature (e.g., 75°C).

[0176] A suitably protected diamine (XII) was obtained from a commercial supplier or prepared by a method known in the art. Compound (VI-b) may be prepared as shown in scheme 10b.

[0177] [ka] In the formula, W is as already defined, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTf, and R 4 Boc is a suitable protecting group, and R 3 R is a small alkyl such as methyl or ethyl, and 1 , R 2 , R 30 , R 31 X1 and X2 are preferred groups selected from those already defined, and Z is a well-defined, appropriately substituted methylene linker.

[0178] An alternative route to the cyclic lactam compound (Ih) is shown in Scheme 7c. Compound (III-j) can be prepared by the reaction of a suitably protected diamine (XII) using a halo-aromatic or equivalent (VI-b). The substitution of Y with diamine (XII) can be carried out at high temperatures (e.g., 100°C) in a suitable solvent such as THF, typically using a base such as DIPEA. The conversion from (III-j) to (II-j) can be carried out using the conditions already described in Scheme 2a. The conversion from (II-j) to (Ij) can be carried out using the conditions already described in Scheme 1. The formation of the cyclic lactam compound (Ih) can be achieved from compound (Ij) by a one-pot method. Amine deprotection can be achieved by adding an acid (such as HCl in dioxane) at high temperatures (e.g., 70°C) in a suitable solvent (e.g., THF). Subsequently, cyclization at insights can be achieved by adding an excess amount of base (such as triethylamine) at high temperatures (e.g., 70°C).

[0179] A suitably protected diamine (XII) was obtained from a commercial supplier or prepared by a method known in the art. Compound (VI-b) may be prepared as shown in scheme 10b.

[0180] [ka] In the formula, Y is a halogen such as Cl, Br, I, or a suitable substitute such as OTs, and R 1 , R 30 , R 31 X1 and X2 are preferred groups selected from those already defined, and Z is a suitably substituted ethylene linker that has already been defined.

[0181] Compound (III-d) can be formed by cyclization at the 3-position of quinolinone, replacing the leaving group Y. Preferred conditions for this conversion include the use of high temperatures (e.g., 160°C) with the addition of a base (e.g., DIPEA) in a suitable solvent (e.g., NMP). The alkylating agent (VIII-d) can be formed from the corresponding alcohol (Va). Various conditions for the activation of this alcohol are known in the art; preferred methods include tosylation with tosylloride at ambient temperature in pyridine / DCM. Compound (Va) can be prepared as described in scheme 6a.

[0182] [ka] In the formula, Y 2 is a halogen such as Cl, Br, I, or a suitable substitute such as OTf, W is as already defined, and R 1 , R 30 , R 31 , X 1 , X 2 Ring A is a preferred group selected from those already defined.

[0183] R in the later stages 1 The introduction of the group into compound (XIII) can be carried out by alkylation to form compound (III). Alkylation conditions are well known in the art and may be carried out in a suitable solvent such as DMF, in the presence of a base such as sodium hydride or cesium carbonate, at ambient temperature or high temperature (e.g., 80°C) with an alkyl halide or equivalent (R 1 -Y2 , R 1 This includes the use of CH2cPr (such as bromomethylcyclopropane). Alkylation can occur on oxygen or nitrogen; selectivity can be adjusted by the selection of reaction conditions, and these positional isomers are typically separable using known methods. Compound (XIII) is R 1 It can be prepared as described in schemes 4a-c and 7a-b where =H. Further manipulation of compound (III) by known methods, R 1 It is possible to modify it.

[0184] [ka] In the formula, Y is a halogen such as Cl, and R 1 X1 and X2 are preferred bases selected from those already defined.

[0185] R to compound (A-III) 1 The introduction of the group can be carried out by alkylation to form compound (VI-a). Alkylation conditions are well known in the art and include alkylation of an alkyl halide or equivalent (R) in a suitable solvent such as DMF, in the presence of a base such as sodium hydride or cesium carbonate, at ambient temperature or high temperature (e.g., 80°C). 1 -Y 2 , R 1 This includes the use of iodomethane (=Me). Alkylation may occur on oxygen or nitrogen; selectivity may be adjusted by the selection of reaction conditions, and these positional isomers are typically separable using known methods. Compounds (A-III) are commercially available or can be prepared by known methods such as the nitration of compound (A-II) using conditions including those described in Oeveren et al., Bioorg. Med. Chem. Lett. 2007, 17, 1527. Compound (A-II) is commercially available or can be prepared by known methods such as the hydrolysis of dihalo derivatives (AI) using conditions including those described in Naik et al., J. Med. Chem. 2014, 57, 5419.

[0186] [ka] In the formula, W is as already defined, and Y and Y 3 This is independently selected from halogens such as F, Cl, Br, I, or suitable substitutes such as OTf or OTs, Y 2 This is independently selected from halogens such as Cl, Br, I, or suitable substitutes such as OTf or OTs, R 2 and R 3 is a small alkyl such as methyl or ethyl, and R 1 X1 and X2 are preferred bases selected from those already defined.

[0187] R to compound (BI) 1 The introduction of the group can be carried out by alkylation to form compound (B-II). Alkylation conditions are well known in the art, and include alkyl halides or equivalents (R) in a suitable solvent such as DMF, in the presence of a base such as sodium hydride or cesium carbonate, at ambient temperature or high temperature (e.g., 80°C). 1 -Y 2 , R 1 This involves the use of iodomethane (=Me). Alkylation may occur on oxygen or nitrogen; selectivity may be adjusted by the selection of reaction conditions, and these positional isomers are typically separable by known methods. Compounds (VI-b) and (VI-c) can be prepared by a multi-step process starting from compound (B-II), similar to the process described in the literature (Coppola et al., Synthesis 1981, 391; Stadlbauer et al., J.Het.Chem. 1998, 35, 627; Tomassoli et al., Eur.J.Med.Chem. 2011, 46, 1; Ohashi et al., Bioorg.Med.Chem. 2012, 20, 5496; Tomassoli et al., Monatsh.Chem. 2016, 147, 1069; Gaeta et al., International Publication No. 02 / 094203).

[0188] Alternatively, R to compound (CI) 1 The introduction of the group is by Y substituted amine. 3 This can be done by substitution of the base. N Ar conditions are well known in the art, and involve substituted amines (R) in a suitable solvent such as THF at ambient temperature or high temperature (e.g., 40°C). 1 -NH2, R 1 This includes the use of a compound (=Me, such as methylamine). Compound (C-III) can be formed by one-potamide bond formation / cyclization of compound (C-II). Preferred conditions for this conversion include the use of high temperatures (e.g., 60°C) with the addition of a base (such as triethylamine) and a suitable acylation reagent (e.g., ethyl 3-chloro-3-oxopropanoate) in a suitable solvent (e.g., DCM). Compound (C-III) is well known in the art and can be converted to the corresponding halide (VI-b) by using conditions including the use of POCl3 at high temperatures (e.g., 80°C).

[0189] biological activity The biological assays described in the Examples section of this specification may be used to measure the pharmacological effects of the compounds of the present invention.

[0190] The pharmacological properties of the compound of formula I vary with structural changes, but as expected, the compound of the present invention was found to be active in the HTRF in vitro assay, the NanoBRET cell assay, and in some cases, in the SUDHL 4-degradation assay described in the Examples section.

[0191] Typically, as shown by the example compound data in Table 1, the compounds of the present invention exhibit an IC50 of 2.5 μM or less in the HTRF assay described in the Examples section. 50 This demonstrates that the pIC is 5.6 or higher. 50 This corresponds to a pIC of 6.3 or higher. Preferred compounds of the present invention are those with a pIC of 6.3 or higher. 50 ICs equivalent to 500nM or less 50Demonstrate or achieve a pIC of 6.6 or higher. 50 ICs equivalent to 250nM or less 50 This demonstrates that a more preferred compound of the present invention has a pC of 7.0 or higher. 50 ICs equivalent to 100nM or less 50 This demonstrates that the most preferred compound of the present invention has a pIC of 8.0 or higher. 50 ICs equivalent to 10nM or less 50 This will be demonstrated.

[0192] In the NanoBRET cell assay described herein in the Examples chapter, as shown by the example compound data in Table 2, the compound of formula I typically produces a pIC of 5.0 or higher (preferably 6.0 or higher). 50 This demonstrates that the most preferred compound of the present invention has a pIC of 7.0 or higher. 50 This will be demonstrated.

[0193] In the SUDHL4 degradation assay described herein in the Examples chapter, as shown by the example compound data in Table 3, the compound of formula I also has a pDC of 6.0 or higher (preferably 6.5 or higher). 50 This can be demonstrated.

[0194] The following data was created for the example.

[0195] [Table 1]

[0196] [Table 2]

[0197] [Table 3]

[0198] [Table 4]

[0199] Pharmaceutical composition In a further aspect of the present invention, a pharmaceutical composition is provided comprising the compound of the present invention as defined herein above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, together with a pharmaceutically acceptable diluent or carrier.

[0200] The compositions of the present invention may be in forms suitable for oral use (e.g., as tablets, licks, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, aqueous or oily solutions or suspensions), administration by inhalation (e.g., as fine powders or liquid aerosols), administration by blowing (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0201] The compositions of the present invention can be obtained by conventional methods using conventional pharmaceutical excipients that are well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0202] The effective amount of the compound of the present invention for therapeutic use is sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the hyperplasiasm described herein.

[0203] The amount of the active formulation component, combined with one or more excipients to produce a single dosage form, will inevitably vary depending on the individual being treated and the specific route of administration. For example, formulations intended for oral administration to humans will generally contain, for example, 0.5 mg to 0.5 g of the active agent (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg), along with a suitable and convenient amount of excipients, which may vary in weight from about 5 to about 98 percent of the total composition.

[0204] It is natural that the single dose of the compound of formula I for therapeutic or prophylactic purposes will vary depending on the nature and severity of the animal's or patient's condition, age, sex, and route of administration, in accordance with well-known principles relating to the formulation.

[0205] In the use of the compounds of the present invention for therapeutic or preventive purposes, the daily dose of the compounds is generally administered in a range of, for example, 0.1 mg / kg to 75 mg / kg based on body weight (administered in multiple doses as necessary). Generally, when parenteral routes are employed, lower doses are administered. Therefore, for example, for intravenous or intraperitoneal administration, doses in the range of 0.1 mg / kg to 30 mg / kg based on body weight are generally used. Similarly, for administration by inhalation, doses in the range of 0.05 mg / kg to 25 mg / kg based on body weight are used. Oral administration may also be particularly preferred in tablet form. Typically, a unit dosage form will contain about 0.5 mg to 0.5 g of the compound of the present invention.

[0206] Therapeutic uses and applications This invention provides compounds that function as inhibitors of BCL6 activity.

[0207] Accordingly, the present invention provides a method for inhibiting BCL6 activity in vitro or in vivo, the method comprising the step of contacting cells with an effective amount of the compound defined herein above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0208] The present invention also provides a method for treating a patient who requires treatment for a disease or disorder related to BCL6 activity, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

[0209] The present invention provides a method for inhibiting cell proliferation in vitro or in vivo, the method comprising the step of contacting cells with an effective amount of a compound as defined herein above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0210] The present invention provides a method for treating a patient requiring treatment for a proliferative disorder, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

[0211] The present invention provides a method for treating cancer, which is to be performed in a patient in need of such treatment, the method comprising the step of administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0212] The present invention provides compounds, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions as defined herein, for use in therapeutic purposes.

[0213] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for use in the treatment of hyperplasia.

[0214] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, or pharmaceutical compositions for use in the treatment of cancer. In certain embodiments, cancer is human cancer.

[0215] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in inhibiting BCL6 activity (i.e., in inhibiting BCL6 transcription and / or corepressor binding).

[0216] Certain compounds of the present invention have been found to bind to BCL6 and initiate its decomposition. Therefore, the present invention also provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in the decomposition of BCL6.

[0217] The present invention provides compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in the treatment of diseases or disorders associated with BCL6 activity.

[0218] The present invention provides for the use of compounds defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof in the manufacture of pharmaceuticals for the treatment of hyperplasia.

[0219] The present invention provides for the use of compounds defined herein or pharmaceutically acceptable salts, hydrates, or solvates thereof in the manufacture of pharmaceuticals for the treatment of cancer. Preferably, the pharmaceuticals are for use in the treatment of human cancer.

[0220] The present invention provides for the use of compounds as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for inhibiting BCL6 activity (i.e., inhibiting BCL6 transcriptional repression and / or corepressor binding).

[0221] The present invention provides for the use of the compounds defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for the decomposition of BCL6.

[0222] The present invention provides for the use of the compounds defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, in the manufacture of pharmaceuticals for the treatment of diseases or disorders related to BCL6 activity.

[0223] The terms “proliferative disorder” and “proliferative state” are used synonymously herein and relate to unwanted, excessive, or abnormal cell proliferation, such as neoplastic or hyperplastic proliferation in vitro or in vivo. Examples of proliferative conditions include, but are not limited to, malignant neoplasms and tumors, cancer (including breast cancer, non-small cell lung cancer (NSCLC) and squamous cell carcinoma (SCC) (including SCC of the head and neck, esophagus, lung and ovary), leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), lymphoma (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissue), and pre-malignant and malignant cell proliferation including atherosclerosis. Any type of cell, including lymphoid, hematopoietic, lung, colon, breast, ovarian, prostate, liver, pancreatic, brain and skin cells, may be treated, but are not limited to these.

[0224] Anticancer effects may arise through one or more mechanisms, including, but are not limited to, regulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of tumor from its origin), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

[0225] Compounds of formula (I) or pharmaceutically acceptable salts thereof that are inhibitors of BCL6 have potential therapeutic uses in various BCL6-mediated disease conditions. BCL6 expression has been associated with various lymphomas (Wagner et al., British J Haematology, 2010, 152, 3-12). BCL6 is involved in chromosomal translocations in diffuse large B-cell lymphoma (DLBCL), and BCL6 inhibitors have been reported to kill DLBCL cells (Cerchietti et al., Cancer Cell, 2010, 17, 400-411), primary low-grade follicular lymphoma cells (Cardenas et al., Clin Cancer Res, 2017, 23(4), 885-893), and Burkitt lymphoma cells (Polo et al., Nat Med, 2004, 10, 1329-1335). BCL6 is required for the formation of follicular helper T cells (Hatzi et al., J Exp Med, 2015, 212(4), 539-553), which raises the possibility that BCL6 inhibitors may be used to treat angioimmunoblastic T-cell lymphoma (AITL), in which BCL6 is strongly expressed (Cortes & Palomero, Curr Opin Hematol, 2016, 23, 434-443).

[0226] BCL6 is also involved in leukemia cells that develop acquired resistance to tyrosine kinase inhibitors (TKIs). Typically, TKIs fail to eradicate leukemia stem cells, leading to frequent leukemia relapses after initial treatment. BCL6 has been identified as a key component of the TKI drug resistance pathway in both Ph+ acute lymphoblastic leukemia (ALL) (Duy et al., Nature, 2011, 473, 384-388) and Ph+ chronic myeloid leukemia (CML) (Hurtz et al., J Exp Med, 2011, 208(11), 2163-2174). BCL6 inhibitors can therefore be used in combination with TKIs to treat ALL and CML.

[0227] Furthermore, non-hematopoietic solid tumors can be treated with BCL6 inhibitors. BCL6 is amplified in approximately 50% of breast tumors and is expressed in many breast cancer cell lines, including triple-negative breast cancer cell lines (Walker et al., Oncogene, 2015, 34, 1073-1082). BCL6 is also important for the survival and proliferation of non-small cell lung cancer (NSCLC) cells, mainly by suppressing genes involved in DNA damage repair (Marullo et al., Proc 107). th Annual Meeting AACR, 2016, Abstract nr 1271 and Deb et al., Cancer Res., 2017, Apr. 4, doi:10.1158 / 0008-5472.CAN-15-3052). BCL6 amplification can also be commonly seen in squamous cell carcinoma (SCC) (including head and neck, esophageal, pulmonary, and ovarian SCC). Furthermore, in recent years, inhibition of BCL6 has been reported as a suitable therapeutic target for glial cell tumors and glioblastomas (Xu et al., Proc. Natl. Acad. Sci. USA, 2017, 114(15), 3981-3986).

[0228] Further embodiments of this specification provide compounds of formula (I) as defined above, or pharmaceutically acceptable salts thereof, for use in the treatment of hematological malignancies including lymphoma (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and angioimmunoblastic T-cell lymphoma (AITL)), leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), and multiple myeloma, as well as solid tumors (including glial cell tumors, breast cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinoma (SCC) (including SCC of the head and neck, esophagus, lung, and ovary)).

[0229] Further features of this embodiment of the Specified Publication provide a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, for use in the treatment of lymphomas including DLBCL, FL, BL, and AITL.

[0230] Further features of this embodiment of the Specified Information provide a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, for use in the treatment of DLBCL and FL.

[0231] Further features of this specification are provided, which include a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof, for use in the treatment of ALL and CML leukemia.

[0232] Further features of this specification provide for use in the treatment of solid tumors, including glial cell tumors, breast cancer, NSCLC, and SCC, of ​​a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0233] Further features of this specification include a method for treating hematological malignancies such as lymphoma (including DLBCL, FL, BL, and AITL), leukemia (including ALL and CML), and multiple myeloma, as well as solid tumors (including glial cell tumors, breast cancer, NSCLC, and SCC (including head and neck, esophageal, lung, and ovarian SCC)) in warm-blooded animals such as humans who require such treatment, the method comprising the step of administering an effective amount of a compound of formula (I) as defined above in this specification or a pharmaceutically acceptable salt thereof.

[0234] Further features of this specification include a method for treating lymphomas, including DLBCL, FL, BL, and AITL, in warm-blooded animals such as humans that require such treatment, the method comprising the step of administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0235] Further features of this specification include a method for treating DLBCL and FL in warm-blooded animals such as humans who require such treatment, the method comprising the step of administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0236] Further features of this specification include a method for treating leukemia, including ALL and CML, in warm-blooded animals such as humans that require such treatment, the method comprising the step of administering an effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0237] Further features of this specification include a method for treating solid tumors (including glial cell tumors, breast cancer, NSCLC and SCC (including head and neck, esophageal, lung and ovarian SCC)) in warm-blooded animals such as humans that require such treatment, the method comprising the step of administering an effective amount of a compound of formula (I) as defined above in this specification or a pharmaceutically acceptable salt thereof.

[0238] Further features of this specification provide for the use of compounds of formula (I) as defined above or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals used in the treatment of hematological malignancies such as lymphoma (including DLBCL, FL, BL, and AITL), leukemia (including ALL and CML), and multiple myeloma, as well as in the treatment of solid tumors (including glial cell tumors, breast cancer, NSCLC, and SCC (including head and neck, esophageal, lung, and ovarian SCC)).

[0239] Further features of this specification provide for the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product used in the treatment of lymphomas including DLBCL, FL, BL, and AITL.

[0240] Further features of this embodiment of the Specified Specification provide the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product used in the treatment of DLBCL and FL.

[0241] Further features of this specification provide for the use of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product used in the treatment of leukemia, including ALL and CML.

[0242] Further features of this specification provide for the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical product used in the treatment of solid tumors (including glial cell tumors, breast cancer, NSCLC and SCC (including SCC of the head and neck, esophagus, lung and ovary)).

[0243] Route of administration The compounds of the present invention or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, either systemically / peripherally or topically (i.e., at the desired site of action).

[0244] Routes of administration are not limited to these, but include: oral (e.g., by ingestion); intrabuccal; sublingual; transdermal (e.g., including by patches, plasters, etc.); transmucosal (e.g., including by patches, plasters, etc.); intranasal (e.g., by nasal spray); transocular (e.g., by eye drops); transpulmonary (e.g., by inhalation or inhalation therapy using aerosols, etc., via the mouth or nose); rectal (e.g., by suppositories or enemas); transvaginal (e.g., by vaginal suppositories); parenteral routes by injection, including, for example, subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intraarticular, intra-articular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intraarticular, subarachnoid, and intestinal; and parenteral routes by implantation of long-acting formulations or reservoirs, such as subcutaneous or intramuscular.

[0245] Combination therapy The antiproliferative treatments defined herein may be applied as a single treatment or may include conventional surgery, radiotherapy, or chemotherapy in addition to the compounds of the present invention. Such chemotherapy may include one or more of the following categories of antitumor agents. (i) Alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide and nitrosourea); antimetabolites (e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, gemcitabine and folate antimetabolites such as larcitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin) Other antiproliferative / antineoplastic agents and combinations thereof used in medical oncology, such as anthracyclines like cin, mitomycin-C, dactinomycin, and mitramycin; mitotic inhibitors (e.g., vinca alkaloids like vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids like taxol and taxotere, and polokinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins like etoposide and teniposide, amsacrin, topotecan, and camptothecin); (ii) Cell division inhibitors such as anti-estrogen agents (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, doroxifene and iodoxifene), anti-androgen agents (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin and buserelin), progestogens (e.g., megestrol acetate) and steroid hormones including corticosteroids (e.g., dexamethasone, prednisone and prednisolone), aromatase inhibitors (e.g., anastrozole, letrozole, borazole and exemestane), and 5α-reductase inhibitors such as finasteride; (iii) Anti-infiltration agents [e.g., c-Src kinase family inhibitors such as 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Publication No. 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl) Piperazine-1-yl]-2-methylpyrimidine-4-ylaminothiazole-5-carboxamide (dastinib, BMS-354825; J.Med.Chem., 2004, 47, 6658-6661) and bosunitib (SKI-606), as well as metalloproteinase inhibitors such as marimastat, inhibitors of urokinase-type plasminogen activator receptor function, or antibodies against heparanase; (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody tratuzumab [Herceptin®], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Erbitux, C225], and Stern et al. (Critical reviews in Examples of such inhibitors include any growth factor or growth factor receptor antibody disclosed in oncology / haematology, 2005, Vol. 54, pp. 11-29; also, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine (erlotinib, OSI-774), and 6-acrylamide-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazoline-4-amine (CI Examples include EGFR family tyrosine kinase inhibitors such as 1033), erbB2 tyrosine kinase inhibitors such as lapatinib; inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); and serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors such as farnesyltransferase inhibitors, e.g., sorafenib (BAY)). 43-9006), tipifarnib (R115777) and ronafarnib (SCH66336), inhibitors of cell signaling mediated by MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and AX39459), and cyclin-dependent kinase inhibitors such as CDK2 and / or CDK4 inhibitors; (v) Angiogenesis inhibitors such as those that inhibit the effects of vascular endothelial growth factor [e.g., anti-vascular endothelial growth factor antibody bevacizumab (Avastin®), and e.g., vandetanib (ZD6474), batalanib (PTK787), sunitinib (SU11248), axinitib (AG-013736), pazopanib (GW786034) and 4-(4-fluoro-2-methylindole-5-yloxy)-6-methoxy-7-(3-pyrrolidine-1-ylpropoxy)quinazoline (A Compounds such as VEGF receptor tyrosine kinase inhibitors (e.g., Example 240 in International Publication No. 00 / 47212, ZD2171), those disclosed in International Patent Application No. 97 / 22596, International Publication No. 97 / 30035, International Publication No. 97 / 32856 and International Publication No. 98 / 13354, and compounds acting by other mechanisms (e.g., linamide, integrin αvβ3 function inhibitors and angiostatins); (vi) Vascular damage agents such as Combrestatin A4, and compounds disclosed in International Publication No. 99 / 02166, International Publication No. 00 / 40529, International Publication No. 00 / 41669, International Publication No. 01 / 92224, International Publication No. 02 / 04434 and International Publication No. 02 / 08213; (vii) Endothelin receptor antagonists, such as dibotentan (ZD4054) or atrasentan; (viii) Antisense therapies such as ISIS2503, anti-ras antisense, and other antisense therapies that target the listed above; (ix) gene therapy approaches that include, for example, approaches that replace abnormal genes (abnormal p53 or abnormal BRCA1 or BRCA2, GDEPT (gene-directed enzyme prodrug therapy) approaches (such as those using cytosine deaminase, thymidine kinase or bacterial nitroreductase), and approaches that increase patient resistance to chemotherapy or radiotherapy (such as multidrug resistance gene therapy); and (x) Immunotherapy approaches including, for example, exovivo and in vivo approaches that enhance the immunogenicity of patient tumor cells (such as transfusion with cytokines such as interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor), approaches that reduce T cell anergy, approaches that use transfusion immune cells such as cytokine-transfusion dendritic cells, approaches that use cytokine-transfusion tumor cell lines, and approaches that use anti-idiotype antibodies.

[0246] In certain embodiments, the antiproliferative treatment as defined herein may include, in addition to the compounds of the present invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more antitumor agents selected from procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide and vincristine.

[0247] In other specific embodiments, the antiproliferative therapy as defined above herein may include, in addition to the compounds of the present invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may include one or more chemotherapeutic agents selected from BCL-2 family inhibitors (e.g., Venetoclax and / or Navitoclax), BTK inhibitors (e.g., ibrutinib, acalabrutinib, tirabrutinib (ONO / GS-4059), BGB-3111 or spbrutinib (CC-292), TNF inhibitors (e.g., lenalidomide) or EZH2 inhibitors (e.g., Tazmetostat, CPI-1205, PF-06821497, GSK343 ​​or EPZ011989).

[0248] Such conjoint treatments can be achieved by simultaneous, sequential, or divided administration of the individual components of the treatment. Such combination products employ the compounds of the present invention within the dosage ranges described herein and other pharmaceutically active agents within the approved dosage ranges.

[0249] According to this aspect of the present invention, combinations for use in the treatment of cancer (e.g., cancers involving solid tumors) are provided, comprising the compounds of the present invention as defined above herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and other antitumor agents.

[0250] According to this aspect of the present invention, a combination is provided for use in the treatment of proliferative disorders such as cancer (e.g., cancers involving solid tumors), comprising any of the compounds of the present invention as defined herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and any one of the antitumor agents listed herein above.

[0251] According to this aspect of the present invention, a combination is provided for use in the treatment of cancer, comprising the compounds of the present invention as defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and tyrosine kinase inhibitors.

[0252] According to this aspect of the present invention, a combination is provided for use in the treatment of leukemia (such as ALL or CML), comprising the compounds of the present invention as defined herein above, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and tyrosine kinase inhibitors.

[0253] According to this aspect of the present invention, a combination is provided for use in the treatment of lymphoma, comprising the compounds of the present invention as defined above herein, or pharmaceutically acceptable salts, hydrates, or solvates thereof, and an EZH2 inhibitor.

[0254] Further embodiments of the present invention provide compounds of the present invention, or pharmaceutically acceptable salts, hydrates, or solvates thereof, for use in the treatment of cancer, in combination with other antitumor agents optionally selected from those listed above herein.

[0255] In further embodiments of the present invention, compounds of the present invention or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided for use in combination with a tyrosine kinase inhibitor optionally selected from those listed above herein in the treatment of cancer.

[0256] In further embodiments of the present invention, compounds of the present invention or pharmaceutically acceptable salts, hydrates, or solvates thereof are provided for use in combination with a tyrosine kinase inhibitor optionally selected from those listed above herein, in the treatment of leukemia (such as ALL or CML).

[0257] In further embodiments of the present invention, compounds of the present invention, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use in combination with an EZH2 inhibitor selected from those listed above herein in the treatment of cancer.

[0258] In further embodiments of the present invention, compounds of the present invention, or pharmaceutically acceptable salts, hydrates, or solvates thereof, are provided for use in combination with an EZH2 inhibitor selected from those listed above herein in the treatment of lymphoma.

[0259] In this specification, where the term “combined administration” is used, it should be understood to mean simultaneous, divided, or sequential administration. In one embodiment of the present invention, “combined administration” means simultaneous administration. In another embodiment of the present invention, “combined administration” means divided administration. In a further embodiment of the present invention, “combined administration” means sequential administration. When administration is carried out sequentially or in divided doses, any delay in the administration of the second component should not impair the beneficial effect of the combined administration.

[0260] A further aspect of the present invention provides a pharmaceutical composition comprising the compound of the present invention, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with an antitumor agent (optionally selected from those listed above herein) with a pharmaceutically acceptable diluent or carrier. [Examples]

[0261] Abbreviation APCI (Atmospheric Pressure Chemical Ionization) aq. Water-based Argon br broad (in the NMR spectrum) conc. concentration d. Doublet (in the NMR spectrum) DBA Dibenzylideneacetone DCM Dichloromethane DIPEA N,N-diisopropylethylamine DMA (Dimethylacetamide) DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) ESI Electrospray Ionization Et2O Diethyl ether HCl ethyl acetate EtOH Ethanol FID (Free Induction Attenuation) h time HATU N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridine-1-ylmethylene]-N-methylmethaneaminium hexafluorophosphate N-oxide HPLC (High-Performance Liquid Chromatography) HRMS high-resolution mass spectrometry KP-Sil Biotage KP-Sil (50uM amorphous silica) LCMS Liquid Chromatography and Mass Spectroscopy MeOH methanol MeCN acetonitrile MS mass spectrometry Ms Mesyl (Methanesulfonyl) m multiplet (in NMR spectrum) MHz (megahertz) min minutes mins mL (milliliter) m / z mass-to-charge ratio NMP (N-methylpyrrolidinone) NMR nuclear magnetic resonance Pd / C Palladium Carbon ppm parts per million q Quadratic (in NMR spectrum) QToF quadrupole time-of-flight quintet (in NMR spectrum) Rt, RT residence time (during LCMS) rt room temperature s Singlet (in NMR spectrum) SCX-2 strong cation exchange (e.g., Isolute® SCX-2 column) sex. Sextet (in NMR spectrum) t Triplet (in NMR spectrum) Tf Triflate (Trifluoromethanesulfonate) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) T3P Propylphosphonic Acid Anhydride μL (microliter) UPLC Ultra High Performance Liquid Chromatography Xanthophos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

[0262] Analysis method: LCMS Method T2 LC / MS and HRMS analysis were performed using an Agilent 1200 series HPLC coupled to a 6210 time-of-flight mass spectrometer and a dual multimode APCI / ESI source, along with a diode array detector. Analytical separation was performed at 40°C using a Merck Chromolith Flash column (RP-18e, 25×2 mm) with a gradient elution of 1.5 mL / min over 2 minutes and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: from 5:95(A / B) to 100:0(A / B) over 1.25 minutes, then 0.5 minutes at 100:0(A / B), then back to 5:95(A / B) over 0.05 minutes, and finally 0.2 minutes at 5:95(A / B).

[0263] Method T4 Method T2 was followed, except that a flow rate of 0.75 mL / min was used for a 4-minute gradient elution at 30°C as follows: from 5:95(A / B) to 100:0(A / B) over 2.5 minutes, then 100:0(A / B) for 1 minute, then back to 5:95(A / B) over 0.1 minutes, and finally 5:95(A / B) for 0.4 minutes.

[0264] Method X2 LC / MS and HRMS analysis were performed using a Waters Acquity UPLC and diode array detector coupled to a Waters G2 QToF mass spectrometer equipped with a multimode ESI / APCI source. Analytical separation was performed at 30°C using a Phenomenex Kinetex C18 column (30 × 2.1 mm, 2.6 u, 100 A) with a gradient elution of 0.5 mL / min over 2 minutes and detection at 254 nm. The mobile phase was a mixture of methanol (solvent A) and water (solvent B), both containing 0.1% formic acid. The gradient elution was as follows: from 10:90(A / B) to 90:10(A / B) over 1.25 minutes, then 0.5 minutes at 90:10(A / B), then back to 10:90(A / B) over 0.15 minutes, and finally 0.1 minutes at 10:90(A / B).

[0265] Method X4 The method is the same as X2, except that a flow rate of 0.3 mL / min was used during the 4-minute gradient elution: from 10:90(A / B) to 90:10(A / B) over 3 minutes, then 90:10(A / B) for 0.5 minutes, then back to 10:90(A / B) over 0.3 minutes, and finally 10:90(A / B) for 0.2 minutes.

[0266] Analysis method: NMR NMR data were collected using a Bruker Avance 500 spectrometer equipped with a 5 mm BBO / QNP probe, or a Bruker Avance Neo 600 spectrometer equipped with a 5 mm TCI Cryo-Probe. 1 H and 13 The 1C spectrum was referenced against the internal deuterated solvent. All NMR data were acquired at a temperature of 298 K. All data were processed using Bruker Topspin 2.1 or Bruker Topspin 4.

[0267] 1 1H-NMR spectra were acquired using a Bruker standard 1D zg30 (16-scan pulse sequence). The sweep width was 20.5 ppm, and the FID included 64k time-domain data points.

[0268] Purification method Unless otherwise specified in the text, preparative HPLC purification is performed using an ACE 5 C18-PFP 250×21.2 mm (or 30 mm) column with a 15-minute gradient of water:methanol (both denatured with 0.1% formic acid) (e.g., 90:10 to 0:100, or 60:40 to 0:100) at a rate of 20 mL·min. -1 Flow rate (or 40 mL·min for a 30 mm column) -1 The procedure was performed using an Agilent 6120 MS-Prep LC with the specified flow rate.

[0269] Flash column chromatography was performed using pre-packed Biotage SNAP KP-Sil columns. Reverse-phase chromatography was performed using Biotage SNAP Ultra C-18 12g and 30g columns as needed.

[0270] Example Compounds Example 1a: (S)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino-[2,3-c]quinoline-10-yl)amino)nicotinonitrile [ka] (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1a, 9 mg, 0.034 mmol) and 2,4-dichloropyridine-3-carbonitrile (9 mg, 0.054 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous NMP (0.6 mL) was added, followed by triethylamine (14 μL, 0.10 mmol). The reaction mixture was heated at 160 °C under microwave irradiation for 90 minutes. The reaction mixture was cooled to room temperature, diluted with DMSO (0.8 mL), and directly purified by reverse-phase chromatography (Biotage 12 g C-18;H2O containing 10% to 100% MeOH (both containing 0.1% formic acid) to obtain the title compound (7 mg, 53%) as an off-white solid. 1H NMR(600MHz, methanol-d4)δ 7.98(d,J=6.2Hz,1H),7.94(d,J=1.9Hz,1H),7.61(d,J=8.9Hz,1H),7.50(dd,J=8.9,1.9Hz,1H),6.69(d,J=6.2Hz,1H),4.37-4.30(m ,1H),4.28-4.22(m,1H),4.07-4.00(m,1H),3.73(s,3H),2.26-2.19(m,1H),1.92-1.84(m,1H),1.38(d,J=6.6Hz,3H);LCMS(Method T4)RT 2.58 min;C 20 H 19 ClN5O2 + [M+H] + The calculated m / z value is 396.1222, and the measured value is 396.1215.

[0271] The examples shown in the table below were prepared starting from the intermediates shown in the table, using the same method as used for the preparation of Example 1a. For Example 1c, DIPEA was used instead of triethylamine, and purification was performed by HPLC. For Example 1t, an additional purification step was performed by preparative HPLC. For Example 1u, DIPEA was used instead of trimethylamine, and the reaction product was heated at 140°C under microwave irradiation for 4 hours.

[0272] [Table 5]

[0273] [Table 6]

[0274] [Table 7]

[0275] [Table 8]

[0276] [Table 9]

[0277] [Table 10]

[0278] Example 2a: (S)-6-chloro-5-cyano-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)amino)picolinic acid [ka] (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1a, 13 mg, 0.049 mmol) and 4,6-dichloro-5-cyanopicolinic acid (15 mg, 0.071 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous NMP (0.5 mL) was added, and the reaction mixture was heated at 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with DMSO (0.8 mL), and directly purified by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; containing 10-100% MeOH in H2O (0.1% formic acid)) to obtain the title compound (13 mg, 61%) as a yellow solid. 11H NMR (500 MHz, DMSO-d6) δ 13.67 (br s, 1H), 9.89 (s, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.46 (dd, J = 9.0, 2.1 Hz, 1H), 7.18 (s, 1H), 5.64 (d, J = 2.8 Hz, 1H), 4.20 - 4.09 (m, 2H), 3.92 - 3.86 (m, 1H), 3.58 (s, 3H), 2.13 - 2.06 (m, 1H), 1.81 - 1.73 (m, 1H), 1.29 (d, J = 6.6 Hz, 3H); LCMS (method T4) RT 2.46 min; C 21 H 19 ClN5O4 + [M + H] + The calculated m / z value of [M + H]: 440.1120, measured value: 440.1114.

[0279] The following examples shown in the table were prepared in the same manner as those used in the preparation of Example 2a starting from the intermediates shown in the table.

[0280]

Table 11

[0281] Example 3a: (S)-6-(azetidine-1-carbonyl)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinolin-10-yl)amino)nicotinonitrile

Chemical formula

[0282] The examples shown in the table below were prepared using the same method as that used for the preparation of Example 3a, starting from the intermediates and suitable amines shown in the table.

[0283] [Table 12]

[0284] Example 4a: (S)-10-((2,3-dichloropyridine-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1a, 7 mg, 0.027 mmol), 2,3-dichloro-4-iodopyridine (9 mg, 0.032 mmol), cesium carbonate (71 mg, 0.22 mmol), Pd2(dba)3 (2.5 mg, 0.003 mmol), and xanthophos (9 mg, 0.016 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar and sealed with caps. Anhydrous DMF (0.2 mL) and toluene (0.6 mL) were added, and Ar was passed through the reaction mixture for 5 minutes. The reaction mixture was heated at 80°C under microwave irradiation for 1 hour. The reaction mixture was cooled to room temperature. Water (10 mL) was added, and the aqueous mixture was extracted with SiO2 (3 × 10 mL). The organic extracts were combined, washed with brine (10 mL), dried, and concentrated under reduced pressure. The crude product was dissolved in DMSO (1.2 mL) and directly purified by reversed-phase chromatography (Biotage reversed-phase 12 g Ultra C-18 column; 10-100% MeOH in H2O (containing 0.1% formic acid)) to obtain the title compound (5 mg, 48%) as an off-white solid. 1 H NMR(600MHz, methanol-d4)δ 7.91(d,J=1.8Hz,1H),7.82(d,J=5.8Hz,1H),7.60(d,J=8.9Hz,1H),7.50(dd,J=8.9,1.8Hz,1H),6.71(d,J=5.8Hz,1H),4.37-4.31(m ,1H),4.28-4.23(m,1H),4.07-4.00(m,1H),3.73(s,3H),2.25-2.19(m,1H),1.92-1.85(m,1H),1.38(d,J=6.6Hz,3H);LCMS(Method T4)RT 2.72 min;C19 H 19 Cl2N4O2 + [M+H] + Calculated m / z value: 405.0880, measured value: 405.0879.

[0285] The examples presented in the table below were prepared by the same method as that used for the preparation of Example 4a, starting from the intermediates shown in the table. Example 4b was purified by preparative HPLC. For Example 4d, the reaction mixture was heated at 80 °C for 4 hours under microwave irradiation.

[0286]

Table 13

[0287]

Table 14

[0288] Example 5a: (R)-10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinolin-6(7H)-one

Chemical formula

[0289] Step 2: (R)-10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazole-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (R)-2-cyclopropyl-10-((2,5-dichloropyrimidine-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (derived from Step 1; 9 mg, 0.021 mmol), 3-(trifluoromethyl)-1H-pyrazole (28 mg, 0.207 mmol), and cesium carbonate (67 mg, 0.204 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous NMP (0.8 mL) was added. The reaction mixture was heated at 180 °C under microwave irradiation for 1 hour. The reaction mixture was cooled to room temperature, diluted with DMSO (0.8 mL), and directly purified by reverse-phase chromatography (Biotage reverse-phase 12 g C-18 column; containing 10-50-100% MeOH in H2O (0.1% formic acid)) to obtain the title compound (7 mg, 62%) as a beige solid. 1 H NMR(600MHz,CDCl3)δ 8.48(br d,J=2.4Hz,1H),8.44(s,1H),8.03(d,J=1.9Hz,1H),7.64(dd,J=8.9,1.9Hz,1H),7. 48(s,1H),7.39(d,J=8.9Hz,1H),6.70(d,J=2.4Hz,1H),4.54-4.47(m,1H),4.37(br s,1H),4.35-4.29(m,1H),3.75(s,3H),2.96(dt,J=9.7,3.3Hz,1H),2.41-2.32(m,1H),2.11-2.03(m,1H),1 .13-1.05(m,1H),0.66-0.59(m,1H),0.50-0.43(m,1H),0.35-0.28(m,1H),0.27-0.21(m,1H);LCMS(Method X4)RT 3.25 min;C 24 H 22 ClF3N7O2 + [M+H] + The calculated m / z value is 532.1475, and the measured value is 532.1500.

[0290] The examples shown in the table below were prepared using the same method as used for the preparation of Example 5a, starting from the intermediates and appropriate amines shown in the table. No purification was performed during Step 1 in Examples 5b-5h, 5k, and 5p-5t. In Examples 5d-5i and 5k-5t, DIPEA was used instead of cesium carbonate. Examples 5c-5f were purified by preparative HPLC.

[0291] [Table 15]

[0292] [Table 16]

[0293] [Table 17]

[0294] [Table 18]

[0295] [Table 19]

[0296] [Table 20]

[0297] Example 5u: (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] A microwave vial (volume 0.5-2.0 mL) was charged with (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A5b; 6.5 mg, 0.017 mmol) and DIPEA (12 μL, 0.069 mmol). A solution of (1R,5S,7s)-9-(5-chloro-4-(methylsulfinyl)pyrimidine-2-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (intermediate J1; 7.0 mg, 0.022 mmol) in isopropanol (0.7 mL) was then added, the vial was flushed with Ar, and sealed with a cap. The reaction mixture was heated in a heating block at 140°C for 18 hours. The reaction mixture was then cooled to room temperature, and an additional 20 μL, 0.11 mmol of DIPEA was added. The vial was resealed with a cap, and the mixture was heated again in the heating block at 140°C for a further 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The reaction mixture was dissolved in 1 mL of DMSO and purified directly by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; 60-90% MeOH in H2O (containing 0.1% formic acid)) to obtain the desired product, which eluted along with impurities. The crude product was further purified by flash chromatography (10 g KP-sil; 50-100% ethyl acetate in cyclohexane, followed by 0-20% MeOH in ethyl acetate) to obtain an off-white solid. The solid was dissolved in MeOH and passed through an SCX-2 (1g) column, followed by elution with MeOH (15mL) and then 2N methanolic ammonia (20mL). The basic fraction was concentrated under reduced pressure to obtain the title compound (1.8mg, 17%) as an off-white solid. 1H NMR(600MHz, methanol-d4)δ 8.01(s,1H),7.94(d,J=2.3Hz,1H),7.86(dd,J=9.1,2.3Hz,1H),7.54(d,J=9.1Hz,1H),4.56(dd,J=14.4,7.2 Hz,2H),4.54(dd,J=14.4,6.9Hz,2H),4.41-4.36(m,1H),4.24-4.19(m,1H),3.94-3.86(m,3H),3.80-3.74(m, 2H),2.96(dt,J=9.5,3.6Hz,1H),2.70-2.50(m,5H),2.38-2.30(m,1H),2.25-2.16(m,2H),2.13-2.06(m,1H), 1.82-1.74(m,2H),1.25-1.19(m,1H),0.68-0.61(m,2H),0.44-0.37(m,1H),0.37-0.30(m,1H);LCMS(Method T4)RT 3.02 min;C 31 H 36 ClF2N6O4 + [M+H] + The calculated m / z value is 629.2449, and the measured value is 629.2436.

[0298] Example 6a: (S)-2-chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxaze-pino[6,5-c]quinoline-10-yl)amino)nicotinonitrile [ka] A suspension of DIPEA (10 μL, 0.077 mmol), 2,4-dichloropyridine-3-carbonitrile (6 mg, 0.036 mmol), and (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (intermediate B1a, 7 mg, 0.026 mmol) in NMP (1.5 mL) was stirred at 160 °C for 1 hour under microwave irradiation. The crude reaction mixture was subjected to preparative HPLC (60:40~0:100 H2O:MeOH gradient for 15 minutes (both denatured with 0.1% formic acid); flow rate 20 mL·min). -1The compound in question (1 mg, 10%) was directly purified using ) to obtain the title compound as a light brown solid, which was then washed with Et2O and dried. 1 H NMR(500MHz,DMF-d7)δ 8.43(d,J=2.2Hz,1H),8.27(d,J=6.2Hz,1H),7.87(dd,J=9.0,2.2Hz,1H),7.80(s,1H),7.78(d,J=9.0Hz,1H),7.03(d,J=6.2Hz,1H ),4.81(dd,J=13.0,1.5Hz,1H),4.63(dd,J=13.0,5.5Hz,1H),4.24-4.30(m,1H),3.80(s,3H),1.52(d,J=6.6Hz,3H);LCMS(Method T4)RT 2.35 min;C 20 H 17 ClN5O3 + [M+H]+ m / z calculated value: 410.1014, measured value: 410.1007.

[0299] The examples shown in the table below were prepared starting from the intermediates shown in the table, using the same method as that used for the preparation of Example 6a.

[0300] [Table 21]

[0301] Example 7a: (S)-10-((5-chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione [ka] A mixture of cesium carbonate (95 mg, 0.293 mmol), xanthophos (13 mg, 0.022 mmol), (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (intermediate B1a, 10 mg, 0.037 mmol), 5-chloro-4-iodo-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (intermediate H1, 12 mg, 0.037 mmol), and Pd2(dba)3 (3 mg, 0.004 mmol) was suspended in a mixture of toluene (3 mL) and DMF (0.5 mL). The resulting suspension was stirred at 140°C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature. The suspension was filtered, the filtrate was diluted with water, and extracted with siRNA. The organic extracts were combined, dried (Na2SO4), and concentrated under reduced pressure. Preparative HPLC (60:40~0:100 H2O:MeOH gradient for 15 minutes (both denatured with 0.1% formic acid); flow rate 20 mL·min) -1 Purification by () yielded the title compound (4 mg, 23%) as a bright yellow solid. 1 H NMR(600MHz,DMF-d7)δ 8.50(s,1H),8.38(d,J=2.2Hz,1H),8.19(s,1H),7.85(dd,J=8.9,2.2Hz,1H),7.77(d,J=8.9Hz,1H),7.75(br s,1H),6.20(s,1H),5.28(tt,J=8.6,4.1Hz,1H),4.81(dd,J=12.9,1.6Hz,1H),4.65(dd,J=12.9,5.6Hz,1H),4.32-4.23(m,1H),4.02(dt,J=1 1.5,4.4Hz,2H),3.81(s,3H),3.67(ddd,J=11.5,9.4,2.8Hz,2H),2.21-2.07(m,2H),1.83-1.70(m,2H),1.54(d,J=6.6Hz,3H);LCMS(method 2.49 min;C 24 H 26 ClN4O5 + [M+H] + The calculated m / z value is 485.1586, and the measured value is 485.1542.

[0302] Example 8a: (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione [ka] Step 1: (S)-10-((2,5-dichloropyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino-[6,5-c]quinoline-5,6(1H,7H)-dione A suspension of 2,4,5-trichloropyrimidine (12 mg, 0.066 mmol), (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (intermediate B1a, 20 mg, 0.073 mmol), and DIPEA (20 μL, 0.110 mmol) in NMP (1.5 mL) was stirred at 140 °C for 1 hour under microwave irradiation. The reaction mixture containing (S)-10-((2,5-dichloropyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione was divided into several aliquots for use in the next step without further purification. LCMS (Method T2) RT 1.27min; m / z 420.1[M+H] + .

[0303] Step 2: (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione A mixture of crude (S)-10-((2,5-dichloropyrimidine-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (derived from Step 1; 5 mg, 0.012 mmol), (2R,6S)-2,6-dimethylmorpholine (7 mg, 0.060 mmol), and DIPEA (6 μL, 0.036 mmol) in NMP (1.5 mL) was stirred at 140 °C for 1 hour under microwave irradiation. The crude reaction mixture was subjected to preparative HPLC (3 runs; 60:40~0:100 gradient of H2O:MeOH for 15 minutes (both denatured with 0.1% formic acid); flow rate 20 mL·min) -1 The compound in the title (2 mg, 34% in 2 steps) was obtained as a brown oil by direct purification using ). 1 H NMR(600MHz, methanol-d4)δ 8.20(d,J=2.4Hz,1H),7.98(s,1H),7.88(dd,J=9.0,2.4Hz,1H),7.54(d,J =9.0Hz,1H),4.66(d,J=12.8Hz,1H),4.44(dd,J=12.8,5.0Hz,1H),4.34(d ,J=13.1Hz,2H),4.14-3.98(m,1H),3.67(s,3H),3.61-3.51(m,2H),2.49( dt,J=13.7,10.2Hz,2H),1.41(d,J=6.7Hz,3H),1.15(m,6H);LCMS(Method T4)RT 2.55 min;C 24 H 28 ClN6O4 + [M+H] + The calculated m / z value is 499.1855, and the measured value is 499.1827.

[0304] The examples shown in the table below were prepared using the same method as that used for the preparation of Example 8a, starting from the intermediates and suitable amines shown in the table.

[0305] [Table 22]

[0306] [Table 23]

[0307] [Table 24]

[0308] [Table 25]

[0309] [Table 26]

[0310] The examples shown in the table below were prepared by the same method as that used for the preparation of Example 8a. Examples 8p and 8q represent a pair of diastereoisomers in which one oxazepinone ring is cis- and the other is trans-. The compounds were subjected to preparative HPLC (60:40~0:100 H2O:MeOH gradient for 15 minutes (both denatured with 0.1% formic acid); flow rate 20 mL·min). -1 The compounds were separated by first eluting Example 8p, followed by Example 8q. It was not clearly determined which was in the cis or trans structure. Both compounds are racemic.

[0311] [Table 27]

[0312] Example 9a: (S)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,5,6,7-hexahydro-[1,4]oxaze-pino[6,5-c]quinoline-10-yl)amino)nicotinonitrile [ka] A suspension of DIPEA (7 μL, 0.041 mmol), 2,4-dichloropyridine-3-carbonitrile (3 mg, 0.019 mmol), and (S)-10-amino-2,7-dimethyl-2,3,5,7-tetrahydro-[1,4]oxazepino[6,5-c]quinoline-6(1H)-one (intermediate B2a, 4 mg, 0.014 mmol) in NMP (1.5 mL) was stirred at 160 °C for 1 hour under microwave irradiation. The crude reaction mixture was subjected to preparative HPLC (60:40~0:100 H2O:MeOH gradient for 15 minutes (both denatured with 0.1% formic acid); flow rate 20 mL·min). -1 The compound in the title (1 mg, 19%) was obtained as a yellow solid by direct purification using ). 1 H NMR(600MHz, methanol-d4)δ 8.06(d,J=2.2Hz,1H),8.00(d,J=6.2Hz,1H),7.65(d,J=8.9Hz,1H),7.58(dd, J=8.9,2.2Hz,1H),6.71(d,J=6.2Hz,1H),4.94(d,J=14.4Hz,1H),4.84(d,J=1 4.4Hz,1H),3.96(ddd,J=9.2,6.5,3.0Hz,1H),3.93(dd,J=11.1,3.0Hz,1H),3 .72(s,3H),3.64(dd,J=11.1,8.9Hz,1H),1.27(d,J=6.6Hz,3H).LCMS(Method T4)RT 2.53 min;C 20 H 19 ClN5O2+[M+H] + The calculated m / z value is 396.1222, and the measured value is 396.1214.

[0313] The examples shown in the table below were prepared using the same method as that used for the preparation of Example 9a, starting from the intermediates and suitable amines shown in the table.

[0314] [Table 28]

[0315] Example 10a: 2-Chloro-4-((2,6-dimethyl-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]-naphthyridine-9-yl)amino)nicotinonitrile [ka] 9-amino-2,6-dimethyl-2,3,4,6-tetrahydrobenzo[h][1,6]naphthyrizine-5(1H)-one (intermediate C1; 12 mg, 0.05 mmol) was added to a microwave vial (0.5-2.0 mL volume) containing 2,4-dichloropyridine-3-carbonitride (11 mg, 0.06 mmol), NMP (0.51 mL), and triethylamine (14 μL, 0.10 mmol). The vial was sealed and purged with argon for 5 minutes. The vial was then heated under microwave irradiation at 160 °C for 1 hour. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with MeCN and preparative HPLC (60:40-0:100 H2O:MeOH gradient for 15 minutes (both denatured with 0.1% formic acid); flow rate 20 mL·min) -1 The compound in question (10 mg, 51%) was obtained as an off-white solid by direct purification using [method / method name]. 1 H NMR(500MHz,CDCl3)δ 8.04(d,J=6.1Hz,1H),7.44-7.37(m,3H),6.92(s,1H),6.59(d,J=6.1Hz,1H),4.51(s,1H),3.70(s,3H),3.58-3.47(m,1H),2.86(ddd,J LCMS (Method X4) RT 2.60 min;C 20 H 19 ClN5O + [M+H] + The calculated m / z value is 380.1278, and the measured value is 380.1280.

[0316] Example 11a: 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Microwave vials (volume 0.5-2.0 mL) were charged with 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1l; 15 mg, 0.047 mmol) and (1R,5S,7s)-9-(5-chloro-4-(methylsulfonyl)-pyrimidine-2-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (intermediate J2; 17 mg, 0.050 mmol). 2,2,2-trifluoroethanol (1.0 mL) was added, followed by trifluoroacetic acid (4.00 μL, 0.052 mmol). The reaction vials were flushed with Ar and sealed with caps. The reaction mixture was heated in a heating block at 70°C for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in DMSO (1 mL) and directly purified by reverse-phase chromatography (Biotage reverse-phase 12 g C-18 column; containing 10-100% MeOH in H2O (0.1% formic acid)) to obtain the title compound (7 mg, 27%) as an off-white solid. 11H NMR (600MHz, methanol-d4)δ 8.02-7.99(m,2H),7.88(dd,J=9.1,1.7Hz,1H),7.54(d,J=9.1Hz,1H),4.62- 4.37(m,4H),3.94-3.84(m,3H),3.79-3.73(m,2H),3.71(s,3H),3.30-3.26(m ,1H),2.24-2.14(m,2H),1.83-1.73(m,2H),1.43-1.36(m,1H),0.82-0.76(m ,1H),0.69-0.63(m,1H),0.63-0.57(m,1H),0.37-0.31(m,1H);LCMS(Method X4)RT 2.95 min;C 27 H 30 ClF2N6O4 + [M+H] + The calculated m / z value is 575.1985, and the measured value is 575.1973.

[0317] The examples shown in the table below were prepared using the same method as that used for the preparation of Example 11a, starting from the intermediates and suitable amines shown in the table.

[0318] [Table 29]

[0319] Example 11c: (S)-10-((5-chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]-nonane-9-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1m; 29 mg, 0.09 mmol) and (1R,5S,7s)-9-(5-chloro-4-(methylsulfonyl)-pyrimidine-2-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (intermediate J2; 36 mg, 0.11 mmol) were charged into microwave vials (volume 2-5 mL). Trifluoroethanol (1.0 mL) was added, followed by trifluoroacetic acid (7.7 μL, 0.10 mmol). The reaction vials were flushed with Ar and sealed with caps. The reaction mixture was heated in a heating block at 70°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was redissolved in DMSO (1 mL) and directly purified by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; 10-100% MeOH in H2O (containing 0.1% formic acid)). The fraction containing the product was passed through an SCX-2 (2 g) column and eluted with MeOH (15 mL), followed by 2N methanolic ammonia (30 mL). The basic fraction was concentrated under reduced pressure to obtain the title compound (16 mg, 31%) as an off-white solid. 1 1H NMR (600MHz, methanol-d4)δ 8.02-7.99(m,2H),7.88(dd,J=9.1,1.7Hz,1H),7.54(d,J=9.1Hz,1H),4.62- 4.37(m,4H),3.94-3.84(m,3H),3.79-3.73(m,2H),3.71(s,3H),3.30-3.26(m ,1H),2.24-2.14(m,2H),1.83-1.73(m,2H),1.43-1.36(m,1H),0.82-0.76(m ,1H),0.69-0.63(m,1H),0.63-0.57(m,1H),0.37-0.31(m,1H);LCMS(Method X4)RT 2.98 min;C 27 H 30 ClF2N6O4 + [M+H] + The calculated m / z value is 575.1985, and the measured value is 575.1987.

[0320] Example 12a: (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] (S)-2-cyclopropyl-10-((2,5-dichloropyrimidine-4-yl)amino)-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A10a; 7 mg, 0.015 mmol), 1-methylpiperazine-2-one (4 mg, 0.037 mmol), and DIPEA (13 μL, 0.075 mmol) were charged into microwave vials (volume 0.5-2.0 mL) that had been dried in an oven. The reaction vials were flushed with Ar and sealed with caps. NMP (0.65 mL) was added, and the reaction mixture was heated at 140 °C under microwave irradiation for 1 hour. The reaction mixture was dissolved in DMSO (0.8 mL) and purified directly by reversed-phase chromatography (Biotage reversed-phase 12 g Ultra C-18 column; 10-60-80-100% MeOH in H2O (containing 0.1% formic acid)). The fractions containing the product were combined and passed through SCX-2 (1 g), followed by an additional 10 mL of MeOH, and the product was eluted with 2 N methanolic ammonia (25 mL). The solvent was removed under reduced pressure to obtain the title compound (5 mg, 57%) as an off-white solid. 1H NMR(600MHz, methanol-d4)δ 8.04(d,J=2.2Hz,1H),8.01(s,1H),7.92(dd,J=9.1,2.2Hz,1H),7.57(d,J=9.1Hz,1H) ,4.53-4.38(m,2H),4.24(d,J=18.2Hz,1H),4.18(d,J=18.2Hz,1H),3.98-3.92(m,1H), 3.92-3.87(m,1H),3.73(s,3H),3.47-3.39(m,2H),3.35-3.28(m,1H),2.98(s,3H),1. 42-1.37(m,1H),0.82-0.75(m,1H)0.68-0.57(m,2H),0.37-0.31(m,1H);LCMS(Method X4)RT 2.85 min;C 25 H 27 ClF2N7O3 + [M+H] + The calculated m / z value is 546.1832, and the measured value is 546.18342.

[0321] The examples shown in the table below were prepared using the same method as used for the preparation of Example 12a, starting from the intermediates and suitable amines shown in the table. For Examples 12c, 12d, 12e, and 12u, the reaction mixture was heated in a heating block at 140°C for 2 to 3 hours. For Examples 12f, 12i, 12p, 12s, 12t, and 12x, the reaction mixture was heated under microwave irradiation at 140°C for 90 minutes to 3 hours. For Examples 12n and 12o, the reaction mixture was heated under microwave irradiation at 140°C for 1 hour, followed by heating in a heating block at 140°C for 4 hours. For Example 12v, the reaction mixture was heated in a heating block at 140°C for 6 hours. For Example 12h, the reaction mixture was heated in a heating block at 160°C overnight. For Examples 12j and 12w, the reaction mixture was heated at 160°C for 10-12 hours under microwave irradiation. For Examples 12c and 12d, the SCX-2 purification step was not performed. An additional purification step by normal-phase chromatography was required for Examples 12h and 12x.

[0322] Table 30

[0323] Table 31

[0324] Table 32

[0325] Table 33

[0326] Table 34

[0327] Table 35

[0328] Table 36

[0329] Table 37

[0330] Table 38

[0331] Table 39

[0332] The examples shown in the table below were prepared starting from intermediate A10b: (R)-2-cyclopropyl-10-((2,5-dichloropyrimidine-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one and rac-4,4-difluoropiperidine-3-ol hydrochloride, using the same method as used for the preparation of Example 12a. Examples 12y and 12z represent a pair of enantiomers, one being (R)- and the other (S)-piperidinol. It was not determined which was the (R) enantiomer and which was the (S) enantiomer. The compounds were separated by preparative chiral SFC using the following method. The racemic mixture was dissolved at 9 mg / mL in EtOH:CH2Cl2 (5:4), and then SFC (Lux A1 (21.2 mm × 250 mm, 5 μm), 40:60 EtOH:CO2 (0.2% v / v NH3); flow rate 50 mL·min) was used. -1 The solution was purified using ). The enantiomer that eluted earlier was identified as Example 12y, and the enantiomer that eluted later was identified as Example 12z. Next, each combined fraction was concentrated under reduced pressure, and then stored in a vacuum oven at 35°C and 5 mbar to obtain Example 12y (19 mg) and Example 12z (17 mg) as white solids. Chiral purity analysis was performed using SFC(Amy-C (4.6 mm × 250 mm, 5 μm), 40:60 EtOH:CO2 (0.2% v / v NH3); flow rate 4 mL·min). -1 The determination was made by ( ).

[0333] [Table 40]

[0334] The examples shown in the table below were prepared using the same method as used for the preparation of Example 12a, starting from the intermediates and appropriate amines shown in the table. For Example 13a, the reaction mixture was heated at 140°C under microwave irradiation for 8 hours. For Examples 13b and 13c, the reaction mixture was heated at 160°C under microwave irradiation for 8 hours and 12 hours, respectively. For Example 13f, the reaction mixture was heated at 120°C under microwave irradiation for 1 hour. For Examples 13g and 13h, acetonitrile was used instead of NMP, and the reaction mixture was heated in a heating block at 80°C for 1 hour and 12 hours, respectively. For Example 13i, the reaction mixture was heated at 140°C under microwave irradiation for 10 hours. For Example 13j, the reaction mixture was heated in a heating block at 140°C for 46 hours. For Examples 13a to 13c, purification was carried out using preparative HPLC. Example 13b was isolated as a mixture of diastereoisomers. Example 13c was isolated as a mixture of endo- and exo-isomers. The SCX-2 purification step was not performed for Examples 13g and 13h.

[0335] [Table 41]

[0336] [Table 42]

[0337] [Table 43]

[0338] [Table 44]

[0339] [Table 45]

[0340] [Table 46]

[0341] Example 14a: (R)-10-((5-chloro-2-((S)-4,4-difluoro-3-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one or (R)-10-((5-chloro-2-((R)-4,4-difluoro-3-methylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] A vial containing (S)-4,5-dichloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)pyrimidine or (R)-4,5-dichloro-2-(4,4-difluoro-3-methylpiperidine-1-yl)pyrimidine (intermediate L2a; 10 mg, 0.035 mmol), DIPEA (20 μL, 0.089 mmol), and (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1d; 10 mg, 0.035 mmol) in NMP (0.56 mL) was heated at 140 °C under microwave irradiation for 3 hours. The reaction mixture was directly purified by reverse-phase chromatography (Biotage reverse-phase 12g Ultra C-18 column; containing 45-100% MeOH in H2O (0.1% formic acid)). To the resulting mixture, (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxaze-pino[2,3-c]quinoline-6(7H)-one (intermediate A1d; 10 mg, 0.035 mmol), NMP (0.56 mL), and 3M aqueous HCl (0.1 mL) were added, and the reaction mixture was heated in a heating block at 80°C for 22 hours. The reaction mixture was directly purified by reversed-phase chromatography (Biotage reversed-phase 12g Ultra C-18 column; containing 45-100% MeOH in H2O (0.1% formic acid)) to obtain the title compound (4 mg, 21%) as a gray solid. 11H NMR (600 MHz, methanol-d4) δ 8.34 (s, 1H), 8.18 (s, 1H), 7.91 (dd, J = 9.2, 2.0 Hz, 1H), 7.84 (dd, J = 9.2, 2.0 Hz, 1H), 4.52 - 4.44 (m, 1H), 4.41 - 4.34 (m, 1H), 4.20 (d, J = 13.9 Hz, 1H), 4.10 (d, J = 13.0 Hz, 1H), 3.89 (d, J = 1.5 Hz, 3H), 3.47 - 3.39 (m, 1H), 3.20 - 3.13 (m, 2H), 2.48 - 2.40 (m, 1H), 2.29 - 2.14 (m, 3H), 2.13 - 2.01 (m, 1H), 1.37 - 1.29 (m, 1H), 1.04 (d, J = 6.7 Hz, 3H), 0.73 - 0.64 (m, 2H), 0.51 - 0.45 (m, 1H), 0.40 - 0.34 (m, 1H); LCMS (method X4) RT 3.47 min; C 26 H 30 ClF2N6O2 + [M + H] + The calculated m / z value of [M + H]: 531.2087, the measured value: 531.2091.

[0342] The following examples presented in a table were prepared in the same manner as those used for the preparation of Example 14a starting from the intermediates shown in the table.

[0343]

Table 47

[0344] Example 15a: (R)-10 - ((5-chloro-2 - ((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinolin-6(7H)-one

Chemical Structure

[0345] The examples shown in the table below were prepared using the same method as used for the preparation of Example 15a, starting from the intermediates and suitable substituted pyrimidines shown in the table. For Examples 15b and 15c, the reaction was stirred at 60°C immediately after the addition of the sulfone. Furthermore, to hydrolyze the sulfone starting material under reaction conditions, equivalent sulfones were sequentially added to achieve a higher conversion rate to the desired product.

[0346] [Table 48]

[0347] [Table 49]

[0348] Example 16a: (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Sodium borohydride (1.4 mg, 0.037 mmol) was added to a stirred solution of 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-7(2H)-yl)acetaldehyde (intermediate A12a; 5.4 mg, 0.009 mmol) in anhydrous methanol (0.5 mL) at 0°C under an Ar atmosphere. The reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was deactivated with saturated NaHCO3 aqueous solution (0.1 mL) and stirred for 15 minutes. DMSO (0.5 mL) was added, and the reaction mixture was concentrated under reduced pressure to remove MeOH. The crude reaction mixture in DMSO (the vial was washed with an additional 0.6 mL of DMSO) was directly purified by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; containing 10-30-100% MeOH in H2O (0.1% formic acid)) to obtain the title compound (4 mg, 76%) as an off-white solid. 1H NMR(600MHz, methanol-d4)δ 8.01(d,J=2.2Hz,1H),7.98(s,1H),7.82(dd,J=9.1,2.2Hz,1H),7.64(d,J=9.1Hz,1H),4.58-4.49(m, 2H),4.46(t,J=6.3Hz,2H),4.42-4.37(m,1H),4.24-4.18(m,1H),3.85(t,J=6.3Hz,2H),2.95(dt,J=9. 5,3.5Hz,1H),2.74-2.65(m,2H),2.37-2.30(m,1H),2.14-2.06(m,1H),2.01-1.88(m,2H),1.25-1.19 (m,1H),1.00(d,J=6.7Hz,6H),0.68-0.60(m,2H),0.43-0.37(m,1H),0.35-0.29(m,1H);LCMS(Method X4)RT 3.46 min;C 28 H 34 ClF2N6O3 + [M+H] + The calculated m / z value is 575.2349, and the measured value is 575.2351.

[0349] Example 17a: (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-7-(2-(methylamino)ethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Methylamine (2M in THF; 0.20 mL, 0.400 mmol) was added to a stirred solution of 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-7(2H)-yl)acetaldehyde (intermediate A12a; 6.5 mg, 0.011 mmol) in THF (0.2 mL) under an Ar atmosphere. The reaction mixture was stirred at room temperature for 5 minutes. Sodium triacetoxyborohydride (6.0 mg, 0.028 mmol) was added, and the reaction mixture was stirred at 25°C for 3 days. Subsequently, DCE (0.5 mL), along with additional methylamine (2 M in THF; 1.5 mL) and sodium triacetoxyborohydride (22 mg, 0.1 mmol) were added. The reaction mixture was stirred at 25°C for a further 18 hours. Then, additional methylamine (2 M in THF; 0.5 mL), followed by sodium acetate (12 mg) and sodium triacetoxyborohydride (19 mg) were added. The reaction mixture was stirred at 45°C for 24 hours. Then, a few drops of water were added, and the reaction mixture was concentrated under reduced pressure. The crude reaction mixture was dissolved again in DMSO (0.8 mL) and purified directly by reverse-phase chromatography (Biotage reverse-phase 12 g C-18 column; 10-30-100% MeOH in H2O (containing 0.1% formic acid)) to obtain a mixture of products. The fractions containing the product were combined, concentrated under reduced pressure, and re-purified by flash chromatography (pipette column, 0%-5%-10%-25% MeOH in CH2Cl2) to obtain the title compound (1 mg, 13%) as an off-white solid. 1H NMR(600MHz, methanol-d4)δ 8.11(d,J=2.1Hz,1H),8.00(s,1H),7.86(dd,J=9.2,2.1Hz,1H),7.53(d,J=9.2Hz,1H),4.63-4.59(m ,2H),4.56-4.51(m,2H),4.44-4.38(m,1H),4.27-4.22(m,1H),3.29-3.25(m,2H),2.99(dt,J=9.4,3 .5Hz,1H),2.73-2.66(m,5H),2.39-2.32(m,1H),2.16-2.09(m,1H),2.00-1.91(m,2H),1.27-1.22(m ,1H),1.01(d,J=6.7Hz,6H),0.69-0.61(m,2H),0.42-0.37(m,1H),0.36-0.31(m,1H);LCMS(Method T4)RT 2.85 min;C 29 H 37 ClF2N7O2 + [M+H] + The calculated m / z value is 588.2660, and the measured value is 588.2671.

[0350] Example 18a: 2-Chloro-4-((2,7-dimethyl-5,6-dioxo-2,3,4,5,6,7-hexahydro-1H-[1,4]diazepino[6,5-c]quinoline-10-yl)amino)nicotinonitrile [ka] To a solution of ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-6-((2-chloro-3-cyanopyridine-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (intermediate B3a; 62 mg, 0.11 mmol) in THF (2 mL), 4 M HCl in dioxane (279 μL, 1.12 mmol) was added, and the reaction mixture was heated at 70°C for 15 minutes. Further addition of 4 M HCl in dioxane (279 μL, 1.12 mmol) was made, and heating was continued for 90 minutes. The acidic reaction mixture was deactivated with triethylamine (389 μL, 2.79 mmol) and heated at 70°C overnight. The reaction mixture was cooled to room temperature and diluted with water. The organic solvent was removed under reduced pressure, and the reaction mixture was purified by reversed-phase chromatography (Biotage reversed-phase 12g C-18 column; containing 5-50% MeOH in H2O (0.1% formic acid)) to obtain the title compound (9 mg, 18%) as an off-white solid. 1 H NMR(500MHz, methanol-d4)δ 8.03-8.01(m,1H),8.00(d,J=6.2Hz,1H),7.62-7.61(m,2H),6.71(d,J=6.2Hz,1H),3.97-3.93(m,1H ),3.67(s,3H),3.58(dd,J=13.4,1.7Hz,1H),3.39-3.27(m,1H),1.32(d,J=6.5Hz,3H);LCMS(Method X4)RT 2.01 min;C 20 H 18 ClN6O2 + [M+H] + The calculated m / z value is 409.1180, and the measured value is 409.1088.

[0351] intermediate compound Intermediate A1a: (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Step 1: (S)-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one 4-chloro-1-methyl-6-nitroquinoline-2(1H)-one (intermediate F1; 800 mg, 3.4 mmol) and (S)-3-aminobutan-1-ol (446 mg, 5.0 mmol) were charged into microwave vials (volume 10-20 mL) dried in an oven. The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous NMP (10 mL) was added, followed by DIPEA (1.2 mL, 6.9 mmol). The reaction mixture was heated in a heating block at 160 °C for 20 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water (100 mL), and the aqueous mixture was extracted with ethyl acetate (100 mL). The organic extracts were washed with water (2 × 25 mL). The aqueous washing solutions were combined and further extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were dried, concentrated under reduced pressure in (Na₂SO₄). The crude reaction mixture was dry-loaded onto silica and purified by flash chromatography (50 g KP-sil; 0%-10% MeOH in CH2Cl2) to obtain (S)-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (547 mg, 56%) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ 9.11(d,J=2.5Hz,1H),8.37(dd,J=9.4,2.5Hz,1H),7.60(d,J=9.4Hz,1H),7.11(d,J=7.9Hz,1H),5.59(s,1H),4.57(t,J=5 .0Hz,1H),3.80-3.71(m,1H),3.55(s,3H),3.53-3.48(m,2H),1.94-1.87(m,1H),1.67-1.60(m,1H),1.23(d,J=6.4Hz,3H).

[0352] Step 2: (S)-3-bromo-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one Trifluoroacetic acid (0.72 mL, 9.4 mmol) was added at 0°C under an Ar atmosphere to a stirred mixture of N-bromosuccinimide (509 mg, 2.9 mmol) and (S)-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (derived from Step 1; 547 mg, 1.9 mmol) in anhydrous CH2Cl2 (10 mL). The reaction mixture was stirred at 0°C for 10 minutes, then stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (30 mL), followed by saturated aqueous NaHCO3 solution (3 × 30 mL). The aqueous washing solutions were combined and further extracted with ethyl acetate (30 mL). The organic extracts were combined, dried, and concentrated under reduced pressure in (Na2SO4). The crude reaction mixture was dry-loaded onto silica and purified by flash chromatography (25 g KP-sil; 0%-10% MeOH in CH2Cl2) to obtain (S)-3-bromo-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (532 mg, 77%) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ 8.89(d,J=2.6Hz,1H),8.42(dd,J=9.4,2.6Hz,1H),7.72(d,J=9.4Hz,1H),5.82(d,J=9.8Hz,1H),4.51(t,J=4.7Hz,1 H),4.28-4.19(m,1H),3.69(s,3H),3.51-3.46(m,2H),1.90-1.82(m,1H),1.79-1.71(m,1H),1.29(d,J=6.5Hz,3H).

[0353] Step 3: (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (S)-3-bromo-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (derived from Step 2; 111 mg, 0.30 mmol) was charged into oven-dried microwave vials (volume 2.0-5.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous DMSO (4 mL) was added, followed by potassium tert-butoxide (1 M in THF; 0.54 mL, 0.54 mmol). The reaction mixture was heated under microwave irradiation at 60°C for 50 minutes. The reaction mixture was cooled to room temperature. Water (10 mL) was added, followed by ethyl acetate (10 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (10 mL). The organic extracts were combined and concentrated under reduced pressure. The crude product was dissolved in DMSO (1.2 mL) and directly purified by reverse-phase chromatography (Biotage reverse-phase 12 g C-18 column; containing 45-75% MeOH in H2O (0.1% formic acid)) to obtain (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (36 mg, 41%) as a deep yellow solid. 1 H NMR(600MHz,CDCl3)δ 8.93(d,J=2.1Hz,1H),8.33(dd,J=9.2,2.1Hz,1H),7.40(d,J=9.2Hz,1H),4.49-4.38(m,2H),4.14-4.08(m,1H),4.01(br s,1H),3.76(s,3H),2.23-2.26(m,1H),1.91-1.84(m,1H),1.47(d,J=6.3Hz,3H).

[0354] Step 4: (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (derived from step 3; 356 mg, 0.12 mmol), Pd / C (10% by weight, 6.3 mg), and ammonium formate (53 mg, 0.85 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous methanol (1.2 mL) was added. The reaction mixture was stirred at 80°C for 20 minutes. The reaction mixture was cooled to room temperature, the caps were removed, and additional ammonium formate (33 mg, 0.52 mmol) and Pd / C (10% by weight, 2.6 mg) were added. The reaction vials were resealed and heated at 80°C for a further 10 minutes. The reaction mixture was cooled to room temperature, filtered through Celite®, and the solid was washed with MeOH (40 mL). The filtrate was concentrated under reduced pressure, redissolved in MeOH, and passed through an SCX-2 (2 g) column. Elution was performed with MeOH (40 mL) followed by 2N methanolic ammonia (40 mL). The methanolic ammonia fraction was concentrated under reduced pressure to obtain the title compound (22 mg, 67%) as a deep yellow solid, which was used without further purification. LC-MS (Method T2) RT 0.41 min; m / z 260.1382 [M+H] + .

[0355] The examples shown in the table below were prepared starting from the amino alcohols shown in the table, using the same method as that used for the preparation of intermediate A1a. An alternative method to Step 1 was used for the preparation of intermediate A1l. Details of this method are described below in relation to the preparation of intermediate A1d.

[0356] [Table 50]

[0357] [Table 51]

[0358] [Table 52]

[0359] [Table 53]

[0360] Intermediate A1m: (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Step 1: (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (S)-3-amino-3-cyclopropyl-2,2-difluoropropane-1-ol hydrochloride (1.02 g, 5.43 mmol) and ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (intermediate F2; 1.41 g, 4.52 mmol) were charged into microwave vials (volume 10-20 mL) that had been dried in an oven. The reaction vials were flushed with Ar and sealed with caps. Anhydrous acetonitrile (15 mL) was added, followed by DIPEA (2 mL, 11.48 mmol). The reaction mixture was heated at 160 °C for 12 hours under microwave irradiation. The reaction mixture was transferred to a flask and 2 M sodium hydroxide (13.5 mL, 27 mmol) was added. A reflux condenser was attached, and the reaction mixture was heated at 85 °C for 2 hours. The reaction mixture was cooled to room temperature. Water (40 mL) was added, and the reaction mixture was acidified to pH 5 with 3 M HCl. The resulting precipitate was filtered, washed with H2O (150 mL), and dried to obtain (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (1.41 g, 88%) as an off-white solid, which was used without further purification.1 H NMR(500MHz,DMSO-d6)δ 9.31(d,J=2.5Hz,1H),8.40(dd,J=9.4,2.5Hz,1H),7.62(d,J=9.4Hz,1H),7.48(d,J=8.7Hz,1H),5.72(s,1H),5.60(t,J=6.1Hz,1H),3.90-3 .71(m,2H),3.57-3.45(m,4H),1.38-1.29(m,1H),0.71-0.64(m,1H),0.63-0.56(m,1H),0.53-0.46(m,1H),0.27-0.20(m,1H);LCMS(Method X2)RT 1.15 min; m / z 354.1270[M+H] + .

[0361] Step 2: (S)-3-bromo-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2(1H)-one Trifluoroacetic acid (1.2 mL, 15.67 mmol) was added at 0°C under an Ar atmosphere to a stirred mixture in anhydrous CH2Cl2 (21 mL) containing (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (derived from Step 1; 1.14 g, 3.21 mmol) and newly recrystallized N-bromosuccinimide (572 mg, 3.21 mmol). The reaction mixture was stirred at 0°C for 15 minutes. The reaction mixture was diluted with CH2Cl2 (60 mL) and washed with saturated NaHCO3 aqueous solution (3 × 30 mL). The aqueous washing solution was further extracted with CH2Cl2 (60 mL). The organic extracts were combined, washed with brine (30 mL), dried, and concentrated under reduced pressure to obtain (S)-3-bromo-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (1.39 g, 100%) as a yellow solid, which was used without further purification. 1H NMR(500MHz,DMSO-d6)δ 8.95(d,J=2.5Hz,1H),8.43(dd,J=9.4,2.5Hz,1H),7.75(d,J=9.4Hz,1H),5.86(d,J=11.1Hz,1H),5.63(t,J=5.9Hz,1H),4.05-3.95 (m,1H),3.89-3.74(m,2H),3.71(s,3H),1.29-1.21(m,1H),0.68-0.62(m,1H),0.62-0.51(m,2H),0.50-0.44(m,1H);LCMS(Method X2)RT 1.31 min;m / z 432.0369[M+H] + .

[0362] Step 3: (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one Lithium tert-butoxide (1 M in THF; 5.14 mL, 5.14 mmol) was added to a suspension of (S)-3-bromo-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitro-quinoline-2(1H)-one (derived from Step 2; 1.39 g, 3.21 mmol) in THF (32 mL) under an Ar atmosphere. A reflux condenser and Ar balloon were attached, and the reaction mixture was heated at 60°C for 15 minutes. The reaction mixture was cooled to room temperature. Water (40 mL) was added, and the aqueous mixture was extracted with CH2Cl2 (3 × 40 mL). The organic extracts were combined, washed with brine (2 × 40 mL), dried (Na2SO4), and concentrated under reduced pressure to obtain (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (1.08 g, 96%) as a yellow solid, which was used without further purification. 1H NMR(500MHz,DMSO-d6)δ 9.12(d,J=2.5Hz,1H),8.35(dd,J=9.4,2.5Hz,1H),7.66(d,J=9.4Hz,1H),7.01(d,J=4.4Hz,1H),4.54-4.37(m,2H),3.62( s,3H,NCH3),3.29-3.22(m,1H),1.39-1.31(m,1H),0.76-0.69(m,1H),0.58-0.49(m,2H),0.37-0.30(m,1H);LCMS(Method X2)RT 1.29 min;m / z 352.1105[M+H] + .

[0363] Step 4: (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one In a 100 mL flask, (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (derived from Step 3; 1.08 g, 3.09 mmol) and 10 wt% Pd / C (108 mg) were charged. The reaction vial was flushed with Ar and ethanol (15 mL) was added. The reaction mixture was stirred at 60 °C under an H2 atmosphere for 1 hour. The reaction mixture was cooled to room temperature. The reaction mixture was filtered through Celite, and the solids were washed with EtOH (60 mL). The filtrate was concentrated under reduced pressure to obtain the title compound (1.03 g, 100%) as an orange solid, which was used without further purification. LC-MS (Method X2) RT 0.89 min; m / z 322.1370 [M+H] + .

[0364] This alternative synthesis was also used for larger-scale synthesis of intermediates A1a and A1d.

[0365] Intermediate A2a: 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Step 1: 4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one Ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (intermediate F2; 310 mg, 1.0 mmol) and 3-amino-3-methylbutan-1-ol (178 mg, 1.7 mmol) were charged into microwave vials (volume 2.0-5.0 mL) dried in an oven. The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous NMP (3.5 mL) was added, followed by DIPEA (0.52 mL, 2.9855 mmol). The reaction mixture was heated at 160 °C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature. The caps were removed, and lithium chloride (239 mg, 5.6 mmol) was added. The reaction vials were resealed with caps and heated in a heating block at 160 °C for 3 hours. The reaction mixture was cooled to room temperature. Next, the reaction mixture was added dropwise to water (25 mL). The aqueous mixture was extracted with SiO2 (3 × 30 mL). The organic extracts were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude product was dissolved in DMSO (1.5 mL) and purified directly by reversed-phase chromatography (two runs; Biotage reversed-phase 12 g C-18 column; 10-100% MeOH in H2O (containing 0.1% formic acid)). The fraction containing impurities was combined, concentrated under reduced pressure, and dissolved in DMF (1.5 mL). The DMF mixture was added dropwise to stirred water (10 mL). The aqueous mixture was stirred for 30 minutes. The resulting suspension was filtered, the solid was washed with water (50 mL), and dried to obtain 4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (29 mg, 10%) as a cream-colored solid. 1H NMR(500MHz,DMSO-d6)δ 8.83(d,J=2.5Hz,1H),8.37(dd,J=9.3,2.5Hz,1H),7.61(d,J=9.3Hz,1H),7.07(s,1H),5.74(s, 1H),5.12(t,J=4.5Hz,1H),3.66-3.62(m,2H),3.55(s,3H),1.93(t,J=6.3Hz,2H),1.44(s,6H).

[0366] Step 2: 3-Bromo-4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one Trifluoroacetic acid (15 μL, 0.20 mmol) was added at 0°C under an Ar atmosphere to a stirred mixture of N-bromosuccinimide (22 mg, 0.13 mmol) and 4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (derived from Step 1; 29 mg, 0.10 mmol) in anhydrous CH2Cl2 (0.5 mL). The reaction mixture was stirred at 0°C for 20 minutes. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 solution (2 × 20 mL). The aqueous washing solutions were combined and extracted with ethyl acetate (20 mL). The organic extracts were combined, dried, and concentrated under reduced pressure in (Na2SO4). The crude reaction mixture was dry-loaded onto silica and purified by flash chromatography (10 g KP-sil; 0%-10% MeOH in CH2Cl2) to obtain 3-bromo-4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (20 mg, 53%) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ 8.86(d,J=2.7Hz,1H),8.42(dd,J=9.4,2.7Hz,1H),7.75(d,J=9.4Hz,1H),5.05(br s, 1H), 3.75-3.73 (m, 2H), 3.72 (s, 3H), 1.90 (t, J=6.7Hz, 2H), 1.22 (s, 6H).

[0367] Step 3: 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one 3-bromo-4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (derived from Step 2; 20 mg, 0.05 mmol) was charged into a microwave vial (volume 0.5-2.0 mL). The reaction vial was flushed with Ar, sealed with a cap, and then flushed again with Ar. Anhydrous DMSO (0.68 mL) was added, followed by potassium tert-butoxide (1 M in THF; 92 μL, 0.09 mmol). The reaction mixture was heated at 60°C under microwave irradiation for 50 minutes. The reaction mixture was cooled to room temperature. Water (10 mL) was added, followed by ethyl acetate (10 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (2 × 10 mL). The organic extracts were combined and concentrated under reduced pressure. The crude product was dissolved in DMSO (1 mL) and directly purified by reverse-phase chromatography (Biotage reverse-phase 12 g C-18 column; containing 45-65% MeOH in H2O (0.1% formic acid)) to obtain 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (5 mg, 29%) as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ 8.99(d,J=2.5Hz,1H),8.31(dd,J=9.3,2.5Hz,1H),7.61(d,J=9.3Hz,1H),6.01 (s,1H),4.13(t,J=6.1Hz,2H),3.62(s,3H),1.92(t,J=6.1Hz,2H),1.41(s,6H).

[0368] Step 4: 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (derived from step 3; 5 mg, 0.015 mmol), Pd / C (10% by weight, 0.5 mg), and ammonium formate (8 mg, 0.13 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous methanol (0.5 mL) was added. The reaction mixture was stirred at 80°C for 10 minutes. The reaction mixture was cooled to room temperature, the caps were removed, and additional ammonium formate (5 mg, 0.08 mmol) and Pd / C (10% by weight, 0.5 mg) were added. The reaction vials were resealed with caps and heated at 80°C for a further 10 minutes. The reaction mixture was cooled to room temperature, filtered through Celite®, and the solid was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure, redissolved in MeOH, and passed through an SCX-2 (1 g) column. Elution was performed with MeOH (20 mL) followed by 2N methanolic ammonia (30 mL). The methanolic ammonia fraction was concentrated under reduced pressure to obtain the title compound (4 mg, 99%) as a yellow solid, which was used without further purification. LC-MS (Method T2) RT 0.72 min; m / z 274.1538 [M+H] + .

[0369] The examples shown in the table below were prepared using the same method as that used to prepare intermediate A2a, starting from the amino alcohols shown in the table.

[0370] [Table 54]

[0371] Intermediate A3: 9-amino-2,6-dimethyl-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinoline-5(6H)-one [ka] Step 1: 4-((1-hydroxypropan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one A suspension of 4-chloro-1-methyl-6-nitroquinoline-2(1H)-one (intermediate F1; 250 mg, 1.05 mmol), 2-aminopropan-1-ol (236 mg, 3.14 mmol), and DIPEA (0.36 mL, 2.10 mmol) in NMP (4.19 mL) was heated in a heating block at 160 °C for 24 hours. The reaction mixture was cooled to room temperature. When water (3 mL) was added to the reaction mixture, a yellow precipitate formed after 5 minutes. The aqueous mixture was added to water (20 mL). After 15 minutes, the precipitate was filtered, washed with water (100 mL), and dried to obtain 4-((1-hydroxypropan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one as a yellow solid. 1 H NMR(500MHz,DMSO-d6)δ 9.12(d,J=2.5Hz,1H),8.37(dd,J=9.4,2.5Hz,1H),7.60(d,J=9.4Hz,1H),7.02(d,J=7.4Hz,1H), 5.62(s,1H),4.82(t,J=5.8Hz,1H),3.66-3.52(m,5H),3.43-3.36(m,1H),1.22(d,J=6.4Hz,3H).

[0372] Step 2: 4-((1-hydroxypropan-2-yl)amino)-3-iodo-1-methyl-6-nitroquinoline-2(1H)-one 4-((1-hydroxypropan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (derived from Step 1; 52 mg, 0.19 mmol) and iodine (145 mg, 0.57 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous methanol (1.2 mL) was added, and the reaction mixture was heated under microwave irradiation at 60°C for 30 minutes. Water (0.6 mL) was added, and the reaction mixture was heated under microwave irradiation at 60°C for a further 90 minutes. The reaction mixture was cooled to room temperature, diluted with MeOH, and dry-loaded directly onto silica. Purification by flash chromatography (10 g KP-sil; 0%-15% MeOH in CH2Cl2) yielded 4-((1-hydroxypropan-2-yl)amino)-3-iodo-1-methyl-6-nitroquinoline-2(1H)-one (29 mg, 38%) as a yellow solid. 1 H NMR(500MHz,CDCl3)δ 8.92(d,J=2.6Hz,1H),8.40(dd,J=9.3,2.6Hz,1H),7.46(d,J=9.3Hz,1H),4.62(d,J=10.6Hz,1 H),3.99-3.90(m,1H),3.86-3.76(m,5H),3.71(dd,J=11.2,5.9Hz,1H),1.37(d,J=6.6Hz,3H).

[0373] Step 3: 2,6-dimethyl-9-nitro-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinoline-5(6H)-one 4-((1-hydroxypropan-2-yl)amino)-3-iodo-1-methyl-6-nitroquinoline-2(1H)-one (derived from step 2; 29 mg, 0.07 mmol), 1,10-phenanthroline (6 mg, 0.03 mmol), copper(I) iodide (3 mg, 0.02 mmol), and cesium carbonate (46 mg, 0.14 mmol) were charged into a microwave vial (volume 2.0-5.0 mL). The reaction vial was evacuated under reduced pressure for 30 minutes. The reaction vial was flushed with Ar, sealed with a cap, and then flushed again with Ar. Anhydrous NMP (2.4 mL) was added. The reaction mixture was heated at 120 °C under microwave irradiation for 1 hour. The reaction mixture was cooled to room temperature. Water (5 mL) was added, and the aqueous mixture was extracted with CH2Cl2 (3 × 15 mL). The organic extracts were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by flash chromatography (10 g KP-sil; 0%-15% MeOH in CH2Cl2). The fractions containing the product were combined, concentrated under reduced pressure, passed through an SCX-2 column (5 g), and eluted with MeOH (50 mL), followed by 2N methanolic ammonia (50 mL). The MeOH fraction was collected and concentrated under reduced pressure. The impure product was diluted with DMSO (0.8 mL) and purified by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; 10-100% MeOH in H2O (containing 0.1% formic acid) to obtain 2,6-dimethyl-9-nitro-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinoline-5(6H)-one (8 mg, 41%) as a yellow solid. 1 H NMR(500MHz,CDCl3)δ 8.45(d,J=2.2Hz,1H),8.32(dd,J=9.3,2.2Hz,1H),7.43(d,J=9.3Hz,1H),4.43(br s,1H),4.39(dd,J=10.5,2.7Hz,1H),3.82(dd,J=10.5,7.3Hz,1H),3.79(s,3H),3.76-3.72(m,1H),1.39(d,J=6.4Hz,3H).

[0374] Step 4: 9-amino-2,6-dimethyl-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinoline-5(6H)-one Microwave vials (volume 0.5-2.0 mL) were charged with 2,6-dimethyl-9-nitro-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinoline-5(6H)-one (derived from step 3; 11 mg, 0.0392 mmol), Pd / C (10 wt%, 2 mg), and ammonium formate (13 mg, 0.20 mmol). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. Anhydrous methanol (0.4 mL) was added, and the reaction mixture was stirred at 80°C for 90 minutes. The reaction mixture was cooled to room temperature, filtered through Celite®, and the solids were washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure, redissolved in MeOH, passed through an SCX-2 (2 g) column, and eluted with MeOH (30 mL), followed by 2N methanolic ammonia (30 mL). The methanolic ammonia fraction was concentrated under reduced pressure to obtain the title compound (8 mg, 81%) as an off-white solid, which was used without further purification. LC-MS (Method T2) RT 0.21 min; m / z 246.1253 [M+H] + .

[0375] Intermediate A4: (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Step 1: (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one A mixture of ethyl 4-chloro-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (intermediate F3; 2.0 g, 6.74 mmol), (R)-3-amino-3-cyclopropylpropan-1-ol (intermediate D1a; 1.09 g, 9.44 mmol), and DIPEA (2.94 mL, 16.9 mmol) in acetonitrile (13.5 mL) was heated overnight at 80°C. The reaction mixture was cooled to room temperature, 2 M sodium hydroxide (16.9 mL, 33.7 mmol) was added, and the reaction mixture was stirred at 80°C for 13 hours. Additional 2 M sodium hydroxide (16.9 mL, 33.7 mmol) was added, and stirring at 80°C was continued for a further 16 hours. The organic solvent was removed under reduced pressure, and the aqueous mixture was acidified to pH 4 with 2 M aqueous HCl. The aqueous suspension was then washed with ELISA (10 × 200 mL). The organic solvent was removed under reduced pressure, and the crude product was purified by flash chromatography (0%-20% MeOH in 25 g KP-sil;SiO) to obtain a yellow solid (1.7 g). The crude product was suspended in water, filtered, further washed with 100 mL of water, and dried overnight in air to obtain (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one (1.14 g, 56%) as a yellow solid. LC-MS (Method T2) RT 1.19 min; m / z 304.13 [M+H] + .

[0376] Step 2: (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one Trifluoroacetic acid (1.44 mL, 18.74 mmol) was added at 0°C to a stirred mixture of N-bromosuccinimide (1.01 g, 5.67 mmol) and (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one (derived from Step 1; 1.14 g, 3.76 mmol) in anhydrous CH2Cl2 (38 mL). The reaction mixture was stirred at 0°C for 10 minutes. The reaction mixture was divided into ethyl acetate (50 mL) and water (75 mL). The aqueous layer was extracted twice with ELISA (50 mL), combined with organic matter, washed with saturated NaHCO3 aqueous solution, dried, and concentrated under reduced pressure to obtain (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one (1.69 g) as a dark green solid containing 0.5 equivalents of succinimide (as determined by NMR). This solid was used without further purification. LC-MS (Method T2) RT 1.33 min; m / z 384.04 [M+H] + .

[0377] Step 3: (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one (100 mg, 0.26 mmol) and DMSO (1.0 mL) were charged into microwave vials (volume 0.5-2.0 mL), the vials were evacuated, and the vials were refilled with argon. Potassium tert-butoxide (1 M in THF; 0.47 mL, 0.47 mmol) was then added, and the reaction mixture was heated at 65°C for 1 hour under microwave irradiation.

[0378] The procedure was repeated in four batches as described above. One batch was performed using 67 mg of (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one, 0.32 mL of potassium tert-butoxide (1 M in THF), and 1.00 mL of DMSO. All batches were combined for purification. The title compound was obtained as a brown solid (110 mg, 38% in two steps) by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; 30-70% MeOH in H2O (containing 0.1% formic acid)). LC-MS (Method T2) RT 1.28 min; m / z 302.12 [M+H] + .

[0379] Intermediate A5a:(R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetra-hydro[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] Step 1: (R)-2-Cyclopropyl-7-(Cyclopropylmethyl)-10-Nitro-1,2,3,4-Tetrahydro-[1,4]Oxazepino-[2,3-c]Quinoline-6(7H)-one A suspension of (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A4) (46 mg, 0.15 mmol) and cesium carbonate (74 mg, 0.23 mmol) in DMF (1.4 mL) was stirred at room temperature under an argon atmosphere for 15 minutes. Bromomethylcyclopropane (29 μL, 0.30 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Water was added, and the aqueous mixture was extracted with SiO2 (4 × 10 mL). The combined organic layers were dried and concentrated under reduced pressure using (Na2SO4). Purification by flash chromatography (10 g, KP-Sil, 30%-80% ethyl ethyl in cyclohexane) yielded (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one (30 mg, 56%) as a yellow oil. 1 ¹H NNMR (500 MHz, CDCl3)δ 8.50(d,J=2.4Hz,1H),8.33(dd,J=9.3,2.4Hz,1H),7.55(d,J=9.4Hz,1H),4.49 (ddd,J=12.0,8.8,5.3Hz,1H),4.38-4.32(m,1H),4.27(dd,J=6.9,4.5Hz,2H), 3.09-2.99(m,1H),2.40(ddt,J=19.6,6.8,3.8Hz,1H),1.43(s,5H),1.23-1.11 (m,2H),0.80-0.69(m,2H),0.64-0.48(m,4H),0.42-0.34(m,2H);LCMS(Method T2)RT 1.50 min;m / z 356[M+H] + .

[0380] Step 2: (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one (derived from Step 1; 30 mg, 0.08 mmol) was suspended in ethanol (8.0 mL), to which ammonium formate (53 mg, 0.84 mmol) and Pd / C (10 wt%, 9 mg) were added. The flask was flushed with nitrogen and heated to 80°C for 30 minutes. The product was loaded directly onto an SCX-2 (2 g) column and washed with methanol. The product was eluted with 2 M methanolic ammonia and concentrated under reduced pressure to obtain the title compound (12 mg, 42%) as a brown solid. 1 H NMR(500MHz, methanol-d4)δ 7.43(d,J=9.0Hz,1H),7.14(d,J=2.4Hz,1H),7.04(dd,J=9.0,2.5Hz,1H),4.38(ddd,J=11.8,7. 5,5.4Hz,1H),4.21(dd,J=6.9,1.4Hz,2H),4.13(dt,J=11.8,5.9Hz,1H),2.86(td,J=9.6,3.6Hz, 1H),2.31(dddd,J=13.6,7.5,5.9,3.6Hz,1H),2.08(ddt,J=13.8,9.6,5.6Hz,1H),1.32-1.17(m ,2H),0.70-0.61(m,2H),0.52-0.45(m,4H),0.45-0.36(m,1H),0.36-0.31(m,1H);LCMS(Method T2)RT 1.09 min;m / z 326[M+H] + .

[0381] The examples shown in the table below were prepared starting from the intermediates shown in the table, using the same method as that used for the preparation of intermediate A5a. For intermediate A5b, reversed-phase chromatography was performed after the reduction step.

[0382] [Table 55]

[0383] Intermediate A6a:(R)-10-amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] A mixture of (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A4; 12 mg, 0.04 mmol) and tin(II) chloride (30 mg, 0.16 mmol) was suspended in ethanol (0.23 mL) and trifluoroethanol (0.08 mL) and heated at 120°C for 1 hour under microwave irradiation. The crude mixture was used directly without any purification. LC-MS (Method T2) RT 0.50 min; m / z 272.14 [M+H] + .

[0384] Intermediate A7a:(R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxaze-pino[2,3-c][1,8]naphthyridine-6(7H)-one [ka] Step 1: (R)-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridine-2(1H)-one Microwave vials (volume 2.0-5.0 mL) were charged with (R)-3-amino-3-cyclopropylpropan-1-ol (intermediate D1a; 139 mg, 1.2 mmol), ethyl 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (intermediate F4; 201 mg, 0.67 mmol), DIPEA (0.30 mL, 1.7 mmol), and MeCN (2.7 mL). The reaction vials were flushed with Ar and sealed with caps. The reaction mixture was heated at 90°C for 2 hours under microwave irradiation. The reaction mixture was transferred to a flask and 2M sodium hydroxide (2.0 mL, 4.0 mmol) was added. The reaction mixture was heated at 95°C for 1 hour. The reaction mixture was cooled to room temperature, the resulting precipitate was filtered, washed with water (10 mL), and dried to obtain (R)-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyrizine-2(1H)-one (136 mg, 66%) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 8.75(d,J=2.3Hz,1H),8.62(d,J=2.3Hz,1H),6.77(d,J=8.3Hz,1H),5.5 4(s,1H),4.49(t,J=4.9Hz,1H),3.57-3.50(m,4H),3.50-3.44(m,1H),3. 27-3.20(m,1H),1.89-1.82(m,1H),1.82-1.73(m,1H),1.08-1.00(m,1H) ,0.52-0.47(m,1H),0.41-0.36(m,1H),0.28-0.21(m,2H);LCMS(Method T2)RT 1.40 min;m / z 308.116[M+H] +

[0385] Step 2: (R)-3-bromo-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridine-2(1H)-one Trifluoroacetic acid (0.17 mL, 2.2 mmol) was added at 0°C under an Ar atmosphere to a stirred mixture of N-bromosuccinimide (117 mg, 0.66 mmol) and (R)-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyrizine-2(1H)-one (derived from Step 1; 135 mg, 0.44 mmol) in anhydrous CH2Cl2 (3.0 mL). The reaction mixture was stirred at 0°C for 25 minutes. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 solution (2 × 10 mL). The aqueous washing solutions were combined and extracted with ethyl acetate (20 mL). The organic extracts were combined, dried, and concentrated under reduced pressure in (Na2SO4). Purification by flash chromatography (10 g KP-sil; 0%-10% MeOH in CH2Cl2) yielded (R)-3-bromo-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyrizine-2(1H)-one (137 mg, 81%) as an off-white solid. 1 1H NMR (500MHz, DMSO-d6)δ 8.72(d,J=2.4Hz,1H),8.69(d,J=2.4Hz,1H),5.57(d,J=10.4Hz,1H),4.62(d d,J=5.1,4.3Hz,1H),3.69-3.63(m,4H),3.63-3.57(m,1H),3.57-3.51(m,1H ),1.98-1.91(m,1H),1.91-1.82(m,1H),1.08-1.00(m,1H),0.44-0.36(m,1H ),0.31-0.24(m,1H),0.19-0.11(m,1H),-0.01--0.07(m,1H);LCMS(Method T2)RT 1.45 min; m / z 386.025[M+H] +

[0386] Step 3: (R)-10-chloro-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]-naphthyridine-6(7H)-one (R)-3-bromo-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyrizine-2(1H)-one (derived from Step 2; 137 mg, 0.35 mmol) was charged into a microwave vial (volume 2-5 mL). The reaction vial was flushed with Ar, sealed with a cap, and then flushed again with Ar. Anhydrous DMSO (4.71 mL) was added, followed by potassium tert-butoxide (1 M in THF; 0.64 mL, 0.64 mmol). The reaction mixture was heated under microwave irradiation at 60°C for 80 minutes. The reaction mixture was cooled to room temperature. Water (20 mL) was added, followed by ethyl acetate (20 mL). The layers were separated, and the aqueous layer was further extracted with ethyl acetate (2 × 20 mL). The organic extracts were combined, washed with brine (10 mL), and concentrated under reduced pressure. The crude product was dissolved in DMSO (1 mL) and directly purified by reverse-phase chromatography (Biotage reverse-phase 12 g C-18 column; containing 60-84% MeOH in H2O (0.1% formic acid)) to obtain (R)-10-chloro-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthirizine-6(7H)-one (41 mg, 38%) as an off-white solid. 1 H NMR(500MHz,DMSO-d6)δ 8.69(d,J=2.4Hz,1H),8.55(d,J=2.4Hz,1H),6.22(d,J=3.6Hz,1H),4.27-4.15(m,2H),3.57(s,3H),2.93-2.86(m,1H),2.24 -2.16(m,1H),2.03-1.95(m,1H),1.22-1.14(m,1H),0.57-0.48(m,2H),0.38-0.33(m,1H),0.29-0.23(m,1H);LCMS(Method T2)RT 1.45 min;m / z 306.117[M+H] +

[0387] Step 4: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]-naphthyridine-6(7H)-one (R)-10-chloro-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one (derived from step 3; 32 mg, 0.10 mmol), benzophenone imine (27 mg, 0.15 mmol), sodium tert-butoxide (15 mg, 0.15 mmol), palladium(II) acetate (2.3 mg, 0.010 mmol), and Josiphos (5.7 mg, 0.010 mmol) were charged into oven-dried microwave vials (volume 0.5-2.0 mL). Anhydrous 1,2-dimethoxyethane (0.40 mL) was added, the vials were sealed with caps, and Ar was aerated into the reaction mixture. The reaction mixture was heated in a heating block at 70°C for 2 hours. The reaction mixture was cooled to room temperature, and 3M HCl (0.9 mL) was added for imine hydrolysis. The mixture was stirred at room temperature for 2 hours. The reaction mixture was passed directly through an SCX-2 (2 g) column and eluted with water (10 mL), MeOH (20 mL), and 2N methanolic ammonia (20 mL). The basic fraction was concentrated under reduced pressure to obtain the title compound (30 mg, 99%, 0.12 mmol) as a deep yellow solid, which was used without further purification. LC-MS (Method T2) RT 1.10 min; m / z 287.139 [M+H]+.

[0388] Intermediate A8a:(R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro[1,4]thiase-pino[2,3-c]quinoline-6(7H)-one [ka] Step 1: (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)-3-cyclopropylpropyl 4-methylbenzenesulfonate The starting material, (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2(1H)-one, was prepared using steps 1-2 described for intermediate A1d.

[0389] To a solution of (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (200 mg, 0.50 mmol) cooled to 0°C in pyridine (5.0 mL), tosyl chloride (289 mg, 1.51 mmol) was added. The mixture was stirred for 2 hours while being warmed to room temperature. Additional tosyl chloride (289 mg, 1.51 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into 5% aqueous HCl and then extracted with CH2Cl2. The organic extracts were combined, washed with 5% aqueous HCl, dried, and concentrated under reduced pressure in (MgSO4). The residue was purified by flash chromatography (25 g KP-sil; 20%-75% ethyl phosphate in cyclohexane) to obtain (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)-3-cyclopropylpropyl 4-methylbenzenesulfonate (127 mg, 46%) as a yellow solid. LC-MS (Method T2) RT 1.56 min; m / z 550.06 [M+H] + .

[0390] Step 2: (R)-S-(3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)-3-cyclopropylpropyl)ethanethioate (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)-3-cyclopropylpropyl 4-methylbenzenesulfonate (derived from Step 1; 60 mg, 0.11 mmol) was dissolved in DMF (1.1 mL), to which potassium thioacetate (25 mg, 0.22 mmol) was added, followed by sodium iodide (1.6 mg, 0.01 mmol). The solution was heated to 50°C and stirred for 4 hours. The mixture was cooled to room temperature and deactivated by the addition of water. The mixture was extracted with ethyl acetate. The combined organic extract was washed with water and brine, dried, and concentrated under reduced pressure in (MgSO4). The residue (diluted with DMSO (1 mL)) was purified using reverse-phase flash chromatography (Biotage 12 g SNAP Ultra C-18, 30-100% MeOH in H2O (containing 0.1% formic acid)) to obtain (R)-S-(3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)-3-cyclopropylpropyl)ethanethioate (38 mg, 77%) as a brown oil. LC-MS (Method T2) RT 1.56 min; m / z 456.04 [M+H] + .

[0391] Step 3: (R)-2-Cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one (R)-S-(3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)-3-cyclopropylpropyl)ethanethioate (derived from Step 2; 38 mg, 0.084 mmol) was cooled to 0°C under an air atmosphere and suspended in methanol (0.84 mL). 15% aqueous NaOH (0.50 mL, 0.084 mmol) was added to the suspension. The mixture was kept warm at room temperature overnight while stirring was continued. The mixture was concentrated under reduced pressure to remove methanol. Then, DMSO (1.5 mL) and a few drops of water were added. The solution was purified using reverse-phase flash chromatography (Biotage 12g SNAP Ultra C-18, 30-100% MeOH in H2O (containing 0.1% formic acid)) to obtain (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one (17 mg, 61%) as a yellow oil. LC-MS (Method T2) RT 1.45 min; m / z 332.11 [M+H] + .

[0392] Step 4: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one (derived from step 3; 17 mg, 0.051 mmol) was suspended in ethanol (1.0 mL), to which ammonium formate (32 mg, 0.51 mmol) and Pd / C (10 wt%, 10) were added. The vial was sealed, evacuated, and then refilled with argon three times. The vial was then placed in a drysyn block preheated to 60°C and stirred for 1 hour. The reaction mixture was passed directly through an SCX-2 (2 g) column, and the title compound product was eluted with methanolic ammonia. (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiase-pino[2,3-c]quinoline-6(7H)-one (6 mg, 39%) was obtained as a yellow solid. LC-MS (Method T2) RT 1.07 min; m / z 302.13 [M+H] + .

[0393] The examples shown in the table below were prepared using the same method as that used to prepare intermediate A8a, starting from the amino alcohols shown in the table.

[0394] [Table 56]

[0395] Intermediate A8c:(R)-N-(2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepino[2,3-c]quinoline-10-yl)formamide [ka] Step 1 is the same as that used for the preparation of intermediate A8a.

[0396] Step 2: (R)-2-Cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one To a solution of (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)-3-cyclopropylpropyl 4-methylbenzenesulfonate (derived from Step 1; 176 mg, 0.32 mmol) in DMF (3.2 mL), potassium thioacetate (73 mg, 0.64 mmol), followed by sodium iodide (5 mg, 0.032 mmol), was added. The solution was heated to 50°C and stirred for 3 hours. After cooling to room temperature, 15% aqueous sodium hydroxide (1.00 mL, 0.32 mmol) was added by syringe. The mixture was stirred overnight at room temperature. Water (5 mL) was added to the mixture to form a precipitate, which was collected by vacuum filtration, washed further with water, and dried under reduced pressure to obtain (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one, which was used without further purification. LC-MS (Method X2) RT 1.35 min; m / z 354.09 [M+H] + .

[0397] Step 3: (R)-N-(2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepino[2,3-c]quinoline-10-yl)formamide (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one (derived from step 2; 106 mg, 0.32 mmol) was suspended in ethanol (3.2 mL) and ammonium formate (202 mg, 3.20 mmol) and 10% by weight of Pd / C (34 mg) were added. The vial was sealed, evacuated, and then refilled with argon three times. The vial was then placed in a drysyn block preheated to 60°C. After stirring for 1 hour, additional Pd / C and ammonium formate (same amount as above) were added, and stirring was continued at 60°C for a further 2 hours. The mixture was filtered through a Celite pad and concentrated under reduced pressure. The residue was taken into ethanol (4 mL) and tin(II) chloride (243 mg, 1.28 mmol) was added. The mixture was heated under microwave irradiation at 120°C for a total of 9 hours and 30 minutes. The reaction mixture was cooled to room temperature, 15% aqueous NaOH (2 mL) was added, and the reaction mixture was stirred overnight at 60°C. After cooling once, the mixture was concentrated, and the residue was taken into CH2Cl2 and washed with water. The organic extract was dried (MgSO4) and concentrated under reduced pressure. It was purified by flash chromatography (Biotage KP-Sil 25 g; 0-10% MeOH in CH2Cl2). The fractions containing the product were combined, concentrated under reduced pressure, and further purified by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; 10-100% MeOH in H2O (containing 0.1% formic acid)) to obtain the title compound (5 mg, 5% in 2 steps) as a yellow oil. LCMS (Method T2) RT 1.31min; m / z 330.12[M+H] + NB intermediate A8a:(R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro[1,4]thiase-pino[2,3-c]quinoline-6(7H)-one (13 mg, 13% in 2 steps) was also isolated during this reaction.

[0398] Intermediate A9a: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one 5,5-dioxide [ka] Steps 1-3 are the same as those used in the preparation of intermediate A8a.

[0399] Step 4: (R)-2-Cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one 5,5-dioxide 3-Chloroperbenzoic acid (126 mg, 0.56 mmol) was added in several portions to a solution of (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one (62 mg, 0.19 mmol) in a mixture of CH2Cl2 (1.87 mL) and acetonitrile (1.87 mL), cooled to 0°C. After 15 minutes, the mixture was warmed to room temperature and stirred for 24 hours. The mixture was inactivated by adding 10% NaHCO3 aqueous solution and saturated aqueous solution Na2S2O3. The mixture was then extracted three times with ethyl acetate. The combined organic extracts were washed with 10% aqueous Na2CO3 and brine, dried, and concentrated under reduced pressure to obtain (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one 5,5-dioxide (45 mg, 66%) as a yellow solid, which was used without further purification. LC-MS (Method T2) RT 1.20 min; m / z 364.0943 [M+H] + .

[0400] Step 5: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepino[2,3-c]quinoline-6(7H)-one 5,5-dioxide A mixture of (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepino-[2,3-c]quinoline-6(7H)-one 5,5-dioxide (derived from Step 4; 20 mg, 0.055 mmol) and tin(II) chloride (42 mg, 0.22 mmol) in ethanol (0.67 mL) and trifluoroethanol (0.22 mL) was heated at 70°C for 1 hour. The reaction mixture was loaded into an SCX-2 cartridge in a 1:1 ratio of HCl:MeOH, flushed with MeOH, and then eluted with 2 M NH3 in MeOH to obtain the title compound (16 mg, 87%) as a yellow glass, which was used without further purification. LC-MS (Method X2); RT 1.54 min; m / z 334.1224 [M+H] + .

[0401] Intermediate A10a: (S)-2-cyclopropyl-10-((2,5-dichloropyrimidine-4-yl)amino)-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one [ka] (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1m; 800 mg, 2.49 mmol) and 2,4,5-trichloropyrimidine (531 mg, 2.89 mmol) were charged into microwave vials (volume 0.5-2.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. NMP (3 mL) was added, followed by DIPEA (1.7 mL, 9.76 mmol). The reaction mixture was heated under microwave irradiation at 140°C for 1 hour. The reaction mixture was cooled to room temperature. When the reaction mixture was added to water (10 mL), a beige precipitate formed. Additional water (10 mL) was added, and the aqueous mixture was stirred for 5 minutes. The precipitate was filtered, washed with water (25 mL), and dried to obtain the title compound (1.16 g, 100%) as a beige solid, which was used without further purification. 1 H NMR(600MHz,DMSO-d6)δ 9.74(s,1H),8.39(s,1H),8.15(d,J=2.1Hz,1H),7.61(dd,J=9.0,2.1Hz,1H),7.50(d,J=9.0Hz,1H),6.25(d,J=2.7Hz,1H),4.52-4.44(m,1H), 4.43-4.34(m,1H),3.58(s,3H),3.28-3.23(m,1H),1.35-1.27(m,1H),0 .77-0.67(m,1H),0.56-0.49(m,2H),0.36-0.30(m,1H);LCMS(Method X2);RT 1.60 min;m / z 468.0796[M+H] + .

[0402] The examples shown in the table below were prepared starting from the intermediates shown in the table, using the same method as that used to prepare intermediate A10a. For intermediates A10b and A10c, instead of precipitation, the crude reaction mixture was directly purified by reverse-phase chromatography using the conditions shown in the table to obtain the title compound. For intermediate A10d, instead of precipitation, the crude reaction mixture was directly purified by preparative HPLC using the conditions shown in the table.

[0403] [Table 57]

[0404] Intermediate A11a: (R)-N-(2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepino[2,3-c]quinoline-10-yl)formamide [ka] A mixture of (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A1d; 61 mg, 0.21 mmol) and phenyl formate (25 μL, 0.23 mmol) in anhydrous CH2Cl2 (0.60 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (10 g KP-sil; 0%-10% MeOH in CH2Cl2) yielded the title compound (32 mg, 48%) as a yellow solid. LC-MS (Method X2) RT 1.00 min; m / z 314.1499 [M+H] +

[0405] Intermediate A12a: 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-7(2H)-yl)acetaldehyde [ka] Step 1: (R)-2-cyclopropyl-7-(2,2-dimethoxyethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (intermediate A4; 69 mg, 0.23 mmol) and cesium carbonate (82 mg, 0.25 mmol) were charged into microwave vials (volume 2.0-5.0 mL). The reaction vials were flushed with Ar, sealed with caps, and then flushed again with Ar. DMF (1.5 mL) was added, and the mixture was stirred at room temperature for 30 minutes. 2-bromo-1,1-dimethoxyethane (82 μL, 0.69 mmol) was added, and the reaction mixture was heated at 100 °C for 3 hours. Subsequently, an additional 2-bromo-1,1-dimethoxyethane (40 μL, 0.34 mmol) was added, and the reaction mixture was heated at 100 °C for a further 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), and water (10 mL) was added. The layers were separated, and the aqueous mixture was extracted with ethyl acetate (2 × 15 mL). The organic extracts were combined, washed with brine (10 mL), dried, and concentrated under reduced pressure using (Na₂SO₄). Purification by flash chromatography (10 g KP-sil; 60%–100% ethyl acetate (5 CV) in cyclohexane, followed by 0%–3% MeOH (10 CV) in ethyl acetate) yielded (R)-2-cyclopropyl-7-(2,2-dimethoxyethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (42 mg, 47%) as a deep yellow solid. 1H NMR(500MHz, methanol-d4)δ 8.96(d,J=2.5Hz,1H),8.34(dd,J=9.5,2.5Hz,1H),7.84(d,J=9.5Hz,1H),4.69(t,J =5.3Hz,1H),4.54-4.45(m,2H),4.45-4.38(m,1H),4.33-4.26(m,1H),3.41(s,3H),3 .40(s,3H),3.02(dt,J=9.1,3.9Hz,1H),2.41-2.33(m,1H),2.20-2.11(m,1H),1.34- 1.28(m,1H),0.77-0.63(m,2H),0.48-0.43(m,1H),0.36-0.31(m,1H);LCMS(Method X2)RT 1.34 min;m / z 358.1378[M-MeOH+H] +

[0406] Step 2: (R)-10-amino-2-cyclopropyl-7-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one A microwave vial (volume 2.0-5.0 mL) was charged with (R)-2-cyclopropyl-7-(2,2-dimethoxyethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (derived from Step 1; 42 mg, 0.11 mmol) and 10 wt% Pd / C (5 mg). The reaction vial was flushed with Ar, sealed with a cap, and then flushed again with Ar. Ethanol (1 mL) was added. The reaction mixture was stirred at 60°C under an H2 atmosphere for 1 hour. The reaction mixture was cooled to room temperature. The reaction mixture was filtered through Celite, and the solids were washed with EtOH (25 mL). The filtrate was concentrated under reduced pressure to obtain (R)-10-amino-2-cyclopropyl-7-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (38 mg, 99%) as a yellow solid, which was used without further purification. LC-MS (Method X2) RT 0.89 min; m / z 328.1776 [M-MeOH+H] + .

[0407] Step 3: 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)pyrimidine-4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-7(2H)-yl)acetaldehyde (R)-10-amino-2-cyclopropyl-7-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one (derived from step 2; 36 mg, 0.10 mmol) and 5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)-4-(methylsulfonyl)pyrimidine (intermediate J3; 70 mg, 0.21 mmol) were charged into microwave vials (volume 0.5-2.0 mL). Trifluoroethanol (1 mL) was added, followed by trifluoroacetic acid (8.4 μL, 0.11 mmol). The reaction vial was flushed with Ar by passing the reaction mixture through it, and then sealed with a cap. The reaction mixture was heated in a heating block at 60°C for 2 hours and 30 minutes. Subsequently, the cap was removed, and additional 5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidine-1-yl)-4-(methylsulfonyl)pyrimidine (intermediate J3; 41 mg, 0.12 mmol) and trifluoroacetic acid (8.4 μL, 0.11 mmol) were added. The vial was resealed, and the mixture was heated at 60°C for an additional 16 hours. The reaction mixture was cooled to room temperature, the resulting precipitate was filtered, and washed with Et2O. The precipitate was confirmed to be the hydrolyzed intermediate J3. The filtrate was transferred to a microwave vial (volume 0.5-2.0 mL) using methanol. Trifluoroacetic acid (0.3 mL) and water (0.5 mL) were added to promote deprotection of the acetal. This reaction vial was resealed with a cap, and heated in a heating block at 60°C for 1 hour, followed by 80°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude aqueous mixture was diluted with DMSO (0.8 mL) and directly purified by reversed-phase chromatography (Biotage reversed-phase 12 g C-18 column; 10-30-100% MeOH in H2O (containing 0.1% formic acid)) to obtain the title compound (7 mg, 11%) as an off-white solid. LC-MS (Method X2) RT 1.62 min; m / z 605.2466 [M+MeOH+H] + .

[0408] Intermediate B1a: (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione [ka] Step 1: (S)-2,7-dimethyl-10-nitro-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione A suspension of ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (intermediate F2; 132 mg, 0.43 mmol), (S)-2-aminopropan-1-ol (64 mg, 0.85 mmol), and DIPEA (0.15 mL, 0.85 mmol) in NMP (1.5 mL) was stirred at 160°C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature. The cap was removed, and then lithium chloride (108 mg, 2.55 mmol) was added. The reaction vial was resealed with the cap, and the mixture was further stirred at 160°C for 1 hour under microwave irradiation. The crude reaction mixture was subjected to preparative HPLC (60:40~0:100 H2O:MeOH gradient for 15 minutes (both denatured with 0.1% formic acid); flow rate 20 mL·min) -1 (S)-2,7-dimethyl-10-nitro-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (48 mg, 37%) was obtained as a light brown solid by direct purification using ). 1 H NMR(500MHz,DMF-d7)δ 9.20(d,J=2.4Hz,1H),8.48(dd,J=9.4,2.4Hz,1H),8.20(br s,1H),7.72(d,J=9.4Hz,1H),4.72(dd,J=13.0,1.2Hz,1H),4.49(dd,J=13.0,5.1Hz,1H),4.20(q,J=6.4Hz,1H),3.66(s,3H),1.42(d,J=6.4Hz,3H).

[0409] Step 2: (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (S)-2,7-dimethyl-10-nitro-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (derived from Step 1; 48 mg, 0.16 mmol) and Pd / C (10 wt%, 3 mg) were suspended in EtOH (4 mL) under an Ar atmosphere. The mixture was evacuated and H2 was packed three times. The reaction mixture was stirred under an H2 atmosphere for 16 hours. The reaction mixture was filtered through Celite® and the solids were washed with MeOH. The filtrate was concentrated under reduced pressure to obtain the title compound (40 mg, 92%) as a yellow oil, which was used without further purification. LC-MS (Method T2) RT 0.19 min; m / z 274.1 [M+H] + .

[0410] The examples shown in the table below were prepared using the same method as that used to prepare intermediate B1a, starting from the amino alcohols shown in the table.

[0411] [Table 58]

[0412] Intermediate B2a: (S)-10-amino-2,7-dimethyl-2,3,5,7-tetrahydro-[1,4]oxazepino[6,5-c]quinoline-6(1H)-one [ka] Diethyl boron trifluoride etherate (approximately 50% BF3; 0.1 mL, 0.41 mmol) was added at 0°C to a stirred suspension of (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepino[6,5-c]quinoline-5,6(1H,7H)-dione (intermediate B1a; 12 mg, 0.042 mmol) in THF (4 mL). The reaction mixture was stirred at 0°C for 15 minutes, after which sodium borohydride (5 mg, 0.127 mmol) was added. The reaction mixture was stirred at 0°C for a further 2 hours. The reaction products were deactivated by adding methanol. The reaction mixture was concentrated under reduced pressure. Salt water was added to the residue, and the aqueous mixture was extracted with SiO2. The organic layer was dried and concentrated under reduced pressure (Na2SO4). Purification by flash chromatography (5% MeOH in 10g KP-sil;Â) yielded the title compound (4mg, 32%) as a yellow solid. 1 H NMR(500MHz, methanol-d4)δ 7.34(dd,J=9.0,1.4Hz,1H),7.23(dd,J=2.4,1.4Hz,1H),7.10(dd,J=9.0,2.4Hz,1H),4.96(d,J=14.4Hz,1H),4.77(d,J=14.4Hz,1H),3 .92(dt,J=11.2,2.9Hz,1H),3.86(ddt,J=12.1,6.6,3.0Hz,1H),3.60(s,3H),3.60(ddd,J=11.2,8.8,2.0Hz,1H),1.29(d,J=6.6Hz,3H).

[0413] Intermediate B3a: Ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-6-((2-chloro-3-cyanopyridine-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate [ka] Step 1: Ethyl 4-((1-((t-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate Ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (intermediate F2; 325 mg, 1.05 mmol), tert-butyl(2-aminopropyl)carbamate (200 mg, 1.15 mmol), and DIPEA (0.2 mL, 1.15 mmol) were combined in a microwave vial and dissolved in THF (5.2 mL). The reaction mixture was then heated at 100 °C for 16 hours. An excess amount of amine was added to 1 mL of THF, followed by the addition of DIPEA (50 μL), and heating was continued for 2 hours. The reaction mixture was cooled to room temperature and divided between EtOAC (25 mL) and water (25 mL). The aqueous layer was further extracted with ELISA (25 mL), the organic extract was combined, washed with brine (50 mL), dried, and concentrated under reduced pressure to obtain ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (606 mg, 129%) as a yellow solid, which was used without further purification. LC-MS (Method T4); RT 2.87 min; m / z 449.2078 [M+H] + Note: LC-MS showed a mixture of the desired product and the amine starting material. This mixture was then used, assuming a 100% conversion rate.

[0414] Step 2: Ethyl 6-amino-4-((1-((t-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate Ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (derived from Step 1; 50 mg, 0.11 mmol), Pd / C (10% by weight; 1.2 mg), and ammonium formate (70 mg, 1.11 mmol) were combined in a microwave vial, sealed, and placed under an argon atmosphere by alternating between vacuum and argon atmosphere three times. Ethanol (0.64 mL) was then added, and the reaction mixture was heated at 70°C for 2 hours. The reaction mixture was filtered through Celite, and the solvent was removed under reduced pressure. The crude product was divided between siRNA (20 mL) and water (20 mL). The organic layer was further washed with water (2 × 20 mL), then dried, filtered through hydrophobic frit, and then filtered through (MgSO4). The solvent was removed under reduced pressure to obtain ethyl 6-amino-4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (44 mg, 94%) as a green oil, which was used without further purification. LC-MS (Method T2); RT 1.23 min; m / z 419.2728 [M+H] + .

[0415] Step 3: Ethyl 4-((1-((t-butoxycarbonyl)amino)propan-2-yl)amino)-6-((2-chloro-3-cyanopyridine-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate Ethyl 6-amino-4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (derived from Step 2; 50 mg, 0.12 mmol), 2,4-dichloronicotinonitrile (21 mg, 0.12 mmol), and DIPEA (62 μL, 0.36 mmol) were combined in a microwave vial and dissolved in NMP (1 mL). The reaction mixture was heated at 110°C under microwave irradiation for 90 minutes, and then heated further at 110°C for 8 hours in a heating block. The reaction mixture was cooled to room temperature, trifluoroacetic acid (183 μL, 2.39 mmol) was added, and the reaction mixture was stirred at 70°C for 30 minutes. The reaction mixture was cooled to room temperature, and DIPEA (0.5 mL) was added. The reaction mixture was stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature and divided into toluene (20 mL) and water (20 mL). The aqueous layer was extracted once with toluene (20 mL), the organic extract was combined, washed twice with brine, dried, and concentrated under reduced pressure to obtain the title compound (62 mg, 94%) as a brown oil, which was used without further purification. LC-MS (Method T4); RT 2.91 min; m / z 555.211 [M+H] + .

[0416] Intermediate C1: 9-amino-2,6-dimethyl-2,3,4,6-tetrahydrobenzo[h][1,6]naphthyridine-5(1H)-one [ka] Step 1: 4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one A mixture of 4-chloro-1-methyl-6-nitroquinoline-2(1H)-one (intermediate F1; 250 mg, 1.05 mmol), 3-aminobutan-1-ol (280 mg, 3.14 mmol), and DIPEA (0.36 mL, 2.10 mmol) in NMP (1.9 mL) was stirred at 160 °C for 20 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried, and concentrated under reduced pressure using (Na2SO4). Purification by flash chromatography (50 g KP-sil; CH2Cl2) with 0%-10% MeOH yielded 4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (200 mg, 66%). 1 H NMR(500MHz,CDCl3)δ 8.48(d,J=2.5Hz,1H),8.36(dd,J=9.3,2.5Hz,1H),7.38(d,J=9.3Hz,1H),6.05(d,J=6.6Hz,1H),5.80(s,1H),4.10-3.97(m,1H) ),3.96-3.82(m,2H),3.68(s,3H),2.08-1.95(m,2H),1.89(dtd,J=14.8,6.3,3.5Hz,1H),1.35(d,J=6.4Hz,3H).LCMS(Method T2)RT 1.21 min,m / z 292.13[M+H] + .

[0417] Step 2: 3-((1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-4-yl)amino)butyl 4-methylbenzene sulfonate Tosylloride (61 mg, 0.32 mmol) was added at 0°C to a stirre...

Claims

1. Compound represented by formula (III-a): 【Chemistry 1】 Equation (III-a) (In the formula: Z is (-CH ２ -), (-CH ２ CH ２ -), (-CF ２ CH ２ ) or (-CH(Me)CH ２ -) is an alkylene group selected from (1-2C), W is NO ２ Selected from the group consisting of halogens and OTf; X １ is selected from N or CR ａ , where R ａ is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NR ｂ R ｃ , where R ｂ and R ｃ are each independently selected from hydrogen or (1-2C) alkyl; X ２ These are N, CH, CF, CCl, or C-CH ３ Selected from; R １ is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent, or O, C(O), C(O)O or C(O)N(R) ｅ ) and here, R ｅ is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR ｇ R ｈ OR ｇ It is further substituted by one or more substituents independently selected from; where R ｇ and R ｈ (Each of these elements is independently selected from hydrogen or (1-4C) alkyl groups.) Selected from; R ３０ The substituent is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR ｕ R ｖ , further substituted with one or more substituents selected from (1-2C)aminoalkyl or halo, where R ｕ and R ｖ is independently selected from hydrogen or (1-2C) alkyl; R ３１ This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y ５ -L ５ -Z ５ (In the formula: Y ５ is absent, or C(O)O or C(O)N(R) ｗ ) is selected, and here, R ｗ is selected from hydrogen or (1-2C) alkyl; L ５ is absent or (1-2C)alkylene; and Z ５ Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z ５ The following can be optionally selected: (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH ２ (substituted with one or more substituents selected from cyano, nitro, or hydroxy) Selected from; or R ３０ and R ３１ These are bonded together with the carbon atoms to which they are attached, forming a 4- to 6-membered carbon ring or heterocycle.

2. W is NO ２ The compound according to claim 1.

3. below (R)-2-cyclopropyl-7-(cyclopropylmethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; and, (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one A compound according to either claim 1 or 2, selected from the group consisting of the following.

4. The compound according to any one of claims 1 to 3, wherein the compound is (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one.

5. A method for producing a compound represented by formula (III-a) from a compound represented by formula (IV), 【Chemistry 2】 The manufacturing method includes performing an intramolecular cyclization reaction on a compound represented by formula (IV) to obtain a compound represented by formula (III-a). (In the formula, Z is (-CH ２ -), (-CH ２ CH ２ -), (-CF ２ CH ２ ) or (-CH(Me)CH ２ -) is an alkylene group selected from (1-2C), W is NO ２ Selected from the group consisting of halogens and OTf; Y is a halogen, X １ is N or CR ａ Selected from, here, R ａ This includes hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NR ｂ R ｃ Selected from, here, R ｂ and R ｃ Each is independently selected from hydrogen or (1-2C) alkyl; X ２ These are N, CH, CF, CCl, or C-CH ３ Selected from; R １ is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent, or O, C(O), C(O)O or C(O)N(R) ｅ ) and here, R ｅ is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR ｇ R ｈ OR ｇ It is further substituted by one or more substituents independently selected from; where R ｇ and R ｈ (Each of these elements is independently selected from hydrogen or (1-4C) alkyl groups.) Selected from; R ３０ The substituent is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR ｕ R ｖ , further substituted with one or more substituents selected from (1-2C)aminoalkyl or halo, where R ｕ and R ｖ is independently selected from hydrogen or (1-2C) alkyl; R ３１ This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y ５ -L ５ -Z ５ (In the formula: Y ５ is absent, or C(O)O or C(O)N(R) ｗ ) is selected, and here, R ｗ is selected from hydrogen or (1-2C) alkyl; L ５ is absent or (1-2C)alkylene; and Z ５ Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z ５ The following can be optionally selected: (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH ２ (substituted with one or more substituents selected from cyano, nitro, or hydroxy) Selected from; or R ３０ and R ３１ These are bonded together with the carbon atoms to which they are attached, forming a 4- to 6-membered carbon ring or heterocycle.

6. The compound represented by formula (III-a) is as follows: (R)-2-cyclopropyl-7-(cyclopropylmethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino-[2,3-c]quinoline-6(7H)-one; and, (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one A manufacturing method according to claim 5, selected from the group consisting of the following.

7. Compound represented by formula (II): 【Transformation 3】 (In the formula: X １ is selected from N or CR ａ , where R ａ is selected from hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NR ｂ R ｃ , where R ｂ and R ｃ are each independently selected from hydrogen or (1-2C) alkyl; X ２ These are N, CH, CF, CCl, or C-CH ３ Selected from; R １ is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent or is O, C(O), C(O)O or C(O)N(R ｅ ), where R ｅ is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR ｇ R ｈ OR ｇ It is further substituted by one or more substituents independently selected from; where R ｇ and R ｈ (Each of these elements is independently selected from hydrogen or (1-4C) alkyl groups.) Selected from; R ３０ The substituent is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR ｕ R ｖ , further substituted with one or more substituents selected from (1-2C)aminoalkyl or halo, where R ｕ and R ｖ is independently selected from hydrogen or (1-2C) alkyl; R ３１ This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y ５ -L ５ -Z ５ (In the formula: Y ５ is absent, or C(O)O or C(O)N(R) ｗ ) is selected, and here, R ｗ is selected from hydrogen or (1-2C) alkyl; L ５ is absent or (1-2C)alkylene; and Z ５ Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z ５ The following can be optionally selected: (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH ２ (substituted with one or more substituents selected from cyano, nitro, or hydroxy) Selected from; or R ３０ and R ３１ These are bonded together with the carbon atoms to which they are bonded, in order to form a 4- to 6-membered carbon ring or heterocycle; and, Ring A is a six- or seven-membered heterocycle, and it has substituent R ３０ and R ３１ In addition, optionally, oxo, (1-2C) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, NH ２ (Further substituted with one or more substituents selected from cyano or hydroxyl.)

8. below (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-ethyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,3,3,7-tetramethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-2',3'-dimethyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-[1,4]oxazepino[2,3-c]quinoline]-6(7H)-one; (2S,4S)-10-amino-2,4,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-7'-methyl-3',4,4',5-tetrahydro-1'H,2H--spiro[furan-3,2'-[1,4]oxazepino[2,3-c]quinoline]-6'(7'H)-one; 10-amino-2-(difluoromethyl)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; and (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one, A compound according to claim 7, selected from the group consisting of the following.

9. The compound according to claim 7 or claim 8, wherein the compound is (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.

10. A method for producing a compound represented by formula (II) from a compound represented by formula (III), 【Chemistry 4】 The manufacturing method includes a reduction reaction of the W group of formula (III) to obtain the compound represented by formula (II). (In the formula, W is NO ２ And; X １ is N or CR ａ Selected from, here, R ａ This includes hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NR ｂ R ｃ Selected from, here, R ｂ and R ｃ Each is independently selected from hydrogen or (1-2C) alkyl; X ２ These are N, CH, CF, CCl, or C-CH ３ Selected from; R １ is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent, or O, C(O), C(O)O or C(O)N(R) ｅ ) and here, R ｅ is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR ｇ R ｈ OR ｇ It is further substituted by one or more substituents independently selected from; where R ｇ and R ｈ (Each of these elements is independently selected from hydrogen or (1-4C) alkyl groups.) Selected from; R ３０ The substituent is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR ｕ R ｖ , further substituted with one or more substituents selected from (1-2C)aminoalkyl or halo, where R ｕ and R ｖ is independently selected from hydrogen or (1-2C) alkyl; R ３１ This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y ５ -L ５ -Z ５ (In the formula: Y ５ is absent, or C(O)O or C(O)N(R) ｗ ) is selected, and here, R ｗ is selected from hydrogen or (1-2C) alkyl; L ５ is absent or (1-2C)alkylene; and Z ５ Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z ５ The following can be optionally selected: (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH ２ (substituted with one or more substituents selected from cyano, nitro, or hydroxy) Selected from; or R ３０ and R ３１ These are bonded together with the carbon atoms to which they are bonded, in order to form a 4- to 6-membered carbon ring or heterocycle; and, Ring A is a six- or seven-membered heterocycle, and it has substituent R ３０ and R ３１ In addition, optionally, oxo, (1-2C) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, NH ２ (Further substituted with one or more substituents selected from cyano or hydroxyl.)

11. The manufacturing method according to claim 10, wherein the reduction reaction of the W group includes (1) a hydrogenation reaction in the presence of a metal catalyst; (2) a reaction using tin(II) chloride; or (3) a reaction using iron or zinc metal.

12. A method for producing a compound represented by formula (II) from a compound represented by formula (III), 【Transformation 5】 The manufacturing method includes reacting a compound represented by formula (III) under conditions for W group amination to obtain a compound represented by formula (II). (In the formula, W is a halogen or OTf; X １ is N or CR ａ Selected from, here, R ａ This includes hydrogen, (1-2C) alkyl, halogen, (1-2C) alkoxy, (1-2C) haloalkyl, (1-2C) haloalkoxy, cyano or NR ｂ R ｃ Selected from, here, R ｂ and R ｃ Each is independently selected from hydrogen or (1-2C) alkyl; X ２ These are N, CH, CF, CCl, or C-CH ３ Selected from; R １ is hydrogen or a group of the following formula: -L-Y-Z (In the formula: L is either absent or (1-3C) alkylene; Y is absent, or O, C(O), C(O)O or C(O)N(R) ｅ ) and here, R ｅ is selected from hydrogen or (1-4C) alkyl; and Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, (3-6C) cycloalkenyl, 5 or 6-membered heteroaryl, or 4-7-membered heterocyclyl; where Z is optionally oxo, (1-2C) alkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) aminoalkyl, cyano, NR ｇ R ｈ OR ｇ It is further substituted by one or more substituents independently selected from; where R ｇ and R ｈ (Each of these elements is independently selected from hydrogen or (1-4C) alkyl groups.) Selected from; R ３０ The substituent is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, where each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR ｕ R ｖ , further substituted with one or more substituents selected from (1-2C)aminoalkyl or halo, where R ｕ and R ｖ is independently selected from hydrogen or (1-2C) alkyl; R ３１ This includes hydrogen, (1-4C) alkyl, cyano, (1-4C) haloalkyl, or the following formula: Y ５ -L ５ -Z ５ (In the formula: Y ５ is absent, or C(O)O or C(O)N(R) ｗ ) is selected, and here, R ｗ is selected from hydrogen or (1-2C) alkyl; L ５ is absent or (1-2C)alkylene; and Z ５ Z is hydrogen, (1-6C) alkyl, aryl, (3-6C) cycloalkyl, 5 or 6-membered heteroaryl, or 4-6-membered heterocyclyl; where Z ５ The following can be optionally selected: (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH ２ (substituted with one or more substituents selected from cyano, nitro, or hydroxy) Selected from; or R ３０ and R ３１ These are bonded together with the carbon atoms to which they are bonded, in order to form a 4- to 6-membered carbon ring or heterocycle; and, Ring A is a six- or seven-membered heterocycle, and it has substituent R ３０ and R ３１ In addition, optionally, oxo, (1-2C) alkyl, cyclopropyl, spiro-cyclopropyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, NH ２ (Further substituted with one or more substituents selected from cyano or hydroxyl.)

13. The manufacturing method according to claim 12, wherein the amination conditions include amination by a metal catalyst.

14. The compound represented by formula (II) is the following: (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-ethyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,3,3,7-tetramethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-2',3'-dimethyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-[1,4]oxazepino[2,3-c]quinoline]-6(7H)-one; (2S,4S)-10-amino-2,4,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10-amino-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; 10'-amino-7'-methyl-3',4,4',5-tetrahydro-1'H,2H--spiro[furan-3,2'-[1,4]oxazepino[2,3-c]quinoline]-6'(7'H)-one; 10-amino-2-(difluoromethyl)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; (R)-10-amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one; and (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c][1,8]naphthyridine-6(7H)-one, A manufacturing method according to any one of claims 10 to 13, selected from the group consisting of the following:

15. The method for producing a product according to any one of claims 10 to 14, wherein the compound represented by formula (II) is (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepino[2,3-c]quinoline-6(7H)-one.

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