Compound serving as BCL6 inhibitor and preparation method thereof

Abstract

The present invention relates to compounds having formula (III-a) and formula (II) as BCL6 inhibitors, wherein Z, W, X1, X2, R1, R30, R31, and ring A are each as defined herein. The invention also relates to processes for preparing these compounds, pharmaceutical compositions comprising these compounds, and the use of these compounds in the treatment of proliferative disorders such as cancer as well as other diseases or conditions involving BCL6 activity. # imgabs0 #

Description

[0001] This application is a divisional application of an invention patent application with an international application date of April 12, 2019, a Chinese national application number of 201980039513.4, and an invention name of “BCL6 inhibitor”.

[0002] introduction

[0003] The present invention relates to certain compounds that act as inhibitors of BCL6 (B-cell lymphoma 6) activity. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the treatment of proliferative disorders such as cancer and other diseases or conditions involving BCL6 activity. Background Art

[0004] BCL6 is a zinc-finger transcriptional repressor that plays a key role in the formation and development of germinal centers, where B cells undergo somatic hypermutation and immunoglobulin gene recombination to generate diversity in antibodies against a variety of foreign antigens (Dent et al., Science [Science],1997, 276 , 589-592). BCL6 allows the proliferation of antibody-producing B cells by repressing genes involved in the DNA damage response, cell cycle arrest, and apoptosis. BCL6 mediates this repression by recruiting the corepressor proteins SMRT, NCoR, and BCoR to an extended groove motif formed along the dimer interface of the BCL6 BTB (BR-C, Ttk, and Bab) domains (Ahmad et al., 2001). Mol Cell [Molecular Cell], 2003, 12 ,1551-1564; Ghetu et al., Mol Cell [Molecular Cell], 2008, 29 , 384-391). Genetic upregulation of the BCL6 gene leads to proliferation of malignant B cells, as seen in many lymphomas (Hatzi & Melnick, Trends Mol Med [Dynamics in Molecular Medicine], 2014, 20 , 343-352). Therefore, there is a need to develop agents that inhibit the tumorigenic effects of BCL6 by selectively binding to the BTB domain and preventing corepressor recruitment, or by binding to the BTB domain and inducing protein degradation (Kerres et al. Cell Rep. ,2017, 20 ,2860-2875). Summary of the invention

[0005] According to a first aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0006] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in admixture with a pharmaceutically acceptable diluent or carrier.

[0007] According to another aspect of the present invention, there is provided a method for inhibiting BCL6 activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0008] According to another aspect of the present invention, there is provided a method for inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the 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.

[0009] According to another aspect of the present invention, there is provided a method for treating a disease or disorder involving BCL6 activity 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] According to another aspect of the present invention, there is provided a method of treating a proliferative disorder 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.

[0011] According to another aspect of the present invention, there is provided a method of treating cancer 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.

[0012] According to another aspect of the present invention there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in therapy.

[0013] According to another aspect of the present invention there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a proliferative disorder.

[0014] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition for use in the treatment of cancer. In a specific embodiment, the cancer is a human cancer.

[0015] According to another aspect of the present invention, there is provided a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof for use in inhibiting BCL6 activity.

[0016] According to another aspect of the present invention there is provided a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder involving BCL6 activity.

[0017] According to another aspect of the present invention there is provided the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

[0018] Suitably, the proliferative disorder is a cancer, suitably a human cancer (e.g., a haematological cancer such as lymphoma (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL), leukaemia (including acute lymphoblastic leukaemia (ALL) and chronic myeloid leukaemia (CML)) and multiple myeloma, and solid tumours (including glioma, breast cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinoma (SCC) (including SCC of the head and neck, esophagus, lung, and ovary)).

[0019] According to another aspect of the present invention, there is provided use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for treating cancer.

[0020] According to another aspect of the present invention, there is provided use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for inhibiting BCL6 activity.

[0021] According to another aspect of the present invention, there is provided use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for treating a disease or disorder involving BCL6 activity.

[0022] According to another aspect of the present invention, there is provided a process for preparing a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0023] According to another aspect of the present invention there is provided a compound obtainable by, or obtained by, or directly obtained by a process for preparing a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0024] According to another aspect of the present invention there is provided a novel intermediate as defined herein suitable for use in any of the synthetic methods set out herein.

[0025] Features relating to one aspect of the invention (including optional, suitable and preferred features) may also be features relating to any other aspect of the invention (including optional, suitable and preferred features). DETAILED DESCRIPTION

[0026] definition

[0027] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0028] It should be understood that references to "treating" or "treatment" include prevention as well as alleviation of established symptoms of a condition. "Treating" or "treatment" of a condition, disorder, or condition includes: (1) preventing or delaying the onset of clinical symptoms of the condition, disorder, or condition that develops in a person who may have or be susceptible to the condition, disorder, or condition but does not yet experience or display clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., arresting, reducing, or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or the development of at least one clinical or subclinical symptom thereof; or (3) alleviating or relieving the disease, i.e., causing regression of the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0029] "Therapeutically effective amount" means the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to effect such treatment of the disease."Therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0030] In this specification, the term "alkyl" includes both straight and branched chain alkyl groups. References to individual alkyl groups such as "propyl" are specific only to the straight chain version, and references to individual branched chain alkyl groups such as "isopropyl" are specific only to the branched version. For example, "(1-6C)alkyl" includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl, and tert-butyl.

[0031] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix refers to any group having from m to n carbon atoms.

[0032] An "alkylene" group is an alkyl group that is located between and serves to connect two other chemical groups. Thus, "(1-6C)alkylene" means a straight-chain saturated divalent hydrocarbon radical having from one to six carbon atoms or a branched-chain saturated divalent hydrocarbon radical having from three to six carbon atoms, for example, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), 2-methylpropylene (-CH 2 CH(CH 3 )CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -)wait.

[0033] The term "alkenyl" refers to straight and branched chain alkyl groups containing 2 or more carbon atoms, wherein at least one carbon-carbon double bond is present in the group. Examples of alkenyl groups include ethenyl, propenyl, and but-2,3-enyl, and include all possible geometric (E / Z) isomers.

[0034] The term "alkynyl" refers to straight and branched chain alkyl groups containing 2 or more carbon atoms, wherein at least one carbon-carbon triple bond is present in the group. Examples of alkynyl groups include ethynyl and propynyl.

[0035] "(3-10C)cycloalkyl" means a hydrocarbon ring containing 3 to 10 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or bicyclo[2.2.1]heptyl.

[0036] "(3-10C)cycloalkenyl" means a hydrocarbon ring containing 3 to 10 carbon atoms and at least one double bond, for example cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl (eg, 3-cyclohexen-1-yl), or cyclooctenyl.

[0037] The term "alkoxy" refers to O-linked straight and branched chain alkyl groups. Examples of alkoxy groups include methoxy, ethoxy, and tert-butoxy.

[0038] The term "haloalkyl" or "haloalkoxy" is used herein to refer to an alkyl or alkoxy group, respectively, in which one or more hydrogen atoms have been replaced by a halogen (e.g., fluorine) atom. Examples of haloalkyl groups include -CH 2 F, -CHF 2 , and -CF 3 Examples of haloalkoxy groups include -OCH2 F and -OCF 3 .

[0039] The term "aminoalkyl" refers to a group in which one or more hydrogen atoms have been replaced by an amino group (NH 2 ) substituted alkyl group. Examples of aminoalkyl groups include -CH 2 NH 2 and -C 2 H 4 NH 2 .

[0040] The term "halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine, suitably fluorine, chlorine, and bromine, more suitably fluorine and chlorine.

[0041] The term "carbocyclyl", "carbocyclic" or "carbocycle" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic carbon-containing ring systems. Monocyclic carbocycles contain about 3 to 12 (suitably from 3 to 7) ring atoms. Bicyclic carbocycles contain 6 to 17 member atoms in the ring, suitably 7 to 12 member atoms. One or more bicyclic carbocycles can be fused, spiro or bridged ring systems. Examples of carbocyclic groups include cyclopropyl, cyclobutyl, cyclohexenyl and spiro[3.3]heptanyl.

[0042] The term "heterocyclyl", "heterocyclic" or "heterocycle" means one or more non-aromatic, saturated or partially saturated monocyclic, fused, bridged or spirobicyclic heterocyclic ring systems. Monocyclic heterocycles contain about 3 to 12 (suitably 3 to 7) ring atoms, with 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain 7 to 17 member atoms in the ring, suitably 7 to 12 member atoms. One or more bicyclic heterocycles can be fused rings, spiro rings or bridged ring systems. Examples of heterocyclic groups include cyclic ethers, such as oxirane, oxetane, tetrahydrofuranyl, dioxane and substituted cyclic ethers. Nitrogen-containing heterocycles include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, etc. Typical sulfur-containing heterocycles include tetrahydrothiophene, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran and hexahydrothiophene. Other heterocycles include dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl, tetrahydro-dioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl, tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For sulfur-containing heterocycles, SO or SO 2The heterocyclic ring may contain 1 or 2 oxo (=O) or thio (=S) substituents. Suitable values ​​for heterocyclyl groups with 1 or 2 oxo (=O) or thio (=S) substituents are, for example, 2-oxopyrrolidinyl, 2-thiopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Specific heterocyclic radical group is a saturated monocyclic 3 to 7 membered heterocyclic radical 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, piperidyl, homopiperidyl, piperazinyl or homopiperazinyl. As will be appreciated by the technician, any heterocycle can be connected to another group via any suitable atom (such as via carbon or nitrogen atom). However, piperidino or morpholino are mentioned herein to refer to piperidin-1-yl or morpholine-4-yl rings connected via ring nitrogen.

[0043] "Bridged ring system" means a ring system in which two rings share more than two atoms, see, e.g., Advanced Organic Chemistry, edited by Jerry March, 4th edition, Wiley Interscience, pp. 131-133, 1992. Examples of bridged heterocyclyl ring systems include aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

[0044] "Spirobicyclic ring system" means that the two ring systems share a common spiro carbon atom, i.e., the heterocycle is connected to another carbocyclic ring or heterocyclic ring through a single common spiro carbon atom. Examples of spirocyclic 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.

[0045] The term "heteroaryl" or "heteroaromatic" means an aromatic monocyclic, bicyclic or polycyclic ring incorporating one or more (e.g., 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent and divalent substances. Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, and more typically five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic or a 9- or 10-membered bicyclic, such as a bicyclic structure formed by a fused five-membered and six-membered ring or two fused six-membered rings. Each ring can contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more typically up to 2, such as a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in a heteroaryl group (including any amino group substituent of the ring) will be less than five.

[0046] Examples of heteroaryl groups include furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazene, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl , cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]pyranyl, 5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. "Heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems in which at least one ring is aromatic and one or more other rings are non-aromatic, saturated or partially saturated rings, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Examples of some aromatic heteroaryl groups include, for example, tetrahydroisoquinolyl, tetrahydroquinolyl, 2-oxo-1,2,3,4-tetrahydroquinolyl, dihydrobenzothienyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, dihydroindolyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0047] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl groups.

[0048] Examples of six-membered heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0049] The bicyclic heteroaryl group may be, for example, a group selected from:

[0050] a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0051] a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0052] a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0053] a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0054] a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0055] a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0056] an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0057] an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0058] an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0059] a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0060] an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms;

[0061] a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0062] a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms;

[0063] a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and

[0064] A cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms.

[0065] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, dihydroindolyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, and pyrazolopyridinyl groups.

[0066] 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, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0067] The term "aryl" means a ring or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. In a specific embodiment, aryl is phenyl.

[0068] The term "optionally substituted" refers to substituted groups, structures or molecules as well as unsubstituted groups, structures or molecules. 1 One / any CH, CH 2 , CH 3 The term "wherein" suitably means that R 1 (Any) one of the hydrogen radicals of the group is replaced by the relevant specified group.

[0069] When optional substituents are selected from "one or more" groups, it is to be understood that this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups.

[0070] The phrase "compounds of the invention" refers to those compounds disclosed both generally and specifically herein.

[0071] Compounds of the present invention

[0072] In one aspect, the present invention relates to a compound having structural formula (I) as shown below or a pharmaceutically acceptable salt, hydrate or solvate thereof:

[0073]

[0074] in:

[0075] X 1 Select 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;

[0076] X 2 Selected from N, CH, CF, CCl, or C-CH 3 ;

[0077] R 1 is selected from hydrogen or a group having the formula:

[0078] -LYZ

[0079] in:

[0080] L is absent or is (1-3C)alkylene;

[0081] 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

[0082] Z is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; wherein Z is further optionally substituted by one or more substituent groups 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;

[0083] R 2 is selected from the group having the formula A shown below:

[0084]

[0085] in:

[0086] Indicates the attachment point;

[0087] X a is selected from N, CH, or CF;

[0088] X b Select from N or CR x1 , where R x1 is selected from hydrogen, fluorine, chlorine, bromine, (1-2C)alkyl, (1-2C)alkoxy, cyano, ethynyl, CH 2 F. CF 2 H, or CF 3 ;

[0089] R 6 is selected from hydrogen, fluorine, chlorine, bromine, (1-2C)alkyl, (1-2C)alkoxy, cyano, ethynyl, CH 2 F. CF 2 H, or CF 3 ;

[0090] R 7is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, nitro, (2-4C)alkenyl, (2-4C)alkynyl, or a group having the following formula:

[0091] -Y 3 -Z 3

[0092] in:

[0093] Y 3 Does not exist, or is O, S, SO, SO 2 、N(R j )(CR j R k ) q1 (where q 1 is 0, 1, or 2), C(O), C(O)O, OC(O), C(O)N(R j )、N(R j )C(O), N(R j )C(O)N(R k )、N(R j )C(O)O、OC(O)N(R j )、S(O) 2 N(R j ), or N(R j )SO 2 , where R j and R k are each independently selected from hydrogen or (1-4C)alkyl; and

[0094] Z 3 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkenyl, heteroaryl, or 4- to 12-membered heterocyclyl; wherein Z 3 is further optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, (3-6C)cycloalkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, CO 2 H.SO 2 NH 2 、C(O)NR l R m NR l R m , OR l , or SR l , where R l and R mare each independently selected from hydrogen, (1-4C)alkyl, or (3-6C)cycloalkyl; or Z 3 is further optionally substituted with a group having the formula:

[0095] -L Z -W Z

[0096] in:

[0097] L Z is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; and

[0098] W Z is halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, C(O)R xa 、COOR xa 、C(O)NR xa R xb , or NR xa R xb , where R xa and R xb are each independently selected from hydrogen or (1-4C)alkyl;

[0099] R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl, or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is further optionally substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl, or halo, wherein R u and R v independently selected from hydrogen or (1-2C)alkyl;

[0100] R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl, or a group having the formula:

[0101] Y 5 -L 5 -Z 5

[0102] in:

[0103] Y 5 Not present, or selected from C(O)O or C(O)N(R w ), where R w is selected from hydrogen or (1-2C)alkyl;

[0104] L 5 is absent or is (1-2C)alkylene; and

[0105] Z 5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocyclyl; wherein Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH 2 , cyano, nitro, or hydroxyl; or

[0106] R 30 and R 31 are linked so that they, together with the carbon atoms to which they are attached, form a 4-6 membered carbocyclic or heterocyclic ring; and

[0107] Ring A is a 6-membered or 7-membered heterocyclic ring, except for the substituent group R 30 and R 31 , the heterocycle is further optionally substituted by one or more substituent groups selected from oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH 2 , cyano, or hydroxyl.

[0108] In a particular group of compounds of the invention, not more than one X 1 and X 2 It's nitrogen.

[0109] Specific compounds of the present invention include, for example, compounds having Formula I or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise specified, X 1 , X 2 , R 1 , R 2 , R 7 , R 30 , R 31 Each of , Ring A and any associated substituent groups has any meaning as defined above or in any of paragraphs (1) to (64) below: -

[0110] (1)X 1 Select from N or CR a , where R a is selected from hydrogen, (1-2C)alkyl, fluorine, chlorine, (1-2C)alkoxy, CH 2 F. CHF 2 CF 3、OCF 3 , cyano, or NR b R c , where R b and R c independently selected from hydrogen or (1-2C)alkyl;

[0111] (2)X 1 Select from N or CR a , where R a Selected from hydrogen, methyl, fluorine, chlorine, hydroxyl, OCH 3 , CH 2 F. CHF 2 CF 3 、OCF 3 , ethynyl, cyano, or NH 2 ;

[0112] (3)X 1 Select from N or CR a , where R a Selected from hydrogen, methyl, fluorine, chlorine, hydroxyl, OCH 3 , CH 2 F. CHF 2 , ethynyl, or cyano;

[0113] (4)X 1 Select from N or CR a , where R a Selected from hydrogen, methyl, fluorine, chlorine, OCH 3 , ethynyl, or cyano;

[0114] (5)X 1 Select from N or CR a , where R a is selected from hydrogen, (1-2C)alkyl, or (1-2C)alkoxy;

[0115] (6)X 1 Select from N or CR a , where R a Selected from hydrogen, methyl, OCH 3 , fluorine, or chlorine;

[0116] (7)X 1 is selected from N or CH;

[0117] (8)X 1 is N;

[0118] (9)X 1 It is CH;

[0119] (10)X 2 Selected from CH, CF or C-CH 3 ;

[0120] (11)X 2 Selected from CH or CF;

[0121] (12)X 2 It is CH;

[0122] (13)R 1 is selected from hydrogen or a group having the formula:

[0123] -LYZ

[0124] in:

[0125] L is absent or is (1-3C)alkylene;

[0126] 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

[0127] Z is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; wherein Z is further optionally substituted by one or more substituent groups 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;

[0128] (14)R 1 is selected from hydrogen or a group having the formula:

[0129] -LZ

[0130] in:

[0131] L is absent or is (1-3C)alkylene; and

[0132] Z is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, 5- or 6-membered heteroaryl, or 4- to 7-membered heterocyclyl; wherein Z is further optionally substituted by one or more substituent groups 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 Rh are each independently selected from hydrogen or (1-2C)alkyl;

[0133] (15)R 1 is selected from hydrogen or a group having the formula:

[0134] -LZ

[0135] in:

[0136] L is absent or is (1-2C)alkylene; and

[0137] Z is (1-6C)alkyl, (3-6C)cycloalkyl or 4 to 7 membered heterocyclyl; wherein Z is further optionally substituted by one or more substituent groups 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;

[0138] (16)R 1 is selected from hydrogen or a group having the formula:

[0139] -LZ

[0140] in:

[0141] L is absent or is (1-2C)alkylene; and

[0142] Z is (1-6C) alkyl, (3-6C) cycloalkyl, 4 to 7 membered heterocyclyl; wherein Z is further optionally substituted by one or more substituent groups independently selected from oxo, methyl, fluoro, NR g R h , or OR g , where R g and R h are each independently selected from hydrogen or (1-2C)alkyl;

[0143] (17)R 1 is selected from hydrogen, (1-6C)alkyl, or a group having the formula:

[0144] -LZ

[0145] in:

[0146] L is (1-2C)alkylene; and

[0147] Z is (a 3-6C) cycloalkyl or a 4 to 7 membered heterocyclyl; wherein Z is further optionally substituted by one or more substituent groups 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 methyl;

[0148] (18)R 1 is selected from hydrogen or a group having the formula:

[0149] -LZ

[0150] in:

[0151] L is absent or is (1-2C)alkylene; and

[0152] Z is (3-6C) cycloalkyl or 4 to 6 membered heterocyclyl; wherein Z is further optionally substituted by one or more substituent groups independently selected from oxo, methyl, fluoro, NR g R h , or OR g , where R g and R h are each independently selected from hydrogen or (1-2C)alkyl;

[0153] (19)R 1 is selected from hydrogen, (1-6C)alkyl or (3-6C)cycloalkyl, wherein the (1-6C)alkyl or (3-6C)cycloalkyl group is further optionally substituted by one or more substituent groups independently selected from methyl, fluoro, NR g R h OR g , where R g and R h are each independently selected from hydrogen or (1-2C)alkyl;

[0154] (20)R 1 is (1-6C)alkyl further optionally substituted by one or more substituent groups independently selected from fluorine, NR g R h OR g , where R g and R h are each independently selected from hydrogen or (1-2C)alkyl;

[0155] (21)R 1is (1-3C)alkyl further optionally substituted by one or more substituent groups independently selected from NR g R h or OH, where R g and R h are each independently selected from hydrogen or (1-2C)alkyl;

[0156] (22)R 1 is (1-6C)alkyl (e.g. methyl);

[0157] (23)R 1 is a group having the formula:

[0158] -LZ

[0159] in:

[0160] L is (1-2C)alkylene; and

[0161] Z is (3-6C)cycloalkyl; wherein Z is further optionally substituted by one or more substituent groups independently selected from oxo, methyl, fluoro, NR g R h , or OR g , where R g and R h are each independently selected from hydrogen or (1-2C)alkyl;

[0162] (24)R 1 is a group having the formula:

[0163] -LZ

[0164] in:

[0165] L is CH 2 ;and

[0166] Z is (3-4C)cycloalkyl; wherein Z is further optionally substituted with one or more substituent groups independently selected from methyl, fluoro, and OH;

[0167] (25)R 2 is a group having the formula A shown below:

[0168]

[0169] in:

[0170] Indicates the attachment point;

[0171] X a is selected from N, CH or CF;

[0172] Xb Select from N or CR x1 , where R x1 is selected from hydrogen, fluorine, chlorine, bromine, (1-2C)alkyl, (1-2C)alkoxy, cyano, ethynyl, CH 2 F. CF 2 H, or CF 3 ;

[0173] R 6 is selected from hydrogen, fluorine, chlorine, bromine, (1-2C)alkyl, (1-2C)alkoxy, cyano, ethynyl, CH 2 F. CF 2 H, or CF 3 ;

[0174] R 7 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, or a group having the following formula:

[0175] -Y 3 -Z 3

[0176] in:

[0177] Y 3 Does not exist, or is O, S, N (R j )(CR j R k ) q1 (where q 1 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 are each independently selected from hydrogen or (1-4C)alkyl; and

[0178] Z 3 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, (3-6C)cycloalkenyl, 5-membered or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl; wherein Z 3 is further optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, cyclopropyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, C(O)NR l R m NR l R m , or OR l , where R l and Rm are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Z 3 is further optionally substituted with a group having the formula:

[0179] -L Z -W Z

[0180] in:

[0181] L Z is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; and

[0182] W Z is halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, C(O)R xa 、COOR xa 、C(O)NR xa R xb , or NR xa R xb , where R xa and R xb are each independently selected from hydrogen or (1-4C)alkyl;

[0183] (26)R 2 is a group having the formula A shown below:

[0184]

[0185] in:

[0186] Indicates the attachment point;

[0187] X a is selected from N, CH or CF;

[0188] X b Select from N or CR x1 , where R x1 is selected from hydrogen, fluorine, chlorine, bromine, (1-2C)alkyl, cyano, ethynyl, CH 2 F. CF 2 H, or CF 3 ;

[0189] R 6 is selected from hydrogen, fluorine, chlorine, bromine, (1-2C)alkyl, (1-2C)alkoxy, cyano, ethynyl, CH 2 F. CF 2 H, or CF 3 ;

[0190] R 7 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, or a group having the following formula:

[0191] -Y 3 -Z 3

[0192] in:

[0193] Y 3 Does not exist, or is 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

[0194] Z 3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5-membered or 6-membered heteroaryl, or 4- to 12-membered heterocyclyl; wherein Z 3 is further optionally substituted with one or more substituent groups independently selected from (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 OR l , where R l and R m are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0195] (27)R 2 is a group having the formula A shown below:

[0196]

[0197] in:

[0198] Indicates the attachment point;

[0199] X a is selected from N, CH or CF;

[0200] X b Select from N or CR x1 , where R x1 is selected from hydrogen, fluorine, chlorine, bromine or methyl;

[0201] R 6is selected from fluorine, chlorine, bromine, methyl, cyano or ethynyl;

[0202] R 7 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, or a group having the following formula:

[0203] -Y 3 -Z 3

[0204] in:

[0205] Y 3 Not present, or O, C(O), C(O)O, or C(O)N(R j ), where R j is selected from hydrogen or (1-4C)alkyl; and

[0206] Z 3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5-membered or 6-membered heteroaryl, or 4- to 11-membered heterocyclyl; wherein Z 3 is further optionally substituted with one or more substituent groups independently 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 , where R l and R m are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl;

[0207] (28)R 2 is a group having the formula A shown below:

[0208]

[0209] in:

[0210] Indicates the attachment point;

[0211] X a is selected from N or CH;

[0212] X b Select from N or CR x1 , where R x1 is selected from hydrogen, fluorine, chlorine, bromine or methyl;

[0213] R 6is selected from fluorine, chlorine, bromine, methyl, cyano or ethynyl;

[0214] R 7 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, cyano, (2-4C)alkenyl, (2-4C)alkynyl, or a group having the following formula:

[0215] -Y 3 -Z 3

[0216] in:

[0217] Y 3 Not present, or O, C(O), C(O)O, or C(O)N(R j ), where R j is selected from hydrogen or (1-4C)alkyl; and

[0218] Z 3 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, 5-membered or 6-membered heteroaryl, or 4- to 8-membered heterocyclyl; wherein Z 3 is further optionally substituted with one or more substituent groups independently 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 , where R l and R m are each independently selected from hydrogen or (1-4C)alkyl;

[0219] (29)R 2 is a group having the formula A shown below:

[0220]

[0221] in:

[0222] Indicates the attachment point;

[0223] X a is selected from N or CH;

[0224] X b is selected from CH, CCl, CF, CBr, or CCH3;

[0225] R 6 is selected from chlorine, fluorine or cyano;

[0226] R7 is selected from (1-6C)alkyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 8-membered heterocyclyl; wherein each (1-6C)alkyl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 8-membered heterocyclyl is further optionally substituted by one or more substituent groups independently 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 , where R l and R m are each independently selected from hydrogen or (1-4C)alkyl;

[0227] (30)R 2 is a group having the formula A shown below:

[0228]

[0229] in:

[0230] Indicates the attachment point;

[0231] X a is selected from N or CH;

[0232] X b is selected from CH, CCl, CF, CBr, or CCH3;

[0233] R 6 is selected from chlorine, fluorine or cyano;

[0234] R 7 wherein the 5- or 6-membered heteroaryl or 4- to 8-membered heterocyclyl is further optionally substituted by one or more substituent groups independently 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 , where R l and R m are each independently selected from hydrogen or (1-4C)alkyl;

[0235] (31)R 2 is a group having the formula A shown below:

[0236]

[0237] in:

[0238] Indicates the attachment point;

[0239] X a is selected from N or CH;

[0240] X b Selected from CH, CCl or CCH3;

[0241] R 6 is selected from chlorine, fluorine or cyano;

[0242] R 7 is selected from 5- or 6-membered heteroaryl or 4- to 8-membered heterocyclyl; wherein the 5- or 6-membered heteroaryl or 4- to 8-membered heterocyclyl is further optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano or OH;

[0243] (32)R 2 is a group having the formula A shown below:

[0244]

[0245]

[0246] in:

[0247] Indicates the attachment point;

[0248] X a is selected from N or CH;

[0249] X b Selected from CH, CCl or CCH3;

[0250] R 6 is selected from chlorine, fluorine or cyano;

[0251] R 7 is a 4- to 8-membered heterocyclyl (e.g., piperidinyl); wherein the 4- to 8-membered heterocyclyl is further optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, or OH;

[0252] (33)R 2 is a group having the formula A shown below:

[0253]

[0254] in:

[0255] Indicates the attachment point;

[0256] X a is selected from N or CH;

[0257] X b Selected from CH, CCl or CCH3;

[0258] R 6 is selected from chlorine, fluorine or cyano;

[0259] R 7 is piperidinyl or piperazinyl, each optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano or OH;

[0260] (34)R 2 is a group having the formula A shown below:

[0261]

[0262] in:

[0263] Indicates the attachment point;

[0264] X a It is CH;

[0265] X b Selected from CH or CCl;

[0266] R 6 is selected from chlorine, fluorine or cyano;

[0267] R 7 is selected from hydrogen or a group having the formula:

[0268] -Y 3 -Z 3

[0269] in:

[0270] Y 3 is O, C(O), C(O)O, or C(O)N(R j ), where R j is hydrogen or (1-4C)alkyl; and

[0271] Z 3is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or 4- to 11-membered heterocyclyl; wherein Z 3 further optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano or OH;

[0272] (35)R 2 is a group having the formula A shown below:

[0273]

[0274] in:

[0275] Indicates the attachment point;

[0276] X a It is CH;

[0277] X b Selected from CH or CCl;

[0278] R 6 is selected from chlorine, fluorine or cyano;

[0279] R 7 is selected from hydrogen or a group having the formula:

[0280] -Y 3 -Z 3

[0281] in:

[0282] Y 3 is C(O) or C(O)N(R j ), where R j is hydrogen or (1-4C)alkyl; and

[0283] Z 3 is hydrogen, (1-6C)alkyl, or 4 to 11 membered heterocyclyl; wherein Z 3 further optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano or OH;

[0284] (36)R 2 is a group having the formula A shown below:

[0285]

[0286] in:

[0287] Indicates the attachment point;

[0288] X a It is CH;

[0289] X b It is CCl;

[0290] R 6 It is cyano;

[0291] R 7 is selected from hydrogen or a group having the formula:

[0292] -Y 3 -Z 3

[0293] in:

[0294] Y 3 is C(O); and

[0295] Z 3 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; wherein Z 3 further optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, fluoro, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano or OH;

[0296] (37)R 2 is a group having the formula A shown below:

[0297]

[0298] in:

[0299] Indicates the attachment point;

[0300] X a is N;

[0301] X b Selected from CH or CCl;

[0302] R 6 is selected from chlorine, fluorine or cyano;

[0303] R 7 is selected from (3-6C)cycloalkyl, 5-membered or 6-membered heteroaryl, or 4- to 10-membered heterocyclyl; wherein R 7 is further optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)alkoxyalkyl, cyano, C(O)NRl R m NR l R m OR l , where R l and R m are each independently selected from hydrogen or (1-4C)alkyl; or R 7 is further optionally substituted with a group having the formula:

[0304] -L Z -W Z

[0305] in:

[0306] L Z is (1-3C)alkylene; and

[0307] W Z is halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, C(O)R xa 、COOR xa 、C(O)NR xa R xb , or NR xa R xb , where R xa and R xb are each independently selected from hydrogen or (1-4C)alkyl;

[0308] (38)R 2 is a group having the formula A shown below:

[0309]

[0310]

[0311] in:

[0312] Indicates the attachment point;

[0313] X a is N;

[0314] X b Selected from CH or CCl;

[0315] R 6 is chlorine or fluorine;

[0316] R 7 is selected from a 5-membered or 6-membered heteroaryl or a 4- to 10-membered heterocyclic group; each R 7is further optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, OH or C(O)NR l R m , where R l and R m are each independently selected from hydrogen or (1-4C)alkyl; or

[0317] R 7 is further optionally substituted with a group having the formula:

[0318] -L Z -W Z

[0319] in:

[0320] L Z is (1-2C)alkylene; and

[0321] W Z is fluorine, (1-4C)haloalkyl, cyano, hydroxy or (1-2C)alkoxy;

[0322] (39)R 2 is a group having the formula A shown below:

[0323]

[0324] in:

[0325] Indicates the attachment point;

[0326] X a is N;

[0327] X b It is CH;

[0328] R 6 is chlorine or fluorine;

[0329] R 7 is a 4- to 10-membered heterocyclyl group, further optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, OH or C(O)NR l R m , where R l and R m are each independently selected from hydrogen or methyl; or

[0330] R 7 is further optionally substituted with a group having the formula:

[0331] -L Z-W Z

[0332] in:

[0333] L Z Yes CH 2 ;and

[0334] W Z is cyano, hydroxy or methoxy;

[0335] (40)R 2 is a group having the formula A shown below:

[0336]

[0337] in:

[0338] Indicates the attachment point;

[0339] X a is N;

[0340] X b It is CH;

[0341] R 6 is chlorine or fluorine;

[0342] R 7 selected from piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, 7,8-dihydropyrido[4,3-d]pyrimidin-(5H)-yl, 3-oxa-8-azabicyclo[3.2.1]-octyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 2-oxa-6-azaadamantyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl , 3,6-diazabicyclo[3.1.1]heptyl, 3,8-diazabicyclo[3.2.1]octyl, 2,6-diazaspiro[3.3]heptyl, and 3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octyl, each optionally substituted with one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, OH, or C(O)NR l R m , where R l and R m are each independently selected from hydrogen or methyl; or

[0343] R 7 is further optionally substituted with a group having the formula:

[0344] -L Z -W Z

[0345] in:

[0346] L Z Yes CH 2 ;and

[0347] W Z is cyano, hydroxy or methoxy;

[0348] (41)R 2 is a group having the formula A shown below:

[0349]

[0350] in:

[0351] Indicates the attachment point;

[0352] X a is N;

[0353] X b It is CH;

[0354] R 6 is chlorine or fluorine;

[0355] R 7 selected from piperidinyl, piperazinyl, 3-oxa-8-azabicyclo[3.2.1]-octyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, 2-oxa-6-azaadamantyl, 8-azabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, and 3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octyl, each optionally substituted with one or more substituent groups independently selected from methyl, fluoro, oxo, OH and CH 2 OH;

[0356] (42)R 7 It is hydrogen;

[0357] (43)R 7 is a 4- to 10-membered nitrogen-containing bicyclic heterocyclyl group attached 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, wherein the heterocyclyl ring is 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, C(O)NR l R m NR l R m OR l , where R l and Rm are each independently selected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl; or Z 3 is further optionally substituted with a group having the formula:

[0358] -L Z -W Z

[0359] in:

[0360] L Z is (1-5C)alkylene optionally substituted by one or more substituents selected from (1-2C)alkyl or oxo; and

[0361] W Z is halogen, (1-4C)haloalkyl, (1-4C)haloalkoxy, cyano, hydroxy, (1-4C)alkoxy, C(O)R xa 、COOR xa 、C(O)NR xa R xb , or NR xa R xb , where R xa and R xb are each independently selected from hydrogen or (1-4C)alkyl;

[0362] (44)R 7 is a 7- to 10-membered nitrogen-containing bicyclic heterocyclyl group attached 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, wherein the heterocyclyl ring is optionally substituted with one or more substituents independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, hydroxy, C(O)NR l R m NR l R m OR l , where R l and R m are each independently selected from hydrogen and (1-4C)alkyl;

[0363] (45)R 7 One selected from the following heterocyclyl groups:

[0364]

[0365] wherein the heterocyclyl ring is optionally substituted by one or more substituent groups independently selected from (1-4C)alkyl, halo, oxo, (1-4C)haloalkyl, hydroxy, C(O)NR l R m NRl R m OR l , where R l and R m are each independently selected from hydrogen and (1-4C)alkyl; and wherein the heterocyclyl ring is optionally further replaced by CH 2 CN, CH 2 OH or CH 2 OMe replaced;

[0366] (46)R 7 One selected from the following heterocyclyl rings:

[0367]

[0368] wherein the heterocyclic group is optionally substituted by one or more substituents independently selected from methyl, fluoro, oxo, OH and CH 2 OH.

[0369] (47)R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is further optionally substituted by one or more substituents selected from (1-4C)alkyl, cyclopropyl, hydroxy, (1-2C)alkoxy, NR u R v or halogen, where R u and R v independently selected from hydrogen or (1-2C)alkyl;

[0370] (48)R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl, or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is further optionally substituted by one or more substituents selected from (1-4C)alkyl, cyclopropyl, hydroxy, (1-2C)alkoxy, or halo;

[0371] (49)R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is further optionally substituted by one or more substituents selected from (1-4C)alkyl, hydroxy, (1-2C)alkoxy or halo;

[0372] (50)R 30is selected from (1-4C)alkyl, (3-6C)cycloalkyl or (1-4C)fluoroalkyl, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is further optionally substituted by one or more substituents selected from hydroxy, (1-2C)alkoxy or fluoro;

[0373] (51)R 30 is selected from (1-4C)alkyl or (3-4C)cycloalkyl, wherein each (1-4C)alkyl and / or (3-4C)cycloalkyl substituent is optionally further substituted with one or more fluoro groups;

[0374] (52)R 30 is (1-4C)alkyl (e.g. methyl or ethyl) or cyclopropyl;

[0375] (53)R 30 is cyclopropyl;

[0376] (54)R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl, or a group having the formula:

[0377] Y 5 -L 5 -Z 5

[0378] in:

[0379] Y 5 Not present, or selected from C(O)O or C(O)N(R w ), where R w is selected from hydrogen or (1-2C)alkyl;

[0380] L 5 is absent or is (1-2C)alkylene; and

[0381] Z 5 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or 5- or 6-membered heteroaryl; wherein Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH 2 , cyano, nitro, or hydroxyl;

[0382] (55)R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl, or a group having the formula:

[0383] Y 5 -L 5 -Z 5

[0384] in:

[0385] Y 5 does not exist, or is C(O)N(R w ), where R w is selected from hydrogen or methyl;

[0386] L 5 is absent or is (1-2C)alkylene; and

[0387] Z 5 is hydrogen, (1-6C)alkyl, (3-6C)cycloalkyl, or 5- or 6-membered heteroaryl; wherein Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH 2 , cyano, nitro, or hydroxyl;

[0388] (56)R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl, or a group having the formula:

[0389] Y 5 -L 5 -Z 5

[0390] in:

[0391] Y 5 does not exist, or is C(O)N(R w ), where R w is selected from hydrogen or methyl;

[0392] L 5 is absent or is (1-2C)alkylene; and

[0393] Z 5 is hydrogen, (1-6C)alkyl, cyclopropyl or 5- or 6-membered heteroaryl; wherein Z 5 is optionally substituted with one or more substituents selected from (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH 2 , cyano, nitro, or hydroxyl;

[0394] (57)R 31 is selected from hydrogen (1-4C) alkyl, (1-4C) haloalkyl, or a group having the formula:

[0395] Y 5 -L 5 -Z 5

[0396] in:

[0397] Y 5 does not exist, or is C(O)N(R w ), where R w is selected from hydrogen or methyl;

[0398] L 5 is absent or is (1-2C)alkylene; and

[0399] Z 5 is (1-6C)alkyl or cyclopropyl; wherein Z 5 optionally substituted with one or more substituents selected from halo, (1-2C)haloalkyl, (1-2C)alkoxy or cyano;

[0400] (58)R 31 Selected from hydrogen, methyl, CF 3 , CH 2 OCH 3 or C(O)NHCH 3 ;

[0401] (59)R 31 It is hydrogen;

[0402] (60)R 30 and R 31 connected so that they, together with the carbon atoms to which they are attached, form a 4-6 membered carbocyclic ring;

[0403] (61)R 30 and R 31 connected so that they, together with the carbon atoms to which they are attached, form a 4-6 membered heterocyclic ring;

[0404] (62) Ring A is a 7-membered heterocyclic ring, except for the substituent group R 30 and R 31 , the heterocycle is further optionally substituted by one or more substituent groups selected from oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, amino, cyano, or hydroxy;

[0405] (63) Ring A is a 7-membered heterocyclic ring, except for the substituent group R 30 and R 31 , the heterocycle is further optionally substituted by one or more substituent groups selected from oxo, (1-2C)alkyl, cyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, amino, cyano, nitro, or hydroxy;

[0406] (64) Ring A is a 7-membered heterocyclic ring, except for the substituent group R 30 and R 31 , the heterocycle is further optionally substituted by one or more substituent groups selected from oxo, (1-2C)alkyl, cyclopropyl, fluoro, (1-2C)fluoroalkyl, (1-2C)alkoxy or cyano.

[0407] Suitably, the heteroaryl group is a 5- or 6-membered heteroaryl ring comprising one, two or three heteroatoms selected from N, O or S.

[0408] Suitably, the aryl group is phenyl.

[0409] Suitably, X 1 As described in any of paragraphs (1) to (9) above. Most preferably, X 1 As described in paragraph (9) above.

[0410] Suitably, X 2 As described in any of paragraphs (10) to (12) above. Most preferably, X 2 As described in paragraph (12) above.

[0411] Suitably, R 1 As described in any of paragraphs (13) to (24) above. Most preferably, R 1 As described in any of paragraphs (20) to (24) above.

[0412] Suitably, R 2 As described in any of paragraphs (25) to (41) above. More preferably, R 2 As described in any of paragraphs (29) to (41) above. Most preferably, R 2 As described in any of paragraphs (35) to (36) or (40) to (41) above.

[0413] Suitably, R 7 As described in any of paragraphs (42) to (46) above. Most preferably, R 30 As described in paragraph (46) above.

[0414] Suitably, R 30 As described in any of paragraphs (47) to (53) or (60) to (61) above. Most preferably, R 30 As described in paragraph (53) above.

[0415] Suitably, R 31 As described in any of paragraphs (54) to (61) above. Most preferably, R31 As described in paragraph (59) above.

[0416] Suitably, Ring A is as described in any one of paragraphs (62) to (64) above. Most suitably, Ring A is as described in paragraph (64) above.

[0417] In a particular group of compounds of the invention, X 2 is CH, i.e., these compounds have the structural formula Ia (sub-definition of formula (I)) shown below or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0418]

[0419] Where X 1 , R 1 , R 2 , R 30 , R 31 and Ring A are as defined above.

[0420] In embodiments of compounds having Formula Ia:

[0421] X 1 is defined in any of paragraphs (1) to (9) above;

[0422] R 1 is defined in any of paragraphs (13) to (24) above;

[0423] R 2 is defined in any of paragraphs (25) to (41) above;

[0424] R 30 is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0425] R 31 is as defined in any of paragraphs (54) to (61) above; and

[0426] Ring A is as defined in any of paragraphs (62) to (64) above.

[0427] In another embodiment of the compound having Formula Ia:

[0428] X 1 is as defined in paragraph (9) above;

[0429] R 1 is as defined in any of paragraphs (20) to (24) above;

[0430] R 2is as defined in any of paragraphs (35) to (36) or (40) to (41) above;

[0431] R 30 is as defined in paragraph (53) above;

[0432] R 31 is as defined in paragraph (59) above; and

[0433] Ring A is as defined in paragraph (64) above.

[0434] In a particular group of compounds of the invention, X 1 and X 2 is CH, i.e., these compounds have the structural formula Ib (sub-definition of formula (I)) shown below or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0435]

[0436] Where R 1 , R 2 , R 30 , R 31 Each of , and Ring A is as defined above.

[0437] In embodiments of compounds having Formula Ib:

[0438] R 1 is defined in any of paragraphs (13) to (24) above;

[0439] R 2 is defined in any of paragraphs (25) to (41) above;

[0440] R 30 is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0441] R 31 is as defined in any of paragraphs (54) to (61) above; and

[0442] Ring A is as defined in any of paragraphs (62) to (64) above.

[0443] In another embodiment of the compound having Formula Ib:

[0444] R 1 is as defined in any of paragraphs (20) to (24) above;

[0445] R 2is as defined in any of paragraphs (35) to (36) or (40) to (41) above;

[0446] R 30 is as defined in paragraph (53) above;

[0447] R 31 is as defined in paragraph (59) above; and

[0448] Ring A is as defined in paragraph (64) above.

[0449] In a particular group of compounds of the invention, X 1 , X 2 , and X a is CH and R 2 As shown below, these compounds have the structural formula Ic shown below 1 (Sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0450]

[0451] Where R 1 , R 6 , R 7 , X b , R 30 , R 31 Each of , and Ring A is as defined above.

[0452] In the case of having formula Ic 1 In the examples of compounds:

[0453] R 1 is defined in any of paragraphs (13) to (24) above;

[0454] R 6 is defined in any of paragraphs (25) to (36) above;

[0455] R 7 is defined in any of paragraphs (25) to (36) above;

[0456] X b is defined in any of paragraphs (25) to (36) above;

[0457] R 30 is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0458] R 31 is as defined in any of paragraphs (54) to (61) above; and

[0459] Ring A is as defined in any of paragraphs (62) to (64) above.

[0460] In the case of having formula Ic 1 In another embodiment of the compound:

[0461] R 1 is as defined in any of paragraphs (20) to (24) above;

[0462] R 6 is as defined in paragraph (36) above;

[0463] R 7 is as defined in paragraph (36) above;

[0464] X b is as defined in paragraph (36) above;

[0465] R 30 is as defined in paragraph (53) above;

[0466] R 31 is as defined in paragraph (59) above; and

[0467] Ring A is as defined in paragraph (64) above.

[0468] In a particular group of compounds of the invention, X 1 and X 2 It is CH, X a is N and R 2 As shown below, these compounds have the structural formula Ic shown below 2 (Sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0469]

[0470] Where R 1 , R 6 , R 7 , X b , R 30 , R 31 Each of , and Ring A is as defined above.

[0471] In the case of having formula Ic 2 In the examples of compounds:

[0472] R 1 is defined in any of paragraphs (13) to (24) above;

[0473] R 6is as defined in any of paragraphs (25) to (33) and (37) to (41) above;

[0474] R 7 is as defined in any of paragraphs (25) to (33) and (37) to (46) above;

[0475] X b is as defined in any of paragraphs (25) to (33) and (37) to (41) above;

[0476] R 30 is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0477] R 31 is as defined in any of paragraphs (54) to (61) above; and

[0478] Ring A is as defined in any of paragraphs (61) to (64) above.

[0479] In the case of having formula Ic 2 In another embodiment of the compound:

[0480] R 1 is as defined in paragraphs (20) to (24) above;

[0481] R 6 is as defined in paragraph (41) above;

[0482] R 7 is as defined in paragraph (46) above;

[0483] X b is as defined in paragraph (41) above;

[0484] R 30 is as defined in paragraph (53) above;

[0485] R 31 is as defined in paragraph (59) above; and

[0486] Ring A is as defined in paragraph (64) above.

[0487] In a specific group of compounds of the present invention, these compounds have the structural formula Id, Ie, If, or Ig (sub-definition of formula (I)) as shown below, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0488]

[0489] Where X 1, X 2 , R 1 , R 2 , R 30 , and R 31 Each of X is as defined above, 3 Yes CH 2 , O, S, SO 2 or NH and R 40 , R 41 , R 50 and R 51 independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)R z1 , where R z1 and R z2 Each of is independently selected from hydrogen or (1-2C)alkyl; or

[0490] R 40 and R 41 , and / or R 50 and R 51 are linked so that they, together with the carbon atoms to which they are attached, form a 3-6 membered carbocyclic or heterocyclic ring.

[0491] In embodiments of compounds of Formula Id, Formula Ie, Formula If, and / or Formula Ig:

[0492] X 1 is defined in any of paragraphs (1) to (9) above;

[0493] X 2 is as defined in any of paragraphs (10) to (12) above;

[0494] X 3 is O or S;

[0495] R 1 is defined in any of paragraphs (13) to (24) above;

[0496] R 2 is as defined in any of paragraphs (25) to (41) above;

[0497] R 30is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0498] R 31 is as defined in any of paragraphs (54) to (61) above; and

[0499] R 40 , R 41 , R 50 and R 51 independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)R z1 , where R z1 and R z2 are each independently selected from hydrogen or (1-2C)alkyl; or

[0500] R 40 and R 41 , and / or R 50 and R 51 are linked so that they form, together with the carbon atoms to which they are attached, a 3-6 membered carbocyclic ring.

[0501] In another embodiment of compounds having Formula Id, Formula Ie, Formula If, and / or Formula Ig:

[0502] X 1 is as defined in paragraph (9) above;

[0503] X 2 is as defined in paragraph (12) above;

[0504] X 3 is O or S;

[0505] R 1 is as defined in paragraph (22) above;

[0506] R 2 is as defined in paragraph (41) above;

[0507] R 30 is as defined in paragraph (53) above;

[0508] R 31 is as defined in paragraph (59) above;

[0509] R 40 , R 41 and R 50 are independently selected from hydrogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (3-6C)cycloalkyl, halo or cyano; and

[0510] R 51 is hydrogen; or

[0511] R 40 and R 41 , and / or R 50 and R 51 are linked so that they, together with the carbon atoms to which they are attached, form a cyclopropyl ring.

[0512] In a specific group of compounds of the present invention, these compounds have the structural formula Ih, Ij, Ik or Im as shown below (sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0513]

[0514] Where R 1 , R 2 , R 30 and R 31 Each of X is as defined above, 3 Selected from CH 2 , O, S, SO 2 or NH, and R 40 , R 41 , R 50 and R 51 independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)R z1 , where R z1 and R z2 Each of is independently selected from hydrogen or (1-2C)alkyl; or

[0515] R 40 and R 41 , and / or R 50 and R 51 are linked so that they, together with the carbon atoms to which they are attached, form a 3-6 membered carbocyclic or heterocyclic ring.

[0516] In embodiments of compounds having Formula Ih, Ij, Ik and / or Im:

[0517] R 1 is defined in any of paragraphs (13) to (24) above;

[0518] R 2 is as defined in any of paragraphs (25) to (41) above;

[0519] R 30 is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0520] R 31 is defined in any of paragraphs (54) to (61) above;

[0521] X 3 is O or S; and

[0522] R 40 , R 41 , R 50 and R 51 independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)R z1 , where R z1 and R z2 are each independently selected from hydrogen or (1-2C)alkyl; or

[0523] R 40 and R 41 , and / or R 50 and R 51 are linked so that they form, together with the carbon atoms to which they are attached, a 3-6 membered carbocyclic ring.

[0524] In another embodiment of compounds having Formula Ih, Ij, Ik and / or Im:

[0525] R 1 is as defined in paragraph (22) above;

[0526] R 2 is as defined in paragraph (41) above;

[0527] R 30 is as defined in paragraph (53) above;

[0528] R 31 is as defined in paragraph (59) above;

[0529] X 3 is O or S;

[0530] R 40 , R 41 and R 50 are independently selected from hydrogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (3-6C)cycloalkyl, halo or cyano; and

[0531] R 51 is hydrogen; or

[0532] R 40 and R 41 , and / or R 50 and R 51 are linked so that they, together with the carbon atoms to which they are attached, form a cyclopropyl ring.

[0533] In a specific group of compounds of the present invention, these compounds have the structural formula In, Io, Ip or Iq (sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof as shown below:

[0534]

[0535] Where R 1 , R 6 , R 7 , X b , R 30 and R 31 Each of X is as defined above, 3 Selected from CH 2 , O, S, SO 2 or NH and R 40 , R 41 , R 50 and R 51 independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)Rz1 , where R z1 and R z2 Each of is independently selected from hydrogen or (1-2C)alkyl; or

[0536] R 40 and R 41 , and / or R 50 and R 51 are linked so that they, together with the carbon atoms to which they are attached, form a 3-6 membered carbocyclic or heterocyclic ring.

[0537] In embodiments of compounds having formula In, Io, Ip and / or Iq:

[0538] R 1 is defined in any of paragraphs (13) to (24) above;

[0539] R 6 is defined in any of paragraphs (25) to (36) above;

[0540] R 7 is defined in any of paragraphs (25) to (36) or (42) to (46) above;

[0541] X b is defined in any of paragraphs (25) to (36) above;

[0542] R 30 is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0543] R 31 is defined in any of paragraphs (54) to (61) above;

[0544] X 3 is selected from O or S; and

[0545] R 40 , R 41 , R 50 and R 51 independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)R z1 , where R z1 and Rz2 are each independently selected from hydrogen or (1-2C)alkyl; or

[0546] R 40 and R 41 , and / or R 50 and R 51 are linked so that they form, together with the carbon atoms to which they are attached, a 3-6 membered carbocyclic ring.

[0547] In another embodiment of the compound having the formula In, Io, Ip and / or Iq:

[0548] R 1 is as defined in paragraph (22) above;

[0549] R 6 is as defined in paragraph (36) above;

[0550] R 7 is as defined in paragraph (36) above;

[0551] X b is as defined in paragraph (36) above;

[0552] R 30 is as defined in paragraph (53) above;

[0553] R 31 is as defined in paragraph (59) above;

[0554] X 3 is O or S;

[0555] R 40 , R 41 and R 50 are independently selected from hydrogen, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (3-6C)cycloalkyl, halo or cyano; and

[0556] R 51 is hydrogen; or

[0557] R 40 and R 41 , and / or R 50 and R 51 are linked so that they, together with the carbon atoms to which they are attached, form a cyclopropyl ring.

[0558] In a specific group of compounds of the present invention, these compounds have the structural formula Is or It (sub-definition of formula (I)) as shown below or a pharmaceutically acceptable salt, hydrate and / or solvate thereof:

[0559]

[0560] Where R 1 , R 6 , R 7 , R 30 and R 31 Each of X is as defined above, 3 Selected from CH 2 , O, S, SO 2 or NH and R 40 , R 41 and R 50 Each of the following is independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)R z1 , where R z1 and R z2 Each of is independently selected from hydrogen or (1-2C)alkyl; or

[0561] R 40 and R 41 are linked so that they, together with the carbon atoms to which they are attached, form a 3-6 membered carbocyclic or heterocyclic ring.

[0562] In embodiments of compounds having formula Is or It:

[0563] R 1 is defined in any of paragraphs (13) to (24) above;

[0564] R 6 is selected from chlorine, fluorine or cyano;

[0565] R 7 is as defined in any of paragraphs (25) to (33) and (37) to (46) above;

[0566] R 30 is as defined in any of paragraphs (47) to (53) or (60) to (61) above;

[0567] R 31 is defined in any of paragraphs (54) to (61) above;

[0568] X 3 is selected from O or S; and

[0569] R 40 , R 41 and R 50 independently selected from hydrogen, (1-2C) alkyl, (3-6C) cycloalkyl, halo, (1-2C) haloalkyl, (1-2C) haloalkoxy, (1-2C) alkoxy, (1-4C) alkoxyalkyl, (1-2C) aminoalkyl, NH 2 , cyano, nitro, OH, C(O)OR z1 、C(O)N(R z2 )R z1 NR z2 C(O)R z1 , where R z1 and R z2 are each independently selected from hydrogen or (1-2C)alkyl; or

[0570] R 40 and R 41 are linked so that they form, together with the carbon atoms to which they are attached, a 3-6 membered carbocyclic ring.

[0571] In another embodiment of the compound having Formula Is or It:

[0572] R 1 is as defined in paragraph (24) above;

[0573] R 6 is selected from chlorine, fluorine or cyano;

[0574] R 7 is as defined in paragraph (46) above;

[0575] R 30 is as defined in paragraph (53) above;

[0576] R 31 is as defined in paragraph (59) above;

[0577] X 3 is selected from O or S; and

[0578] R 40 , R 41 and R 50 is independently selected from hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl, halo, or hydroxy; or

[0579] R 40 and R 41 are linked so that, together with the carbon atoms to which they are attached, they form a cyclopropyl ring.

[0580] In a specific group of compounds of the present invention, these compounds have any one of the structural formulas Id to It shown above, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R 40 and R 41 are independently selected from hydrogen and fluorine.

[0581] In another embodiment, the compounds have any one of the structural formulas Id to It shown above, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R 40 and R 41 All are fluorine.

[0582] In another embodiment, the compounds have any one of the structural formulas Id to It shown above, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R 40 and R 41 are independently selected from hydrogen and fluorine and R 30 It is cyclopropyl.

[0583] In another embodiment, the compounds have any one of the structural formulas Id to It shown above, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R 40 and R 41 are independently selected from hydrogen and fluorine and R 30 is cyclopropyl and R 31 It's hydrogen.

[0584] In another embodiment, the compounds have any one of the structural formulas Id to It shown above, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R 40 and R 41 are fluorine and R 30 It is cyclopropyl.

[0585] In another embodiment, the compounds have any one of the structural formulas Id to It shown above, or a pharmaceutically acceptable salt, hydrate and / or solvate thereof, wherein R 40 and R 41 are fluorine and R 30 is cyclopropyl and R 31 It's hydrogen.

[0586] In a specific group of compounds of the present invention, these compounds have the structural formula Iu or Iv (subdefinition of formula (I)) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof as shown below:

[0587]

[0588] Where X 1 , R1 , R 2 and R 30 and R 50 Each of is as defined above.

[0589] In embodiments of compounds having Formula Iu or Formula Iv:

[0590] X 1 is defined in any of paragraphs (1) to (9) above;

[0591] R 1 is defined in any of paragraphs (13) to (24) above;

[0592] R 2 is as defined in any of paragraphs (25) to (41) above;

[0593] R 30 is as defined in any of paragraphs (47) to (53) above; and

[0594] R 50 is hydrogen, (1-2C)alkyl, (3-6C)cycloalkyl or halogen.

[0595] In another embodiment of the compound having Formula Iu or Iv:

[0596] X 1 is as defined in paragraph (7) above;

[0597] R 1 as defined in paragraph (22) above;

[0598] R 2 is as defined in paragraph (41) above;

[0599] R 30 is as defined in paragraph (53) above; and

[0600] R 50 It's hydrogen.

[0601] In a specific group of compounds of the present invention, these compounds have the structural formula Iw or Ix (sub-definition of formula (I)) or a pharmaceutically acceptable salt, hydrate and / or solvate thereof as shown below:

[0602]

[0603]

[0604] Where X 1 , R 1 , R 6 , R7 and R 30 Each of X is as defined above and 3 Selected from CH 2 , O, S, SO 2 or NH.

[0605] In embodiments of compounds having Formula Iw or Ix:

[0606] X 1 is defined in any of paragraphs (1) to (9) above;

[0607] R 1 is defined in any of paragraphs (13) to (24) above;

[0608] R 6 is selected from chlorine, fluorine or cyano;

[0609] R 7 is as defined in any of paragraphs (25) to (33) and (37) to (46) above;

[0610] R 30 is as defined in any of paragraphs (47) to (53) above; and

[0611] X 3 Select from O or S.

[0612] In another embodiment of the compound having Formula Iw or Ix:

[0613] X 1 is as defined in paragraph (7) above;

[0614] R 1 is as defined in paragraph (22) above;

[0615] R 6 It is chlorine;

[0616] R 7 is as defined in paragraph (46) above;

[0617] R 30 is as defined in paragraph (53) above; and

[0618] X 3 It's O.

[0619] Specific compounds of the present invention include any compound exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and in particular any one of the following:

[0620] (S)-2-Chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0621] (R)-2-Chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0622] 2-Chloro-4-((2-ethyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0623] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0624] (S)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0625] 2-Chloro-4-((2,2,7-trimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0626] 2-Chloro-4-((2-(methoxymethyl)-2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0627] 2-Chloro-4-((2,3,3,7-tetramethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0628] 2-Chloro-4-((2',7'-dimethyl-6'-oxo-1',2',6',7'-tetrahydro-4'H-spiro[cyclopropane-1,3'-[1,4]oxazepine [2,3-c]quinolin-10'-yl)amino)nicotinonitrile;

[0629] 2-Chloro-4-(((2S,4S)-2,4,7-trimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0630] 2-Chloro-4-((2,6-dimethyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinolin-9-yl)amino)nicotinonitrile;

[0631] 2-Chloro-4-((2-ethyl-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinolin-9-yl)amino)nicotinonitrile;

[0632] 2-Chloro-4-((2-cyclopropyl-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinolin-9-yl)amino)nicotinonitrile;

[0633] 2-Chloro-4-((2-cyclobutyl-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinolin-9-yl)amino)nicotinonitrile;

[0634] 2-Chloro-4-((7'-methyl-6'-oxo-3',4,4',5,6',7'-hexahydro-1'H,2H-spiro[furan-3,2'-[1,4]oxazepine [2,3-c]quinolin-10'-yl)amino)nicotinonitrile;

[0635] 2-Chloro-4-((2-(difluoromethyl)-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0636] 2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0637] (R)-2-Cyclopropyl-10-((5,6-dichloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0638] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0639] (S)-6-Chloro-5-cyano-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)picolinic acid;

[0640] (R)-6-Chloro-5-cyano-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)picolinic acid;

[0641] (S)-6-(azetidine-1-carbonyl)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0642] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)-6-(3-(trifluoromethyl)azetidine-1-carbonyl)nicotinonitrile;

[0643] (S)-10-((2,3-dichloropyridin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0644] (S)-10-((5-chloro-2-((S)-2-(methoxymethyl)pyrrolidine-1-carbonyl)pyridin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0645] (R)-2-Cyclopropyl-10-((2,3-dichloropyridin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0646] (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]oxazepine [2,3-c]quinolin-6(7H)-one;

[0647] 10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0648] (S)-10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0649] (S)-1-(5-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethylpiperidine-4-carboxamide;

[0650] (S)-10-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0651] (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0652] (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0653] (S)-10-((5-chloro-2-morpholinopyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0654] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0655] 10'-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-7'-methyl-3',4,4',5-tetrahydro-1'H,2H-spiro[furan-3,2'-[1,4]oxazepine [2,3-c]quinolinyl]-6'(7'H)-one;

[0656] (R)-10-((5-chloro-2-(2,2,6,6-tetramethylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0657] (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0658] (R)-10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0659] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0660] (R)-10-((2-(2-oxa-6-azaadamantan-6-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0661] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0662] (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0663] (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0664] (R)-10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one;

[0665] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one;

[0666] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0667] (S)-2-Chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0668] (S)-2-Chloro-4-((2-cyclopropyl-7-methyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0669] 2-Chloro-4-((2-cyclopropyl-7-methyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0670] 2-Chloro-4-((2,3,7-trimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0671] (S)-10-((5-chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0672] (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0673] (2S)-10-((2-(8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0674] (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0675] (S)-1-(5-chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethylpiperidine-4-carboxamide;

[0676] (S)-10-((5-chloro-2-(2-methyl-1-oxo-2,9-diazaspiro[5.5]undec-9-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0677] (2S)-10-((5-chloro-2-(3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0678] (S)-10-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0679] (2S)-10-((2-(3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0680] (S)-10-((5-chloro-2-(2-oxopyrrolidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0681] (2S)-10-((2-(8-Azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0682] (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0683] (S)-10-((5-chloro-2-((3R,5S)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0684] (S)-1-(5-chloro-4-((2-cyclopropyl-7-methyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethylpiperidine-4-carboxamide;

[0685] (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0686] 10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0687] rac-(2S,3R)-10-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,3,7-trimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0688] rac-(2S,3S)-10-((5-chloro-2-((3S,5R)-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,3,7-trimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0689] (S)-2-Chloro-4-((2,7-dimethyl-6-oxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0690] (S)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0691] 2-Chloro-4-((2,6-dimethyl-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]naphthyridin-9-yl)amino)nicotinonitrile;

[0692] 2-Chloro-4-((2,6-dimethyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]thiazino[2,3-c]quinolin-9-yl)amino)nicotinonitrile;

[0693] (S)-2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0694] 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0695] (S)-10-((5-Chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0696] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one;

[0697] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c]quinolin-6(7H)-one;

[0698] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c]quinolin-6(7H)-one;

[0699] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0700] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-(2-(methylamino)ethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0701] (R)-10-((5-Chloro-2-((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0702] (R)-10-((5-chloro-2-(3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0703] (R)-10-((5-chloro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0704] (R)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0705] (R)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0706] (R)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0707] (R)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0708] (R)-10-((5-chloro-2-((3S,4R,5R)-4-fluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0709] (R)-10-((5-Chloro-2-((R)-4,4-difluoro-3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0710] (R)-10-((5-Chloro-2-((S)-4,4-difluoro-3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0711] (R)-10-((5-Chloro-2-((R)-4,4-difluoro-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0712] (R)-10-((5-Chloro-2-((S)-4,4-difluoro-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0713] (R)-10-((5-Chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0714] (R)-10-((5-Chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0715] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-5,5-dioxido-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0716] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-7-methyl-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0717] (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0718] (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0719] (S)-10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0720] (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0721] (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0722] (S)-10-((5-Chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0723] (S)-10-((5-Chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0724] (S)-10-((5-chloro-2-morpholinopyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0725] (S)-10-((5-chloro-2-((R)-2-methylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0726] (S)-10-((5-Chloro-2-((S)-2-methylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0727] (S)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0728] (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0729] (S)-10-((5-chloro-2-(3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0730] (S)-10-((5-Chloro-2-((R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0731] 2-Chloro-4-((2,7-dimethyl-5,6-dioxo-2,3,4,5,6,7-hexahydro-1H-[1,4]diazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0732] (S)-10-((5-chloro-2-(4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0733] (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0734] (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0735] (S)-10-((5-chloro-2-((1S,5R)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0736] (S)-10-((5-chloro-2-((1R,5S)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0737] (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]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide;

[0738] (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]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide;

[0739] (S)-10-((3-chloropyridin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0740] (S)-3-(4-(5-chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperazin-1-yl)propionitrile;

[0741] (S)-2-Cyclopropyl-3,3-difluoro-10-((5-fluoro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0742] (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0743] (2S)-10-((5-chloro-2-(3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; or

[0744] (S)-10-((5-chloro-2-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one.

[0745] Additional compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and in particular any of the following:

[0746] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0747] 2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0748] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0749] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-5,5-dioxido-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0750] (S)-2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0751] (S)-6-Chloro-5-cyano-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)picolinic acid;

[0752] (R)-6-Chloro-5-cyano-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)picolinic acid;

[0753] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)-6-(3-(trifluoromethyl)azetidine-1-carbonyl)nicotinonitrile;

[0754] (S)-10-((3-chloropyridin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0755] (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]oxazepine [2,3-c]quinolin-6(7H)-one;

[0756] (S)-10-((5-chloro-2-morpholinopyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0757] (R)-10-((5-chloro-2-(2,2,6,6-tetramethylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0758] (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0759] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0760] (R)-10-((2-(2-oxa-6-azaadamantan-6-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0761] (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0762] (R)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0763] (R)-10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one;

[0764] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0765] (S)-2-Chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0766] 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0767] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one;

[0768] (S)-10-((5-Chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0769] (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0770] (R)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0771] (R)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0772] (R)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0773] (R)-10-((5-Chloro-2-((1R,3R,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0774] (R)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0775] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-7-methyl-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0776] (R)-10-((5-chloro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0777] (R)-10-((5-chloro-2-(3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0778] (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0779] (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0780] (S)-10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0781] (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0782] (S)-10-((5-Chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0783] (S)-10-((5-Chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[0784] (S)-10-((5-chloro-2-morpholinopyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0785] (S)-10-((5-chloro-2-((R)-2-methylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0786] (S)-10-((5-Chloro-2-((S)-2-methylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0787] (S)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0788] (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0789] (S)-10-((5-chloro-2-(3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0790] (S)-10-((5-Chloro-2-((R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0791] (R)-10-((5-Chloro-2-((R)-4,4-difluoro-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0792] (R)-10-((5-Chloro-2-((S)-4,4-difluoro-3-hydroxypiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0793] (S)-10-((5-chloro-2-(4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0794] (S)-10-((5-chloro-2-((1S,5R)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0795] (S)-10-((5-chloro-2-((1R,5S)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0796] (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]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide;

[0797] (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]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide;

[0798] (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0799] (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0800] (S)-3-(4-(5-chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperazin-1-yl)propionitrile;

[0801] (S)-10-((5-chloro-2-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0802] (2S)-10-((5-chloro-2-(3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0803] (S)-2-Cyclopropyl-3,3-difluoro-10-((5-fluoro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0804] (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0805] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c]quinolin-6(7H)-one;

[0806] (R)-10-((5-Chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0807] (R)-10-((5-Chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0808] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; or

[0809] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-(2-(methylamino)ethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one.

[0810] Additional compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and in particular any of the following:

[0811] 2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0812] (R)-2-Chloro-4-((2-cyclopropyl-7-methyl-5,5-dioxido-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0813] (S)-2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0814] (R)-6-Chloro-5-cyano-4-((2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)picolinic acid;

[0815] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0816] 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0817] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one;

[0818] (S)-10-((5-Chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0819] (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0820] (R)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0821] (R)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0822] (S)-10-((5-Chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0823] (S)-10-((5-Chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[0824] (S)-10-((5-chloro-2-morpholinopyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0825] (S)-10-((5-chloro-2-((R)-2-methylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0826] (S)-10-((5-Chloro-2-((S)-2-methylmorpholino)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0827] (S)-10-((2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0828] (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0829] (S)-10-((5-chloro-2-(3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0830] (S)-10-((5-Chloro-2-((R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0831] (S)-10-((5-chloro-2-(4-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0832] (S)-10-((5-chloro-2-((1S,5R)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0833] (S)-10-((5-chloro-2-((1R,5S)-3-methyl-2-oxo-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0834] (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]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide;

[0835] (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]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)-N,N-dimethyl-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxamide;

[0836] (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0837] (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0838] (S)-3-(4-(5-chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)pyrimidin-2-yl)piperazin-1-yl)propionitrile;

[0839] (S)-10-((5-chloro-2-(6-methyl-2,6-diazaspiro[3.3]heptane-2-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0840] (2S)-10-((5-chloro-2-(3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0841] (S)-2-Cyclopropyl-3,3-difluoro-10-((5-fluoro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0842] (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-fluoropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; or

[0843] (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c]quinolin-6(7H)-one.

[0844] Additional compounds of the present invention include any of the compounds exemplified in the present application, or a pharmaceutically acceptable salt or solvate thereof, and in particular any of the following:

[0845] (S)-2-Chloro-4-((2-cyclopropyl-3,3-difluoro-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0846] (R)-10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one;

[0847] (S)-10-((5-Chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0848] (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0849] (S)-10-((5-chloro-2-(4,4-difluoropiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0850] (S)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0851] (S)-10-((5-Chloro-2-((R)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0852] (S)-10-((5-Chloro-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0853] (S)-10-((2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-chloropyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0854] (S)-10-((5-chloro-2-(3,3-dioxido-3-thia-8-azabicyclo[3.2.1]octan-8-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0855] (S)-10-((5-chloro-2-((3R,5S)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0856] (S)-10-((5-chloro-2-((3S,5R)-3-hydroxy-5-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; or

[0857] (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one.

[0858] The various functional groups and substituents that make up the compounds of formula (I) and subformulas Ia to Ix are typically selected so that the molecular weight of the compound of formula (I) does not exceed 1000. More typically, 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 is less than 600, and for example is 550 or less.

[0859] Suitable pharmaceutically acceptable salts of the compounds of the present invention are, for example, sufficiently basic acid addition salts of the compounds of the present invention, such as acid addition salts with, for example, 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 sufficiently acidic compounds of the present invention are alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), ammonium salts, or salts with organic bases providing pharmaceutically acceptable cations (e.g., salts with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine).

[0860] Compounds that have the same molecular formula but differ in the nature or order of bonding of their atoms or the arrangement of their atoms in space are called "isomers". The term "stereoisomer" is an isomer that differs in the spatial arrangement of its atoms. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers". When a compound has an asymmetric center, for example, the asymmetric center is bonded to four different groups, there may be a pair of enantiomers. Enantiomers are characterized by the absolute configuration of their asymmetric center and are described and designated as right-handed or left-handed (i.e., as (+) or (-)-isomers, respectively) by the R- and S-sequencing rules of Cahn and Prelog, or by the method by which the molecule rotates the plane of polarized light. Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture".

[0861] The compounds of the present invention may have one or more asymmetric centers; therefore, such compounds may be generated as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include individual enantiomers and racemic mixtures or other mixtures thereof. Methods for stereochemical determination and separation of 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 raw materials or by resolution of racemic forms. Some compounds of the present invention may have geometric isomeric centers (E- and Z-isomers). It should be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof having antiproliferative activity.

[0862] The present invention also encompasses compounds of the present invention as defined herein that contain 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 the like.

[0863] It will also be appreciated that certain compounds of formula (I) or subformulas Ia to Ix may exist in solvated as well as unsolvated forms, such as hydrated forms. It will be appreciated that the present invention encompasses all such solvated forms which possess antiproliferative activity.

[0864] It is also to be understood that certain compounds of Formula I or Sub-Formulas Ia to Ix may exhibit polymorphism and that the present invention encompasses all such forms that possess anti-proliferative activity.

[0865] Compounds with formula I or subformula Ia to Ix can exist with many different tautomeric forms, and mention that compounds with formula I or subformula Ia to Ix include all such forms. In order to avoid doubt, when compound can exist with one of several tautomeric forms, and only one is specifically described or shown, formula I or subformula Ia to Ix still comprise all other forms. The example of tautomeric form includes ketone, enol and enolate form, for example, in the following tautomer pair: ketone / enol (shown hereinafter), imines / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol and nitro / acid nitro.

[0866]

[0867] Compounds with formula I or sub-formulas Ia to Ix containing amine functional groups can also form N-oxides. Compounds with formula I or sub-formulas Ia to Ix containing amine functional groups mentioned herein also include N-oxides. When the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidant such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry [Higher Organic Chemistry], edited by Jerry March, 4th edition, Wiley International Science Publishers (Wiley Interscience), pages. More specifically, N-oxides can be prepared by the procedure in LW Deady (Syn. Comm. [Synthesis Communication] 1977, 7, 509-514), wherein the amine compound reacts with meta-chloroperbenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

[0868] Compounds with formula (I) or subformulas Ia to Ix can be administered in the form of prodrugs that decompose in the human or animal body to release the compound of the present invention. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present invention. When the compound of the present invention contains a suitable group or substituent to which a modifying group (property-modifying group) can be attached, a prodrug can be formed. Examples of prodrugs include ester derivatives that can be formed in vivo at carboxyl groups or hydroxyl groups in compounds with formula (I) or subformulas Ia to Ix and amide derivatives that can be formed in vivo at carboxyl groups or amino groups in compounds with formula (I) or subformulas Ia to Ix.

[0869] Therefore, the present invention includes those compounds of formula (I) or sub-formulas Ia to Ix as defined above when obtainable by organic synthesis and when obtainable in the human or animal body by cleavage of their prodrugs. Therefore, the present invention includes those compounds of formula I or sub-formulas Ia to Ix produced by organic synthesis, and also such compounds produced in the human or animal body by metabolizing precursor compounds, i.e. compounds of formula (I) or sub-formulas Ia to Ix that can be synthetically produced compounds or metabolically produced compounds.

[0870] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) or subformulas Ia to Ix are pharmaceutically acceptable prodrugs that are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity based on sound medical judgment.

[0871] For example, in the following documents, various forms of prodrugs have been described:-

[0872] a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985);

[0873] b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985);

[0874] c) A Textbook of Drug Design and Development, ed. Krogsgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Pro-drugs", ed. H. Bundgaard, pp. 113-191 (1991);

[0875] d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);

[0876] e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988);

[0877] f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984);

[0878] g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; and

[0879] h) E. Roche (ed.), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0880] Suitable pharmaceutically acceptable prodrugs of compounds of formula I or subformulas Ia to Ix having a carboxyl group are, for example, esters thereof that can be cleaved in vivo. Esters containing a carboxyl group of compounds of formula I or subformulas Ia to Ix that can be cleaved in vivo are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to generate the parent acid. Suitable pharmaceutically acceptable esters of carboxyl groups include (1-6C)alkyl esters (such as methyl, ethyl and tert-butyl), (1-6C)alkoxymethyl esters (such as methoxymethyl ester), (1-6C)alkanoyloxymethyl esters (such as pivaloyloxymethyl ester), 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(1-6C)alkyl esters (such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl ester), 2-oxo-1,3-dioxolmethyl esters (such as 5-methyl-2-oxo-1,3-dioxol-4-ylmethyl ester), and (1-6C)alkoxycarbonyloxy-(1-6C)alkyl esters (such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl ester).

[0881] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or subformulas Ia to Ix having hydroxyl groups are, for example, esters or ethers thereof that can be cleaved in vivo. Esters or ethers containing hydroxyl groups that can be cleaved in vivo of compounds of formula I or subformulas Ia to Ix are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include inorganic esters, such as phosphates (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include (1-10C) alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (1-10C) alkoxycarbonyl groups such as ethoxycarbonyl, N,N-(1-6C) 2 The pharmaceutically acceptable ether forming groups of the hydroxyl groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0882] Suitable pharmaceutically acceptable prodrugs of compounds of formula (I) or subformulae Ia to Ix having a carboxyl group are, for example, amides thereof which may be cleaved in vivo, for example with amines such as ammonia, (1-4C)alkylamines such as methylamine, [(1-4C)alkyl] 2Amines 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 or esters thereof formed by amino acids such as glycine.

[0883] Suitable pharmaceutically acceptable prodrugs with amino groups of compounds of formula I or subformulas Ia to Ix are, for example, amide derivatives that can be cleaved in vivo. Suitable pharmaceutically acceptable amides from amino groups include, for example, amides formed with (1-10C) acyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl 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.

[0884] The in vivo effects of compounds of formula (I) or subformulas Ia to Ix may be exerted in part through one or more metabolites that are formed in the human or animal body after administration of the compounds of formula (I) or subformulas Ia to Ix. As described above, the in vivo effects of compounds of formula (I) or subformulas Ia to Ix may also be exerted by the metabolism of precursor compounds (prodrugs).

[0885] Although the present invention may relate to any compound or specific group of compounds defined herein by way of optional, preferred or suitable features or otherwise with respect to specific embodiments, the present invention may also relate to any compound or specific group of compounds specifically excluding said optional, preferred or suitable features or specific embodiments.

[0886] Suitably, the present invention excludes any individual compound that does not have a biological activity as defined herein. The following compounds were tested in the HTRF assay described in the Examples section below, but they did not show the desired activity as they had an IC of greater than 2.50 μM 50 value:

[0887] (R)-2-Cyclopropyl-10-((2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-5-methoxypyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one;

[0888] 2-Chloro-4-((2,4,4,7-tetramethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0889] 2-Chloro-4-((2,2,7-trimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile;

[0890] (2S)-10-((2-(7-acetyl-3,7-diazabicyclo[3.3.1]non-3-yl)-5-chloropyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione;

[0891] 2-Chloro-4-((2-isopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile;

[0892] 2-chloro-4-((2-(cyclopropylmethyl)-6-methyl-5-oxo-2,3,5,6-tetrahydro-1H-[1,4]oxazino[2,3-c]quinolin-9-yl)amino)nicotinonitrile; and

[0893] 2-Chloro-4-((2-cyclobutyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile.

[0894] In embodiments, the compound of the invention is a compound having formula I as defined above, with the proviso that the compound is not one of the compounds listed in the preceding paragraph.

[0895] synthesis

[0896] The compounds of the present invention can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the accompanying examples.

[0897] In the descriptions of synthetic methods described herein, as well as in any referenced synthetic methods for preparing starting materials, it is understood that all proposed reaction conditions, including the choice of solvents, reaction atmospheres, reaction temperatures, duration of experiments, and work-up procedures, can be selected by one skilled in the art.

[0898] Those skilled in the art of organic synthesis will appreciate that the functionality present on the various parts of the molecule must be compatible with the reagents and reaction conditions employed.

[0899] It should be understood that during the synthesis of the compounds of the invention in the process defined herein, or during the synthesis of certain starting materials, it may be necessary to protect certain substituent groups to prevent their undesirable reactions. A skilled chemist will understand when such protection is required and how such protecting groups can be placed in suitable positions and subsequently removed.

[0900] For examples of protecting groups, see one of the many general texts on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist, suitable for removal of the protecting group in question, such method being selected so as to effect removal of the protecting group with minimal perturbation of groups elsewhere in the molecule.

[0901] Thus, if reactants include, for example, groups such as amino, carboxyl or hydroxy groups, it may be necessary to protect this group in some of the reactions mentioned herein.

[0902] For example, the suitable protecting group of amino or alkylamino group is, for example, acyl group (for example, alkanoyl group such as acetyl), alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group), arylmethoxycarbonyl group (for example, benzyloxycarbonyl) or aroyl group (for example, benzoyl). The deprotection conditions of the above-mentioned protecting group must vary with the selection of the protecting group. Therefore, for example, acyl group such as alkanoyl or alkoxycarbonyl group or aroyl group can be removed by hydrolysis with a suitable base such as alkali metal hydroxide (for example, lithium hydroxide or sodium hydroxide). Alternatively, acyl group such as tert-butoxycarbonyl group can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and arylmethoxycarbonyl group such as benzyloxycarbonyl group can be removed, for example, by hydrogenation over a catalyst such as palladium carbon, or by treatment with Lewis acid such as boron tris (trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0903] Suitable protecting groups for hydroxyl groups are, for example, acyl groups (e.g., alkanoyl groups such as acetyl, aroyl groups such as benzoyl), or arylmethyl groups (e.g., benzyl). The deprotection conditions for the above-mentioned protecting groups will necessarily vary with the selection of the protecting groups. Thus, for example, acyl groups such as alkanoyl or aroyl groups can be removed, for example, by hydrolysis with a suitable base (e.g., an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or ammonia). Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by hydrogenation over a catalyst such as palladium carbon.

[0904] A suitable protecting group for a carboxyl group is, for example, an esterifying group, for example a methyl or ethyl group (which can be removed, for example, by hydrolysis with a base such as sodium hydroxide), or for example a tert-butyl group (which can be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid), or for example a benzyl group (which can be removed, for example, by hydrogenation over a catalyst such as palladium on carbon).

[0905] Resins can also serve as protecting groups.

[0906] The method for synthesizing compounds of formula (I) or subformula Ia to Ix is as follows: 1 , X 2 , R 1 , R 2 , R 30 , R 31 The preferred methods for their preparation are described in the accompanying Examples.

[0907] Once a compound of formula (I) or subformulas Ia to Ix has been synthesized by any of the methods defined herein, these methods may further comprise the following additional step:

[0908] (i) removing any protecting groups present;

[0909] (ii) converting a compound of formula (I) into another compound of formula (I);

[0910] (iii) forming a pharmaceutically acceptable salt, hydrate or solvate thereof; and / or

[0911] (iv) forming a prodrug thereof.

[0912] An example of (ii) above is when a compound having formula (I) is synthesized and then group X 1 , X 2 , R 1 , R 2 , R 30 , R 31, one or more of the rings A may be further reacted to change the nature of the group and provide alternative compounds of formula (I).

[0913] The resulting compounds of formula (I) or subformulas Ia to IxIx can be isolated and purified using techniques well known in the art.

[0914] Compounds 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.

[0915] Solution 1

[0916]

[0917] Wherein Y is a halogen (such as Cl, Br, I) or a suitable alternative (such as OTf, SOMe, or SO 2 Me), R 3 is H or formyl, and R 1 , R 2 , R 30 , R 31 , X 1 , X 2 , and Ring A are suitable groups selected from those defined previously.

[0918] As shown in Scheme 1, to form a compound having formula (I), an aromatic amine (II) and an aryl halide (or equivalent R 2 -Y) can be carried out at elevated temperature (e.g. 60-180°C) (using conventional or microwave heating) in a suitable solvent or solvent mixture (e.g. NMP, DMA, DMF, or acetonitrile). The reaction is carried out in the presence of a base (e.g. triethylamine or DIPEA) or in the absence of a base. Alternative reaction conditions include the use of a suitable solvent or solvent mixture (e.g. toluene, or a mixture of toluene and DMF or NMP) at elevated temperature in the presence of a base such as cesium carbonate, a transition metal catalyst such as Pd in ​​combination with a suitable ligand such as Xantphos. 2 (dba) 3 When Y is SOMe or SO 2 Me, alternative reaction conditions include the use of an acid such as TFA at elevated temperature (e.g. 70°C) using a suitable solvent such as trifluoroethanol. 3 is formyl and Y is SO 2 In the case of Me, alternative reaction conditions include the use of a base such as NaH at elevated temperature (eg 60°C) using a suitable solvent such as THF.

[0919] Compound (II) can be prepared using methods such as those described in Schemes 2 and 3.

[0920] A compound of formula (I) may be converted into another compound of formula (I) by methods known to those skilled in the art.

[0921] Option 2a

[0922]

[0923] Where W is NO 2 or 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 suitable group selected from those defined previously.

[0924] Nitro compounds (III, W = NO 2 ) to the reduction reaction of the amino compound (II) can be carried out by many methods well known in the art. In a suitable solvent or a mixture of solvents (such as ethanol, methanol, ethyl acetate, or ethanol / NMP), at ambient temperature or elevated temperature (such as 40°C-80°C) (using conventional or microwave heating), a hydrogenation reaction is carried out in the presence of a metal catalyst such as palladium (usually in the form of palladium carbon). These reactions are carried out under a hydrogen atmosphere or alternatively by "transfer hydrogenation" using reagents such as ammonium formate or triethylsilane. An alternative method uses tin chloride (II) in a suitable solvent or solvent mixture (such as ethanol and trifluoroethanol) at elevated temperatures such as 120°C (using conventional or microwave heating). Other methods are known in the art, such as iron or zinc metal-mediated reduction reactions.

[0925] The amination reaction of halide 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 reactions can be used using metal sources and ligands. The conditions for this reaction are known in the literature and include the use of palladium acetate and benzophenone imine, as described in Shen et al., Angew. Chem. Int. Ed. [Applied Chemistry International Edition] 2005, 44, 1371. The reaction is typically carried out using a base (e.g., sodium tert-butoxide), in a suitable solvent or solvent mixture (e.g., 1,2-dimethoxyethane), at elevated temperatures. The hydrolysis of the imine intermediate can be carried out in a one-pot process at rt with the addition of an acid such as HCl. Aromatic amines (II) can also be formed by reacting aryl halides (e.g., W=Br) with ammonia (e.g., from ammonium hydroxide solution) in a suitable solvent such as NMP at elevated temperatures (e.g., 140° C.) (using conventional or microwave heating). These reactions are typically catalyzed by metal catalysts such as copper (I) oxide.

[0926] Compound (III) can be prepared by the following methods, including those shown in Schemes 4a-c, 7a-7b, 8, and 9.

[0927] Option 2b

[0928]

[0929] Where R 1 , R 30 , R 31 , X 1 , X 2 , Ring A is a suitable group selected from those defined previously.

[0930] The preparation method of carboxamide compound (II-d) is known in the art. For example, the method is carried out in a suitable solvent such as dichloromethane at ambient temperature in the presence of phenyl formate.

[0931] Compound (II) can be prepared by methods including those shown in Schemes 2a and 3.

[0932] Solution 3

[0933]

[0934] Where R 1 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those defined previously. Z is a suitably substituted methylene group (-CR 40 R 41-), for example (-CH 2 -) or (-CH(Me)-).

[0935] Aniline compound (II-c) can be prepared by reduction of compound (II-b). This reaction can be carried out at low temperature (e.g. 0°C) in a suitable solvent (e.g. THF) with various reducing agents known in the art (e.g. sodium borohydride). Various additives such as Lewis acids (e.g. boron trifluoride etherate complex) can be used.

[0936] Compound (II-b) can be prepared as described in Scheme 2.

[0937] Option 4a

[0938]

[0939] wherein W is as previously defined, Y is a halogen such as Br or I, and R 1 , R 30 , R 31 , X 1 , X 2 , and Z is a suitably substituted (1-2C)alkylene group, for example (-CH 2 -)、(-CH 2 CH 2 -)、(-CF 2 CH 2 ), or (-CH(Me)CH 2 -).

[0940] The cyclized compound (III-a) can be prepared by intramolecular cyclization of the halogenated compound (IV). This reaction can be carried out at elevated 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) combined with a suitable ligand (e.g., 1,10-phenanthroline) in the presence of a base (e.g., cesium carbonate) at elevated temperatures using a suitable solvent (e.g., NMP).

[0941] The halogenated compound (IV) can be prepared as shown in Scheme 5.

[0942] Option 4b

[0943]

[0944] Wherein V is a halogen (such as Cl, Br, I) or a suitable substitute (such as OTs), R2 is a suitable protecting group such as acetate, Y is a halogen such as Br or I, and R 1 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those previously defined, and Z is a suitably substituted linker as previously defined.

[0945] The oxidation reaction of the sulfide compound (III-e) to the sulfone compound (III-i) can be carried out by many methods well known in the art. For example, using a suitable oxidant such as mCPBA, in a suitable solvent or a mixture of solvents (such as dichloromethane / acetonitrile), at low temperature (such as 0°C) or ambient temperature. Compound (III-e) can be formed by deprotection of the thiol of IX-a, followed by in situ displacement of Y at the 3-position of quinolinone (X). Suitable conditions for this transformation include the use of additives (such as sodium hydroxide) at ambient temperature in a suitable solvent (such as methanol). The protected thiol (IX-a) can be formed by displacement of the leaving group V. Suitable conditions for this transformation include the use of elevated temperatures (such as 50°C) in a suitable solvent (such as DMF). Various additives (such as sodium iodide) can also be used. Alkylating agent (VIII-a) can be formed from the corresponding alcohol (IV). Various conditions for this activation of alcohols are known in the art; suitable methods include tosylation with tosyl chloride in pyridine at ambient temperature. Compound (IV) can be prepared as described in Scheme 5.

[0946] Solution 4c

[0947]

[0948] wherein W is as defined above, Y is halogen (such as Cl, Br, I) or a suitable alternative (such as OTs), and R 1 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those defined previously, R 4 is (1-2C)alkyl, cyclopropyl, or (1-2C)haloalkyl, and Z is a suitably substituted linker as defined previously.

[0949] The reduction of the nitro compound (VIII-b) to the intermediate aromatic amine (XI) can be carried out by many methods well known in the art. In a suitable solvent or a mixture of solvents (such as ethanol, methanol, ethyl acetate, or ethanol / NMP), at ambient temperature or elevated temperature (such as 60°C-75°C) (using conventional or microwave heating), a hydrogenation reaction is carried out in the presence of a metal catalyst such as palladium (usually in the form of palladium carbon). These reactions are carried out under a hydrogen atmosphere or alternatively by "transfer hydrogenation" using reagents such as ammonium formate or triethylsilane. An alternative method uses tin (II) chloride in a suitable solvent or solvent mixture (such as ethanol and trifluoroethanol) at elevated temperatures such as 120°C (using conventional or microwave heating). Other methods are known in the art, such as iron or zinc metal-mediated reduction reactions. In situ cyclization to compound (III-f) can occur spontaneously in the reduction step or at ambient temperature with the addition of additives (such as DIPEA). The nitro compound (VIII-b) can be formed from the corresponding alcohol (Vb). Various conditions for this activation of alcohols are known in the art; suitable methods include tosylation with tosyl chloride in DCM using a suitable base (such as triethylamine) at ambient temperature. Various additives (such as DMAP) may also be used. Further functionalization of the C3-nitrogen may be carried out by many methods well known in the art to prepare compound (III-g).

[0950] Compound (Vb) can be prepared as described in Scheme 6b.

[0951] Solution 5

[0952]

[0953] wherein W is as previously defined, Y is a halogen such as Br or I, and R 1 , R 30 , R 31 , X 1 , X 2 , suitable groups are selected from those previously defined and Z is a suitably substituted linker as previously defined.

[0954] Compound (IV) can be prepared by halogenation of compound (Va). This reaction can be carried out in a suitable solvent or solvent mixture (such as DCM, methanol / water) at a temperature range (such as 0°C, rt, or 60°C) with a suitable halogenating agent (such as N-bromosuccinimide). Various additives such as acids (such as TFA) can be used.

[0955] Compound (Va) can be prepared as shown in Scheme 6a.

[0956] Option 6a

[0957]

[0958] Wherein Y is halogen (such as Cl, Br, I) or a suitable substitute (such as OTf), R 3 is a small alkyl group such as methyl or ethyl, and R 1 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those previously defined, and Z is a suitably substituted linker as previously defined.

[0959] Nitro compounds (V) can be prepared by the reaction of amino-alcohols (VII) with halo-aromatics or equivalents (VI-a). This reaction can be carried out at elevated temperatures (e.g., 80°C-200°C) in a suitable solvent or solvent mixture (e.g., NMP, NMP / THF), or using an amine as a solvent. Various additives such as bases (e.g., DIPEA, triethylamine) and nucleophilic catalysts (e.g., DMAP) can be used. For amines with less nucleophilicity and more steric hindrance, alternative conditions may be required. For example, using a metal source and a ligand, a metal-catalyzed amination reaction can be used. The conditions for this reaction are known in the literature and include the use of palladium acetate and BINAP, as described in Naik et al., J. Med. Chem. [Journal of Medicinal Chemistry] 2014, 57, 5419. The reaction is typically carried out using a base such as cesium carbonate in an appropriate solvent or solvent mixture (e.g., toluene) at elevated temperatures. Alternatively, the use of an ester functional group (VI-b) can be used to assist halogen displacement. The displacement of Y with (VII) is carried out at elevated temperature (e.g. 90° C.-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° C.-160° C.). Microwave or conventional heating can be used for the above reaction.

[0960] Amino-alcohols (VII) are obtained from commercial suppliers or prepared by methods known in the art. Compounds (VI-a) and (VI-b) can be prepared as shown in Schemes 10a-b.

[0961] Option 6b

[0962]

[0963] wherein W is as defined previously, Y is a halogen (such as Cl, Br, I) or a suitable alternative (such as OTf), and R 1 , R 30 , R31 , X 1 , X 2 is a suitable group selected from those previously defined, and Z is a suitably substituted linker as previously defined.

[0964] Compound (Vb) can be prepared by the reaction of amino-alcohol (VII) with halo-aromatic or equivalent (VI-c). This reaction can be carried out at an elevated temperature (such as 140° C.) in a suitable solvent (such as NMP) with the use of a suitable base (such as DIPEA). Amino-alcohol (VII) is obtained from a commercial supplier or prepared by methods known in the art. Compound (VI-c) can be prepared as shown in Scheme 10b.

[0965] Option 7a

[0966]

[0967] Wherein Y is halogen (such as Cl, Br, I) or a suitable substitute (such as OTf), R 3 is a small alkyl group such as methyl or ethyl, and R 1 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those previously defined, and Z is a suitably substituted linker as previously defined.

[0968] Nitro compound (III-b) can be prepared by the reaction of amino-alcohol (VII) and compound (VI-b). At elevated temperature (such as 160° C.) in a suitable solvent such as NMP, typically using a base such as DIPEA, replacement of Y with (VII) is performed. Additives (such as lithium chloride) can be added to the reaction mixture and further heated (for example at 160° C.) to cyclize to lactone (III-b). Microwave or conventional heating can be used for the above reaction. This procedure can form a mixture of compound (III-b) and (Va), which can be separated by standard methods.

[0969] Amino-alcohols (VII) are obtained from commercial suppliers or prepared by methods known in the art. Compounds (VI-b) can be prepared as shown in Scheme 10b.

[0970] Option 7b

[0971]

[0972] wherein W is as defined previously, Y is halogen (such as Cl, Br, I) or a suitable alternative (such as OTf), R 2 is a suitable protecting group such as Boc, R3 is a small alkyl group such as methyl or ethyl, R 4 is H, (1-2C)alkyl, cyclopropyl, or (2C)haloalkyl, and R 1 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those previously defined, and Z is a suitably substituted methylene linker as previously defined.

[0973] Cyclic lactam compounds (III-h) can be prepared from compounds (VI-b) in a one-pot process. Compounds (Vd) can be prepared by reaction of appropriately protected diamines (XII) with halo-aromatic (or equivalent) and ester functional groups (VI-b). Displacement of Y with diamine (XII) is carried out at elevated temperatures (e.g. 100° C.) in a suitable solvent such as acetonitrile, typically using a base such as DIPEA. In situ amine deprotection can be achieved with the addition of an acid (e.g. HCl in dioxane) at elevated temperatures (e.g. 75° C.). Cyclization can then be achieved with the addition of an excess of a base (e.g. DIPEA) at elevated temperatures (e.g. 75° C.).

[0974] Suitably protected diamines (XII) are obtained from commercial suppliers or prepared by methods known in the art. Compounds (VI-b) can be prepared as shown in Scheme 10b.

[0975] Solution 7c

[0976]

[0977] wherein W is as defined previously, Y is halogen (such as Cl, Br, I) or a suitable alternative (such as OTf), R 4 is a suitable protecting group such as Boc, R 3 is a small alkyl group such as methyl or ethyl, and R 1 , R 2 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those previously defined, and Z is a suitably substituted methylene linker as previously defined.

[0978] An alternative route to the cyclic lactam compound (Ih) is shown in Scheme 7c. Compound (III-j) can be prepared by reaction of a suitably protected diamine (XII) with a halo-aromatic (or equivalent (VI-b)). Displacement of Y with diamine (XII) can be carried out at elevated temperatures (e.g., 100° C.) in a suitable solvent (e.g., THF), typically using a base such as DIPEA. The conversion of (III-j) to (II-j) can be carried out using the conditions in Scheme 2a described previously. The conversion of (II-j) to (Ij) can be carried out using the conditions in Scheme 1 described previously. The formation of cyclic lactam compound (Ih) can be achieved from compound (Ij) in a one-pot process. Amine deprotection can be achieved at elevated temperatures (e.g., 70° C.) in a suitable solvent (e.g., THF) with the addition of an acid (e.g., HCl in dioxane). In situ cyclization can then be achieved at elevated temperatures (e.g., 70° C.) by adding an excess of a base (e.g., triethylamine).

[0979] Suitably protected diamines (XII) are obtained from commercial suppliers or prepared by methods known in the art. Compounds (VI-b) can be prepared as shown in Scheme 10b.

[0980] Solution 8

[0981]

[0982] Wherein Y is a halogen (such as Cl, Br, I) or a suitable substitute (such as OTs), and R 1 , R 30 , R 31 , X 1 , X 2 is a suitable group selected from those previously defined, and Z is a suitably substituted ethylene linker as previously defined.

[0983] Compound (III-d) can be formed by cyclization at the 3-position of quinolinone (displacing the leaving group Y). Suitable conditions for this transformation include the use of elevated temperatures (e.g., 160° C.) in an appropriate solvent (e.g., NMP) with the addition of a base (e.g., DIPEA). Alkylating agents (VIII-d) can be formed from the corresponding alcohol (Va). Various conditions for this activation of the alcohol are known in the art; suitable methods include tosylation with tosyl chloride in pyridine / DCM at ambient temperature. Compound (Va) can be prepared as described in Scheme 6a.

[0984] Solution 9

[0985]

[0986] where Y 2is halogen (such as Cl, Br, I) or a suitable alternative (such as OTf), W is as previously defined, and R 1 , R 30 , R 31 , X 1 , X 2 , Ring A is a suitable group selected from those defined previously.

[0987] R 1 The later 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 include an alkyl halide or equivalent (R) at ambient or elevated temperature (e.g. 80° C.) in a suitable solvent (e.g. DMF) in the presence of a base (e.g. sodium hydride or cesium carbonate). 1 -Y 2 , such as R 1 =CH 2 cPr) is used. Alkylation can occur on the oxygen or the nitrogen; the choice of reaction conditions can adjust the selectivity, and these regioisomers can typically be separated using known methods. Compound (XIII) can be prepared as in Schemes 4a-c and 7a-b (where R 1 =H). Further manipulation of compound (III) by known methods can be used to modify R 1 .

[0988] Option 10a

[0989]

[0990] Where Y is a halogen such as Cl, and R 1 , X 1 , X 2 is a suitable group selected from those defined previously.

[0991] R 1 The introduction of the group into compound (A-III) can be carried out by alkylation to form compound (VI-a). Alkylation conditions are well known in the art and include an alkyl halide or equivalent (R) at ambient temperature or elevated temperature (e.g. 80° C.) in a suitable solvent (e.g. DMF) in the presence of a base (e.g. sodium hydride or cesium carbonate). 1 -Y 2 , such as R 1=Me) is used. Alkylation can occur on oxygen or nitrogen; the choice of reaction conditions can adjust the selectivity, and these regioisomers can typically be separated using known methods. Compound (A-III) is commercially available or can be prepared by known methods, such as nitration of compound (A-II) including those shown in van Oeveren et al., Bioorg. Med. Chem. Lett. [Biological Organic Chemistry and Medicinal Chemistry Communications] 2007, 17, 1527. Compound (A-II) is commercially available or can be prepared by known methods, such as hydrolysis of dihalogenated derivatives (AI) including those shown in Naik et al., J. Med. Chem. [Journal of Medicinal Chemistry] 2014, 57, 5419.

[0992] Option 10b

[0993]

[0994] where W is as defined previously, Y and Y 3 are independently selected from halogen (such as F, Cl, Br, I) or suitable substitutes (such as OTf or OTs), Y 2 are independently selected from halogen (such as Cl, Br, I) or suitable substitutions (such as OTf or OTs), R 2 and R 3 is a small alkyl group such as methyl or ethyl, and R 1 , X 1 , X 2 is a suitable group selected from those defined previously.

[0995] R 1 The introduction of a group into compound (BI) can be carried out by alkylation to form compound (B-II). Alkylation conditions are well known in the art and include an alkyl halide or equivalent (R) at ambient temperature or elevated temperature (e.g. 80° C.) in a suitable solvent (e.g. DMF) in the presence of a base (e.g. sodium hydride or cesium carbonate). 1 -Y 2 , such as R 1=Me) is used. The alkylation can occur on the oxygen or on the nitrogen; choice of reaction conditions can tune the selectivity, and these regioisomers can typically be separated using known methods. Compounds (VI-b) and (Vi-c) can be prepared by a multistep process starting from compound (B-II) by methods similar to those described in the following 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., WO 02 / 094203).

[0996] Alternatively, R 1 The group-introduced compound (CI) can be obtained by replacing Y with a substituted amine. 3 Group conduct. N Ar conditions are well known in the art and include the reaction of a substituted amine (R 1 -NH 2 , such as R 1 =Me methylamine). Compound (C-III) can be formed by one-pot amide bond formation / cyclization of compound (C-II). Suitable conditions for this transformation include the use of elevated temperature (e.g. 60°C) in a suitable solvent (e.g. DCM) with the addition of a base (e.g. triethylamine) and a suitable acylating agent (e.g. ethyl 3-chloro-3-oxopropanoate). The use of POCl is well known in the art and includes reaction at elevated temperature (e.g. 80°C). 3 Using conditions of , compound (C-III) can be converted into the corresponding halide (VI-b).

[0997] Biological Activity

[0998] The bioassays described in the Examples section herein can be used to measure the pharmacological effects of the compounds of the invention.

[0999] Although the pharmacological properties of compounds of Formula I vary as a function of structure, as expected, compounds of the invention were found to be active in the HTRF in vitro assay, the NanoBRET cellular assay, and in some cases also in the SUDHL4 degradation assay described in the Examples section.

[1000] In general, as shown by the example compound data in Table 1, compounds of the invention demonstrated IC values ​​of 2.5 μM or less in the HTRF described in the Examples section. 50 , which corresponds to a pIC of 5.6 or more 50 Preferred compounds of the invention demonstrate IC values ​​of 500 nM or less 50 , which corresponds to a pIC of 6.3 or more 50 ; or IC of 250nM or less 50 , which corresponds to a pIC of 6.6 or more 50 More preferred compounds of the invention demonstrate IC values ​​of 100 nM or less 50 , which corresponds to a pIC of 7.0 or more 50 The most preferred compounds of the present invention demonstrate IC values ​​of 10 nM or less. 50 , which corresponds to a pIC of 8.0 or more 50 .

[1001] In the NanoBRET cell assay described in the Examples section herein, compounds having Formula I typically demonstrate a pIC of 5.0 or more (preferably 6.0 or more) as shown by the example compounds in Table 2. 50 The most preferred compounds of the present invention demonstrate pIC values ​​of 7.0 or more. 50 .

[1002] In the SUDHL4 degradation assay described in the Examples section herein, compounds having Formula I may also demonstrate pDC values ​​of 6.0 or more (preferably 6.5 or more) as shown by the example compounds in Table 3. 50 .

[1003] The following data is generated for the instance:

[1004] Table 1

[1005]

[1006]

[1007] Table 2

[1008]

[1009]

[1010] Table 3

[1011]

[1012] Pharmaceutical composition

[1013] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with a pharmaceutically acceptable diluent or carrier.

[1014] The compositions of the invention may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as fine powders or liquid aerosols), administration by insufflation (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).

[1015] The compositions of the present invention can be obtained using conventional pharmaceutical excipients by conventional procedures well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[1016] An effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent a proliferative disorder mentioned herein, slow the progression of the disorder, and / or alleviate the symptoms associated with the disorder.

[1017] The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual being treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, 0.5 mg to 0.5 g (more suitably 0.5 mg to 100 mg, e.g. 1 mg to 30 mg) of active agent compounded with an appropriate and convenient amount of excipients (which may vary from about 5% to about 98% by weight of the total composition).

[1018] According to well-known medical principles, for therapeutic or prophylactic purposes, the size of the dose of the compound of formula I will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[1019] When using the compounds of this invention for treatment or prevention purposes, it is usually given so that if divided doses are needed, a daily dose of, for example, 0.1mg / kg to 75mg / kg body weight is accepted. Generally speaking, when parenteral routes are adopted, a lower dose will be applied. Therefore, for example, for intravenous or intraperitoneal administration, a dosage of, for example, 0.1mg / kg to 30mg / kg body weight will usually be used. Similarly, for administration by inhalation, a dosage of, for example, 0.05mg / kg body weight to 25mg / kg body weight will be used. Oral administration may also be suitable, particularly in tablet form. Typically, a unit dosage form will contain about 0.5mg to 0.5g of the compounds of this invention.

[1020] Therapeutic uses and applications

[1021] The present invention provides compounds useful as inhibitors of BCL6 activity.

[1022] The present invention therefore provides a method of inhibiting BCL6 activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[1023] The present invention also provides a method for treating a disease or disorder involving BCL6 activity 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.

[1024] The present invention provides a method of inhibiting cell proliferation in vitro or in vivo, the method comprising contacting the cell with an effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[1025] The present invention provides a method of treating a proliferative disorder in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

[1026] The present invention provides a method of treating cancer in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition.

[1027] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in therapy.

[1028] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition, for use in the treatment of a proliferative disorder.

[1029] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition for use in treating cancer. In particular embodiments, the cancer is a human cancer.

[1030] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in inhibiting BCL6 activity (ie, inhibition of BCL6 transcriptional repression and / or corepressor binding).

[1031] It has been found that certain compounds of the invention bind to BCL6 and trigger degradation of BCL6. Accordingly, the present invention also provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the degradation of BCL6.

[1032] The present invention provides a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of a disease or disorder in which BCL6 activity is implicated.

[1033] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for the treatment of a proliferative disorder.

[1034] The present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt, hydrate or solvate thereof in the manufacture of a medicament for treating cancer. Suitably, the medicament is for use in treating human cancer.

[1035] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for inhibiting BCL6 activity (i.e., inhibition of BCL6 transcriptional repression and / or corepressor binding).

[1036] The present invention provides use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for degrading BCL6.

[1037] The present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for treating a disease or disorder in which BCL6 activity is implicated.

[1038] The terms "proliferative disorder" and "proliferative condition" are used interchangeably herein and relate to the unwanted or uncontrolled cell proliferation of an undesirable excess or abnormal cell (whether in vitro or in vivo), such as neoplastic growth or hyperplastic growth. Examples of proliferative disorders include, but are not limited to, premalignant cell proliferation and malignant cell proliferation, including, but not limited to, malignant neoplasms and tumors, cancers (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), leukemias (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), lymphomas (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)), psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis. Any type of cell can be treated, including, but not limited to, the lymphatic system, blood vessels, lungs, colon, breast, ovaries, prostate, liver, pancreas, brain, and skin.

[1039] The anti-cancer effects may occur through one or more mechanisms including, but not limited to, modulation of cell proliferation, inhibition of angiogenesis (formation of new blood vessels), inhibition of metastasis (spread of a tumor from its origin), inhibition of invasion (spread of tumor cells into adjacent normal structures), or promotion of apoptosis (programmed cell death).

[1040] Compounds of formula (I) or pharmaceutically acceptable salts thereof that are BCL6 inhibitors have potential therapeutic uses in various BCL6-mediated disease states. BCL6 expression is associated with a variety of 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 inhibitors of BCL6 have been reported to kill DLBCL cells (Cerchietti et al., Cancer Cell ,2010, 17 , 400-411), predominantly low-grade follicular lymphoma cells (Cardenas et al., Clin Cancer Res [Clinical Cancer Research],2017, 23(4) , 885-893), and Burkitt's lymphoma cells (Polo et al., Nat Med [Natural Medicine], 2004, 10 , 1329-1335). BCL6 is required for the formation of follicular helper T cells (Hatzi et al., J Exp Med [Journal of Experimental Medicine],2015, 212(4), 539-553), which raised the possibility that BCL6 inhibitors could be used to treat angioimmunoblastic T-cell lymphoma (AITL), in which BCL6 is strongly expressed (Cortes & Palomero, Curr Opin Hematol [Latest Views in Hematology], 2016, 23 ,434-443).

[1041] BCL6 is also implicated in leukemic cells with acquired resistance to tyrosine kinase inhibitors (TKIs). TKIs typically fail to eradicate leukemia-initiating cells, which can often lead to leukemia relapse after initial treatment. BCL6 has been identified as a key regulator in Ph+ acute lymphoblastic leukemia (ALL) (Duy et al., Nature [Nature], 2011, 473 , 384-388) and Ph+ chronic myeloid leukemia (CML) (Hurtz et al., J Exp Med[Journal of Experimental Medicine] ,2011, 208(11) ,2163-2174) are important components of the TKI resistance pathway in both ALL and CML. Therefore, BCL6 can be combined with TKI for the treatment of ALL and CML.

[1042] Additional non-disseminated solid tumors may 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., 2011). Oncogene [Oncogene],2015, 34 , 1073-1082). BCL6 is also important for the survival and proliferation of non-small cell lung cancer (NSCLC) cells, mainly due to the expression of genes involved in DNA damage repair (Marullo et al., The 107th AACR Annual Meeting , 2016, Abstract nr1271 and Deb et al., Cancer Res., April 4, 2017 , doi:10.1158 / 0008-5472.CAN-15-3052). BCL6 amplification is also common in squamous cell carcinomas (SCC), including SCC of the head and neck, esophagus, lung, and ovary. In addition, inhibition of BCL6 has recently been reported to be a suitable therapeutic target for gliomas and glioblastomas (Xu et al., Proc. Natl. Acad. Sci. USA, 2017, 114(15) ,3981-3986).

[1043] According to another aspect of the specification, there is provided a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof for use in the treatment of hematological cancers such as lymphoma (including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma (BL) and angioimmunoblastic T-cell lymphoma (AITL), leukemia (including acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML)) and multiple myeloma, and solid tumors (including glioma, breast cancer, non-small cell lung cancer (NSCLC), and squamous cell carcinoma (SCC) (including SCC of the head and neck, esophagus, lung, and ovary)).

[1044] According to another feature of this aspect of the description, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment of lymphoma (including DLBCL, FL, BL, and AITL).

[1045] According to another feature of this aspect of the description, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment of DLBCL and FL.

[1046] According to another feature of this aspect of the description, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment of leukemia (including ALL and CML).

[1047] According to another feature of this aspect of the description, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein for use in the treatment of solid tumors (including glioma, breast cancer, NSCLC, and SCC).

[1048] According to another feature of this aspect of the description, there is provided a method for treating hematological cancers such as lymphomas (including DLBCL, FL, BL, and AITL), leukemias (including ALL and CML) and multiple myeloma, and solid tumors (including gliomas, breast cancer, NSCLC, and SCC (including SCC of the head and neck, esophagus, lung, and ovary) in a warm-blooded animal (such as a human) in need of such treatment, the method comprising administering an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[1049] According to another feature of this aspect of the description, there is provided a method for treating lymphoma (including DLBCL, FL, BL, and AITL) in a warm-blooded animal (such as a human) in need of such treatment, the method comprising administering an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[1050] According to another feature of this aspect of the description, there is provided a method for treating DLBCL and FL in a warm-blooded animal (such as a human) in need of such treatment, the method comprising administering an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[1051] According to another feature of this aspect of the description, there is provided a method for treating leukemia (including ALL and CML) in a warm-blooded animal (such as a human) in need of such treatment, the method comprising administering an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[1052] According to another feature of this aspect of the description, there is provided a method for treating solid tumors (including gliomas, breast cancer, NSCLC, and SCC (including SCC of the head and neck, esophagus, lung, and ovary) in a warm-blooded animal (such as a human) in need of such treatment, the method comprising administering an effective amount of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[1053] According to another feature of this aspect of the description, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of hematological cancers such as lymphomas (including DLBCL, FL, BL, and AITL), leukemias (including ALL and CML) and multiple myeloma, and solid tumors (including gliomas, breast cancer, NSCLC, and SCC (including SCC of the head and neck, esophagus, lung, and ovary).

[1054] According to another feature of this aspect of the description, there is provided use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of lymphoma (including DLBCL, FL, BL, and AITL).

[1055] According to another feature of this aspect of the description, there is provided use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of DLBCL and FL.

[1056] According to another feature of this aspect of the description, there is provided the use of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of leukemia (including ALL and CML).

[1057] According to another feature of this aspect of the description, there is provided a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for use in the treatment of solid tumors (including gliomas, breast cancer, NSCLC, and SCC (including SCC of the head and neck, esophagus, lung, and ovary).

[1058] Route of administration

[1059] The compounds of the invention, or pharmaceutical compositions comprising these compounds, may be administered to a subject by any convenient route of administration, whether systemically, peripherally or locally (ie, at the site of desired action).

[1060] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy, using, for example, via an aerosol, such as through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by implantation of a reservoir or depot, such as subcutaneous or intramuscular.

[1061] Combination therapy

[1062] The antiproliferative treatment defined above may be applied as the sole therapy or may involve conventional surgery or radiotherapy or chemotherapy in addition to the compounds of the invention. Such chemotherapy may include one or more of the following classes of antineoplastic agents:-

[1063] (i) other antiproliferative / antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, temozolomide, and nitrosoureas); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines (such as 5-fluorouracil and tegafur), raltitrexed, methotrexate, cytarabine, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines, such as aldosterone); antimitotic agents (e.g., vinca alkaloids (like vincristine, vinblastine, vindesine, and vinorelbine) and taxanes (like paclitaxel and taxotere) as well as polo kinase inhibitors); and topoisomerase inhibitors (e.g., epipodophyllotoxins (like etoposide and teniposide), amsacrine, topotecan, and camptothecin);

[1064] (ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), steroid hormones including progestins (e.g., megestrol acetate) and corticosteroids (e.g., dexamethasone, prednisone, and prednisolone), aromatase inhibitors (e.g., such as anastrozole, letrozole, vorazole and exemestane) and 5α-reductase inhibitors (such as finasteride);

[1065] (iii) anti-invasive agents [e.g. inhibitors of the c-Src kinase family like 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825); J.Med.Chem. ,2004, 47 , 6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to heparanase];

[1066] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin TM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab [Erbitux, C225], and any growth factor antibody or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in oncology / haematology [Critical Reviews in Oncology / Haematology], 2005, Vol. 54, pp. 11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 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); serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors such as farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), inhibitors of cell signaling through 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;

[1067] (v) anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM) and for example VEGF receptor tyrosine kinase inhibitors such as vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171; Example 240 in WO 00 / 47212), compounds such as those disclosed in International Patent Applications WO 97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds acting by other mechanisms (e.g. linomide, inhibitors of integrin αvβ3 function and angiostatin));

[1068] (vi) Vascular damaging agents such as Compretin A4 and compounds and international patent applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669,

[1069] Compounds disclosed in WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213;

[1070] (vii) endothelin receptor antagonists, for example zibotentan (ZD4054) or atrasentan;

[1071] (viii) antisense therapies, e.g., those directed against the targets listed above, such as ISIS2503 (an anti-ras antisense therapy);

[1072] (ix) gene therapy approaches, including, for example, approaches that replace abnormal genes, such as 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 tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; and

[1073] (x) Immunotherapy methods, including, for example, ex vivo and in vivo methods to increase the immunogenicity of a patient's tumor cells (such as transfection with cytokines (such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor)), methods to reduce T-cell anergy, methods using transfected immune cells such as cytokine-transfected dendritic cells, methods using cytokine-transfected tumor cell lines, and methods using anti-idiotypic antibodies.

[1074] In a particular embodiment, the antiproliferative treatment defined above may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy, wherein the chemotherapy may comprise one or more antineoplastic agents selected from the group consisting of procarbazine, carmustine, lomustine, irinotecan, temozolomide, cisplatin, carboplatin, methotrexate, etoposide, cyclophosphamide, ifosfamide and vincristine.

[1075] In another specific embodiment, the antiproliferative treatment defined above may involve, in addition to the compounds of the 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., Vicoclair and / or Navitox), BTK inhibitors (e.g., Ibrutinib, Acalabrutinib, Tirabrutinib (ONO / GS-4059), BGB-3111 or Spebrutinib (CC-292), TNF inhibitors (e.g., Lenalidomide) or EZH2 inhibitors (e.g., Tazmetostat, CPI-1205, PF-06821497, GSK126, GSK343 ​​or EPZ011989).

[1076] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[1077] According to this aspect of the invention there is provided a combination for use in the treatment of cancer (eg cancer involving solid tumours) comprising a compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.

[1078] According to this aspect of the invention, there is provided a combination for use in the treatment of a proliferative disorder such as cancer (e.g. cancer involving solid tumours), the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed above.

[1079] According to this aspect of the invention there is provided a combination for use in treating cancer, the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.

[1080] According to this aspect of the invention there is provided a combination for use in the treatment of leukaemias (such as ALL and CML) comprising a compound of the invention as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a tyrosine kinase inhibitor.

[1081] According to this aspect of the invention there is provided a combination for use in the treatment of lymphoma, the combination comprising a compound of the invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and an EZH2 inhibitor.

[1082] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with another anti-tumor agent for use in treating cancer, the other anti-tumor agent being optionally selected from one of the anti-tumor agents listed above.

[1083] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with a tyrosine kinase inhibitor, optionally selected from one of the tyrosine kinase inhibitors listed above, for use in treating cancer.

[1084] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with a tyrosine kinase inhibitor for use in treating leukemia (such as ALL and CML), the tyrosine kinase inhibitor being optionally selected from one of the tyrosine kinase inhibitors listed above.

[1085] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with an EZH2 inhibitor, optionally selected from one of the EZH2 inhibitors listed above, for use in treating cancer.

[1086] In another aspect of the present invention, there is provided a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with an EZH2 inhibitor for use in treating lymphoma, the EZH2 inhibitor being optionally selected from one of the EZH2 inhibitors listed above.

[1087] Here, where the term "combination" is used, it is to be understood that this refers to simultaneous administration, separate administration or sequential administration. In one aspect of the invention, "combination" refers to simultaneous administration. In another aspect of the invention, "combination" refers to separate administration. In another aspect of the invention, "combination" refers to sequential administration. When administered sequentially or separately, a delay in administering the second component should not result in a loss of the beneficial effects of the combination.

[1088] According to another aspect of the present invention, a pharmaceutical composition is provided, comprising a compound of the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof in combination with an anti-tumor agent (optionally selected from one of the anti-tumor agents listed above) in combination with a pharmaceutically acceptable diluent or carrier.

[1089] Examples

[1090] abbreviation

[1091] APCI Atmospheric Pressure Chemical Ionization

[1092] aq. water-based

[1093] Argon

[1094] br Broad peak (in NMR spectrum)

[1095] conc. concentrated d Doublet (in NMR spectrum)

[1096] dba dibenzylideneacetone

[1097] DCM Dichloromethane

[1098] DIPEA N,N-Diisopropylethylamine

[1099] DMA Dimethylacetamide

[1100] DMF N,N-Dimethylformamide

[1101] DMSO Dimethyl sulfoxide

[1102] ESI Electrospray ionization

[1103] Et 2 O Ether

[1104] EtOAc Ethyl acetate

[1105] EtOH

[1106] FID Free Induction Decay

[1107] h hour

[1108] HATU N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethylammonium hexafluorophosphate N-oxide

[1109] HPLC High Performance Liquid Chromatography

[1110] HRMS High Resolution Mass Spectrometry

[1111] KP-Sil Biotage KP-Sil (50uM irregular silicon)

[1112] LCMS Liquid chromatography and mass spectrometry

[1113] MeOH Methanol

[1114] MeCN Acetonitrile

[1115] MS mass spectrometry

[1116] Ms mesyl, methanesulfonyl

[1117] m Multiplet (in NMR spectrum)

[1118] MHz Megahertz

[1119] min

[1120] mins minutes

[1121] mL milliliters

[1122] m / z mass-to-charge ratio

[1123] NMP N-Methylpyrrolidone

[1124] NMR Nuclear Magnetic Resonance

[1125] Palladium on Pd / C activated carbon

[1126] ppm parts per million

[1127] q quartet (in NMR spectrum)

[1128] QToF Quadrupole Time of Flight

[1129] quin. Quintet (in NMR spectrum)

[1130] Rt, RT retention time (in LCMS)

[1131] rt room temperature

[1132] s Singlet (in NMR spectrum)

[1133] SCX-2 Strong cation exchange (e.g. SCX-2 column)

[1134] sex. Sextet (in NMR spectrum)

[1135] t triplet (in NMR spectrum)

[1136] Tf trifluoromethane sulfonate

[1137] TFA Trifluoroacetic acid

[1138] THF Tetrahydrofuran

[1139] T3P Propylphosphonic anhydride

[1140] uL microliter

[1141] UPLC Ultra-Performance Liquid Chromatography

[1142] Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[1143] Analytical method: LCMS

[1144] Method T2

[1145] LC / MS and HRMS analysis were performed on an Agilent 1200 series HPLC and a diode array detector coupled to a 6210 time-of-flight mass spectrometer with a dual multimode APCI / ESI source. Analytical separation was performed at 40°C on a Merck Chromolith fast column (RP-18e, 25x 2mm) (using a flow rate of 1.5mL / min, in a 2-minute gradient elution, detected at 254nm). 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: 5:95 (A / B) to 100:0 (A / B) over 1.25min, 100:0 (A / B) for 0.5min, and then recovered to 5:95 (A / B) over 0.05min, and finally 5:95 (A / B) for 0.2min.

[1146] Method T4

[1147] As method T2, except at 30 °C, using a flow rate of 0.75 mL / min, the gradient elution over 4 minutes was as follows: 5:95 (A / B) to 100:0 (A / B) over 2.5 min, 100:0 (A / B) for 1 min, and then recovered back to 5:95 (A / B) over 0.1 min, and finally 5:95 (A / B) for 0.4 min.

[1148] Method X2

[1149] LC / MS and HRMS analysis were performed on a Waters Acquity UPLC and a diode array detector coupled to a Waters G2QToF mass spectrometer equipped with a multi-mode ESI / APCI source. Analytical separations were performed at 30°C on a Phenomenex Kinetex C18 column (30 x 2.1 mm, 2.6 u, 100 A) (using a flow rate of 0.5 mL / min, in a 2-minute gradient elution, detected 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: 10:90 (A / B) to 90:10 (A / B) over 1.25 min, 90:10 (A / B) for 0.5 min, and then recovered to 10:90 (A / B) over 0.15 min, and finally 10:90 (A / B) for 0.1 min.

[1150] Method X4

[1151] As method X2, except using a flow rate of 0.3 mL / min, the gradient elution over 4 minutes was as follows: 10:90 (A / B) to 90:10 (A / B) over 3 min, 90:10 (A / B) for 0.5 min, and then recovered back to 10:90 (A / B) over 0.3 min, and finally 10:90 (A / B) for 0.2 min.

[1152] Analytical method: NMR

[1153] NMR data were collected on 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 C spectra were referenced to internal deuterated solvent. All NMR data were acquired at a temperature of 298 K. All data were acquired and processed using Bruker Topspin 2.1 or Bruker Topspin 4.

[1154] Acquired using a Bruker standard 1D zg30 pulse sequence with 16 scans 1 H NMR spectrum. Scan width 20.5 ppm and FID containing 64k time domain data points.

[1155] Purification methods

[1156] Unless otherwise stated in the text, preparative HPLC purifications were performed on an Agilent 6120MS-Prep LC using an ACE5C18-PFP 250 x 21.2 mm (or 30 mm) column using a 15 min gradient of water:methanol (both modified with 0.1% formic acid) - e.g. 90:10 to 0:100 or 60:40 to 0:100 - at 20 mL min -1 (or for 30mm column, 40mLmin -1 ) flow rate.

[1157] Flash column chromatography was performed using pre-packed Biotage SNAP KP-Sil columns. Reverse phase chromatography was performed using Biotage SNAP Ultra C-18 12 g and 30 g columns as required.

[1158] Example compounds

[1159] Example 1a: (S)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine -[2,3-c]quinolin-10-yl)amino)nicotinonitrile

[1160]

[1161] A microwave vial (0.5-2.0 mL volume) was charged with (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] quinoline-6 ​​(7H) -one (intermediate A1a, 9mg, 0.034mmol) and 2,4- dichloropyridine -3- carbonitrile (9mg, 0.054mmol). The reaction vial was rinsed with Ar, sealed with a lid, and further rinsed with Ar. Anhydrous NMP (0.6mL) was added followed by triethylamine (14uL, 0.10mmol). The reaction mixture was heated at 160 ° C for 90min under microwave irradiation. The reaction mixture was allowed to cool to room temperature, diluted with DMSO (0.8mL) and reversed phase chromatography (Baitez 12g C-18; in H 2 Direct purification from 10% to 100% MeOH in DOP (each containing 0.1% formic acid) afforded the title compound as an off-white solid (7 mg, 53%). 1 H NMR (600 MHz, methanol-d 4)δ7.98(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 2.58min; m / z for C 20 H 19 C1N 5 O 2 + [M+H] + Calculated value: 396.1222, measured value: 396.1215.

[1162] The examples in the following list were prepared by methods similar to those used to prepare Example 1a (starting from one or more intermediates shown in the table). For Example 1c, DIPEA was used instead of triethylamine and purified 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 was heated at 140°C for 4h under microwave irradiation.

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170] Example 2a: (S)-6-chloro-5-cyano-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxa-azepine [2,3-c]quinolin-10-yl)amino)picolinic acid

[1171]

[1172] A microwave vial (0.5-2.0 mL volume) was charged with (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] quinoline-6 ​​(7H) -one (intermediate A1a, 13mg, 0.049mmol) and 4,6- dichloro -5- cyanopyridine carboxylic acid (15mg, 0.071mmol). The reaction vial was rinsed with Ar, sealed with a lid, and further rinsed with Ar. Anhydrous NMP (0.5mL) was added and the reaction mixture was heated at 100 ° C for 2h. The reaction mixture was cooled to rt, diluted with DMSO (0.8mL) and filtered by reverse phase chromatography (Biotech reverse phase 12g C-18 column; in H 2 Direct purification by 10%-100% MeOH in DOP (containing 0.1% formic acid) afforded the title compound (13 mg, 61%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6 )δ13.67 (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; m / z for C 21 H 19 C1N 5 O 4 + [M+H] + Calculated value: 440.1120, measured value: 440.1114.

[1173] The examples listed below were prepared by methods analogous to those used to prepare Example 2a, starting from one or more of the intermediates shown in the table.

[1174]

[1175] Example 3a: (S)-6-(azetidine-1-carbonyl)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)amino)nicotinonitrile

[1176]

[1177] DIPEA (14 uL, 0.079 mmol) followed by T3P (50 wt% in EtOAc, 25 mg, 0.040 mmol) and azetidine (2 uL, 0.0282 mmol) were added sequentially to (S)-6-chloro-5-cyano-4-((2,7-dimethyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine) at rt. [2,3-c] quinoline-10-yl)amino)picolinic acid (Example 2a, 12 mg, 0.026 mmol) in DMF (0.5 mL). The reaction mixture was stirred at rt for 90 min. Water (8 drops) was added to quench the reaction. The aqueous suspension was dissolved in DMSO (0.8 mL) and purified by reverse phase chromatography (Biotech 12 g C-18 column; in H 2 Direct purification by 10%-100% MeOH in DOP (containing 0.1% formic acid) afforded the title compound as a yellow solid (4 mg, 29%). 1 H NMR (600 MHz, CDCl 3 )δ7.44-7.31 (m, 4H), 7.03 (s, 1H), 4.74-4.66 (m, 2H), 4.48-4.41 (m, 1H), 4.41-4.33 (m, 1H), 4.20-4.14 (m, 2H), 4.08-4.00 (m, 1H), 3.94-3.82 (m, 1H), 3.73 (s, 3H), 2.38-2.32 (m, 2H), 2.29-2.21 (m, 1H), 1.85-1.78 (m, 1H), 1.39 (d, J=6.1 Hz, 3H); LCMS (method T4) RT 2.77 min; m / z for C 24 H 24 C1N 6 O 3 + [M+H] + Calculated value: 479.1593, measured value: 479.1578.

[1178] The examples listed below were prepared by methods analogous to those used to prepare Example 3a, starting from one or more of the intermediates shown in the table and the appropriate amine.

[1179]

[1180] Example 4a: (S)-10-((2,3-dichloropyridin-4-yl)amino)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1181]

[1182] A microwave vial (0.5-2.0 mL volume) was charged with (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-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), Pd 2 (dba) 3 To the 4-nitro-2-yl pyridine ... 2 SO 4 ) and concentrated in vacuo. The crude product was dissolved in DMSO (1.2 mL) and purified by reverse phase chromatography (Bioteqi reverse phase 12 g C-18 column; at H 2 Direct purification using 10%-100% MeOH in DOP (containing 0.1% formic acid) provided the title compound as an off-white solid (5 mg, 48%). 1 H NMR (600 MHz, methanol-d 4 )δ7.91(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 2.72min; m / z for C 19 H 19 Cl 2 N 4 O 2 +[M+H] + Calculated value: 405.0880, measured value: 405.0879.

[1183] The examples in the following list were prepared by methods similar to those used to prepare Example 4a (starting from one or more intermediates as indicated in the table). Example 4b was purified by preparative HPLC. For Example 4d, the reaction mixture was heated at 80°C for 4h under microwave irradiation.

[1184]

[1185]

[1186] 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]oxazepine [2,3-c]Quinolin-6(7H)-one

[1187]

[1188] Step 1: (R)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro- [1,4]Oxaza [2,3-c]Quinolin-6(7H)-one

[1189] An oven-dried microwave vial (0.5-2.0 mL volume) was charged with (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] quinoline-6 ​​(7H) -one (intermediate A1d, 19 mg, 0.065 mmol) and 2,4,5-trichloropyrimidine (20 mg, 0.110 mmol). The reaction vial was rinsed with Ar, sealed with a lid, and further rinsed with Ar. Anhydrous NMP (0.65 mL) was added followed by DIPEA (45 uL, 0.26 mmol). The reaction mixture was heated at 140 ° C for 1 h under microwave irradiation. The reaction mixture was cooled to rt, diluted with DMSO (0.8 mL) and purified by reverse phase chromatography (Biotech reverse phase 12 g C-18 column; at H 2 D (containing 0.1% formic acid) to provide (R)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine as a red / brown solid [2,3-c]Quinolin-6(7H)-one (24 mg, 84%). LCMS (Method X2) RT 1.42 min; m / z 432.1000 [M+H] + .

[1190] Step 2: (R)-10-((5-chloro-2-(3-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-4-yl)amino)-2-cyclopentane Propyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1191] A microwave vial (0.5-2.0 mL volume) was charged with (R)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] quinoline-6 ​​(7H) -one (from step 1; 9mg, 0.021mmol), 3- (trifluoromethyl) -1H- pyrazole (28mg, 0.207mmol) and cesium carbonate (67mg, 0.204mmol). The reaction vial was rinsed with Ar, sealed with a lid, and further rinsed with Ar. Anhydrous NMP (0.8mL) was added. The reaction mixture was heated at 180 ° C for 1h under microwave radiation. The reaction mixture was cooled to rt, diluted with DMSO (0.8mL) and filtered by reverse phase chromatography (Biotech reverse phase 12g C-18 column; in H 2 Direct purification by 10%-50%-100% MeOH in DOP (containing 0.1% formic acid) afforded the title compound as a beige solid (7 mg, 62%). 1 H NMR (600 MHz, CDCl 3 )δ8.48(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, 3.3 Hz, 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; m / z for C 24 H 22 CIF 3 N7 O 2 + [M+H] + Calculated value: 532.1475, measured value: 532.1500.

[1192] The examples in the following list were prepared by a method similar to that used to prepare Example 5a (starting from one or more intermediates shown in the table and appropriate amine). No purification was performed in step 1 in Examples 5b-5h, 5k, and 5p-5t. In Examples 5d-5i and 5k-5t, DIPEA was used to replace cesium carbonate. Examples 5c-5f were purified by preparative HPLC.

[1193]

[1194]

[1195]

[1196]

[1197]

[1198]

[1199]

[1200] Example 5u: (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1201]

[1202] A microwave vial (0.5-2.0 mL volume) was charged with (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (Intermediate A5b; 6.5 mg, 0.017 mmol) and DIPEA (12 uL, 0.069 mmol). A solution of (1R,5S,7s)-9-(5-chloro-4-(methylsulfinyl)pyrimidin-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 and the vial was flushed with Ar and sealed with a cap. The reaction mixture was heated at 140 °C for 18 h in a heating block. Thereafter, the reaction mixture was cooled to rt and additional DIPEA (20 uL, 0.11 mmol) was added. The vial was resealed with a cap and heated at 140 °C for another 6 h in a heating block. The reaction mixture was cooled to rt and concentrated in vacuo. The reaction mixture was dissolved in DMSO (1 mL) and purified by reverse phase chromatography (Biotek reverse phase 12 g C-18 column; in H 2 The crude product was further purified by flash chromatography (10 g KP-sil; 50% to 100% EtOAc in cyclohexane, followed by 0% to 20% MeOH in EtOAc) to provide an off-white solid. The solid was dissolved in MeOH and passed through an SCX-2 (1 g) column, eluting with MeOH (15 mL) followed by 2N methanolic ammonia (20 mL). The basic fraction was concentrated in vacuo to provide the title compound (1.8 mg, 17%) as an off-white solid. 1 H NMR (600 MHz, methanol-d 4 )δ8.01(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. 2Hz,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, 3.6 Hz, 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; m / z for C31 H 36 CIF 2 N 6 O 4 + [M+H] + Calculated value: 629.2449, measured value: 629.2436.

[1203] Example 6a: (S)-2-chloro-4-((2,7-dimethyl-5,6-dioxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine- [6,5-c]quinolin-10-yl)amino)nicotinonitrile

[1204]

[1205] DIPEA (10 uL, 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]oxazepine A suspension of [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 h under microwave irradiation. The crude reaction mixture was purified by preparative HPLC (15 min 60:40 to 0:100 H 2 O: MeOH (modified with 0.1% formic acid) gradient; flow rate 20 mL min -1 ) was directly purified to provide the title compound as a light brown solid (1 mg, 10%), which was subsequently purified with Et 2 O Wash and dry. 1 H NMR (500 MHz, DMF-d 7 )δ8.43(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,1 H), 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 2.35min; m / z for C 20 H 17 C1N 5 O 3 +Calculated for [M+H]+: 410.1014, found: 410.1007.

[1206] The examples listed below were prepared by methods analogous to those used to prepare Example 6a, starting from one or more of the intermediates shown in the table.

[1207]

[1208]

[1209] Example 7a: (S)-10-((5-chloro-2-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]Quinoline-5,6(1H,7H)-dione

[1210]

[1211] Cesium carbonate (95 mg, 0.293 mmol), Xantphos (13 mg, 0.022 mmol), (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [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 Pd 2 (dba) 3 A mixture of 4-(4-(4-nitropropene)-2-nitropropene (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 h under microwave irradiation. The reaction mixture was allowed to cool to room temperature. The suspension was filtered, and the filtrate was diluted with water and extracted with EtOAc. The organic extracts were combined, dried (Na 2 O) and purified by HPLC. 2 SO 4 ) and concentrated in vacuo. The product was purified by preparative HPLC (15 min 60:40 to 0:100 H 2 O: MeOH (modified with 0.1% formic acid) gradient; flow rate 20 mL min -1 ) provided the title compound (4 mg, 23%) as a light yellow solid. 1 H NMR (600 MHz, DMF-d 7)δ8.50(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, 4.1 Hz, 1H), 4.81 (dd, J = 12.9, 1.6 Hz, 1H), 4.65 (dd, J = 12.9, 5.6 Hz, 1H), 4.32-4.23 (m, 1H), 4.02 (dt, J = 11.5, 4.4 Hz, 2H), 3.81 (s, 3H), 3.67 (ddd, J = 11.5, 9.4, 2.8 Hz, 2H), 2.21-2.07 (m, 2H), 1.83-1.70 (m, 2H), 1.54 (d, J = 6.6 Hz, 3H); LCMS (method X4) RT 2.49 min; m / z for C 24 H 26 C1N 4 O 5 + [M+H] + Calculated value: 485.1586, measured value: 485.1542.

[1212] Example 8a: (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]Quinoline-5,6(1H,7H)-dione

[1213]

[1214] Step 1: (S)-10-((2,5-dichloropyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxaplanin Aza -[6,5-c]quinoline-5,6(1H,7H)-dione

[1215] 2,4,5-trichloropyrimidine (12 mg, 0.066 mmol), (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine A suspension of [6,5-c]quinoline-5,6(1H,7H)-dione (Intermediate B1a, 20 mg, 0.073 mmol) and DIPEA (20 uL, 0.110 mmol) in NMP (1.5 mL) was stirred at 140 °C for 1 h under microwave irradiation. The reaction mixture of [6,5-c]quinoline-5,6(1H,7H)-dione was divided into aliquots and used in the next step without further purification. LCMS (Method T2) RT 1.27 min; m / z 420.1 [M+H] + .

[1216] Step 2: (S)-10-((5-chloro-2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)amino)-2,7- Dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]Quinoline-5,6(1H,7H)-dione

[1217] The crude (S)-10-((2,5-dichloropyrimidin-4-yl)amino)-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine A mixture of [6,5-c]quinoline-5,6(1H,7H)-dione (from step 1; 5 mg, 0.012 mmol), (2R,6S)-2,6-dimethylmorpholine (7 mg, 0.060 mmol), and DIPEA (6 uL, 0.036 mmol) in NMP (1.5 mL) was stirred at 140 °C for 1 h under microwave irradiation. The crude reaction mixture was purified by preparative HPLC (3 times; 15 min 60:40 to 0:100 H 2 O: MeOH (modified with 0.1% formic acid) gradient; flow rate 20 mL min -1 ) was directly purified to provide the title compound as a brown oil (2 mg, 34% over 2 steps). 1 H NMR (600 MHz, methanol-d 4 )δ8.20(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 2.55min; m / z for C 24 H 28 C1N 6 O 4 + [M+H] + Calculated value: 499.1855, measured value: 499.1827.

[1218] The examples listed below were prepared by methods analogous to those used to prepare Example 8a, starting from one or more of the intermediates shown in the table and the appropriate amine.

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225] The following list of examples were prepared by methods similar to those used to prepare Example 8a. Example 8p and Example 8q represent a pair of diastereoisomers, in the presence of oxazazepine One of the rings is cis and one is trans. The compound was purified by preparative HPLC (15 min 60:40 to 0:100 H 2 O: MeOH (modified with 0.1% formic acid) gradient; flow rate 20 mL min -1 ) was separated, eluting first with Example 8p followed by addition of Example 8q. It was not clearly determined which was the cis structure and which was the trans structure. Both compounds were racemic.

[1226]

[1227]

[1228] Example 9a: (S)-2-chloro-4-((2,7-dimethyl-6-oxo-1,2,3,5,6,7-hexahydro-[1,4]oxazepine- [6,5-c]quinolin-10-yl)amino)nicotinonitrile

[1229]

[1230] DIPEA (7 uL, 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]oxazepine A suspension of [6,5-c]quinolin-6(1H)-one (Intermediate B2a, 4 mg, 0.014 mmol) in NMP (1.5 mL) was stirred at 160 °C for 1 h under microwave irradiation. The crude reaction mixture was purified by preparative HPLC (15 min 60:40 to 0:100 H 2 O: MeOH (modified with 0.1% formic acid) gradient; flow rate 20 mL min -1 ) was directly purified to provide the title compound (1 mg, 19%) as a yellow solid. 1 H NMR (600 MHz, methanol-d 4 )δ8.06(d,J=2.2Hz,1H),8.00(d,J=6.2Hz,1H),7.65(d,J=8.9Hz,1H),7.5 8(dd,J=8.9,2.2Hz,1H),6.71(d,J=6.2Hz,1H),4.94(d,J=14.4Hz,1H),4.8 4(d,J=14.4Hz,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; m / z for C 20 H 19 C1N 5 O 2 +[M+H] + Calculated value: 396.1222, measured value: 396.1214.

[1231] The examples listed below were prepared by methods analogous to those used to prepare Example 9a, starting from one or more of the intermediates shown in the table and the appropriate amine.

[1232]

[1233] Example 10a: 2-Chloro-4-((2,6-dimethyl-5-oxo-1,2,3,4,5,6-hexahydrobenzo[h][1,6]-naphthyridin-9-yl)amino)nicotinonitrile

[1234]

[1235] 2,4-dichloropyridine-3-carbonitrile (11mg, 0.06mmol), NMP (0.51mL) and triethylamine (14uL, 0.10mmol) were added to a microwave vial (volume of 0.5-2.0mL) containing 9-amino-2,6-dimethyl-2,3,4,6-tetrahydrobenzo[h][1,6]naphthyridine-5(1H)-one (intermediate C1; 12mg, 0.05mmol). The vial was sealed and purged with argon for 5min. The vial was then heated at 160°C for 1h under microwave irradiation. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with MeCN and purified by preparative HPLC (15min 60:40 to 0:100H 2 O: MeOH (modified with 0.1% formic acid) gradient; flow rate 20 mL min -1 ) was directly purified to provide the title compound (10 mg, 51%) as an off-white solid. 1 H NMR (500 MHz, CDCl 3 )δ8.04 (d, J=6.1 Hz, 1H), 7.44-7.37 (m, 3H), 6.92 (s, 1H), 6.59 (d, J=6.1 Hz, 1H), 4.51 (s, 1H), 3.70 (s, 3H), 3.58-3.47 (m, 1H), 2.86 (ddd, J=17.6, 5.3, 3.9 Hz, 1H), 2.60 (ddd, J=17.6, 10.5, 5.9 Hz, 1H), 2.09-2.00 (m, 1H), 1.69-1.52 (m, 1H), 1.34 (d, J=6.4 Hz, 3H); LCMS (method X4) RT 2.60 min; m / z for C 20 H 19 C1N 5 O + [M+H] + Calculated value: 380.1278, measured value: 380.1280.

[1236] Example 11a: 10-((5-chloro-2-((1R,5S,7s)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1237]

[1238] A microwave vial (0.5-2.0 mL volume) was charged with 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (Intermediate A11; 15 mg, 0.047 mmol) and (1R,5S,7s)-9-(5-chloro-4-(methylsulfonyl)-pyrimidin-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 uL, 0.052 mmol). The reaction vial was flushed with Ar and sealed with a cap. The reaction mixture was heated at 70 °C for 18 h in a heating block. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was redissolved in DMSO (1 mL) and purified by reverse phase chromatography (Bioteqi reverse phase 12g-C-18 column; at H 2 Direct purification by 10%-100% MeOH in D2O (containing 0.1% formic acid) afforded the title compound as an off-white solid (7 mg, 27%). 1 H NMR (600 MHz, methanol-d 4 )δ8.02-7.99(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 2.95min; m / z for C 27 H 30 CIF 2 N 6 O 4 + [M+H] + Calculated value: 575.1985, measured value: 575.1973.

[1239] The examples listed below were prepared by methods analogous to those used to prepare Example 11a, starting from one or more of the intermediates shown in the table and the appropriate amine.

[1240]

[1241] Example 11c: (S)-10-((5-chloro-2-((1R,5S,7R)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]-non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1242]

[1243] A microwave vial (2-5 mL volume) was charged with (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (Intermediate A1m; 29 mg, 0.09 mmol) and (1R,5S,7s)-9-(5-chloro-4-(methylsulfonyl)-pyrimidin-2-yl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-ol (Intermediate J2; 36 mg, 0.11 mmol). Trifluoroethanol (1.0 mL) was added followed by trifluoroacetic acid (7.7 uL, 0.10 mmol). The reaction vial was flushed with Ar and sealed with a cap. The reaction mixture was heated at 70 °C for 20 h in a heating block. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was redissolved in DMSO (1 mL) and purified by reverse phase chromatography (Bioteqi reverse phase 12g-C-18 column; at H 2 The product was purified directly by 10%-100% MeOH in 4% 4H2O (containing 0.1% formic acid). The fractions containing the product were passed through an SCX-2 (2 g) column, eluting with MeOH (15 mL) followed by 2N methanolic ammonia (30 mL). The basic fractions were concentrated in vacuo to afford the title compound (16 mg, 31%) as an off-white solid. 1 H NMR (600 MHz, methanol-d 4)δ8.02-7.99(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 2.98min; m / z for C 27 H 30 CIF 2 N 6 O 4 + [M+H] + Calculated value: 575.1985, measured value: 575.1987.

[1244] Example 12a: (S)-10-((5-chloro-2-(4-methyl-3-oxopiperazin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1245]

[1246] To an oven-dried microwave vial (0.5-2.0 mL volume) was charged (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] quinoline-6 ​​(7H) -one (intermediate A10a; 7mg, 0.015mmol), 1-methylpiperazine-2-one (4mg, 0.037mmol), and DIPEA (13uL, 0.075mmol). The reaction vial was rinsed with Ar and sealed with a cap. NMP (0.65mL) was added and the reaction mixture was heated at 140 ° C for 1h under microwave irradiation. The reaction mixture was dissolved in DMSO (0.8mL) and was purified by reverse phase chromatography (Biotech reverse phase 12g ultra C-18 column; in H 2The product was purified directly by 10%-60%-80%-100% MeOH (containing 0.1% formic acid) in 4% dHO. The fractions containing the product were combined, passed through SCX-2 (1 g), additional MeOH (10 mL) was passed through, and the product was eluted with 2N methanolic ammonia (25 mL). The solvent was removed in vacuo to provide the title compound (5 mg, 57%) as an off-white solid. 1 HNMR (600 MHz, methanol-d 4 )δ8.04(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; m / z for C 25 H 27 CIF 2 N 7 O 3 + [M+H] + Calculated value: 546.1832, measured value: 546.18342.

[1247] The examples in the following list were prepared by methods similar to those used to prepare Example 12a (starting from one or more intermediates shown in the table and the appropriate amine). For Example 12c, Example 12d, Example 12e, and Example 12u, the reaction was heated in a heating block at 140°C for 2-3h. For Example 12f, Example 12i, Example 12p, Example 12s, Example 12t, and Example 12x, the reaction was heated at 140°C for 90min-3h under microwave irradiation. For Example 12n and Example 12o, the reaction was heated at 140°C for 1h under microwave irradiation, followed by heating at 140°C for 4h in a heating block. For Example 12v, the reaction was heated at 140°C for 6h in a heating block. For Example 12h, the reaction was heated in a heating block at 160°C overnight. For Example 12j and Example 12w, the reaction was heated at 160°C for 10-12h under microwave irradiation. For Example 12c and Example 12d, no SCX-2 purification step was performed. Example 12h and Example 12x required an additional purification step by normal phase chromatography.

[1248]

[1249]

[1250]

[1251]

[1252]

[1253]

[1254]

[1255]

[1256]

[1257]

[1258]

[1259] By a method similar to that used to prepare Example 12a (from Intermediate A10b: (R)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxa-azepine [2,3-c] quinoline-6 ​​(7H) -one and racemic -4,4- difluoropiperidin-3-ol hydrochloride) were used to prepare the following examples. Example 12y and Example 12z represent a pair of enantiomers, one of which is (R) -piperidinol and the other is (S) -piperidinol. It has not yet been determined which is the (R) -enantiomer and which is the (S) -enantiomer. The following method was used to separate the compounds by preparative chiral SFC. In EtOH: CH 2 Cl 2 The racemic mixture was dissolved to 9 mg / mL in (5:4) and then purified by SFC (Lux A1 (21.2 mm x 250 mm, 5 μm), 40:60 EtOH:CO 2 (0.2% v / v NH 3 ); flow rate 50mLmin -1) was purified. The earlier eluting enantiomer was confirmed as Example 12y and the later eluting enantiomer was confirmed as Example 12z. The combined fractions were then concentrated in vacuo and then stored in a vacuum oven at 35 ° C and 5 mbar to provide Example 12y (19 mg) and Example 12z (17 mg) as white solids. The product was purified by SFC (Amy-C (4.6 mm x 250 mm, 5 μm), 40:60 EtOH:CO 2 (0.2% v / v NH 3 ); flow rate 4mLmin -1 ) to confirm chiral purity analysis.

[1260]

[1261]

[1262] The examples in the following list were prepared by a method similar to that used to prepare Example 12a (starting from one or more intermediates shown in the table and appropriate amines). For Example 13a, the reaction was heated at 140°C for 8h under microwave irradiation. For Example 13b and Example 13c, the reaction was heated at 160°C for 8h and 12h respectively under microwave irradiation. For Example 13f, the reaction was heated at 120°C for 1h under microwave irradiation. For Example 13g and Example 13h, acetonitrile was used to replace NMP and the reaction was heated at 80°C for 1h and 12h respectively in a heating block. For Example 13i, the reaction was heated at 140°C for 10h under microwave irradiation. For Example 13j, the reaction was heated at 140°C for 46h in a heating block. For Example 13a-Example 13c, purification was performed using preparative HPLC. Example 13b was separated into a mixture of diastereomers. Example 13c was isolated as a mixture of endo- and exo-isomers. For Examples 13g and 13h, the SCX-2 purification step was not performed.

[1263]

[1264]

[1265]

[1266]

[1267]

[1268]

[1269] Example 14a: (R)-10-((5-chloro-2-((S)-4,4-difluoro-3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one or (R)-10-((5-chloro-2-((R)-4,4-difluoro-3-methylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1270]

[1271] A 5-well plate containing (S)-4,5-dichloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidine or (R)-4,5-dichloro-2-(4,4-difluoro-3-methylpiperidin-1-yl)pyrimidine (Intermediate L2a; 10 mg, 0.035 mmol), DIPEA (20 uL, 0.089 mmol), and (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine in NMP (0.56 mL) was added. A vial of [2,3-c]quinolin-6(7H)-one (Intermediate A1d; 10 mg, 0.035 mmol) was heated at 140 °C for 3 h under microwave irradiation. The reaction mixture was purified by reverse phase chromatography (Biotec 12 g Ultra C-18 column; H 2 45%-100% MeOH in 2% dHO (containing 0.1% formic acid) was directly purified. To the resulting mixture was added (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine- [2,3-c]quinolin-6(7H)-one (Intermediate A1d; 10 mg, 0.035 mmol), NMP (0.56 mL), and 3M aqueous HCl (0.1 mL), and the reaction was heated in a heating block at 80° C. for 22 h. The reaction mixture was purified by reverse phase chromatography (Biotec reverse phase 12 g Ultra C-18 column; at H 2 Direct purification with 45%-100% MeOH in DOP (containing 0.1% formic acid) afforded the title compound as a grey solid (4 mg, 21%). 1 H NMR (600 MHz, methanol-d 4)δ8.34(s,1H),8.18(s,1H),7.91(dd,J=9.2,2.0Hz,1H),7.84(dd,J=9.2,2.0Hz,1H),4.52-4.44(m, 1H),4.41-4.34(m,1H),4.20(d,J=13.9Hz,1H),4.10(d,J=13.0Hz,1H),3.89(d,J=1.5Hz,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; m / z for C 26 H 30 CIF 2 N 6 O 2 + [M+H] + Calculated value: 531.2087, measured value: 531.2091.

[1272] The examples in the following list were prepared by methods analogous to those used to prepare Example 14a, starting from one or more of the intermediates shown in the table.

[1273]

[1274] Example 15a: (R)-10-((5-chloro-2-((1R,5S,7S)-7-hydroxy-3-oxa-9-azabicyclo[3.3.1]-non-9-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c]Quinolin-6(7H)-one

[1275]

[1276] To (R)-N-(2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine To a solution of [2,3-c]quinolin-10-yl)formamide (Intermediate A8c; 5 mg, 0.015 mmol) in THF (0.30 mL) was added sodium hydride (60% dispersion in mineral oil; 10 mg, 0.25 mmol). The mixture was stirred for 15 min then cooled to 0 °C and (1R,5S,7s)-9-(5-chloro-4-(methylsulfonyl)pyrimidin-2-yl)-3-oxa-9-azabicyclo[3.3.1]-nonan-7-ol (Intermediate J2; 15 mg, 0.045 mmol) was added. The mixture was stirred at 0 °C for 1 hour. THF (0.3 mL) and sodium hydride (60% dispersion in mineral oil; 10 mg, 0.25 mmol) were further added and the mixture was warmed to rt and stirred overnight. The mixture was then heated at 60 °C in a sealed vial for 3 h. The reaction mixture was cooled to rt, water was carefully added to the mixture, and then it was concentrated to remove THF. The residue was diluted with DMSO (1.2 mL) and purified by reverse phase chromatography (Biotech 12 g ultra C-18 column; at H 2 Direct purification was performed using 10%-100% MeOH in D2O (containing 0.1% formic acid). Fractions containing product were combined, passed through SCX-2 (2 g) and the product eluted with 2N methanolic ammonia. The solvent was removed in vacuo to afford the title compound as a light yellow solid (3 mg, 36%). 1 H NMR (600 MHz, CDCl 3 )δ8.03(s,1H),7.74-7.61(m,1H),7.56(s,1H),7.30(d,J=9.0Hz,1H),7.06(s,1H),5.67-5.53(m,1H), 4.74-4.65(m,1H),4.54-4.46(m,1H),4.33-4.29(m,1H),3.98-3.89(m,4H),3.83-3.78(m,2H),3.75-3. 69 (m, 1H), 3.69 (s, 3H), 2.95 (dd, J = 14.6, 6.2 Hz, 1H), 2.27-2.15 (m, 3H), 2.06-1.98 (m, 1H), 1.92-1.83 (m, 2H), 1.03-0.94 (m, 1H), 0.75-0.66 (m, 1H), 0.62-0.54 (m, 1H), 0.44-0.37 (m, 1H), 0.31-0.22 (m, 1H). LCMS (method T4) RT 2.93 min; m / z for C 27 H 32 C1N 6 O 3 S + [M+H] +Calculated value: 555.1940, measured value: 555.1931.

[1277] The examples in the following list were prepared by methods similar to those used to prepare Example 15a (starting from one or more of the intermediates shown in the table and the appropriately substituted pyrimidine). For Examples 15b and 15c, the reaction was stirred at 60°C immediately after the addition of the sulfone. Additionally, due to the hydrolysis of the sulfone starting material under the reaction conditions, additional equivalents of sulfone were added sequentially to achieve higher conversions to the desired product.

[1278]

[1279]

[1280] Example 16a: (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-(2-hydroxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1281]

[1282] Sodium borohydride (1.4 mg, 0.037 mmol) was added to 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepine at 0 °C under Ar. [2,3-c]quinolin-7(2H)-yl)acetaldehyde (Intermediate A12a; 5.4 mg, 0.009 mmol) was stirred in anhydrous methanol (0.5 mL). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was washed with saturated aqueous NaHCO 3 The mixture was quenched with 1% paraformaldehyde (0.1 mL) and stirred for 15 min. DMSO (0.5 mL) was added and the reaction mixture was concentrated in vacuo to remove MeOH. The crude reaction mixture in DMSO (additional 0.6 mL of DMSO was used to wash the vial) was subjected to reverse phase chromatography (Biotech reverse phase 12 g ultra C-18 column; in H 2 Direct purification by 10%-30%-100% MeOH in DOP (containing 0.1% formic acid) afforded the title compound as an off-white solid (4 mg, 76%). 1 H NMR (600 MHz, methanol-d 4)δ8.01(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 3.46min; m / z for C 28 H 34 CIF 2 N 6 O 3 + [M+H] + Calculated value: 575.2349, measured value: 575.2351.

[1283] Example 17a: (R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-7-(2-(methylamino)ethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1284]

[1285] Under Ar, methylamine (2 M in THF; 0.20 mL, 0.400 mmol) was added to 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-7(2H)-yl)acetaldehyde (Intermediate A12a; 6.5 mg, 0.011 mmol) was in a stirred solution in THF (0.2 mL). The reaction mixture was stirred at rt for 5 min. Sodium triacetoxyborohydride (6.0 mg, 0.028 mmol) was added and the reaction mixture was stirred at 25 °C for 3 d. Thereafter, DCE (0.5 mL) was added along with additional methylamine (2 M in THF; 1.5 mL) and sodium triacetoxyborohydride (22 mg, 0.1 mmol). The reaction mixture was stirred at 25 °C for an additional 18 h. Thereafter, additional methylamine (2 M in THF; 0.5 mL) was added followed by sodium acetate (12 mg) and sodium triacetoxyborohydride (19 mg). The reaction mixture was stirred at 45 °C for 24 h. Thereafter, a few drops of water were added and the reaction mixture was concentrated in vacuo. The crude reaction mixture was redissolved in DMSO (0.8 mL) and purified by reverse phase chromatography (Biotec reverse phase 12 g Ultra C-18 column; in H 2 Direct purification with 10%-30%-100% MeOH (containing 0.1% formic acid) in 0.5% ethanol provided a mixture of products. Fractions containing product were combined, concentrated in vacuo and purified by flash chromatography (pipette column, in CH 2 Cl 2 Repurification by 0%-5%-10%-25% MeOH in PBS (0%-5%-10%-25% MeOH in PBS) provided the title compound as an off-white solid (1 mg, 13%). 1 H NMR (600 MHz, methanol-d 4 )δ8.11(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,2 H),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,1 H), 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=6.7 Hz, 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; m / z for C 29 H 37 CIF 2 N 7 O 2+ [M+H] + Calculated value: 588.2660, measured value: 588.2671.

[1286] Example 18a: 2-Chloro-4-((2,7-dimethyl-5,6-dioxo-2,3,4,5,6,7-hexahydro-1H-[1,4]diazepine [6,5-c]quinolin-10-yl)amino)nicotinonitrile

[1287]

[1288] To a solution of ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-6-((2-chloro-3-cyanopyridin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (Intermediate B3a; 62 mg, 0.11 mmol) in THF (2 mL) was added 4M HCl in dioxane (279 uL, 1.12 mmol) and the reaction mixture was heated to 70 °C for 15 min. Further 4M HCl in dioxane (279 uL, 1.12 mmol) was added and heating was continued for 90 min. The acidic reaction mixture was quenched with triethylamine (389 uL, 2.79 mmol) and heated at 70 °C overnight. The reaction mixture was cooled to rt and diluted with water. The organic solvent was removed in vacuo and the reaction mixture was purified by reverse phase chromatography (Bioteqi reverse phase 12g Ultra C-18 column; in H 2 Purification by 5%-50% MeOH in D2O (containing 0.1% formic acid) provided the title compound (9 mg, 18%) as an off-white solid. 1 HNMR (500 MHz, methanol-d 4 )δ8.03-8.01 (m, 1H), 8.00 (d, J = 6.2 Hz, 1H), 7.62-7.61 (m, 2H), 6.71 (d, J = 6.2 Hz, 1H), 3.97-3.93 (m, 1H), 3.67 (s, 3H), 3.58 (dd, J = 13.4, 1.7 Hz, 1H), 3.39-3.27 (m, 1H), 1.32 (d, J = 6.5 Hz, 3H); LCMS (method X4) RT 2.01 min; m / z for C 20 H 18 C1N 6 O 2 + [M+H] + Calculated value: 409.1180, measured value: 409.1088.

[1289] Intermediate CompoundsIntermediate A1a: (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1290]

[1291] Step 1: (S)-4-((4-Hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one

[1292] Into a dried microwave vial (volume of 10-20 mL) was charged 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). The reaction vial was flushed with Ar, sealed with a cap, and further flushed with Ar. Anhydrous NMP (10 mL) was added followed by DIPEA (1.2 mL, 6.9 mmol). The reaction mixture was heated at 160 ° C for 20 h in a heating block. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with water (100 mL) and the aqueous mixture was extracted with EtOAc (100 mL). The organic extract was washed with water (2x 25 mL). The aqueous washes were combined and further extracted with EtOAc (3x 50 mL). The organic extracts were combined, dried (Na 2 SO 4 ) and concentrated in vacuo. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography (50 g KP-sil; in CH 2 Cl 2 Purification by 0% to 10% MeOH in 4% ethanol (5% to 10% MeOH in 4% ethanol) provided (S)-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one as a yellow solid (547 mg, 56%). 1 H NMR (500 MHz, DMSO-d 6 )δ9.11(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).

[1293] Step 2: (S)-3-Bromo-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one

[1294] Trifluoroacetic acid (0.72 mL, 9.4 mmol) was added to N-bromosuccinimide (509 mg, 2.9 mmol) and (S)-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (from step 1; 547 mg, 1.9 mmol) in anhydrous CHCl at 0 °C under Ar. 2 Cl 2 The reaction mixture was stirred at 0 °C for 10 min and then at rt for 30 min. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (30 mL) followed by saturated aqueous NaHCO 3 The aqueous washes were combined and further extracted with EtOAc (30 mL). The organic extracts were combined, dried (Na 2 SO 4 ) and concentrated in vacuo. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography (25 g KP-sil; in CH 2 Cl 2 Purification by 0% to 10% MeOH in 4% ethanol (5% to 10% MeOH) provided (S)-3-bromo-4-((4-hydroxybutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one as a yellow solid (532 mg, 77%). 1 H NMR (500 MHz, DMSO-d 6 )δ8.89(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, 1H), 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).

[1295] Step 3: (S)-2,7-Dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinoline- 6(7H)-Keto

[1296] (S)-3-bromo-4-((4-hydroxybutyl-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (from step 2; 111 mg, 0.30 mmol) was loaded into a dried microwave vial (volume of 2.0-5.0 mL). The reaction vial was rinsed with Ar, sealed with a lid, and further rinsed 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 at 60 ° C for 50 min under microwave irradiation. The reaction mixture was allowed to cool to room temperature. Water (10 mL) was added followed by EtOAc (10 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (10 mL). The organic extracts were combined and concentrated in vacuo. The crude product was dissolved in DMSO (1.2 mL) and purified by reverse phase chromatography (Biotech 12 g C-18 column; in H 2 D (containing 0.1% formic acid) to provide (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine as a dark yellow solid [2,3-c]Quinolin-6(7H)-one (36 mg, 41%). 1 H NMR (600 MHz, CDCl 3 )δ8.93(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(brs,1H),3.76(s,3H),2.23-2.26(m,1H),1.91-1.84(m,1H),1.47(d,J=6.3Hz,3H).

[1297] Step 4: (S)-10-amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinoline- 6(7H)-Keto

[1298] A microwave vial (0.5-2.0 mL volume) was charged with (S)-2,7-dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (from step 3; 356 mg, 0.12 mmol), Pd / C (10 wt%, 6.3 mg), and ammonium formate (53 mg, 0.85 mmol). The reaction vial was flushed with Ar, sealed with a cap, and further flushed with Ar. Anhydrous methanol (1.2 mL) was added. The reaction mixture was stirred at 80 °C for 20 min. The reaction mixture was cooled to rt, the cap was removed and additional ammonium formate (33 mg, 0.52 mmol) and Pd / C (10 wt%, 2.6 mg) were added. The reaction vial was resealed and heated at 80 °C for another 10 min. The reaction mixture was allowed to cool to rt and filtered through Celite TM Filtered and the solids were washed with MeOH (40 mL). The filtrate was concentrated in vacuo, redissolved in MeOH and passed through an SCX-2 (2 g) column, eluting with MeOH (40 mL) followed by 2N methanolic ammonia (40 mL). The methanolic ammonia fractions were concentrated in vacuo to provide the title compound (22 mg, 67%) as a dark yellow solid, which was used without further purification. LCMS (Method T2) RT 0.41 min; m / z 260.1382 [M+H] + .

[1299] The examples in the following list were prepared by methods analogous to those used to prepare Intermediate A1a (starting from the amino alcohols indicated in the table). An alternative procedure to step 1 was followed for the preparation of Intermediate A11. The details of this procedure are described below for the preparation of Intermediate A1d.

[1300]

[1301]

[1302]

[1303] Intermediate A1m: (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1304]

[1305] Step 1: (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline-2 (1H)-Keto

[1306] (S)-3-amino-3-cyclopropyl-2,2-difluoropropane-1-ol hydrochloride (1.02g, 5.43mmol) and ethyl 4-chloro-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (intermediate F2; 1.41g, 4.52mmol) were loaded into a microwave vial (volume of 10-20mL) for drying. The reaction vial was rinsed with Ar and sealed with a lid. Anhydrous acetonitrile (15mL) was added followed by DIPEA (2mL, 11.48mmol). The reaction mixture was heated at 160°C for 12h under microwave radiation. The reaction mixture was transferred to a flask, and 2M sodium hydroxide (13.5mL, 27mmol) was added. A reflux condenser was connected and the reaction mixture was heated at 85°C for 2h. The reaction mixture was cooled to rt. Water (40mL) was added and the reaction mixture was acidified to pH 5 with 3M HCl. The resulting precipitate was filtered and washed with H 2 O (150 mL) and dried to provide (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (1.41 g, 88%) as an off-white solid, which was used without further purification. 1 H NMR (500 MHz, DMSO-d 6 )δ9.31(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 1.15min; m / z 354.1270[M+H] + .

[1307] Step 2: (S)-3-Bromo-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinoline Lin-2(1H)-one

[1308] Trifluoroacetic acid (1.2 mL, 15.67 mmol) was added to (S)-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (from step 1; 1.14 g, 3.21 mmol) and freshly recrystallized N-bromosuccinimide (572 mg, 3.21 mmol) in anhydrous CHCl at 0 °C under Ar. 2 Cl2 The reaction mixture was stirred at 0 °C for 15 min. The reaction mixture was washed with CH 2 Cl 2 (60 mL) and washed with saturated aqueous NaHCO 3 (3x 30 mL). 2 Cl 2 The aqueous washes were further extracted with 1% ethanol (60 mL). The organic extracts were combined, washed with brine (30 mL), and dried (Na 2 SO 4 ) and concentrated in vacuo to provide (S)-3-bromo-4-((1-cyclopropyl-2,2-difluoro-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (1.39 g, 100%) as a yellow solid which was used without further purification. 1 H NMR (500 MHz, DMSO-d 6 )δ8.95(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),4.05-3.9 5(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 1.31min; m / z 432.0369[M+H] + .

[1309] Step 3: (S)-2-Cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine -[2,3-c]quinolin-6(7H)-one

[1310] Under Ar, 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-quinolin-2(1H)-one (from step 2; 1.39 g, 3.21 mmol) in THF (32 mL). A reflux condenser and an Ar balloon were equipped, and the reaction mixture was heated at 60 °C for 15 min. The reaction mixture was cooled to rt. Water (40 mL) was added and CH 2 Cl 2 The aqueous mixture was extracted with 4% paraformaldehyde (3 x 40 mL). The organic extracts were combined, washed with brine (2 x 40 mL), and dried (Na 2SO 4 ) and concentrated in vacuo to provide (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine as a yellow solid [2,3-c]Quinolin-6(7H)-one (1.08 g, 96%) was used without further purification. 1 H NMR (500 MHz, DMSO-d 6 )δ9.12(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,NCH 3 ), 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] + .

[1311] Step 4: (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1312] In a 100 mL flask, add (S)-2-cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (from step 3; 1.08 g, 3.09 mmol) and 10 wt% Pd / C (108 mg). The reaction vial was flushed with Ar and ethanol (15 mL) was added. The reaction mixture was heated at 60 °C under H 2 Stir for 1 h under atmosphere. Allow the reaction mixture to cool to room temperature. The reaction mixture was filtered through a pad of celite and the solids were washed with EtOH (60 mL). The filtrate was concentrated in vacuo to provide the title compound (1.03 g, 100%) as an orange solid, which was used without further purification. LCMS (Method X2) RT 0.89 min; m / z 322.1370 [M+H] + .

[1313] This alternative synthesis has also been used for the large-scale synthesis of intermediates A1a and A1d.

[1314] Intermediate A2a: 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1315]

[1316] Step 1: 4-((4-Hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one

[1317] 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 loaded into a dried microwave vial (volume of 2.0-5.0 mL). The reaction vial was rinsed with Ar, sealed with a lid, and further rinsed 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 h under microwave irradiation. The reaction was allowed to cool to room temperature. The lid was removed and lithium chloride (239 mg, 5.6 mmol) was added. The reaction vial was resealed with a lid and heated in a heating block at 160 ° C for 3 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was then added dropwise to water (25 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL). The organic extracts were combined and dried (Na 2 SO 4 ) and concentrated in vacuo. The crude product was dissolved in DMSO (1.5 mL) and purified by reverse phase chromatography (2 rounds; Biotage reverse phase 12 g Ultra C-18 column; at H 2 The product was directly purified by 10%-100% MeOH (containing 0.1% formic acid) in 0.5% MgSO4 (0.1% MgSO4). The fractions containing impure products were combined and concentrated in vacuo, and dissolved in DMF (1.5mL). The DMF mixture was added dropwise to stirring water (10mL). The aqueous mixture was stirred for 30min. The resulting suspension was filtered, and the solid was washed with water (50mL) and dried to provide 4-((4-hydroxy-2-methylbutyl-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (29mg, 10%) as a cream solid. 1 HNMR (500 MHz, DMSO-d 6 )δ8.83(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).

[1318] Step 2: 3-Bromo-4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one

[1319] Trifluoroacetic acid (15 uL, 0.20 mmol) was added to N-bromosuccinimide (22 mg, 0.13 mmol) and 4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (from step 1; 29 mg, 0.10 mmol) in anhydrous CHCl at 0 °C under Ar. 2 Cl 2 (0.5 mL). The reaction mixture was stirred at 0 °C for 20 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO 3 The aqueous washes were combined and extracted with EtOAc (20 mL). The organic extracts were combined, dried (Na 2 SO 4 ) and concentrated in vacuo. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography (10 g KP-sil; in CH 2 Cl 2 Purification by 0% to 10% MeOH in 4% ethanol (0% to 10% MeOH in 4% ethanol) provided 3-bromo-4-((4-hydroxy-2-methylbutan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (20 mg, 53%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6 )δ8.86(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).

[1320] Step 3: 2,2,7-Trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinoline-6 (7H)-Keto

[1321] 3-bromo-4-((4-hydroxy-2-methylbutyl-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (from step 2; 20 mg, 0.05 mmol) was loaded into a microwave vial (volume of 0.5-2.0 mL). The reaction vial was flushed with Ar, sealed with a lid, and further flushed with Ar. Anhydrous DMSO (0.68 mL) was added, followed by potassium tert-butoxide (1 M in THF; 92 uL, 0.09 mmol). The reaction mixture was heated at 60 ° C for 50 min under microwave irradiation. The reaction mixture was allowed to cool to room temperature. Water (10 mL) was added followed by EtOAc (10 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 x 10 mL). The organic extracts were combined and concentrated in vacuo. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase chromatography (Biotek reverse phase 12 g C-18 column; in H 2 Direct purification of the product using 45%-65% MeOH in 2% O (containing 0.1% formic acid) provided 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine as a yellow solid [2,3-c]Quinolin-6(7H)-one (5 mg, 29%). 1 H NMR (500 MHz, DMSO-d 6 )δ8.99(d,J=2.5Hz,1H),8.31(dd,J=9.3,2.5Hz,1H),7.61(d,J=9.3Hz,1H),6.0 1(s,1H),4.13(t,J=6.1Hz,2H),3.62(s,3H),1.92(t,J=6.1Hz,2H),1.41(s,6H).

[1322] Step 4: 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinoline-6 (7H)-Keto

[1323] A microwave vial (0.5-2.0 mL volume) was charged with 2,2,7-trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (from step 3; 5 mg, 0.015 mmol), Pd / C (10 wt%, 0.5 mg), and ammonium formate (8 mg, 0.13 mmol). The reaction vial was flushed with Ar, sealed with a cap, and further flushed with Ar. Anhydrous methanol (0.5 mL) was added. The reaction mixture was stirred at 80 °C for 10 min. The reaction mixture was cooled to rt, the cap was removed and additional ammonium formate (5 mg, 0.08 mmol) and Pd / C (10 wt%, 0.5 mg) were added. The reaction vial was resealed with a cap and heated at 80 °C for another 10 min. The reaction mixture was allowed to cool to rt and filtered through Celite TM Filtered, and the solid was washed with MeOH (30 mL). The filtrate was concentrated in vacuo, redissolved in MeOH and passed through an SCX-2 (1 g) column, eluting with MeOH (20 mL) followed by 2N methanolic ammonia (30 mL). The methanolic ammonia fraction was concentrated in vacuo to provide the title compound (4 mg, 99%) as a yellow solid, which was used without further purification. LCMS (Method T2) RT 0.72 min; m / z 274.1538 [M+H] + .

[1324] The examples listed below were prepared by methods analogous to those used to prepare Intermediate A2a, starting from the amino alcohols indicated in the table.

[1325]

[1326] Intermediate A3: 9-amino-2,6-dimethyl-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinolin-5(6H)-one

[1327]

[1328] Step 1: 4-((1-Hydroxypropan-2-yl)amino)-1-methyl-6-nitroquinolin-2(1H)-one

[1329] By 4- chloro-1-methyl -6- nitroquinoline -2 (1H) -one (intermediate F1; 250mg, 1.05mmol), 2- aminopropan-1-ol (236mg, 3.14mmol) and DIPEA (0.36mL, 2.10mmol) in NMP (4.19mL) suspension in heating block at 160 DEG C for 24h.Allow the reaction mixture to cool to room temperature.Water (3mL) is added in the reaction mixture, and after 5min, a yellow precipitate is formed.Aqueous mixture is added in water (20mL).After 15min, the precipitate is filtered, washed with water (100mL), and dried to provide 4- ((1- hydroxypropyl -2- bases) amino) -1- methyl -6- nitroquinoline -2 (1H) -one as a yellow solid. 1 H NMR (500 MHz, DMSO-d 6 )δ9.12(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).

[1330] Step 2: 4-((1-Hydroxypropan-2-yl)amino)-3-iodo-1-methyl-6-nitroquinolin-2(1H)-one

[1331] Into a microwave vial (volume of 0.5-2.0mL) was loaded 4-((1-hydroxypropyl-2-yl)amino)-1-methyl-6-nitroquinoline-2(1H)-one (from step 1; 52mg, 0.19mmol) and iodine (145mg, 0.57mmol). The reaction vial was flushed with Ar, sealed with a lid, and further flushed with Ar. Anhydrous methanol (1.2mL) was added and the reaction mixture was heated at 60°C for 30min under microwave irradiation. Water (0.6mL) was added and the reaction mixture was heated at 60°C for another 90min under microwave irradiation. The reaction mixture was allowed to cool to room temperature, diluted with MeOH, and dry loaded directly onto silica gel. The reaction mixture was purified by flash chromatography (10g KP-sil; at CH 2 Cl 2 Purification by 0% to 15% MeOH in 4% iodine (0% to 15% MeOH in 4% iodine) provided 4-((1-hydroxypropan-2-yl)amino)-3-iodo-1-methyl-6-nitroquinolin-2(1H)-one (29 mg, 38%) as a yellow solid. 1 H NMR (500 MHz, CDCl 3)δ8.92(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, 1H), 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).

[1332] Step 3: 2,6-Dimethyl-9-nitro-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinolin-5(6H)-one

[1333] Into a microwave vial (volume of 2.0-5.0mL), 4-((1-hydroxypropyl-2-yl)amino)-3-iodo-1-methyl-6-nitroquinoline-2(1H)-one (from step 2; 29mg, 0.07mmol), 1,10-phenanthroline (6mg, 0.03mmol), copper(I) iodide (3mg, 0.02mmol), and cesium carbonate (46mg, 0.14mmol) were loaded. The reaction vial was evacuated under reduced pressure for 30min. The reaction vial was rinsed with Ar, sealed with a lid, and further rinsed with Ar. Anhydrous NMP (2.4mL) was added. The reaction mixture was heated at 120°C for 1h under microwave irradiation. The reaction mixture was cooled to rt. Water (5mL) was added and washed with CH 2 Cl 2 The aqueous mixture was extracted with 1% ethyl acetate (3 x 15 mL). The organic extracts were combined and dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography (10 g KP-sil; in CH 2 Cl 2 The crude product was purified by HPLC (0% to 15% MeOH in 4% NaOH). The fractions containing the product were combined, concentrated in vacuo, and passed through an SCX-2 column (5 g), eluted with MeOH (50 mL) followed by 2N methanolic ammonia (50 mL). The MeOH fractions were collected and concentrated in vacuo. The impure product was diluted with DMSO (0.8 mL) and purified by reverse phase chromatography (Biotech 12 g C-18 column; in H 2 Purification by 10%-100% MeOH in DMF (containing 0.1% formic acid) provided 2,6-dimethyl-9-nitro-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinolin-5(6H)-one (8 mg, 41%) as a yellow solid. 1 H NMR (500 MHz, CDCl 3)δ8.45(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).

[1334] Step 4: 9-amino-2,6-dimethyl-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinolin-5(6H)-one

[1335] A microwave vial (volume 0.5-2.0 mL) was charged with 2,6-dimethyl-9-nitro-2,3-dihydro-1H-[1,4]oxazino[2,3-c]quinolin-5(6H)-one (from step 3; 11 mg, 0.0392 mmol), Pd / C (10 wt%, 2 mg), and ammonium formate (13 mg, 0.20 mmol). The reaction vial was flushed with Ar, sealed with a cap, and further flushed with Ar. Anhydrous methanol (0.4 mL) was added and the reaction mixture was stirred at 80 °C for 90 min. The reaction mixture was allowed to cool to rt and filtered through Celite TM Filtered and the solid was washed with MeOH (20 mL). The filtrate was concentrated in vacuo, redissolved in MeOH and passed through an SCX-2 (2 g) column, eluting with MeOH (30 mL) followed by 2N methanolic ammonia (30 mL). The methanolic ammonia fraction was concentrated in vacuo to provide the title compound (8 mg, 81%) as an off-white solid, which was used without further purification. LCMS (Method T2) RT 0.21 min; m / z 246.1253 [M+H] + .

[1336] Intermediate A4: (R)-2-Cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1337]

[1338] Step 1: (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one

[1339] 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 at 80 °C overnight. The reaction mixture was cooled to rt, and 2M sodium hydroxide (16.9 mL, 33.7 mmol) was added, and the reaction mixture was stirred at 80 °C for 13 h. Additional 2M sodium hydroxide (16.9 mL, 33.7 mmol) was added, and stirring was continued at 80 °C for another 16 h. The organic solvent was removed in vacuo and the aqueous mixture was acidified to pH 4 using 2M aqueous HCl. The aqueous suspension was then washed with EtOAc (10 x 200 mL). The solvent was removed under vacuum and the crude product was purified by flash chromatography (25 g KP-sil; 0%-20% MeOH in EtOAc) to provide a crude product (1.7 g) as a yellow solid. The crude product was suspended in water and filtered, further washed with 100 mL of water, and dried in air overnight to provide (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinoline-2(1H)-one (1.14 g, 56%) as a yellow solid. LCMS (method T2) RT 1.19 min; m / z 304.13 [M+H] + .

[1340] Step 2: (R)-3-Bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one

[1341] Trifluoroacetic acid (1.44 mL, 18.74 mmol) was added to N-bromosuccinimide (1.01 g, 5.67 mmol) and (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one (from step 1; 1.14 g, 3.76 mmol) in anhydrous CHCl at 0 °C. 2 Cl 2 (38 mL). The reaction mixture was stirred at 0 ° C for 10 min. The reaction mixture was distributed between EtOAc (50 mL) and water (75 mL). The aqueous layer was extracted twice with EtOAc (50 mL), and the organics were combined and washed with saturated aqueous NaHCO 3 Wash, dry (MgSO 4) bar was concentrated in vacuo to provide (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one (1.69 g) as a dark green solid containing 0.5 equivalents of succinimide (by NMR), which was used without further purification. LCMS (Method T2) RT 1.33 min; m / z 384.04 [M+H] + . Step 3: (R)-2-Cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine miscellaneous [2,3-c]Quinolin-6(7H)-one

[1342] A microwave vial (volume 0.5-2.0 mL) was charged with (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one (100 mg, 0.26 mmol) and DMSO (1.0 mL), evacuated and backfilled with argon. Potassium tert-butoxide (1 M in THF; 0.47 mL, 0.47 mmol) was then added and the reaction mixture was heated to 65 °C under microwave irradiation for 1 h.

[1343] Repeat 4 batches as above. One batch was performed using 67 mg of (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one and 0.32 mL of potassium tert-butoxide (1 M in THF) and 1.00 mL of DMSO. All batches were combined for purification. The product was purified by reverse phase chromatography (Bioteqi reverse phase 12 g C-18 column; at H 2 Purification by 30%-70% MeOH in D (containing 0.1% formic acid) provided the title compound as a brown solid (110 mg, 38% over 2 steps). LCMS (Method T2) RT 1.28 min; m / z 302.12 [M+H] + .

[1344] Intermediate A5a: (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1345]

[1346] Step 1: (R)-2-Cyclopropyl-7-(cyclopropylmethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine -[2,3-c]quinolin-6(7H)-one

[1347] Under argon, (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine A suspension of [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 rt for 15 min. Bromomethylcyclopropane (29 uL, 0.30 mmol) was added thereto and the reaction mixture was stirred at rt overnight. Water was added and the aqueous mixture was extracted with EtOAc (4 x 10 mL). Drying (Na 2 O) was performed. 2 SO 4 ) The combined organic layers were concentrated in vacuo. Flash chromatography (10 g, KP-Sil, 30%-80% EtOAc in cyclohexane) provided (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one (30 mg, 56%) as a yellow oil. 1 H NNMR (500MHz, CDCl 3 )δ8.50(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 1.50min; m / z 356 [M+H] + .

[1348] Step 2: (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine -[2,3-c]quinolin-6(7H)-one

[1349] To a suspension of (R)-4-((1-cyclopropyl-3-hydroxypropyl)amino)-6-nitroquinolin-2(1H)-one (from step 1; 30 mg, 0.08 mmol) in ethanol (8.0 mL) was added ammonium formate (53 mg, 0.84 mmol) and Pd / C (10 wt%, 9 mg). The flask was flushed with nitrogen and heated to 80 °C for 30 min. The product was directly loaded onto an SCX-2 (2 g) column and washed with methanol. The product was eluted with 2M methanolic ammonia and concentrated in vacuo to provide the title compound (12 mg, 42%) as a brown solid. 1 H NMR (500 MHz, methanol-d 4)δ7.43(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, 3.6 Hz, 1H), 2.08 (ddt, J = 13.8, 9.6, 5.6 Hz, 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] + .

[1350] The examples in the following list were prepared by methods analogous to those used to prepare intermediate A5a (starting from one or more of the intermediates shown in the table). For intermediate A5b, the reduction step was followed by reverse phase chromatography.

[1351]

[1352] Intermediate A6a: (R)-10-amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1353]

[1354] (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine A mixture of [2,3-c]quinolin-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 h under microwave irradiation. The crude mixture was used further without any purification. LCMS (Method T2) RT 0.50 min; m / z 272.14 [M+H] + .

[1355] Intermediate A7a: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine- [2,3-c][1,8]naphthyridin-6(7H)-one

[1356]

[1357] Step 1: (R)-6-Chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one

[1358] Into a microwave vial (volume of 2.0-5.0mL), (R)-3-amino-3-cyclopropylpropan-1-ol (intermediate D1a; 139mg, 1.2mmol), ethyl 4,6-dichloro-1-methyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (intermediate F4; 201mg, 0.67mmol), DIPEA (0.30mL, 1.7mmol) and MeCN (2.7mL) were loaded. The reaction vial was rinsed with Ar and sealed with a lid. The reaction mixture was heated at 90°C for 2h under microwave radiation. The reaction mixture was transferred to a flask, and 2M sodium hydroxide (2.0mL, 4.0mmol) was added. The reaction mixture was heated at 95°C for 1h. The reaction mixture was cooled to rt and the resulting precipitate was filtered, washed with water (10 mL), and dried to afford (R)-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one (136 mg, 66%) as an off-white solid. 1 H NMR (500 MHz, DMSO-d 6 )δ8.75(d,J=2.3Hz,1H),8.62(d,J=2.3Hz,1H),6.77(d,J=8.3Hz,1H),5. 54(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 1.40min;m / z 308.116[M+H] +

[1359] Step 2: (R)-3-bromo-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridine-2-yl)- (1H)-Keto

[1360] Trifluoroacetic acid (0.17 mL, 2.2 mmol) was added to N-bromosuccinimide (117 mg, 0.66 mmol) and (R)-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one (from step 1; 135 mg, 0.44 mmol) in anhydrous CHCl at 0 °C under Ar. 2 Cl 2 The reaction mixture was stirred at 0 °C for 25 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous NaHCO 3 The aqueous washes were combined and extracted with EtOAc (20 mL). The organic extracts were combined, dried (Na 2 SO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography (10 g KP-sil; in CH 2 Cl 2 Purification of (R)-3-bromo-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one (137 mg, 81%) as an off-white solid. 1 HNMR (500 MHz, DMSO-d 6 )δ8.72(d,J=2.4Hz,1H),8.69(d,J=2.4Hz,1H),5.57(d,J=10.4Hz,1H),4.62 (dd,J=5.1,4.3Hz,1H),3.69-3.63(m,4H),3.63-3.57(m,1H),3.57-3.51(m,1 H),1.98-1.91(m,1H),1.91-1.82(m,1H),1.08-1.00(m,1H),0.44-0.36(m,1 H),0.31-0.24(m,1H),0.19-0.11(m,1H),-0.01--0.07(m,1H); LCMS(Method T2)RT 1.45min; m / z 386.025 [M+H] +

[1361] Step 3: (R)-10-chloro-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] [1,8]-Naphthyridin-6(7H)-one

[1362] Into a microwave vial (volume of 2-5mL) was loaded (R)-3-bromo-6-chloro-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-1,8-naphthyridin-2(1H)-one (from step 2; 137mg, 0.35mmol). The reaction vial was rinsed with Ar, sealed with a cap, and further rinsed with Ar. Anhydrous DMSO (4.71mL) was added, followed by potassium tert-butoxide (1M in THF; 0.64mL, 0.64mmol). The reaction mixture was heated at 60°C for 80 minutes under microwave irradiation. The reaction mixture was allowed to cool to room temperature. Water (20mL) was added followed by EtOAc (20mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2x20mL). The organic extracts were combined, washed with brine (10mL) and concentrated in vacuo. The crude product was dissolved in DMSO (1 mL) and purified by reverse phase chromatography (Biotek reverse phase 12 g C-18 column; in H 2 D (containing 0.1% formic acid) to provide (R)-10-chloro-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine as an off-white solid [2,3-c][1,8]naphthyridin-6(7H)-one (41 mg, 38%). 1 H NMR (500 MHz, DMSO-d 6 )δ8.69(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),2.24-2.1 6(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) RT1.45min; m / z 306.117[M+H] +

[1363] Step 4: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] [1,8]-Naphthyridin-6(7H)-one

[1364] An oven-dried microwave vial (0.5-2.0 mL volume) was charged with (R)-10-chloro-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridine-6(7H)-one (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). Anhydrous 1,2-dimethoxyethane (0.40 mL) was added, and the vial was sealed with a cap and Ar was bubbled through the reaction mixture. The reaction mixture was heated at 70 ° C for 2 h in a heating block. The reaction mixture was cooled to rt and 3M HCl (0.9 mL) was added for imine hydrolysis. The mixture was stirred at rt for 2 h. The reaction mixture was passed directly through an SCX-2 (2 g) column, eluted with water (10 mL), MeOH (20 mL) and 2N methanolic ammonia (20 mL). The basic fractions were concentrated in vacuo to provide the title compound as a dark yellow solid (30 mg, 99%, 0.12 mmol) which was used without further purification. LCMS (Method T2) RT 1.10 min; m / z 287.139 [M+H]+. Intermediate A8a: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro[1,4]thiazepine- [2,3-c]Quinolin-6(7H)-one

[1365]

[1366] Step 1: (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl)amino)-3-cyclohexane Propyl 4-methylbenzenesulfonate

[1367] Starting Material T: (R)-3-Bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one was prepared using steps 1-2 as shown for Intermediate A1d.

[1368] To a solution of (R)-3-bromo-4-((1-cyclopropyl-3-hydroxypropyl)amino)-1-methyl-6-nitroquinolin-2(1H)-one (200 mg, 0.50 mmol) in pyridine (5.0 mL) cooled to 0° C. was added tosyl chloride (289 mg, 1.51 mmol). The mixture was heated to rt with stirring for 2 h. Additional tosyl chloride (289 mg, 1.51 mmol) was added and the mixture was stirred at rt overnight. The reaction mixture was poured into 5% aqueous HCl and then washed with CH 2 Cl 2 The organic extracts were combined, washed with 5% aqueous HCl, and dried (MgSO 4) and concentrated in vacuo. The residue was purified by flash chromatography (25 g KP-sil; 20%-75% EtOAc in cyclohexane) to provide (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl)amino)-3-cyclopropylpropyl 4-methylbenzenesulfonate (127 mg, 46%) as a yellow solid. LCMS (Method T2) RT 1.56 min; m / z 550.06 [M+H] + .

[1369] Step 2: (R)-S-(3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl)amino)-3- Cyclopropyl)ethanethioate

[1370] To a solution of (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl)amino)-3-cyclopropylpropyl 4-methylbenzenesulfonate (from step 1; 60 mg, 0.11 mmol) in DMF (1.1 mL) was added potassium thioacetate (25 mg, 0.22 mmol) followed by sodium iodide (1.6 mg, 0.01 mmol). The solution was heated to 50 °C and stirred for 4 h. The mixture was cooled to rt and quenched by adding water. The mixture was extracted with EtOAc. The combined organic extracts were washed with water, dried (MgSO 4 ) and concentrated in vacuo. Reverse phase flash chromatography (Biotech 12 g SNAP Ultra C-18, H 2 The residue was purified by 30-100% MeOH in 4% 4-nitropropanediol (containing 0.1% formic acid) (diluted in DMSO (1 mL)) to afford (R)-S-(3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl)amino)-3-cyclopropylpropyl)ethanethioate (38 mg, 77%) as a brown oil. LCMS (Method T2) RT 1.56 min; m / z 456.04 [M+H] + .

[1371] Step 3: (R)-2-Cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c] Quinolin-6(7H)-one

[1372] To a suspension of (R)-S-(3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl)amino)-3-cyclopropylpropyl)ethanethioate (from step 2; 38 mg, 0.084 mmol) in methanol (0.84 mL) cooled to 0°C under air atmosphere was added 15% aqueous NaOH (0.50 mL, 0.084 mmol). Stirring was continued and the temperature was raised to rt overnight. The mixture was concentrated in vacuo to remove methanol. DMSO (1.5 mL) and a few drops of water were then added. Reverse phase flash chromatography (Bioteqi 12 g SNAP Ultra C-18, in H 2 The solution was purified by 30-100% MeOH (containing 0.1% formic acid) in 2% CO to afford (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine as a yellow oil. [2,3-c]Quinolin-6(7H)-one (17 mg, 61%). LCMS (method T2) RT 1.45 min; m / z 332.11 [M+H] + .

[1373] Step 4: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c] Quinolin-6(7H)-one

[1374] To (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c] quinolin-6 (7H) -one (from step 3; 17mg, 0.051mmol) A suspension in ethanol (1.0mL) was added ammonium formate (32mg, 0.51mmol) and Pd / C (10wt%, 10). The vial was sealed and evacuated, then refilled with argon 3 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 (2g) 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]thiazepine- [2,3-c]Quinolin-6(7H)-one (6 mg, 39%). LCMS (method T2) RT 1.07 min; m / z 302.13 [M+H] + .

[1375] The examples listed below were prepared by methods analogous to those used to prepare Intermediate A8a, starting from the amino alcohols indicated in the table.

[1376]

[1377] Intermediate A8c: (R)-N-(2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine [2,3-c]quinolin-10-yl)formamide

[1378]

[1379] Step 1 is similar to the method used to prepare intermediate A8a.

[1380] Step 2: (R)-2-Cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c] Quinolin-6(7H)-one

[1381] To a solution of (R)-3-((3-bromo-1-methyl-6-nitro-2-oxo-1,2-dihydroquinolin-4-yl)amino)-3-cyclopropylpropyl 4-methylbenzenesulfonate (from step 1; 176 mg, 0.32 mmol) in DMF (3.2 mL) was added potassium thioacetate (73 mg, 0.64 mmol) followed by sodium iodide (5 mg, 0.032 mmol). The solution was heated to 50 °C and stirred for 3 h. Once cooled to rt, 15% aqueous sodium hydroxide (1.00 mL, 0.32 mmol) was added via a syringe. The mixture was allowed to stir at rt overnight. Water (5 mL) was added to the mixture to form a precipitate, which was collected under vacuum filtration and further washed with water and dried under vacuum to provide (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c]Quinolin-6(7H)-one was used without further purification. LCMS (Method X2) RT 1.35 min; m / z 354.09 [M+H] + .

[1382] Step 3: (R)-N-(2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]thiazepine [2,3-c]quinolin-10-yl)formamide

[1383] To (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c] quinoline-6 ​​(7H) -one (from step 2; 106 mg, 0.32 mmol) was added ammonium formate (202 mg, 3.20 mmol) and 10 wt% Pd / C (34 mg) in a suspension in ethanol (3.2 mL). The vial was sealed and evacuated, and then refilled with argon 3 times. The vial was then placed in a drysyn block preheated to 60 ° C. After stirring for 1 h, additional Pd / C and ammonium formate (same amount as above) were added and further stirred at 60 ° C for 2 h. The mixture was filtered through a diatomaceous earth pad and concentrated in vacuo. The residue was absorbed in ethanol (4 mL) and tin (II) chloride (243 mg, 1.28 mmol) was added. The mixture was heated for a total of 9 h 30 min at 120 ° C under microwave irradiation. The reaction mixture was cooled to rt, and 15% aqueous NaOH (2 mL) was added and the reaction mixture was stirred at 60 ° C overnight. Once cooled, the mixture was concentrated and the residue was taken up in CH 2 Cl 2 The organic extract was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash chromatography (Biotech KP-Sil 25 g; in CH 2 Cl 2 The product-containing fractions were combined, concentrated in vacuo and purified by reverse phase chromatography (Biotec reverse phase 12 g C-18 column; in H 2 Further purification with 10%-100% MeOH in D (containing 0.1% formic acid) provided the title compound as a yellow oil (5 mg, 5% over 2 steps). LCMS (Method T2) RT 1.31 min; m / z 330.12 [M+H] + NB intermediate A8a: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro[1,4]thiazepine- [2,3-c]Quinolin-6(7H)-one (13 mg, 13% over 2 steps) was also isolated in this reaction.

[1384] Intermediate A9a: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c]Quinolin-6(7H)-one 5,5-dioxide

[1385]

[1386] Steps 1-3 are similar to the method used in the preparation of intermediate A8a.

[1387] Step 4: (R)-2-Cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c] Quinolin-6(7H)-one 5,5-dioxide

[1388] 3-Chloroperoxybenzoic acid (126 mg, 0.56 mmol) was added portionwise to a solution of (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine cooled to 0 °C. [2,3-c]Quinolin-6(7H)-one (62 mg, 0.19 mmol) in CH 2 Cl 2 (1.87 mL) and acetonitrile (1.87 mL). After 15 min, the mixture was allowed to warm to rt and stirred for 24 h. The reaction mixture was stirred by adding 10% aqueous NaHCO 3 and saturated aqueous Na 2 S 2 O 3 The mixture was quenched. The mixture was then extracted 3 times with EtOAc. The combined organic extracts were washed with 10% aqueous Na 2 CO 3 , washed with brine, dried (MgSO 4 ) and concentrated in vacuo to provide (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine as a yellow solid [2,3-c]Quinolin-6(7H)-one 5,5-dioxide (45 mg, 66%) was used without further purification. LCMS (Method T2) RT 1.20 min; m / z 364.0943 [M+H] + .

[1389] Step 5: (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]thiazepine [2,3-c] Quinolin-6(7H)-one 5,5-dioxide

[1390] (R)-2-cyclopropyl-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]thiazepine A mixture of -[2,3-c]quinolin-6(7H)-one 5,5-dioxide (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 h. The reaction mixture was loaded onto an SCX-2 cartridge in 1:1 1M HCl:MeOH, eluted with MeOH and then 2M NH3 in MeOH to provide the title compound as a yellow glass (16 mg, 87%), which was used without further purification. LCMS (Method X2); RT 1.54 min; m / z 334.1224 [M+H] + Intermediate A10a: (S)-2-cyclopropyl-10-((2,5-dichloropyrimidin-4-yl)amino)-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]Quinolin-6(7H)-one

[1391]

[1392] A microwave vial (0.5-2.0 mL volume) was charged with (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c] quinoline-6 ​​(7H) -one (intermediate A1m; 800mg, 2.49mmol) and 2,4,5- trichloropyrimidine (531mg, 2.89mmol). The reaction vial was rinsed with Ar, sealed with a cap, and further rinsed with Ar. NMP (3mL) was added followed by DIPEA (1.7mL, 9.76mmol). The reaction mixture was heated at 140 ° C for 1h under microwave irradiation. The reaction mixture was cooled to rt. The reaction mixture was added to water (10mL) and a beige precipitate was formed. Additional water (10mL) was added and the aqueous mixture was stirred for 5min. The precipitate was filtered, washed with water (25mL), and dried to provide the title compound (1.16g, 100%) as a beige solid, which was used without further purification. 1 HNMR (600 MHz, DMSO-d 6)δ9.74(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 1.60min; m / z 468.0796[M+H] + .

[1393] The examples in the following list were prepared by methods similar to those used to prepare Intermediate A10a (starting from one or more of the intermediates shown in the table). For Intermediate A10b and Intermediate A10c; the crude reaction mixture was purified directly by reverse phase chromatography using the conditions shown in the table, rather than the precipitate, to provide the title compounds. For Intermediate A10d; the crude reaction mixture was purified directly by preparative HPLC using the conditions shown in the table, rather than the precipitate.

[1394]

[1395]

[1396] Intermediate A11a: (R)-N-(2-cyclopropyl-7-methyl-6-oxo-1,2,3,4,6,7-hexahydro-[1,4]oxazepine [2,3-c]quinolin-10-yl)formamide

[1397]

[1398] (R)-10-amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (Intermediate A1d; 61 mg, 0.21 mmol) and phenyl formate (25 uL, 0.23 mmol) were dissolved in anhydrous CH 2 Cl 2 The mixture in 4% ethyl acetate (0.60 mL) was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (10 g KP-sil; in CH 2 Cl 2Purification by 0% to 10% MeOH in 4% HCl (pH 7.0) provided the title compound as a yellow solid (32 mg, 48%). LCMS (Method X2) RT 1.00 min; m / z 314.1499 [M+H] + Intermediate A12a: 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-7(2H)-yl)acetaldehyde

[1399]

[1400] Step 1: (R)-2-cyclopropyl-7-(2,2-dimethoxyethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxy Aza -[2,3-c]quinolin-6(7H)-one

[1401] A microwave vial (2.0-5.0 mL volume) was charged with (R)-2-cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (Intermediate A4; 69 mg, 0.23 mmol) and cesium carbonate (82 mg, 0.25 mmol). The reaction vial was flushed with Ar, sealed with a cap, and further flushed with Ar. DMF (1.5 mL) was added and the mixture was stirred at rt for 30 min. 2-Bromo-1,1-dimethoxyethane (82 uL, 0.69 mmol) was added and the reaction mixture was heated at 100 °C for 3 h. Thereafter, additional 2-bromo-1,1-dimethoxyethane (40 uL, 0.34 mmol) was added and the reaction mixture was heated at 100 °C for another 2 h. The reaction mixture was cooled to rt, diluted with EtOAc (15 mL) and water (10 mL) was added. The layers were separated and the aqueous mixture was extracted with EtOAc (2 x 15 mL). The organic extracts were combined, washed with brine (10 mL), dried (Na 2 O) and purified by column chromatography. 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography (10 g KP-sil; 60% to 100% EtOAc in cyclohexane (5 CV) followed by 0% to 3% MeOH in EtOAc (10 CV)) provided (R)-2-cyclopropyl-7-(2,2-dimethoxyethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine as a dark yellow solid [2,3-c]Quinolin-6(7H)-one (42 mg, 47%). 1 H NMR (500 MHz, methanol-d4 )δ8.96(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 1.34min; m / z 358.1378[M-MeOH+H] +

[1402] Step 2: (R)-10-amino-2-cyclopropyl-7-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-[1,4]oxy Aza [2,3-c]Quinolin-6(7H)-one

[1403] A microwave vial (2.0-5.0 mL volume) was charged with (R)-2-cyclopropyl-7-(2,2-dimethoxyethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (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 further flushed with Ar. Ethanol (1 mL) was added. The reaction mixture was heated at 60 °C under H 2 Atmosphere is stirred for 1h.The reaction mixture is allowed to cool to room temperature.The reaction mixture is filtered through a celite pad and the solid is washed with EtOH (25mL).The filtrate is concentrated in vacuo to provide (R) -10- amino -2- cyclopropyl -7- (2,2- dimethoxyethyl) -1,2,3,4- tetrahydro -[1,4] oxazepine as a yellow solid [2,3-c]Quinolin-6(7H)-one (38 mg, 99%) was used without further purification. LCMS (Method X2) RT 0.89 min; m / z 328.1776 [M-MeOH+H] + .

[1404] Step 3: 2-((R)-10-((5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidine- 4-yl)amino)-2-cyclopropyl-6-oxo-1,3,4,6-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-7(2H)-yl) Acetaldehyde

[1405] A microwave vial (0.5-2.0 mL volume) was charged with (R)-10-amino-2-cyclopropyl-7-(2,2-dimethoxyethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one (from step 2; 36 mg, 0.10 mmol) and 5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-4-(methylsulfonyl)pyrimidine (Intermediate J3; 70 mg, 0.21 mmol). Trifluoroethanol (1 mL) was added followed by trifluoroacetic acid (8.4 uL, 0.11 mmol). The reaction vial was flushed with Ar, bubbled through the reaction mixture with Ar, and sealed with a cap. The reaction mixture was heated in a heating block at 60 °C for 2h 30min. After this time, the cap was removed and additional 5-chloro-2-((3S,5R)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)-4-(methylsulfonyl)pyrimidine (Intermediate J3; 41 mg, 0.12 mmol) and trifluoroacetic acid (8.4 uL, 0.11 mmol) were added. The vial was resealed and heated at 60° C. for an additional 16 h. The reaction mixture was cooled to rt and the resulting precipitate was filtered and washed with Et 2 The precipitate is confirmed as the intermediate J3 of hydrolysis. The filtrate is transferred to a microwave vial (volume of 0.5-2.0 mL) using methanol. Trifluoroacetic acid (0.3 mL) and water (0.5 mL) are added to promote acetal deprotection. The reaction vial is sealed with a cap and heated at 60 ° C for 1 h in a heating block, followed by heating at 80 ° C for 1 h. The reaction mixture is cooled to rt, and concentrated in a vacuum. The crude aqueous mixture is diluted with DMSO (0.8 mL) and by reverse phase chromatography (Bai Taiqi reverse phase 12 g C-18 column; in H 2 Direct purification with 10%-30%-100% MeOH in D (containing 0.1% formic acid) provided the title compound as an off-white solid (7 mg, 11%). LCMS (Method X2) RT 1.62 min; m / z 605.2466 [M+MeOH+H] + .

[1406] Intermediate B1a: (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]Quinoline-5,6(1H,7H)-dione

[1407]

[1408] Step 1: (S)-2,7-Dimethyl-10-nitro-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6 (1H,7H)-dione

[1409] The 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 h under microwave irradiation. The reaction mixture was allowed to cool to room temperature. The lid was removed and lithium chloride (108 mg, 2.55 mmol) was then added. The reaction vial was resealed with a lid, and the mixture was further stirred at 160 ° C for 1 h under microwave irradiation. The crude reaction mixture was purified by preparative HPLC (15 min 60:40 to 0:100 H 2 O: MeOH (modified with 0.1% formic acid) gradient; flow rate 20 mLmin -1 ) to provide (S)-2,7-dimethyl-10-nitro-2,3-dihydro-[1,4]oxazepine as a light brown solid [6,5-c]Quinoline-5,6(1H,7H)-dione (48 mg, 37%). 1 H NMR (500 MHz, DMF-d 7 )δ9.20(d,J=2.4 Hz,1 H),8.48(dd,J=9.4,2.4 Hz,1H),8.20(br s,1 H),7.72(d,J=9.4 Hz,1 H),4.72(dd,J=13.0,1.2 Hz,1 H),4.49(dd,J=13.0,5.1 Hz, 1 H), 4.20 (q, J = 6.4 Hz, 1 H), 3.66 (s, 3 H), 1.42 (d, J = 6.4 Hz, 3 H).

[1410] Step 2: (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6 (1H,7H)-dione

[1411] (S)-2,7-dimethyl-10-nitro-2,3-dihydro-[1,4]oxazepine [6,5-c]Quinoline-5,6(1H,7H)-dione (from step 1; 48 mg, 0.16 mmol) and Pd / C (10 wt%, 3 mg) were suspended in EtOH (4 mL). The mixture was evacuated and washed with H 2 Fill 3 times. The reaction mixture was stirred at 4 ℃ for 1 h. 2 The reaction mixture was stirred for 16 h under a Celite TMFilter and wash the solid with MeOH. The filtrate was concentrated in vacuo to provide the title compound (40 mg, 92%) as a yellow oil which was used without further purification. LCMS (Method T2) RT 0.19 min; m / z 274.1 [M+H] + .

[1412] The examples in the following list were prepared by methods analogous to those used to prepare intermediate Bl a, starting from the amino alcohols indicated in the table.

[1413]

[1414] Intermediate B2a: (S)-10-amino-2,7-dimethyl-2,3,5,7-tetrahydro-[1,4]oxazepine [6,5-c]Quinolin-6(1H)-one

[1415]

[1416] Boron trifluoride diethyl ether (about 50% BF 3 ; 0.1 mL, 0.41 mmol) was added to (S)-10-amino-2,7-dimethyl-2,3-dihydro-[1,4]oxazepine [6,5-c]quinoline-5,6(1H,7H)-dione (Intermediate B1a; 12 mg, 0.042 mmol) was in a stirred suspension in THF (4 mL). The reaction mixture was stirred at 0 °C for 15 min, then sodium borohydride (5 mg, 0.127 mmol) was added. The reaction mixture was stirred at 0 °C for another 2 h. The reaction was quenched by the addition of methanol. The reaction mixture was concentrated in vacuo. Brine was added to the residue and the aqueous mixture was extracted with EtOAc. The organic layer was dried (Na 2 SO 4 ) and concentrated in vacuo. Purification by flash chromatography (10 g KP-sil; 5% MeOH in EtOAc) provided the title compound (4 mg, 32%) as a yellow solid. 1 H NMR (500 MHz, methanol-d 4)δ7.34(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).

[1417] Intermediate B3a: Ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-6-((2-chloro-3-cyanopyridin-4-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate

[1418]

[1419] Step 1: Ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-6-nitro-2-oxy 1,2-Dihydroquinoline-3-carboxylate

[1420] 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 to 100 °C for 16 h. Excess amine was added to 1 mL of THF, followed by DIPEA (50 uL), and heated continuously for 2 h. The reaction mixture was cooled to rt and distributed between EtOAC (25 mL) and water (25 mL). The aqueous layer was further extracted with EtOAc (25 mL) and the organic extracts were combined, washed with brine (50 mL), dried (MgSO 4 ), and concentrated in vacuo to provide 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. LCMS (Method T4); RT 2.87 min; m / z 449.2078 [M+H] + Note: LCMS showed a mixture of desired product and amine starting material. This mixture was carried forward assuming 100% conversion.

[1421] Step 2: Ethyl 6-amino-4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-2-oxo 1,2-Dihydroquinoline-3-carboxylate

[1422] Ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-6-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate (from step 1; 50 mg, 0.11 mmol), Pd / C (10 wt%; 1.2 mg) and ammonium formate (70 mg, 1.11 mmol) were combined in a microwave vial, which was sealed and placed under an argon atmosphere by alternating vacuum and argon three times. Ethanol (0.64 mL) was then added and the reaction mixture was heated to 70 °C for 2 h. The reaction mixture was filtered through celite and the solvent was removed in vacuo. The crude product was partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was washed with additional water (2 x 20 mL) and then dried (MgSO 4 ) and filtered through a hydrophobic frit. The solvent was removed in vacuo to provide 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. LCMS (Method T2); RT 1.23 min; m / z 419.2728 [M+H] + .

[1423] Step 3: Ethyl 4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-6-((2-chloro-3-cyanopyridine (4-pyridin-1-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate

[1424] Ethyl 6-amino-4-((1-((tert-butoxycarbonyl)amino)propan-2-yl)amino)-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylate (from step 2; 50 mg, 0.12 mmol), 2,4-dichloronicotinonitrile (21 mg, 0.12 mmol) and DIPEA (62 uL, 0.36 mmol) were combined in a microwave vial and dissolved in NMP (1 mL). The reaction mixture was heated at 110 °C for 90 min under microwave irradi...

Claims

1. Compounds of formula (III-a): in: Z is (1-2C)alkylene selected from (-CH2-), (-CH2CH2-), (-CF2CH2) and (-CH(Me)CH2-); W is selected from the group consisting of NO2, halogen and OTf; X1 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; X2 is selected from N, CH, CF, CCl or C-CH3; R 1 A group selected from hydrogen or the following formula: -LYZ in: L is absent or is (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- to 7-membered heterocyclyl; wherein Z is optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, cyano, NR g R h OR g ; where R g and R h are each independently selected from hydrogen or (1-4C)alkyl; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, wherein R u and R v independently selected from hydrogen or (1-2C)alkyl; R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl or a group of the formula: Y5-L5-Z5 in: Y5 is absent or selected from C(O)O or C(O)N(R w ), where R w is selected from hydrogen or (1-2C)alkyl; L5 is absent or is (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocyclyl; wherein 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; or R 30 and R 31 are linked so that they, together with the carbon atoms to which they are attached, form a 4-6 membered carbocyclic or heterocyclic ring.

2. The compound according to claim 1, wherein W is NO2.

3. The compound according to any one of claims 1-2, wherein the compound is selected from the group consisting of: (R)-2-Cyclopropyl-7-(cyclopropylmethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine -[2,3-c]quinolin-6(7H)-one; (R)-2-Cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 2,2,7-Trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (S)-2-Cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine -[2,3-c]quinolin-6(7H)-one; and (S)-2,7-Dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one.

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]oxazepine -[2,3-c]quinolin-6(7H)-one.

5. A method for synthesizing a compound of formula (III-a) from a compound of formula (IV): The method comprises intramolecularly cyclizing a compound of formula (IV) to provide a compound of formula (III-a), wherein: Z is (1-2C)alkylene selected from (-CH2-), (-CH2CH2-), (-CF2CH2) and (-CH(Me)CH2-); W is selected from the group consisting of NO2, halogen and OTf; Y is a halogen, such as Br or I; X1 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; X2 is selected from N, CH, CF, CCl or C-CH3; R 1 A group selected from hydrogen or the following formula: -LYZ in: L is absent or is (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- to 7-membered heterocyclyl; wherein Z is optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, cyano, NR g R h OR g ; where R g and R h are each independently selected from hydrogen or (1-4C)alkyl; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, wherein R u and R v independently selected from hydrogen or (1-2C)alkyl; R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl or a group of the formula: Y5-L5-Z5 in: Y5 is absent or selected from C(O)O or C(O)N(R w ), where R w is selected from hydrogen or (1-2C)alkyl; L5 is absent or is (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocyclyl; wherein 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; or R 30 and R 31 are linked so that they, together with the carbon atoms to which they are attached, form a 4-6 membered carbocyclic or heterocyclic ring.

6. The method according to claim 5, wherein the compound of formula (III-a) is selected from the group consisting of: (R)-2-Cyclopropyl-7-(cyclopropylmethyl)-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine -[2,3-c]quinolin-6(7H)-one; (R)-2-Cyclopropyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 2,2,7-Trimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (S)-2-Cyclopropyl-3,3-difluoro-7-methyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine -[2,3-c]quinolin-6(7H)-one; and (S)-2,7-Dimethyl-10-nitro-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one.

7. Compounds of formula (II): in: X1 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; X2 is selected from N, CH, CF, CCl or C-CH3; R 1 A group selected from hydrogen or the following formula: -LYZ in: L is absent or is (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- to 7-membered heterocyclyl; wherein Z is optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, cyano, NR g R h OR g ; where R g and R h are each independently selected from hydrogen or (1-4C)alkyl; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, wherein R u and R v independently selected from hydrogen or (1-2C)alkyl; R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl or a group of the formula: Y5-L5-Z5 in: Y5 is absent or selected from C(O)O or C(O)N(R w ), where R w is selected from hydrogen or (1-2C)alkyl; L5 is absent or is (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocyclyl; wherein Z5 is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halo, (1-2C) haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, nitro or hydroxy; or R 30 and R 31 are linked so that they, together with the carbon atoms to which they are attached, form a 4-6 membered carbocyclic or heterocyclic ring; and Ring A is a 6-membered or 7-membered heterocyclic ring, except for the substituent group R 30 and R 31 , the heterocycle is further optionally substituted by one or more substituents selected from the group consisting of oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, or hydroxy.

8. The compound according to claim 7, selected from the group consisting of: (S)-10-Amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (R)-10-Amino-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 10-Amino-2-ethyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (S)-10-Amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (R)-10-Amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 10-Amino-2,3,3,7-tetramethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 10'-amino-2',7'-dimethyl-1',2'-dihydro-4'H-spiro[cyclopropane-1,3'-[1,4]oxazepine [2,3-c]quinolinyl]-6'(7'H)-one; (2S,4S)-10-Amino-2,4,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (S)-10-Amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 10-amino-2,2,7-trimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 10-amino-2-(methoxymethyl)-2,7-dimethyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; 10'-amino-7'-methyl-3',4,4',5-tetrahydro-1'H,2H-spiro[furan-3,2'-[1,4]oxazepine [2,3-c]quinolinyl]-6'(7'H)-one; 10-amino-2-(difluoromethyl)-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-(cyclopropylmethyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (R)-10-amino-2-cyclopropyl-7-((3,3-difluorocyclobutyl)methyl)-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; (R)-10-Amino-2-cyclopropyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one; and (R)-10-Amino-2-cyclopropyl-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c][1,8]naphthyridin-6(7H)-one.

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

10. A method for synthesizing a compound of formula (II) from a compound of formula (III): The method comprises reducing the W group of formula (III) to provide a compound of formula (II), wherein: W is NO2; X1 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; X2 is selected from N, CH, CF, CCl or C-CH3; R 1 A group selected from hydrogen or the following formula: -LYZ in: L is absent or is (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- to 7-membered heterocyclyl; wherein Z is optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, cyano, NR g R h OR g ; where R g and R h are each independently selected from hydrogen or (1-4C)alkyl; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, wherein R u and R v independently selected from hydrogen or (1-2C)alkyl; R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl or a group of the formula: Y5-L5-Z5 in: Y5 is absent or selected from C(O)O or C(O)N(R w ), where R w is selected from hydrogen or (1-2C)alkyl; L5 is absent or is (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocyclyl; wherein Z5 is optionally substituted by one or more substituents selected from: (1-2C)alkyl, halo, (1-2C) haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, nitro or hydroxy; or R 30 and R 31 are linked so that they, together with the carbon atoms to which they are attached, form a 4-6 membered carbocyclic or heterocyclic ring; and Ring A is a 6-membered or 7-membered heterocyclic ring, except for the substituent group R 30 and R 31 , the heterocycle is further optionally substituted by one or more substituents selected from the group consisting of oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, or hydroxy.

11. The method of claim 10, wherein reducing the W group comprises: (1) carrying out a hydrogenation reaction in the presence of a metal catalyst; (2) reaction with tin(II) chloride; or (3) reaction with iron or zinc metal.

12. A method for synthesizing a compound of formula (II) from a compound of formula (III): The method comprises subjecting a compound of formula (III) to amination conditions of the W group to provide a compound of formula (II), wherein: W is halogen or OTf; X1 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; X2 is selected from N, CH, CF, CCl or C-CH3; R 1 A group selected from hydrogen or the following formula: -LYZ in: L is absent or is (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- to 7-membered heterocyclyl; wherein Z is optionally further substituted by one or more substituents independently selected from the group consisting of oxo, (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)aminoalkyl, cyano, NR g R h OR g ; where R g and R h are each independently selected from hydrogen or (1-4C)alkyl; R 30 is selected from (1-4C)alkyl, (3-6C)cycloalkyl, (1-4C)haloalkyl or cyano, wherein each (1-4C)alkyl and / or (3-6C)cycloalkyl substituent is optionally further substituted by one or more substituents selected from (1-4C)alkyl, (3-6C)cycloalkyl, hydroxy, (1-2C)alkoxy, NR u R v , (1-2C)aminoalkyl or halo, wherein R u and R v independently selected from hydrogen or (1-2C)alkyl; R 31 is selected from hydrogen, (1-4C)alkyl, cyano, (1-4C)haloalkyl or a group of the formula: Y5-L5-Z5 in: Y5 is absent or selected from C(O)O or C(O)N(R w ), where R w is selected from hydrogen or (1-2C)alkyl; L5 is absent or is (1-2C)alkylene; and Z5 is hydrogen, (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5- or 6-membered heteroaryl, or 4- to 6-membered heterocyclyl; wherein Z5 is optionally substituted with one or more substituents selected from the group consisting of (1-2C)alkyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, nitro or hydroxy; or R 30 and R 31 are linked so that they, together with the carbon atoms to which they are attached, form a 4-6 membered carbocyclic or heterocyclic ring; and Ring A is a 6-membered or 7-membered heterocyclic ring, except for the substituent group R 30 and R 31 , the heterocycle is further optionally substituted by one or more substituents selected from the group consisting of oxo, (1-2C)alkyl, cyclopropyl, spirocyclopropyl, halo, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)alkoxy, NH2, cyano, or hydroxy.

13. The method of claim 12, wherein the conditions for the amination reaction comprise a metal-catalyzed amination reaction.

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

15. The method according to any one of claims 10 to 14, wherein the compound of formula (II) is (S)-10-amino-2-cyclopropyl-3,3-difluoro-7-methyl-1,2,3,4-tetrahydro-[1,4]oxazepine [2,3-c]quinolin-6(7H)-one.

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