EP2 antagonist compounds

Abstract

Described herein are compounds that are EP2 antagonists, methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods of using such compounds in the treatment of diseases or conditions associated with EP2 activity.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 214,645, filed June 24, 2021, which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION Described herein are compounds that are inhibitors of prostaglandin E2 receptor 2, also known as EP2, methods for making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods for using such compounds in the treatment of diseases or conditions associated with EP2 activity. [Background technology]

[0003] Background of the Invention EP2 is a prostaglandin receptor that functions, for example, as a mediator of inflammation. EP2 signaling has been implicated in, for example, inflammatory conditions, allergic diseases, eye diseases, nervous system diseases, bone diseases, fibrotic conditions, cardiovascular diseases, and certain forms of cancer. Summary of the Invention [Means for solving the problem]

[0004] Summary of the Invention The compounds described herein are antagonists of EP2. In some embodiments, the compounds described herein are used to treat or prevent diseases and conditions in which EP2 activity contributes to the symptoms or progression of the disease and condition, such as, for example, inflammatory diseases and conditions.

[0005] In one embodiment, a compound having the structure of formula (II): [ka] or a pharmaceutically acceptable salt thereof, as disclosed herein, wherein: R 1 and R 2are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; A 1 -O-, -CR 5 R 6 -, -S-, -S(=O)2- or absent; A 2 -CR 7 R 8 - or -S(=O)2-; A 3 -CR 9 R 10 -or absent; R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 5 and R 6 together with the carbon atoms to which they are attached to form oxetanes; R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R 7 and R 8together with the carbon atoms to which they are attached form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; R A1 is a halogen, C 1~4 alkyl, or cyclopropyl; and R A2 is hydrogen, deuterium, halogen, or optionally deuterated or halogenated methyl; Ring B is C 3~6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B'; Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C1~4 alkyl), -S(O)(C 1~4 alkyl), -S(O)(NH)(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; Ring C is a bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C'; Each R C is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -N(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -S(C 1~4 alkyl), -SO2C 1~4 Alkyl, -SO2NHC 1~4 Alkyl, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; m is 0 to 3; n is 0 to 3; and Ring B' is [ka] selected from the group consisting of: Ring C' is [ka] (selected from the group consisting of:

[0006] In another embodiment, a compound having the structure of Formula III: [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is C 3~6 is cycloalkyl, phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl containing two or more nitrogen atoms; Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)(NH)(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6or two R B together form a carbonyl; Ring C is a bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C'; Each R C is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -N(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -S(C 1~4 alkyl), -SO2C 1~4 Alkyl, -SO2NHC 1~4 Alkyl, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; m is 0 to 3; n is 0 to 3; and Ring C' is [ka] (selected from the group consisting of:

[0007] In another embodiment, the structure of formula (III'): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is C 3~6cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl containing two or more nitrogen atoms; Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)(NH)(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; and (n is 0 to 3).

[0008] In another embodiment, the structure of formula (IIIb'): [ka] or a pharmaceutically acceptable salt thereof or a tautomer thereof, wherein: Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; and Each R C is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -N(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -S(C 1~4 alkyl), -SO2C 1~4 Alkyl, -SO2NHC 1~4 Alkyl, substituted or unsubstituted C 3~6 or two R B together form a carbonyl).

[0009] In another embodiment, the structure of formula (VIII): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen or deuterium; Ring A' is [ka] [ka] selected from the group consisting of: Ring B is a substituted or unsubstituted heterocycle; where, when Ring B is substituted, it contains one or more R B is substituted by a group, and Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 or two R B together form a carbonyl).

[0010] In another aspect, disclosed herein are compounds of Table I, II, III, III', VII, VIII, or IX, or tautomers thereof, or pharmaceutically acceptable salts thereof. In another embodiment, disclosed herein are compounds of Formula I, Formula I', Formula Ia, Formula Ia', Formula Ib, Formula Ib', Formula Ic, Formula Ic', Formula ID, Formula Id', or Formula Id" or tautomers thereof, or pharmaceutically acceptable salts thereof. In another embodiment, disclosed herein are compounds of Formula II, Formula IIa, Formula IIb, Formula IIc, Formula IId, Formula IIe, or Formula II' or tautomers thereof, or pharmaceutically acceptable salts thereof. In another embodiment, disclosed herein are compounds of Formula III, Formula IIIa, Formula IIIb, Formula IIIc, Formula IIId, Formula IIIe, or Formula III' or tautomers thereof, or pharmaceutically acceptable salts thereof.

[0011] In another embodiment, disclosed herein is a compound of Formula IV, Formula IVa, Formula V, Formula VI, Formula VIa, Formula VIb, Formula VIc, Formula VId, Formula VII, Formula VIIa, or Formula VIIb, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. In another embodiment, disclosed herein is a compound of Formula VIII or Formula IX, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0012] In another aspect, disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0013] In another aspect, disclosed herein is a method of modulating the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.

[0014] In another embodiment, disclosed herein is a method of treating a disease or condition that would benefit from modulation of prostaglandin E2 receptor 2 (EP2) activity, comprising administering to a mammal a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.

[0015] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one skilled in the art to provide stable moieties and compounds.

[0016] In another aspect, described herein are pharmaceutical compositions comprising a compound decribed herein or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, or intranasal administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersion, solution, or emulsion.

[0017] In another aspect, described herein is a method of modulating the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0018] In yet another aspect, described herein are methods for treating a disease or condition that would benefit from modulation of prostaglandin E2 receptor 2 (EP2) activity, comprising administering to a mammal a compound described herein, or a pharmaceutically acceptable salt or solvate thereof.

[0019] Other objects, features, and advantages of the compounds, methods, and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description of the Invention Prostaglandins act on prostaglandin receptors such as the prostaglandin DP1 receptor (DP1), prostaglandin DP2 receptor (DP2), prostaglandin EP1 receptor (EP1), prostaglandin EP2 receptor (EP2), prostaglandin EP3 receptor (EP3), prostaglandin EP4 receptor (EP4), prostaglandin F2α receptor (FP1), prostacyclin I2 receptor (IP), and thromboxane A2 receptor (TP), or a combination thereof.

[0021] Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid synthesized by the action of cyclooxygenase and prostaglandin E synthase. PGE2 is produced in almost all organs and tissues and has various physiological effects, including mucosal protection, induction of gastric acid secretion in the stomach, fever, hyperalgesia, inflammation, and immunity. The actions of PGE2 are mediated by four receptors: EP1, EP2, EP3, and EP4. PGE2 has affinity for all four EP receptor subtypes as well as other prostanoid receptors, such as the PGE2 DP1 receptor.

[0022] PGE2 is a downstream product of the cyclooxygenase-2 (COX-2) pathway and a key regulator of inflammation.

[0023] When EP2 binds to PGE2, it s EP2 is a G protein-coupled receptor that recruits proteins and initiates a signaling cascade involving adenylyl cyclase (thereby elevating cAMP) and protein kinase A (PKA). Coupling of EP2 to Gs proteins stimulates adenylyl cyclase, and their activation increases intracellular cAMP levels. This signaling pathway has close implications for inflammation, pain, immune regulation, mitogenesis, plasticity, and cell injury. EP2 interacts with the β-arrestin / JNK pathway, which may affect proliferation and metastasis.

[0024] Expression of the EP2 receptor has been demonstrated in a wide range of cell types and tissues, including lung, gastrointestinal tract, kidney, uterus, myleoid, and thymus, and has been associated with PGE2-mediated vasodilation and smooth muscle relaxation in the lung, gastrointestinal, and reproductive tracts.

[0025] In some embodiments, the compounds described herein modulate the activity of EP2. In some embodiments, the compounds described herein inhibit or reduce the magnitude of inflammatory PGE2 signaling through the EP2 receptor. In some embodiments, the compounds described herein reduce or eliminate one or more symptoms associated with an EP2-mediated disease or disorder (e.g., an EP2-mediated inflammatory disease or disorder).

[0026] Abnormal EP2 expression is observed in several forms of cancer, including colon, prostate, liver, and breast cancer. EP2 activity (e.g., overactivity) has also been associated with cancer risk factors, including chronic inflammation, immune regulation, angiogenesis, metastasis, and multidrug resistance. In some embodiments, methods of treating cancer with the compounds disclosed herein are disclosed herein. As used herein, the term "cancer" refers to the abnormal growth of cells that tend to proliferate uncontrollably and, in some cases, metastasize (spread).

[0027] In some embodiments, the compounds described herein reduce one or more symptoms of EP2-mediated cancer. In some embodiments, the compounds described herein reduce or reverse the progression of EP2-mediated cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is colon cancer.

[0028] In some embodiments, EP2 signaling (i.e., through activation by PGE2) contributes to inflammation by increasing vascular permeability, increasing edema and leukocyte infiltration, thereby allowing more blood flow to inflamed body parts. In some embodiments, modulation of EP2 function has an effect on B lymphocyte, T lymphocyte, cytotoxic T cell function, or a combination thereof.

[0029] In some embodiments, disclosed herein are methods for treating inflammation with the compounds disclosed herein. In some embodiments, the compounds disclosed herein are used to reduce or inhibit inflammation in a mammal. In some embodiments, the compounds disclosed herein are used in the treatment or prevention of inflammation-related conditions (e.g., allergies, pain, etc.).

[0030] In some embodiments, disclosed herein are methods of reducing inflammation in a tissue, comprising contacting an inflamed cell or tissue with a compound disclosed herein in an amount sufficient to reduce or inhibit inflammation. In some embodiments, inflammation includes inflammatory or allergic conditions.

[0031] In some embodiments, the compounds disclosed herein reduce one or more symptoms of a neuroinflammatory disease or disorder, including reducing the activity of EP2 (e.g., by contacting an inflamed tissue with an EP2 antagonist disclosed herein). In some embodiments, disclosed herein are methods of reducing or halting the progression of a neuroinflammatory disease or disorder, including administering a compound disclosed herein to an individual (e.g., a mammal, a human, etc.) in need thereof.

[0032] In some embodiments, reducing inflammation or treating an inflammatory condition comprises reducing or inhibiting the activity of EP2, hi some embodiments, reducing inflammation or treating an inflammatory condition comprises administering an antagonist of EP2 (e.g., an EP2 antagonist disclosed herein).

[0033] In some embodiments, the inflammatory condition is an allergic condition. In some embodiments, the inflammatory condition is asthma. In some embodiments, the inflammatory condition is anaphylaxis. In some embodiments, the inflammatory condition is chronic inflammation. In some embodiments, disclosed herein are methods for treating chronic inflammation, comprising administering an EP2 antagonist (e.g., a compound disclosed herein) to an individual in need thereof.

[0034] compound The compounds described herein are EP2 antagonists, including their pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates. In some embodiments, a compound of any one of the formulas described herein or a pharmaceutically acceptable salt thereof is an EP2 antagonist.

[0035] In one embodiment, a compound of Formula (I) or Formula (I'): [ka] or a tautomer thereof or a pharmaceutically acceptable salt thereof is provided herein, wherein R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; A 1 -O-, -CR 5 R 6 -, -S-, -S(=O)2- or absent; A 2 -CR 7 R 8- or -S(=O)2-; A 3 -CR 9 R 10 -or absent; R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 5 and R 6 together with the carbon atoms to which they are attached to form oxetanes; R 7 and R 8 are independently hydrogen, deuterium, halogen, C 1~4 Alkyl or C 1~4 haloalkyl; or R 7 and R 8 together with the carbon atoms to which they are attached form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; R A1 is a halogen, C 1~4 alkyl, or cyclopropyl; R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or two R B together form a carbonyl; R B’ is hydrogen or C 1~4 is alkyl; R C is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or two R B together form a carbonyl; m is 0 to 3; n is 0 to 3; and Ring C' is [ka] (selected from the group consisting of:

[0036] For each and every embodiment, the substituents are selected from a subset of the listed options. For example, A 1 -O-, -CR 5 R 6 In some embodiments, A may be -, -S-, -S(=O)2-, or absent. 1 is —O—. In some embodiments, A 1 Ha-CR 5 R 6 In some embodiments, A 1 is -S-. In some embodiments, A 1 is -S(=O)2-. In some embodiments, A 1 Similarly, in some embodiments, A 2 -CR 7 R 8 - or -S(=O)2-. In some embodiments, A 2 Ha-CR 7 R 8 In some embodiments, A 2 is -S(=O)2-. In some embodiments, A 3 -CR 9 R 10 - or absent. In some embodiments, A 3 Ha-CR 9 R 10 In some embodiments, A 3 does not exist.

[0037] In some embodiments, A 1 -O-, -CR 5 R 6 -, -S-, -S(=O)2, or absent; A 2 Ha-CR 7 R 8 - and A 3 Ha-CR9 R 10 In some embodiments, A 1 is -O-, -S-, or -S(=O)2; A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 In some embodiments, A 1 is -O-;A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 In some embodiments, A 1 is -S-;A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 In some embodiments, A 1 is -S(=O)2; A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 In some embodiments, A 1 does not exist;A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 In some embodiments, A 1 is -O-;A 2 is -S(=O)2-; and A 3 Ha-CR 9 R 10 In some embodiments, A 1 is -O-;A 2 Ha-CR 7 R 8 - and A 3 does not exist.

[0038] In some embodiments: 1 is -O-, -S-, or -S(=O)2-; A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 -or A 1 is -O-;A 2 -CR 7 R 8 - or -S(=O)2-; and A 3 Ha-CR 9 R 10 -or A 1 does not exist;A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 -or A 1 -O-, -CR 5 R 6 - or absent; A 2 Ha-CR 7 R 8 - and A 3 does not exist.

[0039] In some embodiments, A 1 is -O- or -S(=O)2-; A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 -or A 1 is -O-;A 2 -CR 7 R 8 - or -S(=O)2-; and A 3 Ha-CR 9 R 10 In some embodiments, A 1 does not exist;A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R10 -or A 1 -O-, -CR 5 R 6 - or absent; A 2 Ha-CR 7 R 8 - and A 3 does not exist.

[0040] In some embodiments, A 1 Ha-CR 5 R 6 - and R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 5 and R 6 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 5 and R 6 are each independently hydrogen, deuterium, or —CH; or R 5 and R 6 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 5 and R 6 are each independently hydrogen, deuterium, or —CH. In some embodiments, R 5 is hydrogen and R 6 is hydrogen, deuterium, or —CH. In some embodiments, R 5 and R 6 are each independently hydrogen or deuterium. 5 and R 6 are each hydrogen. In some embodiments, R 5 and R 6 Each is deuterium. In some embodiments, R 5 and R 6 are each -CH3. In some embodiments, R 5 and R 6 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 5and R 6 are each independently hydrogen or deuterium; or R 5 and R 6 together with the carbon atoms to which they are attached form an oxetane.

[0041] In some embodiments, A 2 Ha-CR 7 R 8 - and R 7 and R 8 are independently hydrogen, deuterium, halogen, C 1~4 Alkyl or C 1~4 haloalkyl; or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropane or oxetane. In some embodiments, R 7 and R 8 are each independently hydrogen, deuterium, —CH3, or CF3; or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropane or oxetane. In some embodiments, R 7 and R 8 are each independently hydrogen, deuterium, —CH, or —CF. In some embodiments, R 7 and R 8 are each independently hydrogen, deuterium, or —CH. In some embodiments, R 7 is hydrogen and R 8 is hydrogen, deuterium, —CH, or —CF. In some embodiments, R 7 is hydrogen and R 8 is hydrogen, deuterium, or —CH. In some embodiments, R 7 and R 8 are each independently hydrogen or deuterium. 7 and R 8 are each hydrogen. In some embodiments, R 7 and R 8Each is deuterium. In some embodiments, R 7 and R 8 are each -CH3. In some embodiments, R 7 and R 8 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropane. 7 and R 8 are each independently hydrogen or deuterium; or R 7 and R 8 together with the carbon atoms to which they are attached form an oxetane.

[0042] In some embodiments, A 2 -CR 7 R 8 - or -S(=O)2. In some embodiments, A 2 is -S(=O)2. In some embodiments, A 2 -CR 7 R 8 - or -S(=O)2; and A 3 Ha-CR 9 R 10 In some embodiments, A 2 is -S(=O)2 and A 3 Ha-CR 9 R 10 In some embodiments, A 1 is -O- and A 2 -CR 7 R 8 - or -S(=O)2. In some embodiments, A 1 is -O- and A 2 is -S(=O)2. In some embodiments, A 1 is -O-;A 2 is -S(=O)2-; and A 3 Ha-CR 9 R 10In some embodiments, A 1 is -O-;A 2 -CR 7 R 8 or -S(=O)2-; and A 3 Ha-CR 9 R 10 is.

[0043] In some embodiments, A 3 Ha-CR 9 R 10 - and R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 9 and R 10 are each independently hydrogen, deuterium, or —CH; or R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 9 and R 10 are each independently hydrogen, deuterium, or —CH. In some embodiments, R 9 is hydrogen and R 10 is hydrogen, deuterium, or —CH. In some embodiments, R 9 and R 10 are each independently hydrogen or deuterium. 9 and R 10 are each hydrogen. In some embodiments, R 9 and R 10 Each is deuterium. In some embodiments, R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 9 and R 10 are each independently hydrogen or deuterium; or R 9and R 10 together with the carbon atoms to which they are attached form an oxetane.

[0044] In some embodiments, R 5 and R 6 are each independently hydrogen, deuterium, or —CH; or R 5 and R 6 together with the carbon atoms to which they are attached form an oxetane; R 7 and R 8 are each independently hydrogen, deuterium, or —CH; or R 7 and R 8 together with the carbon atoms to which they are attached form an oxetane; and R 9 and R 10 are each independently hydrogen, deuterium, or —CH; or R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane.

[0045] In some embodiments, A 3 Ha-CR 9 R 10 - or absent. In some embodiments, A 3 is absent. In some embodiments, A 1 is -O-; and A 3 Ha-CR 9 R 10 - or absent. In some embodiments, A 1 is -O-; and A 3 is absent. In some embodiments, A 2 -CR 7 R 8 - or -S(=O)2-; and A 3 -CR 9 R 10 - or absent. In some embodiments, A 2 Ha-CR 7 R 8 - and A 3 -CR 9 R 10- or absent. In some embodiments, A 2 Ha-CR 7 R 8 - and A 3 is absent. In some embodiments, A 1 is -O-;A 2 -CR 7 R 8 - or -S(=O)2-; and A 3 -CR 9 R 10 - or absent. In some embodiments, A 1 is -O-;A 2 -CR 7 R 8 - or -S(=O)2-; and A 3 is absent. In some embodiments, A 1 is -O-;A 2 Ha-CR 7 R 8 - and A 3 does not exist.

[0046] In some embodiments, R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1~4 In some embodiments, R 3 and R 4 are each independently hydrogen, deuterium, or —CH. In some embodiments, R 3 and R 4 are each independently hydrogen or deuterium. 3 and R 4 are each independently hydrogen. In some embodiments, R 3 and R 4 are each independently deuterium.

[0047] In some embodiments, R A1 is a halogen, C 1~4 alkyl, or cyclopropyl. In some embodiments, R A1is halogen. In some embodiments, R A1 is -F, -Cl, -Br, or -I. In some embodiments, R A1 is -F or -Cl. In some embodiments, R A1 is -F. In some embodiments, R A1 is —Cl. In some embodiments, R A1 is C 1~4 In some embodiments, R A1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, or -C(CH3)3. In some embodiments, R A1 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R A1 is —CH3. In some embodiments, R A1 is cyclopropyl.

[0048] In some embodiments, [ka] Or "Ring A" is [ka] is selected from the group consisting of:

[0049] In some embodiments, [ka] teeth [ka] is selected from the group consisting of:

[0050] In some embodiments, A 1 is -O-;A 2 -CR 7 R 8 - or -S(=O)2-; and A 3Ha-CR 9 R 10 In some embodiments, the compound of Formula (I) is a compound of Formula (Ia) or Formula (Ia'): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or deuterium; A 2 -CR 7 R 8 - or -S(=O)2-; R 7 and R 8 are hydrogen or deuterium, respectively; or R 7 and R 8 together with the carbon atoms to which they are attached to form oxetanes; R 9 and R 10 are hydrogen or deuterium, respectively; or R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; R A1 is a halogen, C 1~4 alkyl, or cyclopropyl; and Ring C' is as defined in formula (I).

[0052] In some embodiments, the compound of Formula (I) is a compound of Formula (Ib) or Formula (Ib'): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, R A1is a halogen, C 1~4 alkyl, or cyclopropyl; R 1 and R 2 are each independently hydrogen or deuterium; and Ring C' is as defined in formula (I).

[0054] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0055] In some embodiments, R A1 is a halogen, C 1~4 alkyl, or cyclopropyl; R 1 and R 2 are each independently hydrogen or deuterium; and Ring C' is as defined in formula (I).

[0056] In some embodiments, R 1 , R 2 , R 3 , R 4 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen or deuterium; or R 1 , R 2 , R 3 , R 4 , R 9 , and R 10 are each independently hydrogen or deuterium; and R 7 and R 8 together with the carbon atom to which they are attached form an oxetane; or R 1 , R 2 , R 3 , R 4, R 7 , and R 8 are each independently hydrogen or deuterium; and R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; And R A1 is -F, -Cl, or cyclopropyl.

[0057] In some embodiments, R 3 is H;R 4 is H;R 7 is H;R 8 is H;R 9 is H;R 10 is H; and R A1 is -F; or R 3 is H;R 4 is H;R 7 is H;R 8 is H;R 9 is H;R 10 is H; and R A1 is cyclopropyl; or R 3 is D;R 4 is D;R 7 is H;R 8 is H;R 9 is H;R 10 is H; and R A1 is -Cl; or R 3 is D;R 4 is D;R 7 is D;R 8 is D;R 9 is H;R 10 is H; and R A1 is -Cl; or R 3 is H;R 4 is H;R 7 is D;R 8 is D;R 9 is H;R 10 is H; and RA1 is -Cl; or R 3 is D;R 4 is D;R 7 is D;R 8 is D;R 9 is D;R 10 is D; and R A1 is -Cl; or R 3 is H;R 4 is H;R 7 is H;R 8 is H;R 9 is D;R 10 is D; and R A1 is -Cl; or R 3 is H;R 4 is H;R 7 and R 8 forms an oxetane; R 9 is H;R 10 is H; and R A1 is -Cl; or R 3 is H;R 4 is H;R 7 is H;R 8 is H;R 9 and R 10 forms an oxetane; and R A1 is -Cl.

[0058] In some embodiments, the compound of Formula (I) is a compound of Formula (Id), Formula (Id'), or Formula (Id"): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0059] In some embodiments, the compound of formula (I) is R 1 and R 2 are each independently hydrogen, deuterium, a halogen, or C 1~4 is alkyl; R 7 and R 8 are independently hydrogen, deuterium, halogen, C 1~4 Alkyl or C 1~4 haloalkyl; or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, a halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; R B But halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -NH2, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or two R B together to form a carbonyl; n is 0 to 3; and A compound of formula (Id), formula (Id'), or formula (Id"), wherein ring C' is as defined in formula (I).

[0060] In some embodiments, R 1 and R2 are each independently hydrogen or deuterium; and ring C' is [ka] is selected from the group consisting of:

[0061] In some embodiments, R 1 and R 2 are each hydrogen. In some embodiments, R 1 and R 2 are deuterium atoms.

[0062] In another embodiment, a compound of the following formula disclosed in Table I: [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0063] [Table 1]

[0064] In another embodiment, the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; A 1 -O-, -CR 5 R 6 -, -S-, -S(=O)2- or absent; A 2 -CR 7 R 8 - or -S(=O)2-; A 3 -CR 9 R 10 -or absent; R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 5 and R 6 together with the carbon atoms to which they are attached to form oxetanes; R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R 7 and R 8 together with the carbon atoms to which they are attached form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; R A1 is a halogen, C 1~4 alkyl, or cyclopropyl; and R A2is hydrogen, deuterium, halogen, or optionally deuterated or halogenated methyl; Ring B is C 3~6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B'; Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; Ring C is a bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C', Each R Cis halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -N(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -S(C 1~4 alkyl), -SO2C 1~4 Alkyl, -SO2NHC 1~4 Alkyl, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; m is 0 to 3; n is 0 to 3; and Ring C' is [ka] (selected from the group consisting of:

[0065] In some embodiments, ring B is C 3~6 In some embodiments, ring B is a cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or ring B is ring B'. In some embodiments, ring B is C 3~6 In some embodiments, Ring B is Ring B'. In some embodiments, Ring B' is a Ring B' disclosed in Table VII. In some embodiments, Ring B' is [ka] is selected from the group consisting of:

[0066] In some embodiments, A 1 is —O—. In some embodiments, A 1 is -O-;A 2 Ha-CR 7 R 8 - and A 3 Ha-CR 9 R 10 -It is.

[0067] In some embodiments, A 2 Ha-CR 7 R 8 - and R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R 7 and R 8 together with the carbon atom to which they are attached form a cyclopropane or an oxetane. 2 Ha-CR 7 R 8 - and R 7 and R 8 are independently hydrogen, deuterium, halogen, C 1~4 Alkyl or C 1~4 haloalkyl; or R 7 and R 8together with the carbon atom to which they are attached form a cyclopropane or an oxetane.

[0068] In some embodiments, A 3 Ha-CR 9 R 10 - and R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atom to which they are attached form an oxetane. 3 Ha-CR 9 R 10 - and R 9 and R 10 are each independently hydrogen, deuterium, or methyl. 9 and R 10 are each independently hydrogen. In some embodiments, R 9 and R 10 are each independently deuterium. In some embodiments, R 9 is hydrogen and R 10 is methyl.

[0069] In another embodiment, the compound of formula (IIa): [ka] or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, Ring C is a bicyclic heteroaryl having one or more nitrogen atoms. In some embodiments, Ring C is Ring C'. In some embodiments, Ring C is a bicyclic heteroaryl having one or more nitrogen atoms ... [ka] In some embodiments, Ring C is a substituted indole (e.g., a haloindole or a haloalkylindole, (e.g., a fluoroindole)).

[0071] In some embodiments, ring B is C 3~6 In some embodiments, ring B is selected from the group consisting of cycloalkyl, phenyl, 5-membered heteroaryl, and 6-membered heteroaryl containing two or more nitrogen atoms. 3~6 cycloalkyl, phenyl, 5- or 6-membered heteroaryl containing two or more nitrogen atoms.

[0072] In some embodiments, ring B is C 3~6 In some embodiments, Ring B is substituted or unsubstituted cyclopropyl. In some embodiments, Ring B is substituted or unsubstituted cyclobutyl. In some embodiments, Ring B is substituted or unsubstituted cyclopentyl. In some embodiments, Ring B is substituted or unsubstituted cyclohexyl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is a 5-membered heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl containing two or more nitrogen atoms. In some embodiments, Ring B is a 5-membered heteroaryl containing two or more nitrogen atoms. In some embodiments, Ring B is a 6-membered heteroaryl containing two or more nitrogen atoms.

[0073] In some embodiments, Ring B is a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyrazolidinone, a substituted or unsubstituted imidazole, a substituted or unsubstituted imidazolidinone, or a substituted or unsubstituted triazole. In some embodiments, Ring B is a substituted or unsubstituted pyrazole. In some embodiments, Ring B is a substituted or unsubstituted pyrazolidinone. In some embodiments, Ring B is a substituted or unsubstituted imidazole. In some embodiments, Ring B is a substituted or unsubstituted triazole.

[0074] In some embodiments, Ring B is a substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrimidone, substituted or unsubstituted pyridazine, substituted or unsubstituted pyridazinone, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrazinone, substituted or unsubstituted triazine, or substituted or unsubstituted tetrazine. In some embodiments, Ring B is a substituted or unsubstituted pyrimidine or a substituted or unsubstituted pyrimidone. In some embodiments, Ring B is a substituted pyrimidine. In some embodiments, Ring B is an unsubstituted pyrimidine. In some embodiments, Ring B is a substituted pyrimidone. In some embodiments, Ring B is an unsubstituted pyrimidone. In some embodiments, Ring B is a substituted or unsubstituted pyridazine. In some embodiments, Ring B is a substituted or unsubstituted pyridazinone.

[0075] In some embodiments, the compound of Formula (II) is a compound of Formula (IIb), Formula (IIc), Formula (IId), or Formula (IIe): [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, Ring C is a bicyclic heteroaryl having one or more nitrogen atoms. In some embodiments, Ring C is a substituted or unsubstituted indole, substituted or unsubstituted indazole, substituted or unsubstituted azaindole, substituted or unsubstituted indolizine, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, substituted or unsubstituted pyrazolopyridine, substituted or unsubstituted pyrrolopyrimidine, substituted or unsubstituted imidazopyrimidine, or substituted or unsubstituted pyrazolopyrimidine. In some embodiments, Ring C is a substituted or unsubstituted indole. In some embodiments, Ring C is a substituted or unsubstituted haloindole. In some embodiments, Ring C is a substituted or unsubstituted 5-fluoroindole. In some embodiments, Ring C is 5-fluoroindole.

[0077] In some embodiments, Ring C is a bicyclic heterocycloalkyl having one or more nitrogen atoms. In some embodiments, Ring C is substituted or unsubstituted indoline, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted dihydrobenzoxazine, or substituted or unsubstituted dihydrobenzothiazine. In some embodiments, Ring C is substituted or unsubstituted indoline. In some embodiments, Ring C is substituted haloindoline. In some embodiments, Ring C is substituted or unsubstituted 5-fluoroindoline. In some embodiments, Ring C is 5-fluoroindoline. In some embodiments, Ring C is Ring C'.

[0078] In some embodiments, m is 0. In some embodiments, m is 1 and R C is -D, -F, -Cl, -Br, -CH3, -CH2OCH3, -CH2F, -CHF2, -CF3, -OH, -OCH3, -SCH3, -NH2, -N(CH3)2, or -NHC(O)O(C 1~4 In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C is methyl. In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C is dimethylamino.

[0079] In some embodiments, m is 2 and each R C is independently -D, -F, -Cl, -Br, -CH, -CF, or -OCH. In some embodiments, m is 2 and each R Cis independently -D, -F, -Cl, -Br, or -CH. In some embodiments, m is 2 and each R C is a halogen or C 1~4 In some embodiments, m is 2 and each R C is halogen. In some embodiments, m is 2 and each R C is fluorine or chlorine. In some embodiments, m is 2 and each R C In some embodiments, m is 2 and each R C is deuterium. In some embodiments, m is 3 and each R C is a halogen.

[0080] In another embodiment, the compound of formula (II'): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; A 1 -O-, -CR 5 R 6 -, -S-, -S(=O)2- or absent; A 2 -CR 7 R 8 - or -S(=O)2-; A 3 -CR 9 R 10 -or absent; R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; R 5 and R 6 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 5 and R6 together with the carbon atoms to which they are attached to form oxetanes; R 7 and R 8 are each independently hydrogen, deuterium, halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R 7 and R 8 together with the carbon atoms to which they are attached form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; R A1 is a halogen, C 1~4 alkyl, or cyclopropyl; Ring B is C 3~6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B'; Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; and (n is 0 to 3).

[0081] In some embodiments, R A1 is a halogen, C 1~4 alkyl, or cyclopropyl. In some embodiments, R A1 is halogen. In some embodiments, R A1 is -F, -Cl, -Br, or -I. In some embodiments, R A1 is -F or -Cl. In some embodiments, R A1 is -F. In some embodiments, R A1 is —Cl. In some embodiments, R A1 is C 1~4In some embodiments, R A1 is -CH3, -CH2CH3, -CH(CH3)2, -CH2CH2CH3, or -C(CH3)3. In some embodiments, R A1 is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R A1 is —CH3. In some embodiments, R A1 is cyclopropyl.

[0082] In another embodiment, a compound of the following formula disclosed in Table II: [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0083] [Table 2]

[0084] In some embodiments, [ka] Or "Ring A" is, [ka] is selected from the group consisting of:

[0085] In some embodiments, [ka] teeth [ka] is.

[0086] In some embodiments, the compound of formula (II) is a compound of formula (III): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein: Ring B is C 3~6 cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B'; Each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -NHS(O)C 1~4 Alkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; Ring C is a bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C' Each R C is halogen, -CN, -C1~4 Alkyl, -C 1~4 Haloalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -N(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -S(C 1~4 alkyl), -SO2C 1~4 Alkyl, -SO2NHC 1~4 Alkyl, substituted or unsubstituted C 3~6 or two R B together form a carbonyl; m is 0 to 3; n is 0 to 3; and Ring C' is [ka] (selected from the group consisting of:

[0087] In some embodiments, ring B is C 3~6 In some embodiments, ring B is a cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or ring B is ring B'. In some embodiments, ring B is C 3~6 In some embodiments, Ring B is Ring B'. In some embodiments, Ring B' is a Ring B' disclosed in Table VII. In some embodiments, Ring B' is [ka] is selected from the group consisting of:

[0088] In some embodiments, ring B is C 3~6 In some embodiments, Ring B is substituted or unsubstituted cyclopropyl. In some embodiments, Ring B is substituted or unsubstituted cyclobutyl. In some embodiments, Ring B is substituted or unsubstituted cyclopentyl. In some embodiments, Ring B is substituted or unsubstituted cyclohexyl. In some embodiments, Ring B is phenyl. In some embodiments, Ring B is a 5-membered heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl containing two or more nitrogen atoms. In some embodiments, Ring B is a 5-membered heteroaryl containing two or more nitrogen atoms. In some embodiments, Ring B is a 6-membered heteroaryl containing two or more nitrogen atoms.

[0089] In some embodiments, Ring B is a substituted or unsubstituted pyrazole, a substituted or unsubstituted pyrazolidinone, a substituted or unsubstituted imidazole, a substituted or unsubstituted imidazolidinone, or a substituted or unsubstituted triazole. In some embodiments, Ring B is a substituted or unsubstituted pyrazole. In some embodiments, Ring B is a substituted or unsubstituted pyrazolidinone. In some embodiments, Ring B is a substituted or unsubstituted imidazole. In some embodiments, Ring B is a substituted or unsubstituted triazole.

[0090] In some embodiments, Ring B is a substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrimidone, substituted or unsubstituted pyridazine, substituted or unsubstituted pyridazinone, substituted or unsubstituted pyrazine, substituted or unsubstituted pyrazinone, substituted or unsubstituted triazine, or substituted or unsubstituted tetrazine. In some embodiments, Ring B is a substituted or unsubstituted pyrimidine or a substituted or unsubstituted pyrimidone. In some embodiments, Ring B is a substituted pyrimidine. In some embodiments, Ring B is an unsubstituted pyrimidine. In some embodiments, Ring B is a substituted pyrimidone. In some embodiments, Ring B is an unsubstituted pyrimidone. In some embodiments, Ring B is a substituted or unsubstituted pyridazine. In some embodiments, Ring B is a substituted or unsubstituted pyridazinone.

[0091] In some embodiments, the compound of Formula (III) is a compound of Formula (IIIb), Formula (IIIc), Formula (IIId), or Formula (IIIe): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, ring C is a bicyclic heterocycle having one or more nitrogen atoms. In some embodiments, ring C is a bicyclic heteroaryl having one or more nitrogen atoms. In some embodiments, ring C is a substituted or unsubstituted indole, substituted or unsubstituted indazole, substituted or unsubstituted azaindole, substituted or unsubstituted indolizine, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, substituted or unsubstituted pyrazolopyridine, substituted or unsubstituted pyrrolopyrimidine, substituted or unsubstituted imidazopyrimidine, or substituted or unsubstituted pyrazolopyrimidine. In some embodiments, ring C is a substituted or unsubstituted indole.

[0093] In some embodiments, ring C is [ka] is.

[0094] In some embodiments, each R C is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), or C 3~6 or two R B together form a carbonyl. In some embodiments, each R C is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), or C 3~6 or two R B together form a carbonyl. In some embodiments, R C is -F, -Cl, -Br, -CH3, -CH2F, -CHF2, -CF3, -OH, -OCH3, -SCH3, -NH2, -N(CH3)2, or -NHC(O)O(C 1~4 alkyl). In some embodiments, each R C is independently selected from -F, -Cl, -CN, CH, -CF, -N(CH), -OCH, -SCH, and cyclopropyl. In some embodiments, Ring C is a substituted or unsubstituted haloindole. In some embodiments, Ring C is [ka] is.

[0095] In some embodiments, Ring C is substituted or unsubstituted 5-fluoroindole. In some embodiments, Ring C is 5-fluoroindole. In some embodiments, Ring C is [ka] is.

[0096] In some embodiments, Ring C is a bicyclic heterocycloalkyl having one or more nitrogen atoms. In some embodiments, Ring C is substituted or unsubstituted indoline, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted dihydrobenzoxazine, or substituted or unsubstituted dihydrobenzothiazine. In some embodiments, Ring C is substituted or unsubstituted indoline. In some embodiments, Ring C is substituted haloindoline. In some embodiments, Ring C is substituted or unsubstituted 5-fluoroindoline. In some embodiments, Ring C is 5-fluoroindoline. In some embodiments, Ring C is Ring C'.

[0097] In some embodiments, m is 0. In some embodiments, m is 1 and R C is -D, -F, -Cl, -Br, -CH3, -CH2OCH3, -CH2F, -CHF2, -CF3, -OH, -OCH3, -SCH3, -NH2, -N(CH3)2, or -NHC(O)O(C 1~4 In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C In some embodiments, m is 1 and R C is dimethylamino.

[0098] In some embodiments, m is 2 and each R C is independently -D, -F, -Cl, -Br, -CH, -CF, or -OCH. In some embodiments, m is 2 and each R C is independently -D, -F, -Cl, -Br, or -CH. In some embodiments, m is 2 and each R C is a halogen or C 1~4 In some embodiments, m is 2 and each R C is halogen. In some embodiments, m is 2 and each R C is fluorine or chlorine. In some embodiments, m is 2 and each R C In some embodiments, m is 2 and each R C is deuterium. In some embodiments, m is 3 and each R C is a halogen.

[0099] In some embodiments, ring C is [ka] and wherein the heterocyclic ring is a bicyclic heterocycle having one or more nitrogen atoms selected from the group consisting of:

[0100] In some embodiments, ring C' is [ka] is selected from the group consisting of:

[0101] In some embodiments, ring B is C 3~6 In some embodiments, ring B is cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms. ... B In some embodiments, each R Bis halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -SH, -S(C 1~4 alkyl), -SO(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, substituted or unsubstituted C 3~6 cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R B together form a carbonyl.

[0102] In some embodiments, each R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4alkyl), -NH, -NH(C 1~4 alkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)O(C 1~4 alkyl), -OH, -O(C 1~4 alkyl), -S(O)2(C 1~4 alkyl), and substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R B together form a carbonyl.

[0103] In some embodiments, each R B is -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, -OH, -OCH3-C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), or -C(O)N(C 1~4 alkyl)2, -C(O)(C 1~4 alkyl), -C(O)OH, -NH2, -NH(C 1~4 alkyl), -NH(oxetanyl), -N(C 1~4 alkyl)2, -OH -O(C 1~4 alkyl), or oxo.

[0104] In some embodiments, each R Bare independently selected from the group consisting of -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, CH2NH2, -CH2NHBoc, -CH2OH, -CHOCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)OH, -C(O)OCH3, -NH2, NHCH3, -N(CH3)2, -NH(oxetanyl), -NHC(O)CH3, -NHS(O2)CH3, -OH, -OCH3, -OCH2CF3, methylpyrazolyl, pyrazolyl, and oxo.

[0105] In some embodiments, Ring B is phenyl and n is 0. In some embodiments, Ring B is phenyl and n is 1. In some embodiments, Ring B is phenyl and n is 1 and R B is -F, -Cl, -CN, -CH, -CHF, -CHF, -CF, -OH, or -OCH. In some embodiments, ring B is phenyl, n is 1, and R B In some embodiments, ring B is phenyl, n is 1, and R B In some embodiments, ring B is phenyl, n is 1, and R B In some embodiments, ring B is phenyl, n is 1, and R B In some embodiments, ring B is phenyl, n is 1, and R B In some embodiments, ring B is phenyl, n is 1, and R B is -CF3.

[0106] In some embodiments, Ring B is cyclohexyl and n is 0. In some embodiments, Ring B is cyclohexyl and n is 1. In some embodiments, Ring B is cyclohexyl, n is 1, and R B -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C1~4 alkyl), or -C(O)N(C 1~4 In some embodiments, ring B is cyclohexyl, n is 1, and R B is —C(O)OH. In some embodiments, ring B is cyclohexyl, n is 1, and R B is -C(O)O(C 1~4 In some embodiments, Ring B is cyclohexyl, n is 1, and R B is —C(O)OCH. In some embodiments, Ring B is cyclohexyl, n is 1, and R B is —C(O)NH. In some embodiments, Ring B is cyclohexyl, n is 1, and R B is -C(O)NH(C 1~4 In some embodiments, Ring B is cyclohexyl, n is 1, and R B is —C(O)NHCH. In some embodiments, Ring B is cyclohexyl, n is 1, and R B is -C(O)N(C 1~4 In some embodiments, ring B is cyclohexyl, n is 1, and R B is -C(O)N(CH3)2.

[0107] In some embodiments, Ring B is cyclohexyl and n is 2. In some embodiments, Ring B is cyclohexyl, n is 2, and each R B are independently halogen, C 1~4 Alkyl, C 1~4 Haloalkyl, -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), or -C(O)N(C 1~4 alkyl)2.

[0108] In some embodiments, Ring B is pyrimidinyl and n is 0. In some embodiments, Ring B is pyrimidinyl and n is 1. In some embodiments, Ring B is pyrimidinyl, n is 1, and R B -CH3, -C(O)(C 1~4 alkyl), -C(O)OH, -NH2, -NH(C 1~4 alkyl), -NH(oxetanyl), -N(C 1~4 alkyl)2, -OH or -O(C 1~4 In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is —C(O)OH. In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is —C(O)CH. In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -OH or -O(C 1~4 In some embodiments, Ring B is pyrimidinyl, n is 1, and R B In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -O(C 1~4 In some embodiments, Ring B is pyrimidinyl, n is 1, and R B In some embodiments, Ring B is pyrimidinyl, n is 1, and R B In some embodiments, Ring B is pyrimidinyl, n is 1, and R B is -NH(C 1~4 In some embodiments, Ring B is pyrimidinyl, n is 1, and R B In some embodiments, Ring B is pyrimidinyl, n is 1, and R B -N(C 1~4 In some embodiments, Ring B is pyrimidinyl, n is 1, and R Bis -N(CH3)2. In some embodiments, ring B is pyrimidinyl and n is 2. In some embodiments, ring B is pyrimidinyl, n is 2, and two R B together form a carbonyl. In some embodiments, Ring B is pyrimidinonyl. In some embodiments, Ring B is pyrimidinyl and n is 3. In some embodiments, Ring B is pyrimidinyl, n is 3, and two R B together form a carbonyl. In some embodiments, Ring B is unsubstituted pyrimidinonyl. In some embodiments, Ring B is substituted pyrimidinonyl. In some embodiments, Ring B is methylpyrimidinonyl, aminopyrimidinonyl, hydroxypyrimidinonyl, methoxypyrimidinonyl, methoxyalkylpyrimidinonyl, halopyrimidinonyl, or C 1~4 In some embodiments, Ring B is methylpyrimidinonyl.

[0109] In some embodiments, ring B is ring B'. In some embodiments, ring B' is as described in Table VII. In some embodiments, ring B is [ka] and each of which optionally contains one group R as defined above. B is further substituted by

[0110] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0111] In some embodiments, a compound of the following formula disclosed in Table III: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0112] [Table 3]

[0113] [Table 4]

[0114] [Table 5]

[0115] [Table 6]

[0116] [Table 7]

[0117] [Table 8]

[0118] [Table 9]

[0119] [Table 10]

[0120] [Table 11]

[0121] [Table 12]

[0122] In another embodiment, the compound of formula (III'): [ka] or a pharmaceutically acceptable salt thereof, wherein: Ring B is C 3~6 cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl containing two or more nitrogen atoms; R B is halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4 Methoxyalkyl, -OH, -O(C 1~4 alkyl), -O(C 1~4 haloalkyl), -NH2, -NH(C 1~4 alkyl), -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), -N(C 1~4 alkyl)2, -NHC(O)C 1~4 Alkyl, -NHC(O)O(C 1~4 alkyl), -(C 1~4 alkyl)O(C 1~4 alkyl), -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or two R B together form a carbonyl; and (n is 0 to 3).

[0123] In some embodiments, each R Bare independently selected from -F, -Cl, -CN, -CH3, -CH2F, -CHF2, -CF3, CH2NH2, -CH2NHBoc, -CH2OH, -CHOCH3, -C(O)NH2, -C(O)NHCH3, -C(O)N(CH3)2, -C(O)OH, -C(O)OCH3, -NH2, NHCH3, -N(CH3)2, -NH(oxetanyl), -NHC(O)CH3, -NHS(O2)CH3, -OH, -OCH3, -OCH2CF3, methylpyrazolyl, pyrazolyl, and oxo.

[0124] In some embodiments, the compound of formula (II) is a compound of the following formula disclosed in Table III': [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0125] [Table 13]

[0126] [Table 14]

[0127] [Table 15]

[0128] [Table 16]

[0129] [Table 17]

[0130] [Table 18]

[0131] [Table 19]

[0132] [Table 20]

[0133] [Table 21]

[0134] [Table 22]

[0135] [Table 23]

[0136] [Table 24]

[0137] [Table 25]

[0138] [Table 26]

[0139] In some embodiments, ring B is any one of the B rings disclosed in Tables II, III, and / or III', or a salt thereof.

[0140] In another embodiment, the compound of formula (IV): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof, is provided herein, wherein: R 1 and R 2 are each independently hydrogen or deuterium; A 2 -CR 7 R 8 - or -S(=O)2-; R 3 and R 4 are each independently hydrogen, deuterium, halogen, or C 1~4 is alkyl; R 7 and R 8 are independently hydrogen, deuterium, halogen, C 1~4 Alkyl or C 1~4 haloalkyl; or R 7 and R 8 together with the carbon atoms to which they are attached form a cyclopropane or an oxetane; R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached to form oxetanes; R A1 is a halogen, C 1~4 alkyl, or cyclopropyl; Ring C is a substituted or unsubstituted bicyclic heterocycle containing one or more nitrogen atoms; and Ring B' is [ka] (selected from the group consisting of:

[0141] In some embodiments, A 2 -CR 7 R 8 - or -S(=O)2-. In some embodiments, A 2 is -S(=O)2-. In some embodiments, A 2 Ha-CR7 R 8 -It is.

[0142] In some embodiments, A 2 Ha-CR 7 R 8 - and R 7 and R 8 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 7 and R 8 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 7 and R 8 are each independently hydrogen or deuterium. 7 and R 8 are each hydrogen. In some embodiments, R 7 and R 8 Each is deuterium. In some embodiments, R 7 and R 8 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, each R 7 and R 8 are independently hydrogen or deuterium; or R 7 and R 8 together with the carbon atoms to which they are attached form an oxetane.

[0143] In some embodiments, the compound of formula (IV) is a compound of formula (IVa): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, each R 3 and R 4 are independently hydrogen, deuterium, halogen, or C 1~4 In some embodiments, each R 3 and R 4is independently hydrogen, deuterium, or —CH. In some embodiments, each R 3 and R 4 is independently hydrogen or deuterium. 3 and R 4 is hydrogen. In some embodiments, each R 3 and R 4 is deuterium.

[0145] In some embodiments, R 9 and R 10 are each independently hydrogen, deuterium, halogen, or C 1~4 alkyl; or R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, R 9 and R 10 are each independently hydrogen or deuterium. 9 and R 10 are each hydrogen. In some embodiments, R 9 and R 10 Each is deuterium. In some embodiments, R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, each R 9 and R 10 are independently hydrogen or deuterium; or R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane.

[0146] In some embodiments, each R 3 and R 4 is hydrogen; and each R 7 and R 8 is hydrogen. In some embodiments, each R 3 , R 4 , R 7 , and R 8 is hydrogen; and each R 9 and R 10are independently hydrogen or deuterium; or R 9 and R 10 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, each R 3 and R 4 is hydrogen; and each R 9 and R 10 is hydrogen. In some embodiments, each R 3 , R 4 , R 9 , and R 10 is hydrogen; and each R 7 and R 8 are independently hydrogen or deuterium; or R 7 and R 8 together with the carbon atoms to which they are attached form an oxetane. In some embodiments, each R 7 and R 8 is hydrogen; and each R 9 and R 10 is hydrogen. In some embodiments, each R 7 , R 8 , R 9 , and R 10 is hydrogen; and each R 3 and R 4 are independently hydrogen or deuterium.

[0147] In some embodiments, the compound of formula (IV) is a compound of formula (V): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the compound of formula (IV) is a compound of formula (VI): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, ring C is a substituted or unsubstituted bicyclic heterocycle containing one or more nitrogen atoms. In some embodiments, ring C is a substituted bicyclic heterocycle containing one or two nitrogen atoms. In some embodiments, ring C is an unsubstituted bicyclic heterocycle containing one or two nitrogen atoms. In some embodiments, ring C is a substituted bicyclic heteroaryl containing one or two nitrogen atoms. In some embodiments, ring C is an unsubstituted bicyclic heteroaryl containing one or two nitrogen atoms. In some embodiments, ring C is a fused bicyclic heterocycle containing a 5-membered heterocycle and a 6-membered aryl or heteroaryl.

[0150] In some embodiments, the 6-membered aryl or heteroaryl of Ring C is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl. In some embodiments, the 6-membered aryl or heteroaryl of Ring C is phenyl or pyridinyl.

[0151] In some embodiments, the compound of Formula (IV) is a compound of Formula (VIa) or Formula (VIb): [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, each X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is independently C, CH, CH, N, or NH. In some embodiments, X 1 is -CH=; and X 2 is CH. In some embodiments, X 1 is -CH=; and X 2 is N. In some embodiments, X 1 is -N =; and X 2 is CH. In some embodiments, X 1is -CH2-; and X 2 is CH. In some embodiments, each X 1 and X 2 is independently CH or N; and [ka] teeth [ka] is.

[0153] In some embodiments, the compound of Formula (VI) is a compound of Formula (VIc) or Formula (VId): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0154] In some embodiments, X 2 is CH or N.

[0155] In some embodiments, Ring C is selected from the group consisting of substituted or unsubstituted indole, substituted or unsubstituted indoline, substituted or unsubstituted indazole, substituted or unsubstituted indolizine, substituted or unsubstituted azaindole, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, substituted or unsubstituted pyrazolopyridine, substituted or unsubstituted pyrrolopyrimidine, substituted or unsubstituted pyrazolopyrimidine, and substituted or unsubstituted imidazopyrimidine. In some embodiments, Ring C is selected from the group consisting of substituted or unsubstituted indole, substituted or unsubstituted indoline, substituted or unsubstituted indazole, substituted or unsubstituted indolizine, substituted or unsubstituted pyrrolopyridine, substituted or unsubstituted imidazopyridine, and substituted or unsubstituted pyrazolopyridine. In some embodiments, Ring C is selected from the group consisting of substituted or unsubstituted indole, substituted or unsubstituted 2,3-dihydroindole, substituted or unsubstituted indolizine, substituted or unsubstituted azaindole, and substituted or unsubstituted indazole. In some embodiments, Ring C is a substituted indole. In some embodiments, Ring C is a 5-fluoroindole.

[0156] In some embodiments, Ring C is a fused bicyclic heterocycle comprising a 6-membered heterocycle and a 6-membered aryl or heteroaryl. In some embodiments, Ring C is selected from the group consisting of substituted or unsubstituted quinoline, substituted or unsubstituted isoquinoline, substituted or unsubstituted tetrahydroquinoline, substituted or unsubstituted tetrahydroisioquinoline, substituted or unsubstituted naphthyridine, substituted or unsubstituted quinone, and substituted or unsubstituted quinolinzine.

[0157] In some embodiments, ring C is selected from deuterium, halogen, and C 1~4 In some embodiments, Ring C is substituted with one or more groups selected from halogen and methyl. In some embodiments, Ring C is substituted with -CH.

[0158] In some embodiments, Ring C is substituted by one or more halogen atoms. In some embodiments, Ring C is substituted by one or more -F or -Cl. In some embodiments, Ring C is substituted by -F. In some embodiments, Ring C is substituted by -Cl.

[0159] In some embodiments, ring C is [ka] is selected from the group consisting of:

[0160] In some embodiments, ring C is [ka] is selected from the group consisting of:

[0161] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] In some embodiments, ring C is [ka] is.

[0162] In some embodiments, the compound of formula (IV) is a compound of formula (VII): [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, R 1 and R 2 are each independently hydrogen or deuterium. 1 and R 2 are each hydrogen. In some embodiments, R 1 and R 2 Each is deuterium. In some embodiments, R 1 and R 2 are each independently hydrogen or deuterium; and ring B' is [ka] is selected from the group consisting of:

[0164] In some embodiments, the compound of formula (VII) is 1 , Y 2 , and Y 3 is independently CH, CH, N, or NH: [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0165] In some embodiments, Y 1 is CH and Y 2 is CH and Y 3 is N. In some embodiments, Y 1 is N and Y 2 is CH and Y 3 is CH. In some embodiments, Y 1 is CH and Y 2 is N and Y 3 is CH.

[0166] In some embodiments, the compound of formula (VII) is Y 4 , Y 5 , or Y 6is N and each of the other members is CH, [ka] is.

[0167] In some embodiments, Y 4 is CH and Y 5 is CH and Y 6 is N. In some embodiments, Y 4 is N and Y 5 is CH and Y 6 is CH. In some embodiments, Y 4 is CH and Y 5 is N and Y 6 is CH.

[0168] In another embodiment, the compounds of the following formulae disclosed in Table VII: [ka] or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0169] [Table 27]

[0170] [Table 28]

[0171] [Table 29]

[0172] [Table 30]

[0173] [Table 31]

[0174] [Table 32]

[0175] [Table 33]

[0176] In another embodiment, a compound of formula (VIII): [ka] or a tautomer, or a pharmaceutically acceptable salt thereof, is provided herein, wherein: R 1 and R 2 are each independently hydrogen or deuterium; Ring A' is [ka] selected from the group consisting of: In the formula, # C indicates the bond to the fluoroindole ring; Ring B is a substituted or unsubstituted heterocycle; where, when Ring B is substituted, it contains one or more R B is substituted by a group, and Each R B The groups are hydrogen, deuterium, halogen, C 1~4 Alkyl, -CN, -C(=O)-NH2, -C(=O)-NHC 1~4 Alkyl, -C(=O)-N(C 1~4 alkyl)2, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 alkyl)2, -NH-C(=O)-C 1~4 Alkyl, -OH, -OC 1~4 -Alkyl, -S(=O)-C 1~4 Alkyl, and -S(=O)2-C 1~4alkyl; wherein two R B The groups optionally, together with the carbon atom to which they are attached, form (C=O) or oxetanyl).

[0177] In some embodiments, ring A' is selected from the group consisting of:

[0178] In some embodiments, ring B is a substituted or unsubstituted monocyclic heterocycle. In some embodiments, ring B is a substituted or unsubstituted bicyclic heterocycle. In some embodiments, ring B is a substituted or unsubstituted 5- or 6-membered heterocycle. In some embodiments, ring B is a substituted or unsubstituted 5-membered heterocycle. In some embodiments, ring B is a substituted 5-membered heterocycle. In some embodiments, ring B is an unsubstituted 5-membered heterocycle.

[0179] In some embodiments, ring B is a substituted or unsubstituted 6-membered heterocycle. In some embodiments, ring B is a substituted 6-membered heterocycle. In some embodiments, ring B is an unsubstituted 6-membered heterocycle. In some embodiments, ring B is a substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, substituted or unsubstituted pyrazine, substituted or unsubstituted pyridazine, or substituted or unsubstituted piperidine. In some embodiments, ring B is a substituted pyridine, substituted pyrimidine, substituted pyrazine, substituted pyridazine, or substituted piperidine. In some embodiments, ring B is an unsubstituted pyridine, unsubstituted pyrimidine, unsubstituted pyrazine, unsubstituted pyridazine, or unsubstituted piperidine.

[0180] In some embodiments, Ring B is a substituted or unsubstituted pyridine. In some embodiments, Ring B is a substituted or unsubstituted pyrimidine. In some embodiments, Ring B is a substituted or unsubstituted pyrazine. In some embodiments, Ring B is a substituted or unsubstituted pyridazine. In some embodiments, Ring B is a substituted or unsubstituted piperidine.

[0181] In some embodiments, Ring B is a substituted pyridine. In some embodiments, Ring B is a substituted pyrimidine. In some embodiments, Ring B is a substituted pyrazine.

[0182] In some embodiments, Ring B is a substituted pyridazine. In some embodiments, Ring B is a substituted piperidine. In some embodiments, Ring B is an unsubstituted pyridine. In some embodiments, Ring B is an unsubstituted pyrimidine. In some embodiments, Ring B is an unsubstituted pyrazine. In some embodiments, Ring B is an unsubstituted pyridazine. In some embodiments, Ring B is an unsubstituted piperidine.

[0183] In some embodiments, ring B is one or more R B In some embodiments, Ring B is substituted with a group. In some embodiments, Ring B is a substituted or unsubstituted pyridone. In some embodiments, Ring B is a substituted or unsubstituted pyrimidone. In some embodiments, Ring B is a substituted or unsubstituted pyrazone. In some embodiments, Ring B is a substituted or unsubstituted pyridazone. In some embodiments, Ring B is a substituted or unsubstituted piperidone.

[0184] In some embodiments, ring B is [ka] is selected from the group consisting of:

[0185] In some embodiments, ring B is [ka] In some embodiments, ring B is selected from the group consisting of: [ka] is.

[0186] In some embodiments, each RB are independently hydrogen, deuterium, halogen, C 1~4 Alkyl, -NH2, -NHC 1~4 Alkyl, -N(C 1~4 Alkyl)2, -OH, -OC 1~4 -Alkyl, or -S(=O)2-C 1~4 In some embodiments, each R B are independently hydrogen, -NH2, or -S(=O)2-C 1~4 In some embodiments, each R B is independently hydrogen or —S(═O)—CHCH. In some embodiments, each R B is independently hydrogen or -NH. In some embodiments, each R B is hydrogen, and thus ring B is unsubstituted. In some embodiments, two R B The groups together form an oxo (=O). In some embodiments, two R B The groups together form an oxetanyl.

[0187] In another embodiment, the compounds of the following formulae disclosed in Table VIII: [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0188] [Table 34]

[0189] [Table 35]

[0190] In some embodiments, the compound of formula (VIII) is a compound of formula (IX): [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0191] In some embodiments, R 1 and R 2 are each independently hydrogen or deuterium; and ring A' is [ka] selected from the group consisting of: In the formula, # C indicates the bond to the fluoroindole ring.

[0192] In some embodiments, ring A' is [ka] is selected from the group consisting of:

[0193] In some embodiments, ring A' is [ka] is selected from the group consisting of:

[0194] In another embodiment, a compound of the following formula disclosed in Table IX: [ka] or a tautomer, or a pharmaceutically acceptable salt thereof.

[0195] [Table 36]

[0196] [Table 37]

[0197] [Table 38]

[0198] [Table 39]

[0199] [Table 40]

[0200] Additional forms of the compound In one embodiment, the compounds described herein are in the form of pharmaceutically acceptable salts. Note that the active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. Furthermore, the compounds described herein can exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0201] As used herein, "pharmaceutically acceptable" refers to a material, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and is relatively non-toxic, i.e., a material that may be administered to an individual without causing undesired biological effects or deleteriously interfering with any of the components of the composition in which it is contained.

[0202] The term "pharmaceutically acceptable salt" refers to a therapeutically active agent in cationic form combined with a suitable anion, or in an alternative embodiment, a form consisting of a therapeutically active agent in anionic form combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. SM Berge, LD Bighley, DC Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. PH Stahl and CG Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zuerich:Wiley-VCH / VHCA, 2002. Drug salts are typically more soluble in gastrointestinal fluids and dissolve more rapidly than non-ionic species, making them useful in solid dosage forms. Furthermore, their solubility is often a function of pH, allowing for selective dissolution in one part of the gastrointestinal tract or another, which can be manipulated as an aspect of delayed and sustained release behavior. Also, salt-forming molecules can be in equilibrium with neutral forms, allowing for regulated transport across biological membranes.

[0203] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with an acid. In some embodiments, a compound described herein (i.e., in free base form) is basic and is reacted with an organic or inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor-10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecyl sulfuric acid; ethane-1,2-disulfonic acid; ethanesulfonic acid; gi Acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (-L); malonic acid; mandelic acid (DL); methanesulfonic acid; monomethyl fumarate, naphthalene-1,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (-L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+L); thiocyanic acid; toluenesulfonic acid (p); and undecylenic acid.

[0204] In some embodiments, the compounds described herein are prepared as chloride, sulfate, bromide, mesylate, maleate, citrate, or phosphate salts. In some embodiments, the compounds described herein are prepared as hydrochloride salts.

[0205] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound described herein with a base. In some embodiments, a compound described herein is acidic and is reacted with a base. In such cases, the acidic proton of a compound described herein is replaced with a metal ion, such as a lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, a compound described herein coordinates with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, or tris(hydroxymethyl)methylamine. In other cases, a compound described herein forms a salt with an amino acid, such as, but not limited to, arginine or lysine. Acceptable inorganic bases used to form salts with compounds containing acidic protons include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, and lithium hydroxide. In some embodiments, the compounds provided herein are prepared as sodium, calcium, potassium, magnesium, meglumine, N-methylglucamine, or ammonium salts. In some embodiments, the compounds provided herein are prepared as sodium salts.

[0206] It should be understood that a reference to a pharmaceutically acceptable salt includes solvent addition forms. In some embodiments, solvates contain either stoichiometric or non-stoichiometric amounts of a solvent and are formed during the process of crystallization with a pharmaceutically acceptable solvent, such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0207] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds described herein, as well as active metabolites of these compounds that have the same type of activity.

[0208] In some embodiments, moieties on the organic radicals (e.g., alkyl groups, aromatic rings) of the compounds described herein are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize, or eliminate this metabolic pathway. In specific embodiments, suitable substituents for reducing or eliminating the susceptibility of aromatic rings to metabolic reactions are, by way of example only, halogen, deuterium, alkyl groups, haloalkyl groups, or deuteroalkyl groups.

[0209] In another embodiment, the compounds described herein are labeled with an isotope (e.g., with a radioisotope) or by other means, including, but not limited to, the use of a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0210] The compounds described herein include isotopically labeled compounds that are identical to those listed in the various formulas and structures presented herein except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds include, for example, 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 and isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. In one aspect, isotopically labeled compounds described herein, e.g. 3 H and 14Incorporation of radioactive isotopes such as C is useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium confers certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0211] In some embodiments, the compounds described herein contain one or more stereocenters, and each stereocenter independently exists in either the R or S configuration. The compounds provided herein include all diastereomeric, enantiomeric, atropisomeric, and epimeric forms, as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as the appropriate mixtures thereof.

[0212] Individual stereoisomers can be obtained, if desired, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. In certain embodiments, compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereomeric compounds / salts, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, resolution of enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of steroisomers is carried out by chromatography, or by formation of diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions," John Wiley and Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0213] In some embodiments, the compounds described herein are prepared as prodrugs. A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They may, for example, be bioavailable by oral administration, whereas the parent drug is not. In some situations, the prodrug may cross membranes (e.g., cell membranes, the intestinal lumen, the blood-brain barrier, etc.), whereas the active agent may not. In some situations, a charged or highly polar moiety is masked with a more permeable group that can be cleaved in vivo. The prodrug may be a substrate for a transporter. Additionally or alternatively, the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the prodrug design increases effective water solubility. Without limitation, one example of a prodrug is a compound described herein, which is administered as an ester (the "prodrug"), but is then metabolically hydrolyzed to provide the active agent. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically, or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically, or therapeutically active form of the compound. In some embodiments, a prodrug is enzymatically metabolized in vivo by esterases, proteases, peptidases, hydrolases, etc. to an active form. In some embodiments, a prodrug is converted to an active form of the compound independently of metabolic enzymes (e.g., by hydrolysis or pH-dependent degradation).

[0214] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers (e.g., oxymethyl ethers), carbonates, thiocarbonates, carbamates, anhydrides, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, and sulfonate esters. See, for example, "Design of Prodrugs," Bundgaard, A. Ed., Elseview, 1985, and "Method in Enzymology," Widder, K. et al., Ed.; Academic, 1985, vol. 42, pp. 309-396; "Design and Application of Prodrugs," in "A Textbook of Drug Design and Development," Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, pp. 113-191; and "Bundgaard, H., Advanced Drug Delivery Review," 1992, 8, pp. 1-38, each of which is incorporated herein by reference. In some embodiments, hydroxyl groups in the compounds disclosed herein are used to form prodrugs, and the hydroxyl groups are incorporated into acyloxyalkyl esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sugar esters, ethers, and the like. In some embodiments, the carboxyl group is used to provide an ester or amide (i.e., a prodrug) that is then metabolized in vivo to provide the carboxylic acid group. In some embodiments, the compounds described herein are prepared as alkyl ester prodrugs. In some embodiments, the compounds described herein are prepared as oxymethyl ether or polyoxymethylene dimethyl ether prodrugs.

[0215] Within the scope of the claims are compounds described herein in prodrug form, where the prodrug is metabolized in vivo to yield the compounds described herein. In some cases, some of the compounds described herein are prodrugs of another derivative or active compound.

[0216] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need thereof to produce metabolites, which are then used to produce a desired effect, including a desired therapeutic effect.

[0217] A "metabolite" of a compound disclosed herein is a derivative of that compound formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is altered by an organism, including, but not limited to, hydrolysis and enzyme-catalyzed reactions. Thus, enzymes can produce specific structural changes in a compound. For example, cytochrome P450 catalyzes various oxidation and reduction reactions, while uridine diphosphate glucuronyltransferase catalyzes the transfer of activated glucuronic acid molecules to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines, and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified by administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compounds.

[0218] In some embodiments, the compounds of the present disclosure provide an enhanced pharmacokinetic or pharmacodynamic profile compared to other known EP2 antagonists. For example, the compounds described herein may have increased bioavailability, volume of distribution, absorption, half-life, duration of action, receptor occupancy, cell permeability, blood-brain barrier permeability, plasma stability, metabolic stability, excretion, or toxicity profile compared to currently available EP2 antagonists. In some embodiments, the compounds are formulated as prodrugs, in which case the active metabolite is cleaved in vivo after reaching the target cell or tissue. In other embodiments, the compounds are not cleaved in vivo.

[0219] definition Unless otherwise specified, the following terms used in this application have the definitions given below. The terms "including" and other forms such as "include," "includes," and "included" are open-ended. The section headings used are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0220] As used herein, C1-C x is C1~C2, C1~C3...C1~C x By way of example only, a group designated as "C1-C4" indicates that there are 1 to 4 carbon atoms in the moiety, i.e., the group contains 1, 2, 3, or 4 carbon atoms. Thus, by way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl group, i.e., the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0221] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group is branched or straight-chain. In some embodiments, an "alkyl" group has 1 to 10 carbon atoms, i.e., C1 to C6. 10It is alkyl. Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer within the given range; for example, "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also includes occurrences of the term "alkyl" where no numerical range is given. In some embodiments, alkyl is C1 to C6 alkyl. In one aspect, alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Exemplary alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0222] "Deuteroalkyl" refers to an alkyl group in which one or more of the alkyl's hydrogen atoms has been replaced with deuterium.

[0223] The term "alkenyl" refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR2, where R refers to the remainder of the alkenyl group, which can be the same or different. In some embodiments, R is H or alkyl. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and -CH2CH=CH2.

[0224] The term "alkynyl" refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group has the formula -C≡CR, where R refers to the remainder of the alkynyl group. In some embodiments, R is H or alkyl. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3-C≡CCH2CH3, and -CH2C≡CH.

[0225] An "alkoxy" group refers to an (alkyl)O- group, where alkyl is as defined herein.

[0226] The term "alkylamine" refers to an -N(alkyl) x H y refers to the group where x is 0 and y is 2, or x is 1 and y is 1, or x is 2 and y is 0.

[0227] The term "carbocyclic" or "carbocycle" refers to a ring or ring system in which the atoms forming the backbone of the ring are all carbon atoms. This term therefore distinguishes carbocyclic from "heterocyclic" rings or "heterocycles" in which the ring backbone contains at least one atom other than carbon. In some embodiments, at least one of the two rings in a bicyclic carbocycle is aromatic. In some embodiments, both rings in a bicyclic carbocycle are aromatic.

[0228] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. In one aspect, an aryl is phenyl or naphthyl. In some embodiments, an aryl is phenyl. In some embodiments, an aryl is C6-C 13 Depending on the structure, an aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0229] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. In some embodiments, the cycloalkyl is a spirocyclic or bridged compound. In some embodiments, the cycloalkyl is optionally fused to an aromatic ring, and the point of attachment is to a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having 3 to 10 ring atoms. In some embodiments, the cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, and bicyclic[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl.

[0230] The term "halo" or, alternatively, "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0231] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced by a fluorine atom. In one embodiment, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0232] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl is selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl.

[0233] The term "heterocycle" or "heterocyclic" refers to heteroaromatic (also known as heteroaryl) and heterocycloalkyl (also known as heteroalicyclic) rings containing 1 to 4 heteroatoms in the ring, where each heteroatom in the ring is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, provided that no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyl) contain rings having 3 to 10 atoms in their ring system, and aromatic heterocyclic groups contain rings having 5 to 10 atoms in their ring system. Heterocyclic groups include benzo-fused ring systems. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithio ranyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-1-onyl, isoindolin-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, isoindolin-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-benzo[d]imidazol-2(3H)-onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The above groups are either C-attached (or C-linked) or N-attached where possible. For example, groups derived from pyrrole include both pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked). Furthermore, groups derived from imidazole include imidazol-1-yl or imidazol-3-yl (both N-linked) or imidazol-2-yl, imidazol-4-yl, or imidazol-5-yl (all C-linked). Heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0234] The terms "heteroaryl" or, alternatively, "heteroaromatic" refer to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, the heteroaryl contains 0-4 N atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms in the ring. In some embodiments, the heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, the heteroaryl is a C1-C9 heteroaryl. In some embodiments, the monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, the monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the bicyclic heteroaryl is a C6-C9 heteroaryl.

[0235] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl is fused to an aryl or heteroaryl. In some embodiments, a heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2,5-dithionyl, pyrrolidine-2,5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. The term heteroalicyclic also includes carbohydrates in all ring forms, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, a heterocycloalkyl is a C2-C6 10 In some embodiments, the heterocycloalkyl is a C2-C6 heterocycloalkyl. In some embodiments, the heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, the heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0236] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent, thereby allowing a bond to be formed between the remaining specified groups.

[0237] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical entity embedded in or appended to a molecule.

[0238] The term "optionally substituted" or "substituted" means that the referenced group is optionally substituted with one or more additional groups individually and independently selected from halogen, -CN, -NH, -NH(alkyl), -N(alkyl), -OH, -COH, -COalkyl, -C(=O)NH, -C(=O)NH(alkyl), -C(=O)N(alkyl), -S(=O)NH, -S(=O)NH(alkyl), -S(=O)N(alkyl), alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, the optional substituents are independently selected from halogen, -CN, -NH, -NH(CH), -N(CH), -OH, -COH, -CO(C-C alkyl), -C(=O)NH, -C(=O)NH(C-C alkyl), -C(=O)N(C-C alkyl), -S(=O)NH, -S(=O)NH(C-C alkyl), -S(=O)N(C-C alkyl), C-C alkyl, C-C cycloalkyl, C-C fluoroalkyl, C-C heteroalkyl, C-C alkoxy, C-C fluoroalkoxy, -SC-C alkyl, -S(=O)C-C alkyl, and -S(=O)C-C alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH, -OH, -NH(CH), -N(CH), -CH, -CHCH, -CF, -OCH, and -OCF. In some embodiments, substituted groups are substituted with one or two of the foregoing groups. In some embodiments, optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (=O).

[0239] The term "acceptable," as used herein, with respect to a formulation, composition, or ingredient, means having no lasting adverse effects on the general health of the subject being treated.

[0240] As used herein, the term "modulate" means to interact with a target either directly or indirectly to alter the activity of the target, including, by way of example only, to increase the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to prolong the activity of the target.

[0241] As used herein, the term "modulator" refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, those of an agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an antagonist.

[0242] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a compound or composition to a desired site of biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular, or infusion), topical, and rectal administration. Those skilled in the art are familiar with administration techniques that can be utilized with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0243] As used herein, the term "co-administration" and the like is meant to encompass the administration of selected therapeutic agents to a single patient and is intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0244] As used herein, the term "effective amount" or "therapeutically effective amount" refers to a sufficient quantity of an agent or compound being administered to relieve to some extent one or more of the symptoms of the disease or condition being treated. Results include reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is the quantity of a composition comprising a compound disclosed herein that is required to provide a clinically significant reduction in a disease symptom. An appropriate "effective" amount in any individual case is optionally determined using techniques such as a dose escalation study.

[0245] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term "enhancing" refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. As used herein, an "enhancing-effective amount" refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0246] As used herein, the term "pharmaceutical combination" refers to a product resulting from the mixing or combining of two or more active ingredients, and includes both fixed and loose combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and a co-agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "unfixed combination" means that the active ingredients, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and a co-agent are administered to a patient simultaneously, in parallel, or sequentially with no specific time limit between them, as separate entities, such that such administration provides effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0247] The terms "kit" and "article of manufacture" are used synonymously.

[0248] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates such as chimpanzees, and other ape and monkey species; livestock animals such as cows, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. In one embodiment, the mammal is a human.

[0249] As used herein, the terms "treat," "treating," or "treatment" include alleviating, attenuating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., preventing the onset of a disease or condition, relieving a disease or condition, causing regression of a disease or condition, alleviating conditions caused by a disease or condition, or arresting symptoms of a disease or condition prophylactically and / or therapeutically.

[0250] Pharmaceutical Composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate the processing of active compounds into pharmaceutical preparations. Suitable formulations depend on the selected route of administration. Overviews of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0251] In some embodiments, the compounds described herein are administered alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent in a pharmaceutical composition. Administration of the compounds and compositions described herein can be carried out by any method that allows delivery of the compound to the site of action. These methods include, but are not limited to, enteral routes (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), parenteral routes (injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including transdermal, cutaneous, enema, eye drops, ear drops, intranasal, and intravaginal) administration, although the optimal route may depend, for example, on the condition and disorder of the recipient.

[0252] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

[0253] Orally usable pharmaceutical compositions include tablets, push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. Tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant, or dispersing agent. Molded tablets may be produced by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, tablets are coated or scored and formulated to provide slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be in a dosage suitable for such administration. Push-fit capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added. The dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound dosages.

[0254] In some embodiments, pharmaceutical compositions are formulated for parenteral administration, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with added preservatives. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. The compositions may be presented in unit-dose or multi-dose containers, e.g., sealed ampoules and vials, and may be stored in powder or freeze-dried (lyophilized) form requiring only the addition of a sterile liquid carrier, e.g., saline or sterile pyrogen-free water, immediately prior to use. Injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0255] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions.

[0256] Pharmaceutical compositions can also be formulated as depot preparations. Such long-acting preparations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, such as sparingly soluble salts.

[0257] Methods of administration and treatment regimens In one embodiment, the compounds of formula (I) are used in the preparation of a medicament for the treatment or prevention of diseases and conditions that would benefit from, or result from, the reduction or inhibition of EP2 activity. Additionally, a method of treating any of the diseases and conditions described herein in a mammal in need of such treatment comprises administering to said mammal a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I) or formula (X), or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof.

[0258] In certain embodiments, compositions comprising the compounds described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially prevent at least one symptom of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0259] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition.

[0260] In certain embodiments, the dosage of the drug being administered may be temporarily reduced or even stopped for a specific period of time (ie, a "drug holiday").

[0261] Dosages utilized for adult human treatment typically range from 0.01 mg to 5000 mg per day, or from about 1 mg to about 1000 mg per day, hi one embodiment, the desired dosage is conveniently presented as a single dose or divided doses.

[0262] In certain cases, it may be appropriate to administer at least one compound of Formula (I) or Formula (X) in combination with another therapeutic agent. In a specific embodiment, a compound of Formula (I) or Formula (X) is co-administered with a second therapeutic agent, where the compound of Formula (I) or Formula (X) and the second therapeutic agent modulate different aspects of the disease or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone.

[0263] For the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of co-agent utilized, the specific agent utilized, the disease or condition being treated, etc. In additional embodiments, when co-administered with one or more other therapeutic agents, the compounds provided herein are administered simultaneously with or sequentially with the one or more other therapeutic agents.

[0264] When administration is simultaneous, the multiple therapeutic agents may be given in a single combined form or in multiple forms, by way of example only. [Example]

[0265] Example The following examples are offered for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0266] The compounds described herein are synthesized using standard synthetic techniques or methods known in the art in combination with methods described herein.

[0267] The compounds are listed in March's Advanced Organic Chemistry, 6 th The starting materials are prepared using standard organic chemistry techniques, such as those described in The American Chemical Society, Vol. 1, No. 1, pp. 111-114, 1997. Edition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be utilized, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions. The starting materials are available from commercial sources or are readily prepared.

[0268] Scheme Scheme 1. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H6)-4H-1,4-benzoxazepine [ka] Step 1: Synthesis of 5-bromo-3-chloro-2-hydroxy-N-[2-hydroxy(1,1,2,2-2H4)ethyl]benzamide To a stirred solution of 5-bromo-3-chloro-2-hydroxybenzoic acid (2.5 g, 9.9 mmol) and 2-amino(2H)ethanol (0.65 g, 9.9 mmol) in DCM (50 mL) was added PyBOP (5.2 g, 9.9 mmol) and EtN (2.0 g, 19.9 mmol). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography on silica gel: column, C18 silica gel; mobile phase, 0.05% TFA in water, CHCN, 20% to 70% gradient in 10 min; detector, UV 254 nm to give 5-bromo-3-chloro-2-hydroxy-N-[2-hydroxy(1,1,2,2-2H)ethyl]benzamide (1.5 g, 51%) as a colorless oil.

[0269] Step 2: Synthesis of 4-bromo-2-chloro-6-({[2-hydroxy(1,1,2,2-2H4)ethyl]amino}(2H2)methyl)phenol To a stirred mixture of NaBD4 (1.68 g, 40.190 mmol, 10 equiv) in THF (24 mL) at 0 °C under an atmosphere of N2, BF3.Et2O (5.70 g, 40.2 mmol) was added dropwise. The mixture was stirred at 10 °C for 10 min, and then 5-bromo-3-chloro-2-hydroxy-N-[2-hydroxy(1,1,2,2-2H4)ethyl]benzamide (1.2 g, 4.0 mmol) was added dropwise at 0 °C. The mixture was heated to 55 °C and stirred overnight, then cooled to room temperature, and MeOH was carefully added. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography: column, C18; mobile phase, CHCN in 0.05% TFA in water, 10% to 50% gradient in 30 min; detector, UV 220 nm to give 4-bromo-2-chloro-6-({[2-hydroxy(1,1,2,2-2H4)ethyl]amino}(2H2)methyl)phenol (500 mg, 43%) as an oil.

[0270] Step 3: Synthesis of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)(2H2)methyl]-N-[2-hydroxy(1,1,2,2-2H4)ethyl]carbamate To a stirred solution of 4-bromo-2-chloro-6-({[2-hydroxy(1,1,2,2-2H)ethyl]amino}(2H)methyl)phenol (550 mg, 1.9 mmol) in THF (10 mL) and saturated aqueous NaHCO (5 mL) was added (Boc)O (500 mg, 2.3 mmol). The mixture was stirred at room temperature for 16 h and then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography: column, C18; mobile phase, CHCN in 0.05% TFA in water, 30% to 90% gradient in 90 min; detector, UV 220 nm to give tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)(2H)methyl]-N-[2-hydroxy(1,1,2,2-2H)ethyl]carbamate (300 mg, 40%) as a solid.

[0271] Step 4: Synthesis of tert-butyl 7-bromo-9-chloro(2,2,3,3,5,5-2H6)-1,4-benzoxazepine-4-carboxylate To a stirred solution of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)(2H)methyl]-N-[2-hydroxy(1,1,2,2-2H)ethyl]carbamate (500 mg, 1.29 mmol) and PPh (850 mg, 3.23 mmol) in THF (5 mL) at room temperature under an atmosphere of N was added dropwise DIAD (650 mg, 3.23 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography: column, C18 silica gel; mobile phase, CHCN in 0.05% TFA in water, 20% to 70% gradient in 30 minutes; detector, UV 220 nm to give tert-butyl 7-bromo-9-chloro(2,2,3,3,5,5-2H6)-1,4-benzoxazepine-4-carboxylate (340 mg, 71%) as a solid.

[0272] Step 5: Synthesis of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H6)-1,4-benzoxazepine-4-carboxylate To a stirred solution of tert-butyl 7-bromo-9-chloro(2,2,3,3,5,5-2H)-1,4-benzoxazepine-4-carboxylate (300 mg, 0.81 mmol) and 5-fluoro-1H-indole (170 mg, 1.22 mmol) in 1,4-dioxane (10 mL) at room temperature under an atmosphere of N was added CuI (50 mg, 0.24 mmol), KPO (520 mg, 2.4 mmol) and trans-cyclohexane-1,2-diamine (50 mg, 0.41 mmol). The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, 0.05% TFA in CHCN in water, 40% to 90% gradient in 30 minutes; detector, UV 220 nm) to give tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H6)-1,4-benzoxazepine-4-carboxylate (240 mg, 70%) as a solid.

[0273] Step 6: Synthesis of 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H6)-4H-1,4-benzoxazepine To a stirred solution of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H)-1,4-benzoxazepine-4-carboxylate (120 mg, 0.28 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred for 30 minutes at room temperature, then neutralized with saturated aqueous NaHCO and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give crude 9-chloro-7-(5-fluoroindol-1-yl)(2,2,3,3,5,5-2H)-4H-1,4-benzoxazepine (100 mg, crude) as a solid. The solid was used in the next step without further purification.

[0274] Scheme 2. Preparation of 5-chloro-7-(5-fluoroindol-1-yl)-1,2,3,4-tetrahydroisoquinoline [ka] Step 1: Synthesis of 4-bromo-2-chloro-1-(2-nitrovinyl)benzene A mixture of 4-bromo-2-chlorobenzaldehyde (6.60 g, 30.1 mmol), MeNH.HCl (1.30 g, 19.3 mmol), and NaOAc (1.58 g, 19.3 mmol) in MeNO (12 mL) was stirred at room temperature for 16 h. HO (50 mL) was added, and the mixture was extracted with DCM (50 mL × 2). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase chromatography: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to give 4-bromo-2-chloro-1-(2-nitrovinyl)benzene (3.80 g, 41%) as an oil.

[0275] Step 2: Synthesis of 2-(4-bromo-2-chlorophenyl)ethanamine To a stirred solution of LiBH4 (1.26 g, 57.9 mmol) in THF (30 mL) at room temperature, TMSCl (12.58 g, 115.8 mmol) was added dropwise over 2 min. After stirring for 20 min, the mixture was sparged with N2 to remove the formed trimethylsilane. A solution of 4-bromo-2-chloro-1-[(E)-2-nitroethenyl]benzene (3.80 g, 14.5 mmol) in THF (20 mL) was added dropwise over 4 min at room temperature. The resulting mixture was heated to 70 °C and stirred for 2 h, then concentrated under reduced pressure to give 2-(4-bromo-2-chlorophenyl)ethanamine (4.4 g, crude) as an oil.

[0276] Step 3: Synthesis of N-[2-(4-bromo-2-chlorophenyl)ethyl]-2,2,2-trifluoroacetamide A mixture of 2-(4-bromo-2-chlorophenyl)ethanamine (4.4 g, 18.8 mmol) in TFAA (12 mL) was stirred at room temperature for 30 min and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 15:1) to give N-[2-(4-bromo-2-chlorophenyl)ethyl]-2,2,2-trifluoroacetamide (2.0 g, 32%).

[0277] Step 4: Synthesis of 1-(7-bromo-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone To a mixture of N-[2-(4-bromo-2-chlorophenyl)ethyl]-2,2,2-trifluoroacetamide (1.00 g, 3.0 mmol) and paraformaldehyde (0.44 g, 4.8 mmol) in AcOH (5 mL) at room temperature, HSO (7.5 mL) was added dropwise over 3 min. The mixture was stirred at room temperature for 8 h, then neutralized with saturated aqueous NaHCO and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with HO (50 mL), brine (50 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (PE / EtOAc, 15:1) to give 1-(7-bromo-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (2.2 g, crude) as an oil.

[0278] Step 5: Synthesis of 5-chloro-7-(5-fluoroindol-1-yl)-1,2,3,4-tetrahydroisoquinoline To a stirred solution of 1-(7-bromo-5-chloro-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (600 mg, 1.75 mmol), 5-fluoro-1H-indole (360 mg, 2.62 mmol) in 1,4-dioxane (10 mL) under an atmosphere of N was added KPO (1.1 g, 5.26 mmol), CuI (100 mg, 0.53 mmol), and trans-cyclohexane-1,2-diamine (100 mg, 0.88 mmol). The mixture was heated to 110 °C and stirred for 16 h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 5-chloro-7-(5-fluoroindol-1-yl)-1,2,3,4-tetrahydroisoquinoline (400 mg, 76%) as a solid.

[0279] Scheme 3: Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4,5-dihydro-2H-spiro[1,4-benzoxazepine-3,1'-cyclopropane] [ka] Step 1: Synthesis of 4-bromo-2-chloro-6-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)phenol A mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (1.5 g, 6.4 mmol) and (1-aminocyclopropyl)methanol (0.67 g, 7.7 mmol) in THF (10 mL) and EtOH (10 mL) was stirred for 10 min at room temperature. NaBH (0.14 g, 3.8 mmol) was added to the above mixture, and the mixture was stirred at room temperature for 2 h and then diluted with HO (10 mL) and aqueous NHCl (15 mL). The precipitate that appeared was collected by filtration and dried under vacuum to give 4-bromo-2-chloro-6-({[1-(hydroxymethyl)cyclopropyl]amino}methyl)phenol (1.7 g, 87%) as a solid.

[0280] Step 2: Synthesis of tert-butyl (5-bromo-3-chloro-2-hydroxybenzyl)(1-(hydroxymethyl)cyclopropyl)carbamate To a stirred mixture of 4-bromo-2-chloro-6-({[1-(hydroxymethyl)cyclopropyl]amino}methyl)phenol (2.0 g, 6.5 mmol) and BocO (1.71 g, 7.8 mmol) in THF (10 mL) and MeOH (10 mL) was added EtN (0.99 g, 9.8 mmol). The mixture was heated to 60 °C and stirred for 2 days, then concentrated under reduced pressure, and the residue was purified by reverse-phase chromatography: C18; mobile phase, MeCN in water, 30% to 100% gradient in 30 min; detector, UV 220 nm to give tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-[1-(hydroxymethyl)cyclopropyl]carbamate (700 mg, 26%) as an oil.

[0281] Step 3: Synthesis of tert-butyl 7-bromo-9-chloro-2H-spiro[benzo[f][1,4]oxazepine-3,1'-cyclopropane]-4(5H)-carboxylate To a stirred solution of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-[1-(hydroxymethyl)cyclopropyl]carbamate (600 mg, 1.48 mmol) and PPh (780 mg, 2.95 mmol) in THF (10 mL) at room temperature under an atmosphere of N was added dropwise DIAD (600 mg, 2.95 mmol). The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure, and the residue was purified by trituration with MeOH (3 mL) and filtration to give tert-butyl 7-bromo-9-chloro-2,5-dihydrospiro[1,4-benzoxazepine-3,1'-cyclopropane]-4-carboxylate (380 mg, 66%) as a solid.

[0282] Step 4: Synthesis of tert-butyl 9-chloro-7-(5-fluoro-1H-indol-1-yl)-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-4(5H)-carboxylate A mixture of tert-butyl 7-bromo-9-chloro-2,5-dihydrospiro[1,4-benzoxazepine-3,1′-cyclopropane]-4-carboxylate (450 mg, 1.16 mmol), 5-fluoro-1H-indole (235 mg, 1.74 mmol), KPO (740 mg, 3.47 mmol), CuI (67 mg, 0.35 mmol), and trans-cyclohexane-1,2-diamine (67 mg, 0.58 mmol) in 1,4-dioxane (15 mL) under an atmosphere of N was heated to 100 °C and stirred overnight. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-2,5-dihydrospiro[1,4-benzoxazepine-3,1′-cyclopropane]-4-carboxylate (300 mg, 59%) as a solid.

[0283] Step 5: Synthesis of 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1'-cyclopropane] To a mixture of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-2,5-dihydrospiro[1,4-benzoxazepine-3,1'-cyclopropane]-4-carboxylate (300 mg, 0.68 mmol) in DCM (2 mL) was added TFA (0.4 mL). The mixture was stirred at room temperature overnight, then neutralized with saturated aqueous NaHCO and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over anhydrous MgSO, filtered, and the filtrate was concentrated under reduced pressure to give 9-chloro-7-(5-fluoroindol-1-yl)-4,5-dihydro-2H-spiro[1,4-benzoxazepine-3,1'-cyclopropane] (200 mg, 86%) as a solid.

[0284] Scheme 4: Preparation of 5-[(7-bromo-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)methyl]pyrimidin-2-ol [ka] Step 1: Synthesis of 7-bromo-9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine To a stirred solution of 2-chloropyrimidine-5-carbaldehyde (3.58 g, 25.1 mmol) and 7-bromo-9-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine (6.6 g, 25.1 mmol) in DCM (50 mL) was added AcOH (6.6 mL, 115.2 mmol) and NaBH(OAc) (10.66 g, 50.3 mmol). The mixture was stirred at room temperature for 16 hours, then neutralized with saturated aqueous NaHCO and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:1) to give 7-bromo-9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (3.5 g, 36%) as a solid.

[0285] Step 2: Synthesis of 5-[(7-bromo-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)methyl]pyrimidin-2-ol To a stirred solution of 7-bromo-9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (4.4 g, 11.3 mmol) in DMSO (50 mL) at room temperature was added acetohydroxamic acid (2.55 g, 33.9 mmol) and K2CO3 (7.81 g, 56.6 mmol). The mixture was heated to 80 °C for 3 h, then filtered, and the filter cake was washed with EtOAc (3 × 30 mL). HO (150 mL) was added to the filtrate, and the mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH, 10:1) to give 5-[(7-bromo-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)methyl]pyrimidin-2-ol (3.1 g, 74%) as a solid.

[0286] Scheme 5: Preparation of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine [ka] To a stirred solution of 7-bromo-9-chloro-2,3,4,5-tetrahydro-1,4-benzoxazepine (3.7 g, 14.1 mmol) and 2-methoxypyrimidine-5-carbaldehyde (2.34 g, 16.9 mmol) in DCM (50 mL) was added AcOH (4.04 mL, 70.5 mmol) and NaBH(OAc) (5.97 g, 28.2 mmol). The mixture was stirred at room temperature for 16 hours, then neutralized with saturated aqueous NaHCO and extracted with DCM (3 × 30 mL). The combined organic layers were washed with brine (2 × 30 mL), dried over anhydrous MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:1) to give 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (4 g, 74%) as a solid.

[0287] Scheme 6: Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine [ka] Step 1: Synthesis of 1-(5-bromo-3-chloro-2-hydroxyphenyl)ethanone A stirred solution of 4-bromo-2-chlorophenol (6.0 g, 28.9 mmol) and AcO (13.4 g, 131.3 mmol) in pyridine (10 mL) was heated to 100 °C and stirred for 3 h, then cooled to ambient temperature and poured into 6 M HCl (50 mL). The mixture was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with saturated aqueous NaHCO (3 × 20 mL), dried over NaSO, and filtered. The filtrate was concentrated under reduced pressure, and then AlCl (5.87 g, 44.0 mmol) was added, and the mixture was heated at 150 °C under an atmosphere of N for 3 h. Crushed ice (20 g) was slowly added, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by trituration with MeOH (30 mL) to give 1-(5-bromo-3-chloro-2-hydroxyphenyl)ethanone (3.2 g, 43%) as a solid.

[0288] Step 2: Synthesis of 4-bromo-2-chloro-6-{1-[(2-hydroxyethyl)amino]ethyl}phenol To a mixture of 1-(5-bromo-3-chloro-2-hydroxyphenyl)ethanone (1.0 g, 4.0 mmol) in EtOH (10 mL) and THF (10 mL) was added ethanolamine (489 mg, 8.0 mmol). The mixture was stirred at room temperature for 5 minutes, and then NaBH (75 mg, 2.0 mmol) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. HO (10 mL) and saturated aqueous NHCl (30 mL) were added to the residue, and the precipitate that appeared was collected by filtration to give 4-bromo-2-chloro-6-{1-[(2-hydroxyethyl)amino]ethyl}phenol (1 g, 85%) as a solid.

[0289] Step 3: Synthesis of tert-butyl N-[1-(5-bromo-3-chloro-2-hydroxyphenyl)ethyl]-N-(2-hydroxyethyl)carbamate To a mixture of 4-bromo-2-chloro-6-{1-[(2-hydroxyethyl)amino]ethyl}phenol (2.7 g, 9.2 mmol) in THF (20 mL) and MeOH (5 mL) was added BocO (2.4 g, 11 mmol) and EtN (2.7 g, 27.5 mmol). The mixture was heated to 45 °C and stirred for 48 h, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, ACN in water (0.05% TFA), 50% to 100% gradient in 30 min; detector, UV 254 nm) to give tert-butyl N-[1-(5-bromo-3-chloro-2-hydroxyphenyl)ethyl]-N-(2-hydroxyethyl)carbamate (330 mg, 9%) as an oil.

[0290] Step 4: Synthesis of tert-butyl 7-bromo-9-chloro-5-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a mixture of tert-butyl N-[1-(5-bromo-3-chloro-2-hydroxyphenyl)ethyl]-N-(2-hydroxyethyl)carbamate (240 mg, 0.61 mmol) in toluene (5 mL) under an atmosphere of N was added BuP (307 mg, 1.52 mmol) and ADDP (380 mg, 1.52 mmol). The mixture was heated to 60 °C and stirred for 16 h. Then, it was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, ACN in water (0.05% TFA), 50% to 100% gradient in 30 min; detector, UV 254 nm) to give tert-butyl 7-bromo-9-chloro-5-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (200 mg, 87%) as an oil.

[0291] Step 5: Synthesis of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a mixture of tert-butyl 7-bromo-9-chloro-5-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (180 mg, 0.48 mmol), 5-fluoro-1H-indole (96 mg, 0.72 mmol), and KPO (304 mg, 1.43 mmol) in 1,4-dioxane (5 mL) was added trans-cyclohexane-1,2-diamine (27 mg, 0.24 mmol). The mixture was heated to 100 °C and stirred for 3 h, then filtered, and the filter cake was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, ACN in water (0.05% TFA), 50% to 100% gradient in 20 min; detector, UV 254 nm) to give tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (140 mg, 68%) as an oil.

[0292] Step 6: Synthesis of 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine To a mixture of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (120 mg, 0.28 mmol) in DCM (2 mL) was added TFA (0.4 mL). The mixture was stirred at room temperature for 1 hour, then aqueous NaHCO (2 mL) was added, and the mixture was extracted with DCM (3 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, crude) as an oil.

[0293] Scheme 7: Preparation of (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine [ka] Step 1: Synthesis of 4-bromo-2-chloro-6-({[(2R)-1-hydroxypropan-2-yl]amino}methyl)phenol To a mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (CAS number: 19652-33-6) (5.0 g, 21.2 mmol) in THF (25 mL) and EtOH (25 mL) at room temperature was added (2R)-1-aminopropan-2-ol (2.07 g, 27.6 mmol). The resulting mixture was stirred at room temperature for 10 minutes, and then NaBH (0.5 g, 13.2 mmol) was added. The mixture was concentrated under reduced pressure, and the residue was diluted with HO (30 mL) and NH4Cl (20 mL). The precipitated solid was collected by filtration, washed with HO (2 × 50 mL), and dried under vacuum to give 4-bromo-2-chloro-6-({[(2R)-1-hydroxypropan-2-yl]amino}methyl)phenol (4.0 g, 64%) as a solid.

[0294] Step 2: Synthesis of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-[(2S)-1-hydroxypropan-2-yl]carbamate A mixture of 4-bromo-2-chloro-6-({[(2S)-1-hydroxypropan-2-yl]amino}methyl)phenol (4.0 g, 13.6 mmol), EtN (2.75 g, 27.158 mmol), and BocO (4.45 g, 20.4 mmol) in THF (4 mL) and MeOH (1 mL) at room temperature was stirred overnight. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 10:1) to give tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-[(2S)-1-hydroxypropan-2-yl]carbamate (3.8 g, 71%) as a solid.

[0295] Step 3: Synthesis of tert-butyl (3R)-7-bromo-9-chloro-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a stirred solution of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-[(2S)-1-hydroxypropan-2-yl]carbamate (3.8 g, 9.6 mmol) and PPh (5.05 g, 19.3 mmol) in THF (40 mL) at room temperature under an atmosphere of N was added dropwise DIAD (2.86 mL, 14.4 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 10:1) to give tert-butyl (3R)-7-bromo-9-chloro-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (3.5 g, 97%) as a solid.

[0296] Step 4: Synthesis of tert-butyl (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a stirred solution of tert-butyl (3R)-7-bromo-9-chloro-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (3.5 g, 9.3 mmol) and 5-fluoro-1H-indole (1.51 g, 11.2 mmol) in 1,4-dioxane (40 mL) at room temperature under an atmosphere of N was added trans-cyclohexane-1,2-diamine (0.53 g, 4.7 mmol), CuI (0.53 g, 2.8 mmol), and KPO (5.92 g, 27.9 mmol). The mixture was heated to 100 °C and stirred for 16 h, then filtered, and the filter cake was washed with DCM (2 × 20 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 10:1) to give tert-butyl (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (1.5 g, 38%) as a solid.

[0297] Step 5: Synthesis of (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine To a stirred solution of tert-butyl (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (1.5 g, 3.5 mmol) in DCM (20 mL) was added TFA (6.0 mL, 80.8 mmol). The mixture was stirred at room temperature for 30 minutes, then neutralized with saturated aqueous NaHCO and extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO, filtered, and the filtrate was concentrated under reduced pressure to give (3R)-9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (700 mg, 60%) as a solid.

[0298] Scheme 8: Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine [ka] Step 1: Synthesis of 4-bromo-2-chloro-6-{[(1-hydroxy-3-methoxypropan-2-yl)amino]methyl}phenol To a mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (3 g, 12.7 mmol) in THF (15 mL) and EtOH (15 mL) was added 2-amino-3-methoxypropan-1-ol (1.34 g, 12.7 mmol). The mixture was stirred at room temperature for 10 minutes, and then NaBH (0.3 g, 7.7 mmol) was added. The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 minutes; detector, UV 254 nm) to give 4-bromo-2-chloro-6-{[(1-hydroxy-3-methoxypropan-2-yl)amino]methyl}phenol (2.5 g, 54%) as an oil.

[0299] Step 2: Synthesis of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1,3-dihydroxypropan-2-yl)carbamate To a mixture of 4-bromo-2-chloro-6-{[(1-hydroxy-3-methoxypropan-2-yl)amino]methyl}phenol (2.6 g, 8.0 mmol) in THF (3 mL) was added BocO (2.62 g, 12.0 mmol) and aqueous NaHCO (12 mL). The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to give tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1,3-dihydroxypropan-2-yl)carbamate (500 mg, 15%) as a solid.

[0300] Step 3: Synthesis of tert-butyl 7-bromo-9-chloro-3-(methoxymethyl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a mixture of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1-hydroxy-3-methoxypropan-2-yl)carbamate (500 mg, 1.2 mmol) and PPh (770 mg, 2.9 mmol) in THF (10 mL) under an atmosphere of N was added DIAD (600 mg, 2.9 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to give tert-butyl 7-bromo-9-chloro-3-(methoxymethyl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (250 mg, 48%) as an oil.

[0301] Step 4: Synthesis of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a mixture of tert-butyl 7-bromo-9-chloro-3-(methoxymethyl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (230 mg, 0.57 mmol) in 1,4-dioxane (5 mL) was added 5-fluoro-1H-indole (115 mg, 0.85 mmol), CuI (32 mg, 0.17 mmol), KPO (360 mg, 1.7 mmol), and trans-cyclohexane-1,2-diamine (32 mg, 0.28 mmol). The mixture was heated to 100° C. and stirred for 24 h, then filtered, and the filter cake was washed with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm) to give tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (200 mg, 76%) as a solid.

[0302] Step 5: Synthesis of 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine To a mixture of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (200 mg, 0.43 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour, then neutralized with saturated aqueous NaHCO and extracted with DCM (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 9-chloro-7-(5-fluoroindol-1-yl)-3-(methoxymethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (140 mg, 81%) as an oil. LC / MS: Mass, C 19 H 18 Calculated value for ClFN2O2: 360.1, Found value: 361.0 [M+H] + .

[0303] Scheme 9: Preparation of 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine [ka] Step 1: Synthesis of 4-bromo-2-chloro-6-{[(1-cyclopropyl-2-hydroxyethyl)amino]methyl}phenol To a stirred mixture of 5-bromo-3-chloro-2-hydroxybenzaldehyde (1.0 g, 4.3 mmol) and 2-amino-2-cyclopropylethanol (650 mg, 6.4 mmol) in THF (15 mL) at room temperature was added NaBH (100 mg, 2.6 mmol). The mixture was stirred until the reaction was complete, then filtered, and the filter cake was washed with HO (2 × 20 mL). The filter cake was dried under vacuum to give 4-bromo-2-chloro-6-{[(1-cyclopropyl-2-hydroxyethyl)amino]methyl}phenol (1.2 g, 27%) as a solid.

[0304] Step 2: Synthesis of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1-cyclopropyl-2-hydroxyethyl)carbamate To a stirred mixture of 4-bromo-2-chloro-6-{[(1-cyclopropyl-2-hydroxyethyl)amino]methyl}phenol (1.1 g, 3.4 mmol) in THF (20 mL) was added saturated NaHCO (10 mL) and BocO (1.1 g, 5.2 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 20% to 100% gradient in 30 min; detector, UV 254 nm) to give tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1-cyclopropyl-2-hydroxyethyl)carbamate (400 mg, 25%) as an oil.

[0305] Step 3: Synthesis of tert-butyl 7-bromo-9-chloro-3-cyclopropyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a stirred mixture of tert-butyl N-[(5-bromo-3-chloro-2-hydroxyphenyl)methyl]-N-(1-cyclopropyl-2-hydroxyethyl)carbamate (380 mg, 0.9 mmol) in THF (3 mL) at room temperature under an atmosphere of N was added PPh (616 mg, 2.4 mmol) and DIAD (475 mg, 2.4 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 30% to 100% gradient in 30 min; detector, UV 254 nm) to give tert-butyl 7-bromo-9-chloro-3-cyclopropyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (250 mg, 62%) as an oil.

[0306] Step 4: Synthesis of tert-butyl 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a stirred mixture of tert-butyl 7-bromo-9-chloro-3-cyclopropyl-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (230 mg, 0.57 mmol) and 5-fluoro-1H-indole (125 mg, 0.93 mmol) in 1,4-dioxane (5 mL) was added trans-cyclohexane-1,2-diamine (35 mg, 0.31 mmol), CuI (35 mg, 0.19 mmol), and KPO (450 mg, 2.1 mmol). The mixture was heated to 100° C. and stirred for 16 h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 30% to 100% gradient in 30 min; detector, UV 254 nm) to give tert-butyl 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (180 mg, 67%) as an oil.

[0307] Step 5: Synthesis of 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine To a stirred mixture of tert-butyl 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (180 mg, 0.39 mmol) in DCM (2.5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 30 minutes, then neutralized with saturated NaHCO and extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous MgSO, filtered, and the filtrate was concentrated under reduced pressure to give 9-chloro-3-cyclopropyl-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (126 mg, 84%) as a solid.

[0308] Scheme 10: Preparation of 7-bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-3,5-dihydro-2H-1,4-benzoxazepine [ka] Step 1: Synthesis of 4-bromo-6-chloro-2-({[(2-methoxypyridin-4-yl)methyl]amino}methyl)-3-methylphenol To a stirred mixture of 3-bromo-5-chloro-6-hydroxy-2-methylbenzaldehyde (4.2 g, 16.8 mmol) and 1-(2-methoxypyridin-4-yl)methanamine (2.5 g, 18.1 mmol) in DCM (50 mL) was added NaBH(OAc) (5.3 g, 25.0 mmol) and AcOH (1 mL). The mixture was stirred at room temperature for 3 h, then quenched with aqueous NaHCO (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 1:1) to give 4-bromo-6-chloro-2-({[(2-methoxypyridin-4-yl)methyl]amino}methyl)-3-methylphenol (3.4 g, 45%) as an oil.

[0309] Step 2: Synthesis of 2-bromo-N-[(3-bromo-5-chloro-6-hydroxy-2-methylphenyl)methyl]-N-[(2-methoxypyridin-4-yl)methyl]acetamide To a stirred mixture of 4-bromo-6-chloro-2-({[(2-methoxypyridin-4-yl)methyl]amino}methyl)-3-methylphenol (3.4 g, 9.2 mmol) in DCM (42 mL) at room temperature was added saturated Na2CO3 (42 mL) and bromoacetyl bromide (2.18 g, 10.8 mmol). The mixture was stirred at room temperature for 2 hours and then extracted with DCM (3 x 150 mL). The combined organic layers were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give 2-bromo-N-[(3-bromo-5-chloro-6-hydroxy-2-methylphenyl)methyl]-N-[(2-methoxypyridin-4-yl)methyl]acetamide (4.0 g, 57%) as an oil.

[0310] Step 3: Synthesis of 7-bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-2,5-dihydro-1,4-benzoxazepin-3-one To a stirred mixture of 2-bromo-N-[(3-bromo-5-chloro-6-hydroxy-2-methylphenyl)methyl]-N-[(2-methoxypyridin-4-yl)methyl]acetamide (4.0 g, 8.1 mmol) in DMF (60 mL) was added CS2CO3 (8.0 g, 24.4 mmol). The mixture was heated to 80 °C and stirred for 2 h, then filtered, and the filter cake was washed with EtOAc (3 × 50 mL). The filtrate was washed with HO (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 70% gradient in 30 min; detector, UV 254 nm) to give 7-bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-2,5-dihydro-1,4-benzoxazepin-3-one (2.0 g, 60%) as an oil.

[0311] Step 4: Synthesis of 7-bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of NaBH (922 mg, 24.4 mmol) in THF (10 mL) at room temperature under an atmosphere of N was added BF.EtO (3 mL, 23.7 mmol) dropwise. The mixture was stirred at room temperature for 10 minutes, then cooled to 0 °C, and 7-bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-2,5-dihydro-1,4-benzoxazepin-3-one (1.0 g, 2.4 mmol) in THF (10 mL) was added dropwise over 10 minutes. The mixture was heated to 55 °C and stirred for 16 hours, then quenched by the addition of MeOH (10 mL), and the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (column, silica gel; mobile phase, MeCN in water, 10% to 70% gradient in 20 min; detector, UV 254 nm) to give 7-bromo-9-chloro-4-[(2-methoxypyridin-4-yl)methyl]-6-methyl-3,5-dihydro-2H-1,4-benzoxazepine (470 mg, 46%) as an oil.

[0312] Scheme 11: Lithium imidazo[1,2-a]pyridin-5-yl triisopropoxyboranide [ka] See WO 2017202742.

[0313] EP2 inhibitors Method A: Preparation of 9-chloro-4-((1,5-dimethyl-1H-pyrazol-4-yl)methyl)-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane (compound 106) [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.16 mmol) and 1,5-dimethylpyrazole-4-carbaldehyde (40 mg, 0.32 mmol) in DCM (1 mL) at room temperature was added NaBH(OAc) (70 mg, 0.32 mmol) and AcOH (40 μL). The mixture was stirred overnight at room temperature, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 51% B to 71% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.82) to give 9-chloro-4-[(1,5-dimethylpyrazol-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (14.4 mg, 21%) as a solid. LC / MS: Mass C 23 H 23 Calculated value for ClFNO: 424.2, Found: 425.1 [M+H] + ; 1H NMR(300MHz,CD3OD)δ 7.47(s,1H),7.35-7.42(m,3H),7.25-7.29(m,1H),7.19(s,1H),6.95(t,J=9.3,1H),6.61(d,J= 3.3Hz,1H),4.15-4.17(m,2H),3.85(s,2H),3.73(s,3H),3.57(s,2H),3.05(m,2H),2.22(s,3H). 19 F NMR (282 MHz, CD3OD) δ -126.0.

[0314] Method B: Preparation of 4-((1H-pyrazol-4-yl)methyl)-9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane (compound 103) [ka] To a stirred solution of tert-butyl 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrazole-1-carboxylate (40 mg, 0.08 mmol) in DCM (2 mL) at room temperature was added TFA (0.4 mL). The resulting mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD column, 19 x 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 45% B to 75% B, 75% B in 7 min; Wavelength: 254 nm; RT1 (min): 5) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(1H-pyrazol-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (7.2 mg, 22%) as a solid. LC / MS: Mass C 21 H 18 Calculated value for ClFNO: 396.1, Found: 397.0 [M+H] + ; 1H NMR(300MHz,CD3OD)δ 7.59-7.62(br,2H),7.51(d,J=2.7Hz,1H),7.40-7.45(m,2H),7.24-7.31(m,2H),6.97(t,J=9.3 Hz,1H),6.63(d,J=3.3Hz,1H),4.18-4.24(m,2H),3.90(s,2H),3.73(s,2H),3.09-3.12(m,2H). 19 F NMR (282 MHz, CD3OD) δ -126.2.

[0315] Method C: Preparation of 9-chloro-7-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((2-methoxypyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (compound 33) [ka] To a stirred mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 5-fluoro-1H-pyrrolo[2,3-b]pyridine (27 mg, 0.2 mmol) in 1,4-dioxane (2 mL) under an atmosphere of N was added trans-cyclohexane-1,2-diamine (7 mg, 0.07 mmol), CuI (7 mg, 0.04 mmol), and KPO (83 mg, 0.39 mmol). The resulting mixture was heated to 110 °C and stirred overnight, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B, 60% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.12) to give 9-chloro-7-{5-fluoropyrrolo[2,3-b]pyridin-1-yl}-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (5.1 mg, 9%) as a solid. LC / MS: Mass C22 H 19 Calculated value for ClFN5O2: 439.1, Found value: 440.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.55(s,2H),8.38(s,1H),7.91-8.04(m,3H),7.65(d,J=2.7Hz,1H),6.74(d,J=3 .7Hz,1H),4.17-4.18(m,2H),3.90-3.92(m,5H),3.64(s,2H),3.09-3.10(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -173.1.

[0316] Method D: Preparation of 5-((9-chloro-7-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidin-2(1H)-one (Compound 70) [ka] To a solution of 33% HBr in AcOH (1 mL) was added 9-chloro-7-{5-fluoropyrrolo[2,3-b]pyridin-1-yl}-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol). The mixture was stirred for 2 hours at room temperature, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B, 55% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87) to give 5-[(9-chloro-7-{5-fluoropyrrolo[2,3-b]pyridin-1-yl}-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)methyl]-1H-pyrimidin-2-one (5.0 mg, 10%) as a solid. LC / MS: Mass C 21 H 17 Calculated value for ClFN5O2: 425.1, Found value: 426.0 [M+H]+ ; 1 H NMR(400MHz,CD3OD)δ 8.25-8.31(m,3H),7.77-7.85(m,3H),7.57(d,J=2.8Hz,1H),6.70(d,J=3. 6Hz,1H),4.19-4.21(m,2H),3.98(s,2H),3.59(s,2H),3.22-3.24(m,2H); 19 F NMR (376 MHz, CD3OD) δ -140.0.

[0317] Method E: Preparation of 7-(benzo[b]thiophen-3-yl)-9-chloro-4-((2-methoxypyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 1-benzothiophen-3-ylboronic acid (35 mg, 0.2 mmol) in THF (0.8 mL) and HO (0.2 mL) under an atmosphere of N was added KCO (36 mg, 0.26 mmol) and Pd(PPh) (15 mg, 0.013 mmol). The mixture was heated to 80 °C and stirred for 16 h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 7-(1-benzothiophen-3-yl)-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (6.0 mg, 10%) as a solid. LC / MS: Mass C 23 H 20 Calculated value for ClN3O2S: 437.1, Found: 438.1 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 8.54(s,2H),8.08(d,J=6.0Hz,1H),7.56-7.94(m,3H),7.34-7.53(m,3H),4 .18-4.19(m,2H),3.95(s,2H),3.90(s,3H),3.67(s,2H),3.05-3.06(m,2H).

[0318] Method F: Preparation of 9-chloro-7-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)-4-((2-methoxypyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (Compound 49) [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) in toluene (1.5 mL) under a nitrogen atmosphere was added 6-fluoro-1,2,3,4-tetrahydroquinoline (24 mg, 0.16 mmol), Pd(OAc) (1 mg, 0.004 mmol), tri-tert-butylphosphanide tetrafluoroborane (2 mg, 0.008 mmol), and t-BuONa (25 mg, 0.26 mmol). The mixture was heated to 110° C. and stirred for 16 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 46% B to 76% B, 76% B in 10 min; Wavelength: 254 nm; RT1 (min): 8.95) to give 9-chloro-7-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (7.3 mg, 12%) as a solid. LC / MS: Mass C 24 H 24 Calculated value for ClFN4O2: 454.2, Found value: 455.1 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 8.49(s,2H),7.15(d,J=2.4Hz,1H),6.88-6.95(m,2H),6.76-6.83(m,1H),6.62-6.66(m,1H),4.07-4.08(m,2H),3.90 (s,3H),3.78(s,2H),3.60(s,2H),3.49(t,J=5.7Hz,2H),3.02-3.03(m,2H),2.75(t,J=5.7Hz,2H),1.85-1.93(m,2H); 19 F(282MHz,DMSO-d6)δ -125.5.

[0319] Method G: Preparation of 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4-(oxazol-5-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (compound 93) [ka] To a stirred mixture of 1,3-oxazol-5-ylmethyl methanesulfonate (56 mg, 0.32 mmol) and 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.16 mmol) in THF (1 mL) was added EtN (35 mg, 0.32 mmol). The mixture was heated to 70° C. and stirred for 16 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep C18 OBD column, 19×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 47% B to 77% B, 77% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3-oxazol-5-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (4.2 mg, 7%) as a solid. LC / MS: Mass C 21 H 17 Calculated value for ClFN3O2: 397.1, Found value: 398.0 [M+H] + ; 1H NMR(300MHz,CD3OD)δ 8.20(s,1H),7.50(d,J=2.7Hz,1H),7.41-7.45(m,2H),7.26-7.30(m,2H),7.09(s,1H),6.93-6 .99(m,1H),6.62-6.63(m,1H),4.17-4.20(m,2H),3.95(s,2H),3.89(s,2H),3.13-3.16(m,2H); 19 F NMR (282 MHz, CD3OD) δ -126.1.

[0320] Method I: 9-chloro-7-(5-fluoroindol-1-yl)-4-[(2-oxo-1H-pyridin-4-yl)methyl]-3-(trifluoromethyl)-2,3-dihydro-1,4-benzoxazepin-5-one (Compound 249) [ka] To a mixture of 9-chloro-7-(5-fluoroindol-1-yl)-4-[(2-methoxypyridin-4-yl)methyl]-3-(trifluoromethyl)-2,3-dihydro-1,4-benzoxazepin-5-one (25 mg, 0.05 mmol) in DMF (2 mL) was added pyridine hydrobromide (50 mg, 0.29 mmol). The mixture was heated to 60° C. and stirred for 24 h, then purified by preparative HPLC (Column: XBridge Prep Phenyl OBD column, 19×250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 48% B to 58% B, 58% B in 10 min; Wavelength: 254 nm; RT1 (min): 8.8) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(2-oxo-1H-pyridin-4-yl)methyl]-3-(trifluoromethyl)-2,3-dihydro-1,4-benzoxazepin-5-one (1.8 mg, 7.26%) as an off-solid. LC / MS: Mass C 24 H 16 Calculated value for ClF4N3O3: 505.1, Found value: 506.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 11.55(br,1H),8.10(d,J=4.0Hz,1H),7.82-7.88(m,2H),7.40-7.55(m,3H),7.11(m,1H),6.74(d,J= 4.0Hz,1H),6.44(s,1H),6.32(d,J=8.0Hz,1H),5.24(m,1H),4.93(s,2H),4.70(m,1H),4.57(m,1H); 19 F NMR(376MHz,DMSO-d6)δ -74.5,-123.1.

[0321] Method J: Preparation of cis-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-methylcyclohexane-1-carboxamido[f][1,4]oxazepine (Compound 128) [ka] To a stirred solution of cis-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}cyclohexane-1-carboxylic acid (35 mg, 0.08 mmol) and CHNH HCl (11 mg, 0.15 mmol) in DMF (1 mL) was added HATU (45 mg, 0.12 mmol) and DIPEA (25 mg, 0.19 mmol). The mixture was stirred for 2 h at room temperature, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 85% B, 85% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give cis-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-methylcyclohexane-1-carboxamide (3.3 mg, 9%) as a solid. LC / MS: Mass C 26 H 29Calculated value for ClFN3O2: 469.1, Found value: 469.9 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 7.32-7.36(m,3H),7.16-7.29(m,2H),6.81-6.88(m,1H),6.52-6.53(m,1H),4.03-4.06(m,2H),3.83(s,2H),3 .05-3.06(m,2H),2.58(s,3H),2.40(d,J=7.8Hz,2H)2.13-2.18(m,1H),1.75-1.76(m,1H),1.40-1.67(m,8H); 19 F NMR (400 MHz, CD3OD) δ -126.1.

[0322] Method K: Preparation of trans-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-methylcyclohexane-1-carboxamide [f][1,4]oxazepane (compound 127) [ka] To a mixture of trans-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}cyclohexane-1-carboxylic acid (50 mg, 0.11 mmol) in DCM (1 mL) was added CH3NH2·HCl (15 mg, 0.22 mmol), PyBOP (86 mg, 0.16 mmol), and DIPEA (30 mg, 0.22 mmol). The mixture was stirred at room temperature for 16 h, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3·H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 85% B, 85% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give trans-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-methylcyclohexane-1-carboxamide (15.5 mg, 29%) as a solid; LC / MS: Mass C 26 H 29 Calculated value for ClFN3O2: 469.1, Found value: 469.9 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 7.72(d,J=3.2Hz,1H),7.54-7.59(m,3H),7.45-7.54(m,2H),7.03-7.04 (m,1H),6.68-6.69(m,1H),4.10-4.12(m,2H),3.89(s,2H),3.31-3.34( m,2H),2.50-2.53(m,3H),2.25(d,J=6.9Hz,2H),2.01-2.08(m,1H),1.6 8-1.78(m,4H),1.51-1.56(m,1H),1.31-1.42(m,2H),0.78-0.92(m,2H); 19 F NMR (400 MHz, CD3OD) δ -123.5.

[0323] Method L: Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyran-2-one (compound 174) [ka] To a stirred solution of 9-chloro-4-[(5-chloropyrazin-2-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and acetohydroxamic acid (25 mg, 0.34 mmol) in DMSO (1 mL) was added KCO (80 mg, 0.57 mmol). The mixture was heated to 80 °C and stirred overnight, then filtered. The filtrate was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 37% B to 67% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyrazin-2-one (7.9 mg, 16%) as a solid. LC / MS: Mass C 22 H 18 Calculated value for ClFN4O2: 424.1, Found value: 425.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 12.07(s,1H),7.98(d,J=2.4Hz,1H),7.71(d,J=3.0Hz,1H),7.60(d,J=2.7Hz,1H),7.54(d,J=9.0Hz,1H),7.39-7.45( m,3H),7.07(t,J=9.1Hz,1H),6.69(d,J=3.3Hz,1H),4.17-4.18(m,2H),3.94(s,2H),3.57(s,2H),3.09-3.10(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0324] Method M: 5-[(9-chloro-7-{pyrrolo[2,3-b]pyrazin-5-yl}-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)methyl]-1H-pyrimidin-2-one trifluoroacetic acid (Compound 76) [ka] The title compound was prepared according to Method D. However, the crude product was purified by preparative HPLC (Column: Xselect CSH C18 OBD column 30 x 150 mm 5 μm, n; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 40% B, 40% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.12) to give 5-[(9-chloro-7-{pyrrolo[2,3-b]pyrazin-5-yl}-3,5-dihydro-2H-1,4-benzoxazepin-4-yl)methyl]-1H-pyrimidin-2-one trifluoroacetate (2.8 mg, 7%) as a solid. LC / MS: Mass C 20 H 17 Calculated value for ClN6O2: 408.1, Found value: 409.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.58(d,J=2.6Hz,1H),8.24-8.41(m,4H),8.14(s,1H),7.93(s,1H),6.98(d,J=4.0Hz,1H),4.20-4.50(m,4H),4.00(br,2H),3.00-3.10(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -73.8,-77.7.

[0325] The compounds in Table 1 can be prepared according to the methods described herein.

[0326] [Table 41]

[0327] [Table 42]

[0328] Table 43

[0329] Table 44

[0330] Table 45

[0331] Table 46

[0332] Table 47

[0333] Table 48

[0334] Table 49

[0335] Table 50

[0336] Table 51

[0337] Table 52

[0338] Table 53

[0339] Table 54

[0340] Table 55

[0341] Table 56

[0342] Table 57

[0343] Table 58

[0344] Table 59

[0345] Table 60

[0346] Table 61

[0347] Table 62

[0348] Table 63

[0349] Table 64

[0350] Table 65

[0351] Table 66

[0352] Table 67

[0353] Table 68

[0354] Table 69

[0355] Table 70

[0356] Table 71

[0357] Table 72

[0358] Table 73

[0359] Table 74

[0360] Table 75

[0361] Table 76

[0362] Table 77

[0363] Table 78

[0364] Table 79

[0365] Table 80

[0366] Table 81

[0367] Table 82

[0368] Table 83

[0369] Table 84

[0370] Table 85

[0371] Table 86

[0372] Table 87

[0373] Table 88

[0374] Table 89

[0375] Table 90

[0376]

Table 91

[0377] Table 92

[0378]

Table 93

[0379] Table 94

[0380] [Table 95]

[0381] Synthesis of additional compounds Example S1. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-amine (Compound 11) [ka] 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (75 mg, 0.23 mmol) in DCM (2 mL) was added 2-chloropyrimidine-5-carbaldehyde (64 mg, 0.45 mmol), NaBH(OAc) (96 mg, 0.45 mmol), and AcOH (0.08 mg, 0.001 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated in vacuo, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 80% gradient in 20 minutes; detector, UV 254 nm) to give 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine (35 mg, 32%) as an oil.

[0382] 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-amine A stirred mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepine (30 mg, 0.066 mmol) in 7M NH3 in MeOH (3 mL) was heated to 80° C. and stirred for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 51% B to 71% B, 71% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.40) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3-methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-amine (2 mg, 7%) as a solid. LC / MS: Mass C 23 H 21 Calculated value for ClFNO: 437.1, Found: 438.2 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 8.19(s,2H),7.39-7.55(m,3H),7.25-7.39(m,1H),7.14(d,J=2.7Hz,1H),6.92-7.07(m,1H),6.61-6.68( m,1H),4.25-4.48(m,2H),4.04-4.20(m,1H),3.59-3.82(m,3H),3.43-3.59(m,1H),1.35(d,J=6.9Hz,3H); 19 F NMR (282 MHz, CD3OD) δ -126.2.

[0383] Example S2. Preparation of 9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-7-[3-(trifluoromethyl)indol-1-yl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 17) [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 3-(trifluoromethyl)-1H-indole (24 mg, 0.13 mmol) in 1,4-dioxane (1 mL) under an atmosphere of N was added di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (6 mg), tBuxphos Pd G (10 mg, 0.013 mmol), and CsCO (85 mg, 0.26 mmol). The mixture was heated to 90 °C and stirred for 16 h, then filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 85% B, 85% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.55) to give 9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-7-[3-(trifluoromethyl)indol-1-yl]-3,5-dihydro-2H-1,4-benzoxazepine (4.9 mg, 8%) as a solid. LC / MS: Mass C 24 H 20 Calculated value for ClF3N4O2: 488.1, Found value: 489.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.54(s,2H),8.31(s,1H),7.80-7.67(m,2H),7.57(d,J=8.1Hz,1H),7.49(d,J=2.6Hz,1H),7. 27-7.44(m,2H),4.19-4.22(m,2H),3.97(s,2H),3.90(s,3H),3.66(s,2H),3.06-3.09(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -55.0.

[0384] Example S3. Preparation of 9-chloro-7-{imidazo[1,5-a]pyridin-3-yl}-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 40) [ka] A mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.26 mmol), imidazo[1,5-a]pyridine (31 mg, 0.260 mmol), PPh3 (7 mg, 0.03 mmol), and Bu4NOAc (157 mg, 0.52 mmol) in toluene (3 mL) under an atmosphere of N2 was heated to 100 °C and stirred for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography and preparative HPLC (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 40% B to 63% B, 63% B in 10 min; Wavelength: 254 nm; RT1 (min): 8.36) to give 9-chloro-7-{imidazo[1,5-a]pyridin-3-yl}-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (5.2 mg, 5%) as a solid. LC / MS: Mass C 22 H 20 Calculated value for ClN5O2: 421.1, Found value: 422.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 8.56(s,2H),8.30-8.36(m,1H),7.76(d,J=3.0Hz,1H),7.58-7.65(m,1H),7.50(s,1H),7.45-7.48(d,J=3.0Hz,1H), 6.83-6.94(m,1H),6.74-6.81(m,1H),4.21-4.28(m,2H),4.02(s,3H),3.98(s,2H),3.75(s,2H),3.15-3.21(m,2H).

[0385] Example S4. Preparation of 9-chloro-7-{7-chloroimidazo[1,5-a]pyridin-3-yl}-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 41) [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 7-chloroimidazo[1,5-a]pyridine (20 mg, 0.13 mmol) in toluene (1 mL) under an atmosphere of N was added Pd(OAc) (2 mg, 0.007 mmol), PPh (4 mg, 0.013 mmol), and BuNOAc (78 mg, 0.26 mmol). The mixture was heated to 100° C. and stirred for 16 hours, then concentrated in vacuo, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 65% B, 65% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.25) to give 9-chloro-7-{7-chloroimidazo[1,5-a]pyridin-3-yl}-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (7.3 mg, 12%) as a solid. LC / MS: Mass C 22 H 19 Calculated for Cl2N5O2: 455.0, Found: 456.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.53(s,2H),8.43-8.45(m,1H),7.81-7.83(m,2H),7.60(d,J=2.7Hz,1H),7.52(d,J=2.1Hz,1H), 6.72-6.74(m,1H),4.17-4.20(m,2H),3.97(s,2H),3.90(s,3H),3.65(s,2H),3.01-3.08(m,2H).

[0386] Example S5. Preparation of 9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-7-(4,5,6,7-tetrahydroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 44) [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 4,5,6,7-tetrahydro-1H-indole (19 mg, 0.16 mmol) in 1,4-dioxane (1 mL) under an atmosphere of N was added CsCO (4 mg, 0.013 mmol) and (Pro (2-en-1-yl)benzene; {1-[2,6-bis(2,6-dimethylheptan-4-yl)phenyl]-4,5-dichloro-3-{2-[2,8-dimethyl-3,7-bis(propan-2-yl)nonan-5-yl]-6-(2,6-dimethylheptan-4-yl)phenyl}-2,3-dihydro-1H-imidazol-2-yl}(chloro)palladium (14 mg) were added. The mixture was heated to 90° C. and stirred for 16 hours, then filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 77% B in 10 min; Wavelength: 254 nm; RT1 (min): 9.12) to give 9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-7-(4,5,6,7-tetrahydroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (3.5 mg, 6%) as a solid. LC / MS: Mass C 23 H 25 Calculated value for ClN4O2: 424.1, Found value: 425.1 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 8.50(s,2H),7.37(d,J=2.4Hz,1H),7.13(d,J=2.7Hz,1H),6.82(d,J=3Hz,1H),5.96(d,J=3Hz,1H),4.11-4.13 (m,2H),3.90(d,J=3Hz,5H),3.61(s,2H),3.36(s,2H),3.04(d,J=5.2Hz,2H),2.47-2.51(m,2H),1.70(s,4H).

[0387] Example S6. Preparation of 9-chloro-7-(5-fluoro-2,3-dihydroindol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 45) [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) in toluene (1 mL) under N atmosphere was added 5-fluoro-1H,2H,3H-pyrrolo[2,3-b]pyridine (27 mg, 0.2 mmol), Pd(dba) (6 mg, 0.007 mmol), Ruphos (6 mg, 0.013 mmol), and CsCO (127 mg, 0.39 mmol), and the mixture was heated to 110 °C and stirred for 12 h. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 75% B, 75% B in 9 min; Wavelength: 254 nm; RT1 (min): 8) to give 9-chloro-7-(5-fluoro-2,3-dihydroindol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (13.1 mg, 23%) as a solid. LC / MS: Mass C 23 H 22Calculated value for ClFN4O2: 440.1, Found value: 441.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.50(s,2H),7.10(d,J=3.2Hz,1H),7.02-7.06(m,1H),6.92-6.98(m,2H),6.79-6 .86(m,1H),4.02-4.05(m,2H),3.85-3.90(m,7H),3.59(s,2H),2.99-3.08(m,4H); 19 F(282MHz,DMSO-d6)δ-125.3.

[0388] Example S7. Preparation of 9-chloro-7-(5-chloro-2,3-dihydroindol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 46) [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 5-chloro-2,3-dihydro-1H-indole (30 mg, 0.2 mmol) in toluene (1 mL) under a N atmosphere was added Pd(dba) (6 mg, 0.007 mmol), Ruphos (6 mg, 0.013 mmol), and CsCO (127 mg, 0.39 mmol). The mixture was heated to 110 °C and stirred for 16 h, then filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Column: Xselect CSH F-Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 55% B, 55% B in 9 min; Wavelength: 254 nm; RT1 (min): 7.32) to give 9-chloro-7-(5-chloro-2,3-dihydroindol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (16 mg, 26%) as a solid. LC / MS: Mass C 23 H22 Calculated for Cl2N4O2: 456.1, Found: 457.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.52(s,2H),7.18(d,J=3Hz,2H),7.15-7.08(m,3H),4.05-4.08(m,2H),3.86-3.94(m,7H),3.61(s,2H),3.01-3.12(m,4H).

[0389] Example S8. Preparation of 9-chloro-7-(5-fluoro-1,3-dihydroisoindol-2-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 47) [ka] To a mixture of 5-fluoro-2,3-dihydro-1H-isoindole (27 mg, 0.2 mmol) and 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) in toluene under a N atmosphere was added Pd(dba) (6 mg, 0.007 mmol), RuPhos (6 mg, 0.013 mmol), and CsCO (127 mg, 0.39 mmol). The mixture was heated to 110 °C and stirred overnight, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.12) to give 9-chloro-7-(5-fluoro-1,3-dihydroisoindol-2-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (5.7 mg, 10%) as a solid. LC / MS: Mass C 23 H 22 Calculated value for ClFN4O2: 440.1, Found value: 441.1 [M+H]+ ; 1 H NMR(300MHz,DMSO-d6)δ 8.51(s,2H),7.39-7.44(m,1H),7.25(d,J=8.4Hz,1H),7.15(t,J=9.0Hz,1H), 6.58(d,J=2.4Hz,1H),6.39(d,J=2.4Hz,1H),4.54(d,J=8.7Hz,4H),3.98-3.99 m,2H),3.92(s,3H),3.83(s,2H),3.58(s,2H),3.00-3.01(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -115.9.

[0390] Example S9. Preparation of 9-chloro-7-(6-fluoro-4-methyl-2,3-dihydroquinoxalin-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 50) [ka] To a stirred mixture of 7-fluoro-1-methyl-3,4-dihydro-2H-quinoxaline [CAS number: 1354953-50-6] (36 mg, 0.22 mmol) and 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.26 mmol) in 1,4-dioxane (2 mL) under an atmosphere of N was added Cphos pd G3 (18 mg, 0.02 mmol), Cphos (10 mg, 0.02 mmol), and CsCO (141 mg, 0.43 mmol). The mixture was heated to 90 °C and stirred for 16 h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: HO (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87) to give 9-chloro-7-(6-fluoro-4-methyl-2,3-dihydroquinoxalin-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (3.5 mg, 3%) as a solid. LC / MS: Mass C 24 H 25 Calculated value for ClFN5O2: 469.2, Found value: 470.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.49(s,2H),7.03(d,J=3.0Hz,1H),6.80(d,J=3.0Hz,1H),6.60-6.65(m,1H),6.46-6.51(m,1H),6.25-6.32(m,1H),4 .03-4.06(m,2H),3.91(d,J=6.0Hz,3H),3.76(s,2H),3.56-3.58(m,4H),3.23-3.31(m,2H),3.02(s,2H),2.89(s,3H); 19 F(282MHz,DMSO-d6)δ -120.7.

[0391] Example S10. Preparation of 9-chloro-7-(7-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 51) [ka] To a mixture of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.13 mmol) and 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine (24 mg, 0.16 mmol) in 1,4-dioxane (1 mL) under an atmosphere of N was added Cphos pd G3 (11 mg, 0.013 mmol), Cphos (6 mg, 0.013 mmol), and CsCO (85 mg, 0.26 mmol). The mixture was heated to 90 °C and stirred for 16 h, then filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 75% B, 75% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.25) to give 9-chloro-7-(7-fluoro-2,3-dihydro-1,4-benzoxazin-4-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (6.4 mg, 11%) as a solid. LC / MS: Mass C 23 H 22 Calculated value for ClFN4O3: 456.1, Found value: 457.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ 8.50(s,2H),7.18(d,J=2.8Hz,1H),6.94(d,J=2.8Hz,1H),6.79-6.83(m,1H),6.72-6.75(m,1H),6.59-6.65( m,1H),4.21-4.23(m,2H),4.05-4.11(m,2H),3.90(s,3H),3.79(s,2H),3.58-3.66(m,4H),3.06-2.99(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -122.0.

[0392] Example S11. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3-thiazol-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 100) [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.16 mmol) in THF (1 mL) was added 4-(bromomethyl)-1,3-thiazole (61 mg) and EtN (32 mg, 0.32 mmol). The mixture was heated to 70 °C and stirred for 2 h, then concentrated in vacuo, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 85% B, 85% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3-thiazol-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (8.3 mg, 13%) as a solid. LC / MS: Mass C 21 H 17 Calculated value for ClFN3OS: 413.1, Found value: 414.1 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 9.09(d,J=2.1Hz,1H),7.72(d,J=3.3Hz,1H),7.53-7.61(m,3H),7.37-7.45(m,2H),7.04-7.10 (m,1H),6.68(d,J=3.3Hz,1H),4.14-4.22(m,2H),3.97(s,2H),3.88(s,2H),3.07-3.15(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0393] Example S12. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-[(3-methoxy-1H-pyrazol-4-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 105) [ka] Ethyl 1-(tert-butyldimethylsilyl)-3-hydroxypyrazole-4-carboxylate To a stirred mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (1.0 g, 6.4 mmol) and TBSCl (1.45 g, 9.6 mmol) in DCM was added EtN (1.78 mL, 12.8 mmol) dropwise at room temperature. The mixture was stirred for 1 hour and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 10:1) to give ethyl 1-(tert-butyldimethylsilyl)-3-hydroxypyrazole-4-carboxylate (1.3 g, 75%) as a solid.

[0394] Ethyl 1-(tert-butyldimethylsilyl)-3-methoxypyrazole-4-carboxylate To a stirred mixture of ethyl 1-(tert-butyldimethylsilyl)-3-hydroxypyrazole-4-carboxylate (300 mg, 1.1 mmol) and KCO (300 mg, 2.22 mmol) in MeCN (2 mL) was added MeI (0.21 mL, 3.37 mmol). The mixture was heated to 60° C. and stirred for 6 h, then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 12:1) to give ethyl 1-(tert-butyldimethylsilyl)-3-methoxypyrazole-4-carboxylate (120 mg, 38%) as an oil.

[0395] [1-(tert-butyldimethylsilyl)-3-methoxypyrazol-4-yl]methanol To a stirred solution of ethyl 1-(tert-butyldimethylsilyl)-3-methoxypyrazole-4-carboxylate (460 mg, 1.62 mmol) in THF at 0 °C was added LiAlH (160 mg, 4.2 mmol). The mixture was warmed to room temperature and stirred for 2 h, then cooled to 0 °C again and quenched with NaSO.10H0. The mixture was filtered, and the filter cake was washed with THF (3 × 5 mL). The filtrate was concentrated under reduced pressure to give the title compound (110 mg, crude), which was used directly in the next step without further purification.

[0396] 1-(tert-butyldimethylsilyl)-3-methoxypyrazole-4-carbaldehyde To a stirred solution of [1-(tert-butyldimethylsilyl)-3-methoxypyrazol-4-yl]methanol (70 mg, 0.29 mmol) in DCM was added MnO (250 mg, 2.9 mmol). The mixture was heated to 40 °C and stirred overnight, then filtered, and the filter cake was washed with DCM (3 × 5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc, 2:1) to give 1-(tert-butyldimethylsilyl)-3-methoxypyrazole-4-carbaldehyde (32 mg, 44%) as an oil.

[0397] 4-{[1-(tert-butyldimethylsilyl)-3-methoxypyrazol-4-yl]methyl}-9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred solution of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (42 mg, 0.13 mmol), 1-(tert-butyldimethylsilyl)-3-methoxypyrazole-4-carbaldehyde (32 mg, 0.13 mmol) and NaBH(OAc) (28 mg, 0.13 mmol) in DCM (2 mL) was added AcOH (0.76 μL, 0.013 mmol). The mixture was stirred at room temperature for 5 hours, then concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc, 1:1) to give 4-{[1-(tert-butyldimethylsilyl)-3-methoxypyrazol-4-yl]methyl}-9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (20 mg, 28%) as a solid.

[0398] 9-chloro-7-(5-fluoroindol-1-yl)-4-[(3-methoxy-1H-pyrazol-4-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine To a stirred solution of 4-{[1-(tert-butyldimethylsilyl)-3-methoxypyrazol-4-yl]methyl}-9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (20 mg, 0.037 mmol) in MeOH (1 mL) was added p-TsOH (20 mg, 0.11 mmol). The mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD column, 19 x 250 mm, 5 μm; Mobile phase A: water (0.05% HCl), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 25% B to 48% B, 48% B in 10 min; Wavelength: 254 nm; RT1 (min): 7.3) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(3-methoxy-1H-pyrazol-4-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (4.1 mg, 26%) as a solid. LC / MS: Mass C 22 H 20 Calculated value for ClFN4O2: 426.1, Found value: 427.1 [M+H] + ; 1 H NMR(300MHz,CDCl3)δ 7.38-7.45(m,2H),7.28-7.32(m,2H),7.13(d,J=2.4Hz,1H),6.94-7.05(m,2H),6.58 -6.61(m,1H),4.21-4.24(m,2H),3.93(s,2H),3.64-3.67(m,5H),3.17-3.22(m,2H); 19 F NMR (282 MHz, CDCl3) δ -123.7.

[0399] Example S13. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(2H-1,2,3-triazol-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 108) [ka] 9-chloro-7-(5-fluoroindol-1-yl)-4-(prop-2-yn-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) in THF (1 mL) was added propargyl bromide (56 mg, 0.47 mmol) and EtN (65 mg, 0.63 mmol). The mixture was heated to 70° C. and stirred for 2 h, then concentrated under reduced pressure to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(prop-2-yn-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (150 mg, crude) as an oil.

[0400] 9-chloro-7-(5-fluoroindol-1-yl)-4-(2H-1,2,3-triazol-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-4-(prop-2-yn-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (150 mg, crude) in toluene (3 mL) was added TMSN3 (635 mg, 5.5 mmol). The mixture was heated to 120° C. and stirred for 35 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 65% B, 65% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.17) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(2H-1,2,3-triazol-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (29.6 mg, 24% over two steps) as a solid. LC / MS: Mass C 20 H 17 Calculated value for ClFNO: 397.1, Found value: 398.0 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 11.20(br,1H),7.78(s,1H),7.73(d,J=3Hz,1H),7.52-7.65(m,2H),7.40-7.45(m,1H),7.37(d,J=3Hz,1H) ,7.05-7.12(m,1H),6.69(d,J=3.3Hz,1H),4.14-4.19(m,2H),3.92(s,2H),3.81(s,2H),3.04-3.11(m,2H); 19 F NMR(300MHz,DMSO-d6)δ -123.6.

[0401] Example S14. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(4H-1,2,4-triazol-3-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 109) [ka] 2-Chloro-N'-formylacetimide hydrazide MeONa (0.03 g, 0.6 mmol) was added to an ice-cold solution of chloroacetonitrile (1.5 g, 19.9 mmol) in MeOH (15 mL). After stirring for 45 min, AcOH (0.04 g, 0.6 mmol) was added (to neutralize the methoxide), followed by N-formylhydrazine (1.19 g, 19.9 mmol). The mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure, and the crude product was triturated with ethanol (10 mL) and filtered to give N'-(2-chloroethanimidoyl)formohydrazide (400 mg, 15%) as a solid.

[0402] 9-chloro-7-(5-fluoroindol-1-yl)-4-(4H-1,2,4-triazol-3-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.16 mmol) and N'-(2-chloroethanimidoyl)formohydrazide (33 mg, 0.24 mmol) in DMF (1 mL) was added K2CO3 (670 mg, 0.47 mmol). The mixture was heated to 70°C and stirred for 48 hours, then filtered, and the filtrate was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 µm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 58% B, 58% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.43) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(4H-1,2,4-triazol-3-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (15.7 mg, 24%) as a solid. LC / MS: Mass C 20 H 17 Calculated value for ClFNO: 397.1, Found: 398.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 13.90(s,1H),7.95-8.51(m,1H),7.73(d,J=3.3Hz,1H),7.59-7.69(m,2H),7.36-7.48(m,2H), 7.02-7.15(m,1H),6.69(d,J=3.3Hz,1H),4.17(s,2H),3.96(s,2H),3.81(s,2H),3.14(s,2H); 19 F NMR (300 MHz, CD3OD) δ -123.6.

[0403] Example S15. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3,4-oxadiazol-2-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 111) [ka] Ethyl 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetate To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (200 mg, 0.63 mmol) in THF (2 mL) was added ethyl bromoacetate (210 mg, 1.3 mmol) and EtN (127 mg, 1.3 mmol). The mixture was heated to 70 °C and stirred for 2 h, then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 1:1) to give ethyl 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetate (170 mg, 61%) as an oil.

[0404] 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetohydrazide To a stirred mixture of ethyl 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetate (170 mg, 0.42 mmol) in EtOH (1.5 mL) was added hydrazine hydrate (54 mg, 1.1 mmol). The mixture was heated to 90° C. and stirred for 4 hours, then concentrated under reduced pressure to give 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetohydrazide (137 mg, 81%) as an oil.

[0405] 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3,4-oxadiazol-2-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetohydrazide (127 mg, 0.33 mmol) in trimethyl orthoformate (1 mL) was added p-TsOH (13 mg). The mixture was heated to 100° C. and stirred for 10 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 42% B to 62% B, 62% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.95) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(1,3,4-oxadiazol-2-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (6.3 mg, 5%) as a solid. LC / MS: Mass C 20 H 16 Calculated value for ClFN4O2: 398.0, Found value: 399.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 9.24(s,1H),7.71(d,J=4Hz,1H),7.57-7.65(m,2H),7.55(s,2H),7.03-7.08(m,1H),6 .69(d,J=3.2Hz,1H),4.16-4.21(m,2H),4.06(s,2H),3.98(s,2H),3.15-3.21(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -123.6.

[0406] Example S16. Preparation of 9-chloro-4-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 115) [ka] 9-chloro-4-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (20 mg, 0.06 mmol) in CHCN (1 mL) was added 5-iodo-3-(iodomethyl)-1,2,4-thiadiazole (CAS number: 115443-43-1) (45 mg, 0.13 mmol) and DIPEA (20 mg, 0.16 mmol). The mixture was stirred at room temperature for 18 hours, then concentrated in vacuo, and the residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 55% B to 75% B, 75% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.05) to give 9-chloro-4-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (1.5 mg, 5%) as a solid. LC / MS: Mass C 20 H 15 Calculated value for Cl2FN4OS: 448.0, Found: 449.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 7.72(d,J=3.3Hz,1H),7.52-7.65(m,2H),7.38-7.49(m,2H),7.03-7.10(m,1 H),6.69(d,J=3.3Hz,1H),4.14-4.23(m,2H),4.00(s,4H),3.17-3.26(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.5.

[0407] Example S17. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-[(5-methoxy-1,2,4-thiadiazol-3-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 116) [ka] To a mixture of 9-chloro-4-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (30 mg, 0.07 mmol) in MeOH (1 mL) was added CHONa (12 mg, 0.22 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 59% B to 79% B, 79% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.27) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(5-methoxy-1,2,4-thiadiazol-3-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (1.6 mg, 5%) as an oil. LC / MS: Mass C 21 H 18 Calculated value for ClFN4O2S: 444.0, Found value: 445.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 7.72(d,J=3.3Hz,1H),7.54-7.64(m,2H),7.37-7.49(m,2H),7.02-7.09(m,1H),6.6 9(d,J=3.3Hz,1H),4.00-4.18(m,5H),3.99(s,2H),3.80(s,2H),3.16-3.25(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0408] Example S18. Preparation of 3-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1,2,4-thiadiazol-5-amine (Compound 117) [ka] To a stirred mixture of 9-chloro-4-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (75 mg, 0.17 mmol) in DMF (1 mL) was added NaN3 (22 mg, 0.34 mmol). The mixture was heated to 100°C and stirred for 2 hours, then purified directly by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 µm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 65% B, 65% B in 10 min; Wavelength: 254 nm; RT1 (min): 6.03) to give 3-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1,2,4-thiadiazol-5-amine (3.2 mg, 4%) as a solid. LC / MS: Mass C 20 H 17 Calculated value for ClFN5OS: 429.1, Found value: 430.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 7.89(s,2H),7.72(d,J=3.3Hz,1H),7.52-7.63(m,2H),7.34-7.48(m,2H),7.02-7.09(m,1 H),6.69(d,J=3.3Hz,1H),4.12-4.18(m,2H),3.98(s,2H),3.66(s,2H),3.14-3.19(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0409] Example S19. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-(2H-1,2,3,4-tetrazol-5-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 118) [ka] 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetonitrile To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) in THF (1 mL) was added 2-bromoacetonitrile (57 mg, 0.47 mmol) and EtN (64 mg, 0.63 mmol). The mixture was heated to 70 °C and stirred for 1 h, then concentrated in vacuo, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm) to give 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetonitrile (60 mg, 54%) as a solid.

[0410] 9-chloro-7-(5-fluoroindol-1-yl)-4-(2H-1,2,3,4-tetrazol-5-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 2-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]acetonitrile (60 mg, 0.169 mmol) in DMF (1 mL) was added NaN (109 mg, 1.7 mmol) and NH Cl (89 mg, 1.7 mmol). The mixture was heated to 100°C and stirred for 2 hours, then purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 µm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 23% B to 53% B, 53% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(2H-1,2,3,4-tetrazol-5-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (18 mg, 27%) as a solid. LC / MS: Mass C 19 H 16 Calculated value for ClFNO: 398.1, Found: 399.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 7.72(d,J=3.3Hz,1H),7.58-7.68(m,2H),7.36-7.48(m,2H),7.02-7.09(m,1H ),6.65-6.73(m,1H),4.16-4.19(m,2H),3.92-4.02(m,4H),3.08-3.17(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0411] Example S20. Preparation of 9-chloro-4-(2-(difluoromethyl)benzyl)-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane (Compound 122) [ka] 1-(chloromethyl)-2-(difluoromethyl)benzene To a stirred solution of [2-(difluoromethyl)phenyl]methanol (50 mg, 0.32 mmol) in DCM (1 mL) was added SOCl (0.1 mL, 1.4 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to give 1-(chloromethyl)-2-(difluoromethyl)benzene (60 mg, crude) as an oil.

[0412] 9-chloro-4-{[2-(difluoromethyl)phenyl]methyl}-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine A stirred solution of 1-(chloromethyl)-2-(difluoromethyl)benzene (45 mg, 0.24 mmol) and 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.16 mmol) in THF (1 mL) gave EtN (30 mg, 0.32 mmol). The mixture was heated to 70° C. and stirred for 4 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep C18 OBD column, 19×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 47% B to 77% B, 77% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 9-chloro-4-{[2-(difluoromethyl)phenyl]methyl}-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (5.1 mg, 7%) as a solid. LC / MS: Mass C 25 H 20 Calculated value for ClF3N2O: 456.1, Found: 457.0 [M+H] + ; 1H NMR(300MHz,CD3OD)δ 7.59-7.63(m,1H),7.41-7.46(m,1H),7.36-7.40(m,5H),7.23-7.29(m,2H),7.04-7.13(m,1H),6.98 (t,J=9.1Hz,1H),6.64(d,J=3.3Hz,1H),4.16-4.25(m,2H),3.90(d,J=6.8Hz,4H),3.11-3.20(m,2H); 19 F NMR(300MHz,CD3OD)δ -114.0,-126.2.

[0413] Example S21. Preparation of trans-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methylcyclohexane-1-carboxylic acid (Compound 131) [ka] trans-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methylcyclohexane-1-carboxylic acid A solution of methyl trans-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}cyclohexane-1-carboxylate (50 mg, 0.11 mmol) in 6 M HCl (5 mL) was stirred at 80° C. for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 37% B to 57% B, 57% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.8) to give trans-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methylcyclohexane-1-carboxylic acid (9 mg, 18%) as a solid. LC / MS: Mass C 25 H 26Calculated value for ClFN2O3: 456.2, Found value: 457.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.42-7.47(m,3H),7.26-7.39(m,2H),6.92-6.99(m,1H),6.62-6.64(m,1H),4.14-4.17(m,2H),3.93( s,2H),3.14-3.16(m,2H),2.10-2.42(m,3H),1.91-2.10(m,3H),1.54-1.62(m,2H),0.93-1.46(m,4H); 19 F NMR (282 MHz, CD3OD) δ -126.2.

[0414] Example S22. Preparation of cis-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}cyclohexane-1-carboxylic acid (Compound 132) [ka] A mixture of methyl cis-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}cyclohexane-1-carboxylate (50 mg, 0.11 mmol) in aqueous HCl (7 M) (10 mL) was stirred at 80° C. for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 33% B to 63% B, 63% B in 7 min; Wavelength: 254 nm; RT1 (min): 5) to give cis-4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}cyclohexane-1-carboxylic acid (10.7 mg, 21%) as a solid. LC / MS: Mass C 25 H 26 Calculated value for ClFN2O3: 456.1, Found value: 457.1 [M+H]+ ; 1 H NMR (300 MHz, CD3OD) δ 7.46-7.50(m,2H),7.38-7.47(m,1H),7.38(d,J=3.0Hz,1H),7.28-7.34(m, 1H),6.90-6.70(m,1H),6.65(d,J=3.0Hz,1H),4.13-4.22(m,2H),3.96(s,2H) ),3.13-3.22(m,2H),2.48-2.56(m,1H),2.44(d,J=6.0Hz,2H),1.90-2.00(m ,2H),1.69-1.76(m,1H),1.50-1.65(m,3H),1.54-1.65(m,1H),1.35(m,2H); 19 F NMR (282 MHz, CD3OD) δ -126.2.

[0415] Example S23. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate (Compound 140) and 1-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanamine (Compound 139) [ka] To a mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and potassium tert-butyl N-[(trifluoroboranuidyi)methyl]carbamate (40 mg, 0.17 mmol) in 1,4-dioxane (2 mL) and HO (0.2 mL) under an atmosphere of N was added Pd(OAc) (3 mg, 0.011 mmol), butyl bis[(3R,5S,7s)-adamantan-1-yl]phosphane (20 mg, 0.057 mmol), and CsCO (110 mg, 0.34 mmol). The mixture was heated to 100 °C and stirred for 6 h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L) NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 50% B to 80% B, 80% B in 10 min; wavelength: 254 nm; RT1 (min): 8.67) to give tert-butyl N-[(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methyl]carbamate (7.3 mg, 12%) as a solid and 1-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanamine (3.2 mg, 3%) as a solid.

[0416] 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate LC / MS: Mass C 28 H 29 Calculated value for ClFN5O3: 537.1, Found value: 538.1 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 8.69(s,2H),7.71(d,J=3.3Hz,1H),7.63(d,J=2.7Hz,1H),7.51(d,J=9.3Hz,1H),7.39-7.45(m,2H),7.21(s,1H),7.05(t,J=9.3H) z,1H),6.68(d,J=3.3Hz,1H),4.30(d,J=6.0Hz,2H),4.19-4.20(m,2H),3.98(s,2H),3.72(s,2H),3.05-3.06(m,2H),1.37(s,9H); 19 F NMR(282MHz,DMSO-d6)δ -123.5.

[0417] 1-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanamine LC / MS: Mass C 23 H 21 Calculated for ClFNO: 437.1, Found: 438.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.19(s,2H),7.71(d,J=3.3Hz,1H),7.61(d,J=2.4Hz,1H),7.49-7.53(m,1H),7.37-7.45(m,2H),7.01-7.06(m,2) H),6.68(d,J=3.0Hz,1H),4.16-4.17(m,2H),3.92(s,2H),3.50(s,2H),3.03-3.04(m,2H),2.77(d,J=4.5Hz,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0418] Example S24. Preparation of (5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanol (Compound 141) [ka] To a stirred mixture of methyl 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate (90 mg, 0.19 mmol) in THF (2 mL) was added LiBH (8 mg, 0.39 mmol). The mixture was stirred at room temperature for 1 hour, then HO (10 mL) was added and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 66% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.67) to give (5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanol (2.8 mg, 3%) as a solid. LC / MS: Mass C 23 H 20 Calculated value for ClFN4O2: 438.1, Found value: 439.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.72(s,2H),7.72(d,J=3.3Hz,1H),7.64(d,J=2.6Hz,1H),7.48-7.55(m,1H),7.37-7.47(m,2H),7.00-7.13(m,1H),6.69(d, J=3.3Hz,1H),5.29(t,J=6.3Hz,1H),4.60(d,J=6.0Hz,2H),4.16-4.22(m,2H),3.99(s,2H),3.74(s,2H),3.04-3.10(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.5.

[0419] Example S25. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxamide (Compound 143) [ka] To an 8 mL vial containing NaCN (25 mg, 0.51 mmol), 1,4-diazabicyclo[2.2.2]octane (2 mg, 0.02 mmol), and DMSO (2 mL) was added 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (150 mg, 0.34 mmol) in DMSO (1 mL) dropwise over 5 minutes at room temperature. The mixture was heated to 80° C. and stirred for 16 h, then directly purified by preparative HPLC (column: XBridge Prep Phenyl OBD column, 19×250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: MeOH-HPLC; flow rate: 25 mL / min; gradient: 65% B to 95% B, 95% B in 7 min; wavelength: 25 nm; RT1 (min): 6) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxamide (4.6 mg, 3.0%) as a solid. LC / MS: Mass C 23 H 19 Calculated value for ClFN5O2: 451.1, Found value: 452.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 8.87(s,2H),8.21(s,1H),7.62-7.79(m,3H),7.39-7.54(m,3H),7.04-7.12(m,1H), 6.66-6.71(m,1H),4.18-4.24(m,2H),4.00(s,2H),3.83(s,2H),3.09-3.15(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -123.7.

[0420] Example S26. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylic acid (compound 144) and methyl 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate (compound 145) [ka] 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (200 mg, 0.63 mmol) and 2-chloropyrimidine-5-carbaldehyde (135 mg, 0.95 mmol) in DCM (3 mL) was added NaBH(OAc) (267 mg, 1.26 mmol) and AcOH (0.08 mg, 0.001 mmol). The reaction was stirred at room temperature for 3 hours, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 20 minutes; detector, UV 254 nm) to give 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (180 mg, 61%) as an oil.

[0421] Methyl 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate To a stirred mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (200 mg, 0.45 mmol) in MeOH (5 mL) and DMF (1 mL) was added Pd(dppf)Cl (49 mg, 0.068 mmol) and EtN (137 mg, 1.35 mmol). The mixture was placed under an atmosphere of CO (3 MPa), heated to 120 °C and stirred for 24 h, then concentrated in vacuo, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 70% gradient in 15 min; detector, UV 254 nm) to give methyl 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate (130 mg, 59%) as a solid. LC / MS: Mass C 24 H 20 Calculated value for ClFN4O3: 466.1, Found value: 467.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.92(s,2H),7.71(d,J=3.3Hz,1H),7.64(d,J=2.7Hz,1H),7.50(d,J=9.0Hz,1H),7.40-7.45(m,2H),7.06(t,J=9.3 Hz,1H),6.68(d,J=3.3Hz,1H),4.21(d,J=4.8Hz,2H),3.99(s,2H),3.91(s,3H),3.84(s,2H),3.13(d,J=5.7Hz,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0422] 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylic acid To a stirred mixture of methyl 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate (15 mg, 0.032 mmol) in THF (0.75 mL) was added 2M LiOH (0.5 mL). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 60% B, 60% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylic acid (4.5 mg, 31%) as a solid. LC / MS: Mass C 23 H 18 Calculated value for ClFN4O3: 452.1, Found value: 453.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.77(s,2H),7.72(d,J=3.3Hz,1H),7.64(d,J=2.7Hz,1H),7.47-7.56(m,1H),7.38-7.47(m,2H),7.02 -7.13(m,1H),6.69(d,J=3.3Hz,1H),4.14-4.23(m,2H),3.99(s,2H),3.78(s,2H),3.05-3.14(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.5.

[0423] Example S27. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-(oxetan-3-yl)pyrimidin-2-amine (Compound 149) [ka] To a stirred mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (10 mg, 0.023 mmol) in 1,4-dioxane (1 mL) was added oxetan-3-amine (3 mg, 0.05 mmol) and DIPEA (6 mg, 0.05 mmol). The mixture was heated to 100° C. and stirred for 6 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 69% B, 69% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.25) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-(oxetan-3-yl)pyrimidin-2-amine (3.6 mg, 33%) as a solid. LC / MS: Mass C 25 H 23 Calculated value for ClFN5O2: 479.1, Found value: 480.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 8.28(s,2H),7.53(d,J=2.7Hz,1H),7.39-7.50(m,2H),7.27-7.35(m,1H),7.23(d,J=2.7Hz,1H),6.93-7.05(m,1H),6.62-6.69(m,1) H),4.97-5.11(m,1H),4.94(d,J=6.3Hz,2H),4.63(t,J=6.3Hz,2H),4.17-4.26(m,2H),3.93(s,2H),3.62(s,2H),3.11-3.20(m,2H); 19 F NMR (282 MHz, CD3OD) δ -126.1.

[0424] Example S28. Preparation of N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)acetamide (Compound 150) [ka] A solution of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-amine (50 mg, 0.12 mmol) in AcO (1 mL) was heated to 140 °C and stirred overnight, then concentrated under reduced pressure. Aqueous NH.HO (2 mL) was added, and the mixture was stirred at room temperature for 1 hour, then extracted with DCM (3 × 2 mL). The combined organic layers were washed with brine (2 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: HO (10 mmol / L NHHCO + 0.1% NH.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 60% B, 60% B in 9 min; Wavelength: 254 nm; RT1 (min): 8.23) to give N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanesulfonamide (9.0 mg, 14%) as a solid. LC / MS: Mass C 24 H 21 Calculated value for ClFN5O2: 465.1, Found value: 466.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 10.54(s,1H),8.57(s,2H),7.71(d,J=3.3Hz,1H),7.63(d,J=2.6Hz,1H),7.51(d,J=9.0Hz,1H),7.47-7.37(m,2H),7.0 7(t,J=9.2Hz,1H),6.69(d,J=3.2Hz,1H),4.18-4.19(m,2H),3.97(s,2H),3.67(s,2H),3.07-3.08(m,2H),2.17(s,3H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0425] Example S29. Preparation of N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanesulfonamide (Compound 151) [ka] To a stirred solution of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-amine (50 mg, 0.118 mmol) in DCM (1 mL) at 0 °C was added MsCl (20 μL, 0.24 mmol) and EtN (33 μL, 0.24 mmol). The mixture was warmed to room temperature and stirred for 2 hours at room temperature, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; Mobile phase A: HO (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 60% B, 60% B in 9 min; Wavelength: 254 nm; RT1 (min): 8.23) to give N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)methanesulfonamide (4.4 mg, 7%) as a solid. LC / MS: Mass C 23 H 21 Calculated value for ClFN5O3S: 501.1, Found value: 502.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 11.31(s,1H),8.50(s,2H),7.72(d,J=3.3Hz,1H),7.64(d,J=2.6Hz,1H),7.49-7.53(m 1H),7.42-7.45(m,2H),7.02-7.14(m,1H),6.69(d,J=3.2Hz,1H),4.17- 4.18(m,2H),3.98(s,2H),3.64(s,2H),3.27(s,3H),3.05-3.06(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0426] Example S30. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(1-methylpyrazol-4-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (Compound 153) [ka] To a mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and 1-methylpyrazol-4-ylboronic acid (28 mg, 0.23 mmol) in 1,4-dioxane (1 mL) and HO (0.2 mL) under an atmosphere of N was added KCO (31 mg, 0.23 mmol) and Pd(PPh) (13 mg, 0.011 mmol). The mixture was heated to 80 °C and stirred overnight, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: HO (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 58% B to 88% B, 88% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.98) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(1-methylpyrazol-4-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (14.1 mg, 23%) as a solid. LC / MS: Mass C 26 H 22 Calculated value for ClFNO: 488.1, Found: 489.1 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 8.66(s,2H),8.35(s,1H),8.00(d,J=0.6Hz,1H),7.71(d,J=3.3Hz,1H),7.62(d,J=2.4Hz,1H),7.50(d,J=9.0Hz,1H),7.42(d,J=7.5 Hz,2H),7.02(t,J=6.9Hz,1H),6.68(d,J=2.7Hz,1H),4.19-4.20(m,2H),43.99(s,2H),3.89(s,3H),3.70(s,2H),3.08-3.09(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0427] Example S31. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(pyrazol-1-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (Compound 154) [ka] To a stirred mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and pyrazole (15 mg, 0.23 mmol) in DMF was added KCO (31 mg, 0.23 mmol). The mixture was heated to 140 °C and stirred overnight, then filtered, and the filtrate was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: HO (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 48% B to 78% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.23) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(pyrazol-1-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (11.5 mg, 22%) as a solid. LC / MS: Mass C 25 H 20Calculated value for ClFNO: 474.1, Found value: 475.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.79(s,2H),8.66(d,J=2.1Hz,1H),7.85(s,1H),7.70(d,J=3.3Hz,1H),7.63(d,J=2.4Hz,1H),7.51(d,J=9.0Hz,1H),7.42-7.44(m,2H) ),7.05(t,J=9.3Hz,1H),6.66(d,J=3.3Hz,1H),6.59(d,J=2.7Hz,1H),4.20-4.21(m,2H),4.00(s,2H),3.78(s,2H),3.14-3.15(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.7.

[0428] Example S33. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-4-fluoro-3H-pyrimidin-2-one (Compound 155) and 4-chloro-5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-3H-pyrimidin-2-one (Compound 158) [ka] 9-chloro-4-[(2,4-dichloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (200 mg, 0.63 mmol) and 2,4-dichloropyrimidine-5-carbaldehyde (223 mg, 1.26 mmol) in DCM (4 mL) at room temperature was added NaBH(OAc) (267 mg, 1.26 mmol) and AcOH (0.04 mL). The mixture was stirred at room temperature for 16 hours, then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 3:1) to give 9-chloro-4-[(2,4-dichloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (116 mg, 39%) as a solid.

[0429] 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-4-fluoro-3H-pyrimidin-2-one and 4-chloro-5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-3H-pyrimidin-2-one A mixture of dry Me4NF (389 mg, 4.2 mmol) in MeOH (5 mL) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in 2-methyl-2-butanol (5 mL) and concentrated under reduced pressure—this process was repeated four times. The residue and 9-chloro-4-[(2,4-dichloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.21 mmol) were dissolved in DMSO (2 mL) and heated to 80° C. with stirring for 16 hours. A portion of the mixture was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 24% B to 54% B, 54% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.38) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-4-fluoro-3H-pyrimidin-2-one (1.3 mg, 1%) as a solid. LC / MS: Mass C 22 H 17 Calculated value for ClF2N4O2: 442.1, Found value: 443.1 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ 7.97(d,J=4.0Hz,1H),7.71(d,J=4.0Hz,1H),7.45-7.60(m,3H),7.30-7.37(m,1H),6.94-7. 03(m,1H),6.68(d,J=4.0Hz,1H),4.49(s,2H),4.26-4.39(m,2H),4.13(s,2H),3.62(m,2H); 19F NMR (282 MHz, CD3OD) δ -50.6, 126.2. Another portion of the mixture was purified by preparative HPLC (Column: Xselect CSH C18 OBD column 30 x 150 mm 5 μm, n; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 52% B, 52% B in 10 min; Wavelength: 254 nm; RT1 (min): 8.65) to give 4-chloro-5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-3H-pyrimidin-2-one (1.3 mg, 1%) as a solid. LC / MS: Mass C 22 H 17 Calculated value for Cl2FN4O2: 458.0, Found value: 459.1 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ 7.95(s,1H),7.64(d,J=4.0Hz,1H),7.39-7.55(m,3H),7.26-7.35(m,1H),6.96-7.03(m,1 H),6.67(d,J=4.0Hz,1H),4.30-4.37(m,2H),4.28(s,2H),3.90(s,2H),3.40-3.48(m,2H); 19 F NMR (376 MHz, CD3OD) δ -126.0.

[0430] Example S33. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-4-hydroxy-3H-pyrimidin-2-one (Compound 157) [ka] To a mixture of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-4-fluoro-3H-pyrimidin-2-one (30 mg, 0.07 mmol) in 1,4-dioxane (1 mL) was added NaOH (4 mg, 0.1 mmol) in HO (0.5 mL). The mixture was stirred at room temperature for 4 hours, then acidified with 2M HCl (a few drops) and purified directly by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 60% B, 60% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-4-hydroxy-3H-pyrimidin-2-one (8.3 mg, 28%) as a solid. LC / MS: Mass C 22 H 18 Calculated value for ClFN4O3: 440.1, Found value: 441.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.42-7.56(m,4H),7.26-7.39(m,2H),6.90-7.00(m,1H),6.65(d,J=3.0 Hz,1H),4.17-4.26(m,2H),3.98(s,2H),3.46(s,2H),3.10-3.18(m,2H); 19 F NMR (282 MHz, CD3OD) δ -126.2.

[0431] Example S34. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-(oxetan-3-yl)pyrimidin-2-amine (Compound 162) [ka] To a stirred mixture of 9-chloro-4-[(2-chloropyrimidin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was added oxetan-3-amine (16 mg, 0.23 mmol) and DIPEA (29 mg, 0.23 mmol). The reaction was heated to 100 °C and stirred for 24 h, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 48% B to 68% B, 68% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.32) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-(oxetan-3-yl)pyrimidin-2-amine (6.2 mg, 11%) as a solid. LC / MS: Mass C 25 H 23 Calculated value for ClFN5O2: 479.1, Found value: 480.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 8.25(d,J=5.1Hz,1H),7.54(d,J=2.7Hz,1H),7.39-7.51(m,2H),7.27-7.3 5(m,1H),7.23(d,J=2.7Hz,1H),6.92-7.04(m,1H),6.85(d,J=5.1Hz,1H), 6.62-6.69(m,1H),4.95-5.07(m,1H),4.85(t,J=6.9Hz,2H),4.58(t,J=6. 3Hz,2H),4.18-4.27(m,2H),4.02(s,2H),3.69(s,2H),3.21-3.30(m,2H); 19 F NMR (282 MHz, CD3OD) δ -126.1.

[0432] Example S35. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-amine (Compound 163) [ka] A stirred mixture of 9-chloro-4-[(2-chloropyrimidin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.23 mmol) in 7M NH3 in MeOH (3 mL) was heated to 70° C. and stirred for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep Phenyl OBD Column, 19 × 250 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 46% B to 76% B, 76% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-amine (16.4 mg, 16%) as a solid. LC / MS: Mass C 22 H 19 Calculated value for ClFNO: 423.1, Found: 424.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 8.21(d,J=5.1Hz,1H),7.37-7.53(m,3H),7.18-7.33(m,2H),6.92-7.03(m,1H),6.82(d,J=5. 1Hz,1H),6.59-6.66(m,1H),4.11-4.25(m,2H),3.99(s,2H),3.66(s,2H),3.18-3.27(m,2H); 19 F NMR (282 MHz, CD3OD) δ -126.1.

[0433] Example S36. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2H-pyridazin-3-one (Compound 169) [ka] 5-ethenyl-2-[(4-methoxyphenyl)methyl]pyridazin-3-one To a stirred mixture of 5-iodo-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (700 mg, 2.1 mmol) in methylbenzene (1 mL) under an atmosphere of N was added tributyl(ethenyl)stannane (649 mg, 2.1 mmol) and Pd(dppf)Cl (72 mg, 0.1 mmol). The mixture was heated to 110 °C and stirred for 2 h, then HO (100 mL) was added and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with HO (100 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 2:1) to give 5-ethenyl-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (400 mg, 77%) as a solid.

[0434] 5-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]pyridazin-3-one To a stirred mixture of 5-ethenyl-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (400 mg, 1.7 mmol) in THF (3 mL) and HO (3 mL) was added OsO (4 mg, 0.02 mmol) and NaIO (705 mg, 3.3 mmol) over 2 min. The mixture was stirred at room temperature for 6 h, then NaBH (125 mg, 3.3 mmol) was added. The reaction was stirred at room temperature for 15 min, then HO (15 mL) was added and extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give 5-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (360 mg, 89%) as an oil.

[0435] {1-[(4-methoxyphenyl)methyl]-6-oxopyridazin-4-yl}methyl methanesulfonate To a stirred mixture of 5-(hydroxymethyl)-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (360 mg, 1.5 mmol) in DCM (5 mL) was added MsCl (335 mg, 2.924 mmol) and EtN (300 mg, 2.9 mmol). The reaction was stirred at room temperature for 2 h, then HO (20 mL) was added and the mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with HO (10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure to give {1-[(4-methoxyphenyl)methyl]-6-oxopyridazin-4-yl}methyl methanesulfonate (430 mg, 86%) as an oil.

[0436] 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2-[(4-methoxyphenyl)methyl]pyridazin-3-one To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) in THF (10 mL) was added {1-[(4-methoxyphenyl)methyl]-6-oxopyridazin-4-yl}methyl methanesulfonate (205 mg, 0.63 mmol) and EtN (64 mg, 0.63 mmol). The mixture was stirred at room temperature for 2 hours, then concentrated under reduced pressure, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 minutes; detector, UV 254 nm) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (170 mg, 94%) as an oil.

[0437] 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2H-pyridazin-3-one To a stirred mixture of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (50 mg, 0.09 mmol) in DCM (1 mL) was added CFSOH (2 mg, 0.01 mmol). The mixture was stirred at room temperature for 1 hour, then concentrated in vacuo, and the residue was purified by preparative HPLC (column: Xselect CSH C18 OBD column 30 x 150 mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 37% B to 67% B, 67% B in 7 min; wavelength: 254 nm; RT1 (min): 6.33) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2H-pyridazin-3-one (3.7 mg, 9%) as a solid. LC / MS: Mass C 22 H 18Calculated value for ClFN4O2: 424.1, Found value: 425.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 12.94(s,1H),7.84(d,J=1.8Hz,1H),7.71(d,J=3.3Hz,1H),7.64(d,J=2.7Hz,1H),7.49-7.57(m,1H),7.38-7.48(m,2H) ,7.01-7.13(m,1H),6.77(s,1H),6.69(d,J=3.3Hz,1H),4.16-4.23(m,2H),4.00(s,2H),3.64(s,2H),3.13-3.19(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -80.1,-126.0.

[0438] Example S37. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridine-2-carboxylic acid (Compound 177) [ka] To a stirred solution of methyl 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridine-2-carboxylate (50 mg, 0.11 mmol) in THF (1 mL) at room temperature was added 1 M aqueous LiOH solution (0.5 mL, 0.5 mmol). The mixture was stirred at room temperature for 2 hours, then acidified to pH 6 with 1 M HCl and extracted with DCM (3 × 2 mL). The combined organic layer was washed with brine (2 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: HO (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 27% B to 57% B, 57% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridine-2-carboxylic acid (7.3 mg, 15%) as a solid. LC / MS: Mass C 24 H 19 Calculated value for ClFN3O3: 451.1, Found value: 452.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.57(s,1H),7.97(d,J=8.0Hz,1H),7.85(d,J=8.1Hz,1H),7.72(d,J=3.3Hz,1H),7.64(d,J=2.6Hz,1H),7.39-7.51(m,2H),7. 35(d,J=2.7Hz,1H),7.14-7.02(m,1H),6.68(d,J=3.3Hz,1H),4.18-4.19(m,2H),3.96(s,2H),3.80(s,2H),3.08-3.09(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.5.

[0439] Example S38. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-amine (Compound 179) [ka] To a stirred solution of tert-butyl N-(4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)carbamate (60 mg, 0.12 mmol) in toluene (2 mL) was added silica gel (70 mg, 1.2 mmol). The mixture was heated to 100° C. and stirred for 3 h, then filtered, and the filter cake was washed with DCM (3×3 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 65% B to 85% B, 85% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.32) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-amine (3.7 mg, 8%) as a solid. LC / MS: Mass C 23 H 20 Calculated for ClFNO: 422.1, Found: 423.1 [M+H] + ; 1 H NMR(300MHz,CDCl3)δ 7.89(d,J=5.7Hz,1H),7.46(d,J=2.6Hz,1H),7.26-7.40(m,3H),6.94-7.09(m,2H),6.67-6.77(m,2H) ,6.64(d,J=3.4Hz,1H),5.47(s,1H),4.20-4.29(m,2H),3.92(s,2H),3.67(s,2H),3.16-3.25(m,2H); 19 F NMR (376 MHz, CDCl3) -126.1.

[0440] Example S39. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-methylpyridin-2-amine (Compound 180) [ka] 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) and 2-chloropyridine-4-carbaldehyde (90 mg, 0.63 mmol) in DCM was added NaBH(OAc) (134 mg, 0.63 mmol) and AcOH (2 mg, catalytic amount). The mixture was stirred overnight at room temperature and then concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc, 2:1) to give 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (80 mg, 57%) as a solid.

[0441] 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-methylpyridin-2-amine To a stirred mixture of 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and MeNH2.HCl (23 mg, 0.34 mmol) in NMP (1 mL) was added Et3N (47 μL, 0.34 mmol). The mixture was heated to 200 °C under microwave irradiation and stirred for 2 h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 80% B, 80% B in 8 min; Wavelength: 254 nm; RT1 (min): 7) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-methylpyridin-2-amine (2.0 mg, 4%) as a solid. LC / MS: Mass C 24 H 22 Calculated value for ClFNO: 436.1, Found: 437.0 [M+H] + ; 1 H NMR(300MHz,CDCl3)δ 7.89(d,J=5.7Hz,1H),7.47(d,J=2.7Hz,1H),7.29-7.40(m,3H),6.91-7.03(m,2H),6.61-6.65(m,2H),6.54 (s,1H),6.12(s,1H),4.22-4.24(m,2H),3.90(s,2H),3.66(s,2H),3.18-3.22(m,2H),2.89(d,J=5.1Hz,3H); 19 F NMR (282 MHz, CDCl3) δ -123.0.

[0442] Example 40. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N,N-dimethylpyridin-2-amine) (Compound 181) [ka] A mixture of 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and MeNH (15 mg, 0.34 mmol) in n-butanol (2 mL) was heated to 140 °C under microwave irradiation and stirred for 30 min, then concentrated under reduced pressure to give a residue purified by reparative-HPLC (column: XSelect CSH Prep C18 Purification on an OBD column, 19 x 250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 53% B in 7 min, 53% B; wavelength: 254 nm; RT1 (min): 5.15) gave 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N,N-dimethylpyridin-2-amine) as a solid. LC / MS: Mass C 25 H 24 Calculated value for ClFNO: 450.1, Found: 451.1 [M+H] + ; 1 H NMR(300MHz,CDCl3)δ 8.13(s,1H),7.56(s,1H),7.37-7.41(m,1H),7.29-7.33(m,3H),7.16(s,1H),7.00(t,J=8.4Hz,1H),6.80( s,1H),6.64(d,J=3.0Hz,1H),4.34-4.35(m,2H),4.19(s,2H),4.01(s,2H),3.38-3.39(m,2H),3.31(s,6H); 19 F NMR(282MHz,CDCl3)δ -75.7,-123.2.

[0443] Example S41. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-(oxetan-3-yl)pyridin-2-amine (Compound 182) [ka] To a stirred mixture of 9-chloro-4-[(2-chloropyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.11 mmol) and oxetan-3-amine (25 mg, 0.34 mmol) in 1,4-dioxane was added t-BuBrettPhos Pd G3 (20 mg, 0.023 mmol), t-BuBrettPhos (11 mg, 0.023 mmol), and t-BuOK (25 mg, 0.23 mmol). The mixture was stirred at 90 °C for 16 h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD column, 19 × 250 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 53% B, 53% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.15) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-N-(oxetan-3-yl)pyridin-2-amine (2.2 mg, 4%) as a solid. LC / MS: Mass C 26 H 24 Calculated value for ClFN4O2: 478.1, Found value: 479.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.88(d,J=5.4Hz,1H),7.51(d,J=2.7Hz,1H),7.43(d,J=10.5Hz,2H),7.28(d,J=9.3Hz,1H),7.15(d,J=2.4Hz,1H),6.96(t,J=9.3,2. 6Hz,1H),6.56-6.66(m,2H),6.54(s,1H),4.91(m,3H),4.53(m,2H),4.18-4.21(m,2H),3.92(s,2H),3.64(s,2H),3.15-3.18(m,2H); 19 F NMR (282 MHz, CD3OD) δ -126.1.

[0444] Example S42. Preparation of 1-(4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)methanamine (Compound 184) [ka] (4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)methyl methanesulfonate To a mixture of (4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)methanol (40 mg, 0.09 mmol) in DCM (4 mL) at 0° C. was added MsCl (20 mg, 0.18 mmol) and EtN (18 mg, 0.18 mmol). The mixture was warmed to room temperature and stirred for 1 h, then concentrated under reduced pressure, and the residue was used directly in the next step.

[0445] 1-(4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)methanamine A mixture of (4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)methyl methanesulfonate (40 mg, 0.08 mmol) in 7M NH3 in MeOH (3 mL) was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD column, 19 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 42% B to 72% B in 7 min, 72% B to 72% B in 9 min, 72% B; Wavelength: 254 nm; RT1 (min): 6.47) to give 1-(4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)methanamine (3.3 mg, 10%) as a solid. LC / MS: Mass C 24 H 22 Calculated value for ClFNO: 436.1, Found: 437.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.42(d,J=6.0Hz,1H),7.71(d,J=3.0Hz,1H),7.63(d,J=3.0Hz,1H),7.46-7.53(m,1H),7.38-7.48(m,2H),7.34(d,J=3.0Hz,1H),7.18( d,J=9.0Hz,1H),6.98-7.10(m,1H),6.68(d,J=3.0Hz,1H),4.14-4.27(m,2H),3.96(s,2H),3.76(s,2H),3.73(s,2H)3.04-3.12(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0446] Example S43. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridine-2-carboxylic acid (Compound 185) [ka] To a mixture of methyl 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridine-2-carboxylate (40 mg, 0.09 mmol) in THF (0.2 mL) and MeOH (0.8 mL) was added LiOH.HO (12 mg, 0.29 mmol) in HO (0.1 mL). The mixture was stirred at room temperature for 3 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 50% B to 80% B, 80% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridine-2-carboxylic acid (16.1 mg, 38%) as a solid. LC / MS: Mass C 24 H 19 Calculated value for ClFN3O3: 451.1, Found value: 452.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.62(d,J=6.0Hz,1H),7.95-8.06(m,2H),7.70-7.75(m,1H),7.60-7.68(m,1H),7.25-7.57(m,4H),6.98-7 .10(m,1H),6.60-6.70(m,1H),4.11-4.24(m,2H),3.88-3.96(m,2H),3.78-3.81(m,2H),3.04-3.16(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.5.

[0447] Example S44. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(oxetan-3-yl)pyridin-4-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (Compound 187) [ka] 9-chloro-7-(5-fluoroindol-1-yl)-4-(pyridin-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine To a mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (300 mg, 0.95 mmol) and 4-formylpyridine (131 mg, 1.23 mmol) in DCM (5 mL) was added NaBH(OAc) (400 mg, 1.9 mmol) and AcOH (0.2 mL). The mixture was stirred at room temperature for 2 hours, then quenched with aqueous NaHCO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc, 10:1) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(pyridin-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (370 mg, 96%) as an oil.

[0448] 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(oxetan-3-yl)pyridin-4-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine 30% HO (57 μL, 0.74 mmol) in HO was slowly added dropwise to a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-4-(pyridin-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.25 mmol), HS0 (27 μL, 0.49 mmol), 3-iodooxetane (90 mg, 0.49 mmol), and FeSO.7HO (20.5 mg, 0.07 mmol) in DMSO (2 mL) at 40° C. After 2 min, additional FeSO.7HO (20 mg, 0.07 mmol) was added, and the mixture was stirred at 40° C. for 30 min. Additional 30% HO in HO (57 μL, 0.74 mmol) and FeSO.7HO (20 mg, 0.07 mmol) were added, and the mixture was stirred at 40° C. for 1 h, then diluted with EtOAc (10 mL) and poured into saturated aqueous NaHCO (5 mL). The separated organic layer was washed with brine (5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: water (0.1% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 44% B to 74% B in 7 min, 74% B; Wavelength: 254 nm; RT1 (min): 5) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(oxetan-3-yl)pyridin-4-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (4.0 mg, 4%) as a solid. LC / MS: Mass C 26 H 23 Calculated value for ClFN3O2: 463.1, Found value: 464.1 [M+H] + ; 1H NMR(300MHz,DMSO-d6)δ 8.55(d,J=6.0Hz,1H),7.71(d,J=3.0Hz,1H),7.64(d,J=3.0Hz,1H),7.43 -7.50(m,2H),7.34(d,J=3.0Hz,1H),7.22-7.31(m,2H),7.00-7.10(m,1H ),6.68(d,J=3.0Hz,1H),4.80-4.88(m,2H),4.70-4.78(m,2H),4.28-4.4 4(m,1H),4.12-4.20(m,2H),3.96(s,2H),3.73(s,2H),3.02-3.09(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.8.

[0449] Example S45. Preparation of 4-{[2-(azetidin-3-yl)pyridin-4-yl]methyl}-9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine; trifluoroacetic acid (Compound 188) [ka] tert-Butyl 3-(4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)azetidine-1-carboxylate 30% HO in HO (50 μL, 1.5 mmol) was slowly added to a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-4-(pyridin-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (200 mg, 0.49 mmol), HS0 (96 mg, 0.98 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (277 mg, 0.98 mmol), and FeSO.7HO (40 mg, 0.15 mmol) in DMSO (5 mL) at 60° C. After 2 min, additional FeSO.7HO (41 mg, 0.15 mmol) and 30% HO in HO (50 μL, 1.5 mmol) were added. The mixture was stirred at 60° C. for 1 hour, then poured into 0.1 M NaOH (10 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (20 mL×3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in water (0.05% TFA), 20% to 100% gradient in 40 min; detector, UV 254 nm) to give tert-butyl 3-(4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)azetidine-1-carboxylate (40 mg, 15%) as an oil.

[0450] 4-{[2-(azetidin-3-yl)pyridin-4-yl]methyl}-9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a mixture of tert-butyl 3-(4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridin-2-yl)azetidine-1-carboxylate (50 mg, 0.089 mmol) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD column, 19 x 250 mm, 5 μm; Mobile phase A: water (0.1% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 25% B to 51% B, 51% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.02) to give 4-{[2-(azetidin-3-yl)pyridin-4-yl]methyl}-9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (6.2 mg, 11%) as a solid. LC / MS: Mass C 26 H 23 Calculated value for ClFN3O2: 462.1, Found value: 463.1 [M+H] + ; 1 H NMR(400MHz,CD3OD)δ 8.69(d,J=4.0Hz,1H),7.60(d,J=4.0Hz,1H),7.38-7.52(m,4H),7.31-7.36(m,1H),7.26(d,J=4.0Hz,1H), 6.95-7.02(m,1H),6.67(d,J=8.0Hz,1H),4.21-4.42(m,7H),4.16(s,2H),4.03(s,2H),3.36-3.42(m,2H); 19 F NMR(376MHz,CD3OD)δ -76.8,-126.0.

[0451] Example S46. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyridine-2-thione (Compound 189) [ka] 5-Bromo-3-chloro-2-hydroxy-N-[2-hydroxy(1,1,2,2-2H4)ethyl]benzamide A solution of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyridin-2-one (20 mg, 0.05 mmol) in toluene (1 mL) at 80 °C was treated with Lawesson's reagent (11.0 mg, 0.03 mmol). The resulting mixture was heated to 80° C. and stirred for 16 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30×150 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 74% B, 74% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyridine-2-thione (8.9 mg, 42%) as a solid. LC / MS: Mass C 23 H 19 Calculated value for ClFN3OS: 439.1, Found value: 440.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 13.33(s,1H),7.73(d,J=3.3Hz,1H),7.67-7.60(m,2H),7.50-7.54(m,1H),7.37-7.43(m,2H),7.28(s,1H),7.08-7 .13(m,1H),6.73-6.75(m,1H),6.65-6.67(m,1H),4.16-4.22(m,2H),3.91(s,2H),3.60(s,2H),3.10-3.11(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -123.6.

[0452] Example S47. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-3-methyl-1H-pyridin-2-one (Compound 194) [ka] To a stirred mixture of 9-chloro-4-[(2-chloro-3-methylpyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (40 mg, 0.09 mmol) in HCOOH (1 mL) was added CHCOONH (67 mg, 0.9 mmol). The mixture was heated to 110° C. and stirred for 12 hours, then concentrated in vacuo, and the residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 70% B, 70% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.88) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-3-methyl-1H-pyridin-2-one (5.8 mg, 15%) as a solid. LC / MS: Mass C 24 H 21 Calculated value for ClFN3O2: 437.1, Found value: 438.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 11.37(s,1H),7.70(d,J=3.3Hz,1H),7.62(d,J=2.7Hz,1H),7.38-7.53(m,2H),7.35(d,J=2.7Hz,1H),7.17(d,J=6.9Hz,1H),7.01-7 .12(m,1H),6.65-6.71(m,1H),6.26(d,J=6.9Hz,1H),4.14-4.22(m,2H),3.90(s,2H),3.55(s,2H),3.05-3.11(m,2H),1.91(s,3H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0453] Example S48. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1,3-dihydropyridine-2,6-dione (Compound 204) and 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-6-methoxy-1H-pyridin-2-one (Compound 196) [ka] To a 10 cc glass sealed tube was added 9-chloro-4-[(2,6-dimethoxypyridin-4-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.21 mmol), HCl (1 mL, 32.9 mmol), and AcOH (0.5 mL). The mixture was heated to 80° C. under microwave irradiation and stirred for 10 minutes, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: XSelect CSH Prep C18 Purification on an OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (0.05% TFA), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 30% B to 53% B, 53% B in 7 min; wavelength: 254 nm; RT1 (min): 5.15) gave 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1,3-dihydropyridine-2,6-dione (2.1 mg, 2%) as a solid and 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-6-methoxy-1H-pyridin-2-one (1.8 mg, 2%) as a solid.

[0454] 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1,3-dihydropyridine-2,6-dione LC / MS: Mass C 23 H 19Calculated value for ClFN3O3: 439.1, Found value: 440.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.79(d,J=2.4Hz,1H),7.50-7.63(m,4H),7.31(d,J=9.3Hz,1H),7.01(t,J=9.1Hz,1H),6.6 8(d,J=3.3Hz,1H),4.69(s,2H),4.47(s,2H),4.39(s,2H),3.75-3.78(m,3H),3.29(m,1H); 19 F NMR (282 MHz, CD3OD) δ -125.6.

[0455] 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-6-methoxy-1H-pyridin-2-one LC / MS: Mass C 24 H 21 Calculated value for ClFN3O3: 453.1, Found value: 454.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.78(d,J=2.4Hz,1H),7.50-7.55(m,3H),7.30(d,J=9.3Hz,1H),7.01(t,J=9.3Hz,1H),6.68(d,J =3.3Hz,1H),6.35(s,2H),4.74-4.75(m,2H),4.57-4.67(m,4H),3.89(s,3H),3.75-3.78(m,2H); 19 F NMR (282 MHz, CD3OD) δ -125.6.

[0456] Example S49. Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2,4-dihydropyrazol-3-one (Compound 198) [ka] Ethyl 4-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]-3-oxobutanoate To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.16 mmol) in THF (1 mL) was added ethyl 4-chloro-3-oxobutanoate (40 mg, 0.24 mmol) and EtN (35 mg, 0.32 mmol). The mixture was heated to 70 °C and stirred for 16 h, then concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc, 1:1) to give ethyl 4-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]-3-oxobutanoate (50 mg, 64%) as an oil.

[0457] 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2,4-dihydropyrazol-3-one To a stirred mixture of ethyl 4-[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]-3-oxobutanoate (50 mg, 0.11 mmol) in THF (1 mL) was added NH2NH2.H2O (12 mg, 0.23 mmol). The mixture was stirred at room temperature for 4 hours, then concentrated under reduced pressure, and the residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 26% B to 56% B, 56% B in 7 min; Wavelength: 254 nm; RT1 (min): 6) to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-2,4-dihydropyrazol-3-one (8.9 mg, 19%) as an oil. LC / MS: Mass C 21 H 18Calculated value for ClFN4O2: 412.1, Found value: 413.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 11.43(br,1H),9.45(br,1H),7.72(d,J=3Hz,1H),7.62(d,J=3Hz,1H),7.51-7.56(m,1H),7.41-7.45(m,1H),7.35(d,J=3Hz) 1H),7.04-7.11(m,1H),6.69(d,J=3.3Hz,1H),5.38(s,1H),4.10-4.19(m,2H),3.92(s,2H),3.58(s,2H),3.01-3.06(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -123.6.

[0458] Example S50. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}piperidin-2-one (Compound 200) [ka] 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}piperidin-2-one (2-Oxopiperidin-4-yl)methyl 4-methylbenzenesulfonate (CAS number: 2629362-45-2) (100 mg, 0.35 mmol) was added to a mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (67 mg, 0.21 mmol) and EtN (48 mg, 0.48 mmol) in DMF (10 mL). The mixture was heated to 80 °C and stirred for 16 h. Then HO (10 mL) was added and the mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD column, 19 × 150 mm, 5 μm; Mobile phase A: water (0.05% FA), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 23% B to 33% B, 33% B in 10 min; Wavelength: 254 nm; RT1 (min): 8.6) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}piperidin-2-one (30.9 mg, 20%) as a solid. LC / MS: Mass C 23 H 23 Calculated value for ClFN3O2: 427.1, Found value: 428.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ 7.72(d,J=4.0Hz,1H),7.54-7.62(m,2H),7.40-7.48(m,3H),7.17(br,1H),7.05(m,1H),6.69(d,J=4.0Hz,1H),4.08 -4.16(m,2H),3.92(s,2H),3.14-3.20(m,5H),2.36-2.61(m,2H),2.08-2.10(m,1H),2.03-2.25(m,1H),1.78(m,2H); 19 F NMR(376MHz,DMSO-d6)δ -123.6.

[0459] Example S51. Preparation of 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyran-2-one (Compound 203) [ka] 9-chloro-7-(5-fluoroindol-1-yl)-4-[(tributylstannyl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.32 mmol) in THF (2 mL) at 0 °C was added NaH, 60% in oil (65 mg, 1.58 mmol). The mixture was stirred for 30 minutes, then warmed to room temperature, and tributyl(iodomethyl)stannane (680 mg, 1.58 mmol) was added. The mixture was stirred at room temperature for 24 hours, then cooled to 0 °C, H2O was added, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with H2O (3 × 10 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE / EtOAc, 5:1) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(tributylstannyl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (150 mg, 63%) as an oil.

[0460] 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyran-2-one To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-4-[(tributylstannyl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.08 mmol) in DMF (1.67 mL, 21.6 mmol) was added 4-chloropyran-2-one (16 mg, 0.12 mmol), [4-(N,N-dimethylamino)phenyl]di-tert-butylphosphine (2 mg, 0.008 mmol), and methanesulfonato([4-(N,N-dimethylamino)phenyl]di-tert-butylphosphino)(2-amino-1,1-biphenyl-2-yl)palladium(II) (5 mg, 0.008 mmol). The mixture was heated to 100 °C under microwave irradiation and stirred for 10 min, then filtered. HO (10 mL) was added to the filtrate, and the mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm; Mobile phase A: water (10 mmol / L NHHCO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 47% B to 67% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.33) to give 4-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyran-2-one (10.8 mg, 31%) as a solid. LC / MS: Mass C 23 H 18 Calculated value for ClFN2O3: 424.1, Found value: 425.0 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.62(d,J=5.4Hz,1H),7.50(d,J=2.4Hz,1H),7.42(d,J=7.8Hz,2H),7.19-7.29(m,2H),6.98(t,J=9.0Hz,1H),6.62(d,J=3.3 Hz,1H),6.48(d,J=5.4Hz,1H),6.33-6.37(m,1H),4.17-4.20(m,2H),3.92(s,2H),3.61(d,J=1.2Hz,2H),3.17-3.20(m,2H);19 F NMR (282 MHz, CD3OD) δ -126.0.

[0461] Example S52. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-[1-(2-methoxypyridin-4-yl)ethyl]-3,5-dihydro-2H-1,4-benzoxazepine (Compound 217) [ka] 9-chloro-7-(5-fluoroindol-1-yl)-4-[1-(2-methoxypyridin-4-yl)ethyl]-3,5-dihydro-2H-1,4-benzoxazepine A mixture of 1-(2-methoxypyridin-4-yl)ethanone (143 mg, 0.95 mmol), 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (200 mg, 0.63 mmol), and titanium(IV) isopropoxide (500 μL) was heated to 45° C. and stirred for 4 hours. The mixture was then cooled, diluted with MeOH (4 mL), and NaBHCN (158 mg, 2.5 mmol) was added. The resulting mixture was heated to 45° C. and stirred for 4 hours, then stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: YMC-Actus Triart C18, 30 × 150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 70% B to 90% B, 90% B in 7 min; wavelength: 254 nm; RT1 (min): 6.4) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[1-(2-methoxypyridin-4-yl)ethyl]-3,5-dihydro-2H-1,4-benzoxazepine (70 mg, 24%) as a solid. LC / MS: Mass C 25 H 23 Calculated value for ClFN3O2: 451.1, Found value: 452.2 [M+H] + ; 1H NMR(400MHz,CD3OD)δ 8.08(d,J=5.2Hz,1H),7.49(d,J=2.7Hz,1H),7.35-7.45(m,2H),7.29(m,1H),6.97-7.03(m,3H),6.81(s,1H),6.63( d,J=3.6Hz,1H),4.26-4.11(m,2H),3.95-4.04(m,1H),3.80-3.87(m,5H),3.15-3.27(m,2H),1.40(d,J=6.8Hz,3H); 19 F NMR (376 MHz, CD3OD) δ -126.2.

[0462] Example S53. Preparation of 4-{[(5S)-9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyridin-2-one (Compounds 236 and 237) [ka] The racemate 4-{[9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyridin-2-one (20 mg, 0.046 mmol) was separated by preparative chiral HPLC (column: (R,R)-WHELK-O1-Kromasil, 2.11 × 25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)-HPLC, mobile phase B: EtOH-HPLC; flow rate: 20 mL / min; gradient: 35% B to 35% B in 21 min; wavelength: 220 / 254 nm; RT1 (min): 16.49; RT2 (min): 18.91; sample solvent: EtOH-HPLC; injection volume: 0.5 mL; number of runs: 4) to give two compounds:

[0463] Example P1 (first eluting isomer): 4-{[(5R)-9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyridin-2-one (5.2 mg, 26%) as a solid. LC / MS: Mass C 24 H 21Calculated value for ClFN3O2: 437.1, Found value: 438.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.36-7.54(m,4H),7.29-7.33(m,1H),7.20(d,J=3.0Hz,1H),6.96-7.03(m,1H),6.64(d,J=6.0Hz,1H),6.47-6 .57(m,2H),4.21-4.29(m,1H),4.01-4.14(m,2H),3.52-3.76(m,3H),2.94-3.01(m,1H),1.61(d,J=6.0Hz,3H); 19 F NMR (282 MHz, CD3OD) δ -126.1.

[0464] Example P2 (second eluting isomer): 4-{[(5S)-9-chloro-7-(5-fluoroindol-1-yl)-5-methyl-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-1H-pyridin-2-one (4.6 mg, 23%) as a solid. LC / MS: Mass C 24 H 21 Calculated value for ClFN3O2: 437.1, Found value: 438.1 [M+H] + ; 1 H NMR(300MHz,CD3OD)δ 7.36-7.51(m,4H),7.26-7.31(m,1H),7.20(d,J=3.0Hz,1H),6.95-7.02(m,1H),6.64(d,J=3.0Hz,1H),6.47-6 .58(m,2H),4.20-4.28(m,1H),4.02-4.15(m,2H),3.53-3.77(m,3H),2.94-3.01(m,1H),1.62(d,J=6.0Hz,3H); 19 F NMR (282 MHz, CD3OD) δ -126.1.

[0465] Example S53. Preparation of 2-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)acetonitrile (Compound 252) [ka] To a mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.23 mmol) in DMF (2 mL) under N atmosphere was added 2-(trimethylsilyl)acetonitrile (38 mg, 0.34 mmol), Xantphos (5 mg, 0.009 mmol), Pd(dba) (4 mg, 0.005 mmol), and ZnF (14 mg, 0.14 mmol). The mixture was heated to 140 °C under microwave irradiation and stirred for 30 min. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: HO (Column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; Mobile phase A: HO (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 60% B to 80% B, 80% B in 8 min; Wavelength: 254 nm; RT1 (min): 7.23) to give 2-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)acetonitrile (3.3 mg, 3%) as a solid. LC / MS: Mass C 24 H 19 Calculated for ClFNO: 447.1, Found: 448.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.77(s,2H),7.71(d,J=3.3Hz,1H),7.64(d,J=2.7Hz,1H),7.54-7.59(m,1H),7.41 -7.45(m,2H),7.03-7.10(m,1H),6.69(d,J=3.3Hz,1H),4.40(s,2H),4.18-4.20(m,2H),3.99(s,2H),3.75(s,2H),3.06-3.09(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0466] Example S54. (5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)(imino)methyl-λ 6 Preparation of -sulfanone (compound 254) [ka] 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(methylsulfanyl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine To a mixture of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.23 mmol) in DMF (3 mL) was added (methylsulfanyl)sodium (32 mg, 0.45 mmol). The mixture was heated to 80 °C and stirred for 12 h, then directly purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in HO (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(methylsulfanyl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (60 mg, 58%) as an oil.

[0467] (5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)(imino)methyl-λ 6 -Sulfanone To a mixture of 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(methylsulfanyl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (60 mg, 0.13 mmol) in MeOH (1.5 mL) was added (NH)CO (25 mg, 0.26 mmol) and PhI(OAc) (149 mg, 0.46 mmol). The mixture was heated to 50 °C and stirred for 3 h, then directly purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: H2O (10 mmol / L NH4HCO3 + 0.1% NH3.H2O), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 65% B, 65% B in 10 min; Wavelength: 254 nm; RT1 (min): 8.25) to give (5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)(imino)methyl-λ 6 -sulfanone (9.1 mg, 14%) was obtained as a solid. LC / MS: Mass C 23 H 21 Calculated value for ClFN5O2S: 485.1, Found value: 486.0 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.95(s,2H),7.72(d,J=3.3Hz,1H),7.65(d,J=2.7Hz,1H),7.42-7.55(m,3H),7.01-7.13(m,1 H),6.69(d,J=3.3Hz,1H),4.59(s,1H),4.19-4.22(m,2H),4.04(s,2H),3.84(s,2H),3.29(d,J =2.7Hz,3H),3.09-3.12(m,2H); 19 F NMR(282MHz,DMSO-d6)δ-123.5.

[0468] Example S55. Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(1H-1,2,3,4-tetrazol-5-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (Compound 255) [ka] To a stirred mixture of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carbonitrile (50 mg, 0.12 mmol) and NaN (22 mg, 0.35 mmol) in HO (2 mL) at room temperature was added ZnCl (47 mg, 0.35 mmol) and 2-(trimethylazaniumyl)acetate (2 mg, 0.012 mmol). The mixture was stirred at room temperature for 3 days, and the precipitated solid was collected by filtration. The filter cake was washed with HO (3 × 2 mL). The crude product (30 mg) was purified by preparative HPLC (Column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; Mobile phase A: HO (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 25% B to 55% B, 55% B in 7 min; Wavelength: 254 nm; RT1 (min): 5.87) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(1H-1,2,3,4-tetrazol-5-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (3.6 mg, 6%) as a solid. LC / MS: Mass C 23 H 18 Calculated value for ClFNO: 476.1, Found: 477.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 8.76(s,2H),7.69(d,J=3.2Hz,1H),7.61(d,J=2.6Hz,1H),7.51(d,J=9.0Hz,1H),7.41(d,J=9.4Hz,2H),7. 08(t,J=9.2Hz,1H),6.68(d,J=3.4Hz,1H),4.19-4.20(m,2H),4.00(s,2H),3.76(s,2H),3.10-3.11(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.5.

[0469] Example S56. Preparation of 9-chloro-4-[(2-chloro-4-methylpyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (Compound 256) [ka] (2-chloro-4-methylpyrimidin-5-yl)methyl methanesulfonate To a stirred mixture of (2-chloro-4-methylpyrimidin-5-yl)methanol (30 mg, 0.19 mmol) in DCM (1 mL) was added MsCl (43 mg, 0.38 mmol) and EtN (38 mg, 0.38 mmol). The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure to give (2-chloro-4-methylpyrimidin-5-yl)methyl methanesulfonate (30 mg, crude) as a solid.

[0470] 9-chloro-4-[(2-chloro-4-methylpyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine To a stirred mixture of (2-chloro-4-methylpyrimidin-5-yl)methyl methanesulfonate (30 mg, crude) and 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (40 mg, 0.13 mmol) in THF (1 mL) was added EtN (26 mg, 0.25 mmol). The mixture was heated to 80 °C and stirred overnight, then purified by silica gel column chromatography (PE / EtOAc, 5:1) to give 9-chloro-4-[(2-chloro-4-methylpyrimidin-5-yl)methyl]-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (30 mg, 19%) as a solid.

[0471] Example S57. Preparation of 2-amino-5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-3H-pyrimidin-4-one (Compound 257) [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (30 mg, 0.1 mmol) and 2-amino-4-oxo-3H-pyrimidine-5-carbaldehyde (20 mg, 0.14 mmol) in MeOH (1 mL) was added NaBHCN (12 mg, 0.190 mmol). The mixture was stirred at room temperature for 12 hours, then concentrated in vacuo, and the crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD column, 19 × 250 mm, 10 μm; Mobile phase A: HO (10 mmol / L NH4HCO3 + 0.1% NH3.HO), Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 45% B to 75% B, 75% B in 9 min; Wavelength: 254 nm; RT1 (min): 8.23) to give 2-amino-5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}-3H-pyrimidin-4-one (1.1 mg, 3%) as a solid. LC / MS: Mass C 22 H 19 Calculated value for ClFN5O2: 439.1, Found value: 424.1 [M+H] + ; 1 H NMR(300MHz,DMSO-d6)δ 10.89(s,1H),7.73(d,J=3.3Hz,1H),7.48-7.67(m,3H),7.38-7.48(m,2H),7.00-7.13(m,1H),6. 68(d,J=3.3Hz,1H),6.47(s,2H),4.12-4.18(m,2H),3.91(s,2H),3.34(s,2H),3.01-3.06(m,2H); 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0472] Example S58. Preparation of tert-butyl N-(tert-butoxycarbonyl)-N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridazin-3-yl)carbamate (Compound 259) [ka] tert-Butyl N-(tert-butoxycarbonyl)-N-(5-chloropyridazin-3-yl)carbamate To a stirred mixture of 5-chloropyridazin-3-amine (500 mg, 3.9 mmol) and BocO (1.26 g, 5.8 mmol) in DCM (10 mL) was added EtN (590 mg, 5.8 mmol) and DMAP (47 mg, 0.39 mmol). The mixture was stirred at 40 °C for 2 h, then HO (50 mL) was added, and the mixture was extracted with DCM (3 × 50 mL). The combined organic layers were washed with HO (10 mL), dried over anhydrous MgSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 20:1) to give tert-butyl N-(tert-butoxycarbonyl)-N-(5-chloropyridazin-3-yl)carbamate (350 mg, 40%) as a solid.

[0473] tert-Butyl N-(tert-butoxycarbonyl)-N-(5-ethenylpyridazin-3-yl)carbamate To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-(5-chloropyridazin-3-yl)carbamate (300 mg, 0.91 mmol) in toluene (3 mL) under an atmosphere of N was added tributyl(vinyl)stannane (763 mg, 1.82 mmol) and Pd(pph3)2Cl2 (64 mg, 0.09 mmol). The mixture was heated to 110 °C and stirred for 2 h, then filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc, 5:1) to give tert-butyl N-(tert-butoxycarbonyl)-N-(5-ethenylpyridazin-3-yl)carbamate (280 mg, 91%) as an oil.

[0474] tert-Butyl N-(tert-butoxycarbonyl)-N-[5-(hydroxymethyl)pyridazin-3-yl]carbamate To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-(5-ethenylpyridazin-3-yl)carbamate (270 mg, 0.84 mmol) in THF (2.5 mL) and HO (2.5 mL) at room temperature, OsO (22 mg, 0.084 mmol) was added, followed by NaIO (361 mg, 1.69 mmol). The mixture was stirred at room temperature for 5 h, cooled to 0 °C, and then NaBH (81 mg, 2.14 mmol) was added. The mixture was warmed to room temperature and stirred for 15 min, then HO (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with HO (10 mL), dried over anhydrous NaSO, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE / EtOAc, 5:1) to give tert-butyl N-(tert-butoxycarbonyl)-N-[5-(hydroxymethyl)pyridazin-3-yl]carbamate (160 mg, 53%) as an oil.

[0475] tert-Butyl N-(tert-butoxycarbonyl)-N-[5-(chloromethyl)pyridazin-3-yl]carbamate To a stirred mixture of tert-butyl N-(tert-butoxycarbonyl)-N-[5-(hydroxymethyl)pyridazin-3-yl]carbamate (100 mg, 0.31 mmol) in DCM (2 mL) at 0° C. was added SOCl (44 mg, 0.37 mmol). The mixture was warmed to room temperature and stirred for 1 h, then concentrated in vacuo to give tert-butyl N-(tert-butoxycarbonyl)-N-[5-(chloromethyl)pyridazin-3-yl]carbamate (100 mg, 85%) as an oil, which was used in the next step without further purification.

[0476] tert-Butyl N-(tert-butoxycarbonyl)-N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridazin-3-yl)carbamate To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (70 mg, 0.22 mmol) in THF (1 mL) was added tert-butyl N-(tert-butoxycarbonyl)-N-[5-(chloromethyl)pyridazin-3-yl]carbamate (76 mg, 0.22 mmol), EtN (45 mg, 0.44 mmol) and NaI (66 mg, 0.44 mmol). The mixture was heated to 70° C. and stirred for 2 h, then concentrated in vacuo, and the residue was purified by reverse-phase column chromatography (column, C18 silica gel; mobile phase, MeCN in HO (0.05% NH4HCO3), 20% to 100% gradient in 10 min; detector, UV 254 nm) to give tert-butyl N-(tert-butoxycarbonyl)-N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridazin-3-yl)carbamate (75 mg, 52%) as a solid.

[0477] Biological Examples Example B1: EP2 Potency Assay Compounds of the present disclosure exhibit a half maximal inhibitory concentration (IC) of less than 25 μM. 50 Compound potency was measured using a cAMP TR-FRET assay.

[0478] CHO-K1 cells (ATCC) were cultured at 9.75 × 10 5 The cells were seeded into 6-cm plates at a density of 1000 cells / well. The next day, the cell medium was changed to Opti-Mem I low serum medium (Gibco) and transfected with the plasmid for expression of the EP2 receptor (target receptor) using FuGENE 6 transfection reagent (Promega). After 6 hours of incubation, the cell medium was changed to F12 medium supplemented with 10% FBS and 100 U / ml Pen-Strep. 24 hours after transfection, the cells were harvested and seeded into 384-well plates at a density of 3000 cells / well. A cAMP assay was performed using the LANCE Ultra cAMP Assay Kit (PerkinElmer).

[0479] For each test compound of interest, 10 nL / well of serially diluted test compound was added to each well, resulting in 10 serially diluted compound concentrations ranging from 10,000 nM to 0.038 nM, with each concentration run in duplicate. The plate was then centrifuged at 1,000 rpm for 1 minute, agitated at 600 rpm for 2 minutes at room temperature, and incubated at 25°C for 5 minutes. The reference agonist, prostaglandin E2 (MCE), was added to each well at the appropriate concentration to reach its EC80 value. The plate was then centrifuged at 1,000 rpm for 1 minute, agitated at 600 rpm for 2 minutes at room temperature, and incubated at 25°C for 30 minutes.

[0480] To measure cAMP levels, 5 μl / well of Eu-cAMP working solution and 5 μl / well of Ulight-anti-cAMP working solution were added to each well, and the plate was centrifuged at 1000 rpm for 1 minute, agitated at 600 rpm for 2 minutes at room temperature, and agitated at 25°C for 15 minutes. The level of TR-FRET fluorescence was measured in each well using an EnVision microplate reader (excitation wavelength = 337 nm and emission wavelengths = 615 and 665 nm). Dose-response curves were generated by plotting the percent inhibition of each compound concentration, and IC50s were then calculated by fitting a curve to the plotted values ​​and extrapolating the IC50 concentration.

[0481] The potencies of the compounds disclosed herein are shown in Table B1. Potency data are presented as AA (IC 50 <100 nM); A(IC 50 = 100-500 nM); B(IC 50 = 500 nM to 1 μM); C(IC 50 = 1 μM to 5 μM); and D (IC 50 >5μM).

[0482] [Table 96]

[0483] [Table 97]

[0484] [Table 98]

[0485] Example B2: Human Liver Microsome Stability The compounds to be tested were incubated in duplicate with human liver microsomes (0.5 mg / mL) at 37°C. These incubations were carried out at a final test substance concentration of 2 μM for a total incubation period of 60 minutes. Samples were taken at 0, 15, 30, 45, and 60 minutes, and the reaction was stopped by the addition of 4 volumes of acetonitrile containing internal standards (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM ketoprofen). Diclofenac was used as a positive control in this study. Samples were analyzed by UPLC-MS / MS to determine the concentration of the test compound and to measure percent remaining, intrinsic clearance (in vitro CL). int ) and half-life (T 1 / 2 ) values ​​were calculated.

[0486] Chromatographic analysis was performed on a Shimadzu UPLC system (Kyoto, Japan) consisting of a gradient pump (LC-30AD model), an automatic injector (HTC PAL System model), and an online degasser (DGU-20A5R model). Detection was performed on a triple quadrupole tandem mass spectrometer (API 4000 / Triple Quad 4500 / Triple Quad 5500 / Triple Quad 6500) equipped with a turbo ion spray interface. Data acquisition and integration were performed using LC-MS software (Analyst 1.6) directly coupled to the LC-MS / MS system. Chromatographic separation was achieved on an XSelect Hss T3 2.5μ (2.1 × 30 mm) column. The mobile phases were 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). The flow rate was 1.0 mL / min, and the column was maintained at 40 °C.

[0487] The stability data for the compounds disclosed herein are shown in Table B2. 1 / 2 ) The data is measured in minutes and in Table B2 the data is classified into categories according to the following rules: T 1 / 2( Microsomes): A=100+; B=50-100; C=20-50; D<20.

[0488] In vitro clearance (CL int ) Data is measured in μL / min / mg protein and in Table B2 the data is categorized according to the following rules: CL int (Microsomes): A<20; B=20-50; C=50-100; and D=100+.

[0489] [Table 99]

[0490] The reference compound (“Ref”) in Tables B2 and B3 is 4-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyridin-2(1H)-one, which has the following structure: [ka] .

[0491] Example B3: Human hepatocyte stability The compounds to be tested were cultured in human hepatocytes (0.5 × 10 6 The cells were incubated in duplicate with incubation medium (Williams Medium E with 1x GlutaMAX) containing 1000 cells / mL of ATP. These incubations were performed at a final test concentration of 1 μM for a total incubation period of 120 min. Samples were taken at 0, 15, 30, 60, 90, and 120 min, and the reaction was stopped by the addition of acetonitrile containing internal standards (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine, and 200 nM diclofenac). Verapamil was used as a positive control in this study. Samples were analyzed by UPLC-MS / MS to determine the concentration of the tested compound and to analyze the percentage remaining, intrinsic clearance (in vitro CL), and quantification of the intrinsic clearance (in vitro CL). int ) and half-life (t1 / 2) values ​​were calculated.

[0492] Chromatographic analysis was performed on a Shimadzu UPLC system (Kyoto, Japan) consisting of a gradient pump (LC-30AD model), an automatic injector (HTC PAL System model), and an online degasser (DGU-20A5R model). Detection was performed on a triple quadrupole tandem mass spectrometer (API 4000 / Triple Quad 4500 / Triple Quad 5500 / Triple Quad 6500) equipped with a turbo ion spray interface. Data acquisition and integration were performed using LC-MS software (Analyst 1.6) directly coupled to the LC-MS / MS system. Chromatographic separation was achieved on an XSelect Hss T3 2.5μ (2.1 × 30 mm) column. The mobile phases were 0.1% formic acid in water (A) and 0.1% formic acid in acetonitrile (B). The flow rate was 1.0 mL / min, and the column was maintained at 40 °C.

[0493] The stability data for the compounds disclosed herein are shown in Table B3. 1 / 2 ) The data is measured in minutes and in Table B2 the data is classified into categories according to the following rules: T 1 / 2 (Liver): A = 200+; B = 100-200; C = 50-100; and D < 50.

[0494] In vitro clearance (CL int ) Data are measured in μL / min / mg protein and in Table B3 the data are categorized according to the following rules: CL int (Microsomes): A<5; B=5-10; C=10-20; and D=20+.

[0495] [Table 100]

[0496] Composition Examples Example C-1: Parenteral Pharmaceutical Composition To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, etc.), 100 mg of a water-soluble salt of the compound of formula (I) or formula (X) or a pharmaceutically acceptable salt or solvate thereof is dissolved in sterile water and then mixed with 10 mL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection.

[0497] Example C-2: Oral Pharmaceutical Composition To prepare a pharmaceutical composition for oral delivery, 100 mg of a compound of formula (I) or formula (X) or a pharmaceutically acceptable salt or solvate thereof is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration.

[0498] Example C-3: Gel pharmaceutical composition for external use To prepare a topical gel composition, 100 mg of the compound of formula (I) or formula (X) or a pharmaceutically acceptable salt or solvate thereof is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol USP. The resulting gel mixture is then placed in a container, such as a tube, suitable for topical administration.

[0499] Example C-4: Ophthalmic solution To prepare a pharmaceutical opthalmic solution composition, 100 mg of the compound of formula (I) or formula (X) or its pharmaceutically acceptable salt or solvate is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter.The resulting isotonic solution is then incorporated into an ophthalmic delivery unit, such as an eye dropper, suitable for ocular administration.

[0500] The examples and embodiments described herein are for illustrative purposes only, and various modifications or alterations that occur to those skilled in the art are intended to be included within the spirit and scope of this application and the appended claims.

Claims

1. A compound having the structure of formula (II): 【Chemical 1】 or a pharmaceutically acceptable salt thereof (wherein, R １ and R ２ are each independently hydrogen, deuterium, halogen, or C １～４ alkyl; A １ is -O-, -CR ５ R ６ -, -S-, -S(=O) ２ -, or does not exist; A ２ is -CR ７ R ８ - or -S(=O) ２ - and; A ３ is -CR ９ R １０ - or does not exist; R ３ and R ４ each independently is hydrogen, deuterium, halogen, or C １～４ alkyl; R ５ and R ６ each independently is hydrogen, deuterium, halogen, or C １～４ alkyl; or R ５ and R ６ together with the carbon atom to which they are attached form an oxetane; R ７ and R ８ are each independently hydrogen, deuterium, halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -NH ２ , -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , -(C １～４ alkyl)O(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , substituted or unsubstituted C ３～６ cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocycloalkyl; or R ７ and R ８ together with the carbon atom to which they are attached form cyclopropane or oxetane; R ９ and R １０ are each independently hydrogen, deuterium, halogen, or C １～４ alkyl; or R ９ and R １０ together with the carbon atom to which they are attached form an oxetane; R Ａ１ is a halogen, C １～４ alkyl, or cyclopropyl; and R Ａ２ is hydrogen, deuterium, a halogen, or methyl optionally deuterated or halogenated; Ring B is C ３～６ a cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; or Ring B is Ring B'; Each R Ｂ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -C １～４ aminoalkyl, -C １～４ hydroxyalkyl, -C １～４ methoxyalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -NH(C ３～６ cycloalkyl), -NH(C ３～６ heterocycloalkyl), -N(C １～４ alkyl) ２ , -NHC(O)C １～４ alkyl, -NHC(O)O(C １～４ alkyl), -NHSO ２ C １～４ alkyl, -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -SH, -S(C １～４ alkyl), -S(O)(C １～４ alkyl), -S(O)(NH)(C １～４ alkyl), -S(O) ２ (C １～４ alkyl), -S(O) ２ NH ２ , -S(O ２ )NHCH ３ , or a substituted or unsubstituted C ３～６ cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl; ring C is a bicyclic heterocycle having one or more nitrogen atoms; or ring C is ring C'; Each R Ｃ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -S(C １～４ alkyl), -SO ２ C １～４ alkyl, -SO ２ NHC １～４ alkyl, substituted or unsubstituted C ３～６ cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl; m is 0 to 3; n is 0 to 3; and ring B' is [Chemical Formula 2] selected from the group consisting of; and ring C' is [Chemical Formula 3] selected from the group consisting of).

2. A １ is -O-, -S-, or -S(=O) ２ -; A ２ is -CR ７ R ８ -; and A ３ is -CR ９ R １０ -; or or A １ is -O-; A ２ is, -CR ７ R ８ - or -S(=O) ２ -; and A ３ is -CR ９ R １０ - or or A １ is absent; A ２ is -CR ７ R ８ -; and A ３ is -CR ９ R １０ -; or or A １ is -O-, -CR ５ R ６ -, or does not exist; A ２ is -CR ７ R ８ -; and A ３ does not exist, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. A １ is -O- or -S(=O) ２ -; and A ２ is -CR ７ R ８ -; and A ３ is -CR ９ R １０ -; or or A １ is -O-; A ２ is, -CR ７ R ８ - or -S(=O) ２ -; and A ３ is -CR ９ R １０ - or or A １ is absent; A ２ is -CR ７ R ８ -; and A ３ is -CR ９ R １０ -; or or A １ is -O-, -CR ５ R ６ -, or does not exist; A ２ is -CR ７ R ８ -; and A ３ does not exist, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. R Ａ１ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is halogen.

5. R Ａ１ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is -Cl.

6. 【Fig. 4】 is 【Chemical Formula 5】 selected from the group consisting of, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. Structure: 【Chemical Formula 6】 having, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. The structure of formula III: 【Chemical 7】 having, the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt thereof (wherein, Ring B is C ３～６ a cycloalkyl, phenyl, 5-membered heteroaryl, or 6-membered heteroaryl containing two or more nitrogen atoms; Each R Ｂ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -C １～４ aminoalkyl, -C １～４ hydroxyalkyl, -C １～４ methoxyalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -NH(C ３～６ cycloalkyl), -NH(C ３～６ heterocycloalkyl), -N(C １～４ alkyl) ２ , -NHC(O)C １～４ alkyl, -NHC(O)O(C １～４ alkyl), -NHSO ２ C １～４ alkyl, -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -SH, -S(C １～４ alkyl), -SO(C １～４ alkyl), -S(O)(NH)(C １～４ alkyl), -S(O) ２ (C １～４ alkyl), -S(O) ２ NH ２ , -S(O ２ )NHCH ３ , substituted or unsubstituted C ３～６ cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl; ring C is a bicyclic heterocycle having one or more nitrogen atoms; or ring C is ring C'; Each R Ｃ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -S(C １～４ alkyl), -SO ２ C １～４ alkyl, -SO ２ NHC １～４ alkyl, substituted or unsubstituted C ３～６ cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl; m is 0 to 3; n is 0 to 3; and ring C' is 【Chemical 8】 selected from the group consisting of).

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein ring C is a bicyclic heteroaryl having 1, 2 or 3 nitrogen atoms.

10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein ring C is a bicyclic heteroaryl consisting of a pyrrole ring or a pyrazole ring condensed with a phenyl ring, a pyridine ring, or a pyrimidine ring.

11. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein ring C is a substituted or unsubstituted indole, a substituted or unsubstituted indazole, a substituted or unsubstituted azaindole, a substituted or unsubstituted indolizine, a substituted or unsubstituted pyrrolopyridine, a substituted or unsubstituted imidazopyridine, a substituted or unsubstituted pyrazolopyridine, a substituted or unsubstituted pyrrolopyrimidine, a substituted or unsubstituted imidazopyrimidine, or a substituted or unsubstituted pyrazolopyrimidine.

12. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein ring C is a substituted or unsubstituted indole or a substituted or unsubstituted azaindole.

13. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein ring C is a substituted or unsubstituted indole.

14. ring C is 【Chemical Formula 9】 selected from the group consisting of, a bicyclic heterocycle having one or more nitrogens, the compound according to claim 9.

15. ring C is ring C', and ring C' is 【Chemical Formula 10】 selected from the group consisting of, the compound according to claim 1.

16. R Ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is halogen and m is 0, 1 or 2.

17. Ring C is indole; R Ｃ is halogen and m is 1, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

18. The structure of formula (III’): 【Chemical 11】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof having (wherein, Ring B is C ３～６ a cycloalkyl, phenyl, or a 5- or 6-membered heteroaryl containing two or more nitrogen atoms; Each R Ｂ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -C １～４ aminoalkyl, -C １～４ hydroxyalkyl, -C １～４ methoxyalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -NH(C ３～６ cycloalkyl), -NH(C ３～６ heterocycloalkyl), -N(C １～４ alkyl) ２ , -NHC(O)C １～４ alkyl, -NHC(O)O(C １～４ alkyl), -NHSO ２ C １～４ alkyl, -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -SH, -S(C １～４ alkyl), -SO(C １～４ alkyl), -S(O)(NH)(C １～４ alkyl), -S(O) ２ (C １～４ alkyl), -S(O) ２ NH ２ , -S(O ２ )NHCH ３ , or a substituted or unsubstituted C ３～６ cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl; and n is from 0 to 3).

19. Ring B is C ３～６ a cycloalkyl, phenyl, or 5- or 6-membered heteroaryl containing two or more nitrogen atoms; and Each R Ｂ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -C １～４ aminoalkyl, -C １～４ hydroxyalkyl, -C(O)(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -NH(C ３～６ heterocycloalkyl), -N(C １～４ alkyl) ２ , -NHC(O)C １～４ alkyl, -NHC(O)O(C １～４ alkyl), -NHSO ２ C １～４ alkyl, -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -SO(NH)(C １～４ alkyl), -SO ２ (C １～４ alkyl), and a substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

20. Ring B is C ３～６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring B is cycloalkyl or phenyl.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is cyclohexyl or phenyl and n is 0, 1, or 2.

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is cyclohexyl and n is 1 or 2.

23. Each R Ｂ is, independently, halogen, C １～４ alkyl, C １～４ haloalkyl, -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), or -C(O)N(C １～４ alkyl) ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl and n is 0 or 1.

25. Each R Ｂ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -OH, -O(C １～４ alkyl), and -O(C １～４ haloalkyl), the compound according to claim 24 or a pharmaceutically acceptable salt thereof.

26. Each R Ｂ is independently selected from the group consisting of -F, -Cl, -CN, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , -OH, and -OCH ３ The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is independently selected from the group consisting of.

27. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is a 5-membered heteroaryl.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein ring B is imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, oxadiazolyl, thiadiazolyl, or furazanyl.

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein ring B is a 6-membered heteroaryl containing two or more nitrogen atoms.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein ring B is pyrimidinyl, pyridazinyl, pyrazinyl, or triazinyl, or a tautomer thereof.

31. The compound according to claim 30 or a pharmaceutically acceptable salt thereof, wherein ring B is pyrimidinyl or pyrimidinonyl.

32. Each R Ｂ is independently selected from the group consisting of -F, -Cl, -CN, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , CH ２ NH ２ , -CH ２ NHBoc, -CH ２ OH, -CH ２ OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -NH ２ , -NHCH ３ , -N(CH ３ ) ２ , -NH(oxetanyl), -NH C(O)CH ３ , -NH S(O) ２ CH ３ , -OH, -OCH ３ , -OCH ２ CF ３ , -S(O)(NH)CH ３ , a methylpyrazolyl, pyrazolyl, and oxo, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

33. Structure: 【Chemical Formula 12】 【Chemical 13】 【Chemical Formula 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical 18】 【Chemical Formula 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof having.

34. The structure of formula (IIIb’): 【Chemical 24】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof or a tautomer thereof having (wherein, Each R Ｂ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -C １～４ aminoalkyl, -C １～４ hydroxyalkyl, -C １～４ methoxyalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -NH(C ３～６ cycloalkyl), -NH(C ３～６ heterocycloalkyl), -N(C １～４ alkyl) ２ , -NHC(O)C １～４ alkyl, -NHC(O)O(C １～４ alkyl), -NHSO ２ C １～４ alkyl, -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -SH, -S(C １～４ alkyl), -SO(C １～４ alkyl), -S(O) ２ (C １～４ alkyl), -S(O) ２ NH ２ , -S(O ２ )NHCH ３ , a substituted or unsubstituted C ３～６ cycloalkyl, or a substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl; and Each R Ｃ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -S(C １～４ alkyl), -SO ２ C １～４ alkyl, -SO ２ NHC １～４ alkyl, substituted or unsubstituted C ３～６ cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl).

35. Each R Ｂ is independently selected from the group consisting of -F, -Cl, -CN, -CH ３ , -CH ２ F, -CHF ２ , -CF ３ , CH ２ NH ２ , -CH ２ NHBoc, -CH ２ OH, -CH ２ OCH ３ , -C(O)NH ２ , -C(O)NHCH ３ , -C(O)N(CH ３ ) ２ , -C(O)OH, -C(O)OCH ３ , -NH ２ , NHCH ３ , -N(CH ３ ) ２ , -NH(oxetanyl), -NH C(O)CH ３ , -NH S(O ２ )(CH ３ , -OH, -OCH ３ , -OCH ２ CF ３ , -S(O)(NH)CH ３ The compound according to claim 34, independently selected from the group consisting of methylpyrazolyl, pyrazolyl, and oxo.

36. Each R Ｃ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -NH ２ , -NH(C １～４ alkyl), -N(C １～４ alkyl) ２ , -OH, -O(C １～４ alkyl), or C ３～６ cycloalkyl; or two Rs Ｂ together form a carbonyl, the compound according to claim 34.

37. Each R Ｃ is independently selected from the group consisting of -F, -Cl, -Br, -CH ３ , -CF ３ , -OCH ３ , -SCH ３ , or -N(CH ３ ) ２ The compound according to claim 34, wherein each R is independently selected from the group consisting of -F, -Cl, -Br, -CH

38. Structure: 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 The compound according to claim 34 or a pharmaceutically acceptable salt thereof having.

39. Ring B is ring B’; and B’ is 【Chemical 29】 selected from the group consisting of, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

40. The compound according to claim 39 or a pharmaceutically acceptable salt thereof, wherein ring C is a bicyclic heteroaryl consisting of a pyrrole ring or a pyrazole ring condensed with a phenyl ring, a pyridine ring, or a pyrimidine ring.

41. The compound according to claim 40 or a pharmaceutically acceptable salt thereof, wherein ring C is a substituted or unsubstituted indole or a substituted or unsubstituted azaindole.

42. The compound according to claim 41 or a pharmaceutically acceptable salt thereof, wherein ring C is a substituted or unsubstituted indole.

43. The structure of formula (VII): 【Chemical 30】 (wherein R １ and R ２ are each independently hydrogen or deuterium), the compound according to claim 42 or a pharmaceutically acceptable salt thereof.

44. Structure: 【Chemical 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 The compound according to claim 43 or a pharmaceutically acceptable salt thereof having the same.

45. The structure of formula (VIII): 【Chemical 35】 A compound having the same or a pharmaceutically acceptable salt thereof (wherein, R １ and R ２ are each independently hydrogen or deuterium; Ring A' is 【Chemical 36】 【Chemical 37】 selected from the group consisting of; Ring B is a substituted or unsubstituted complex ring; where, when ring B is substituted, it is substituted by one or more R Ｂ groups and Each R Ｂ is independently selected from the group consisting of halogen, -CN, -C １～４ alkyl, -C １～４ haloalkyl, -C １～４ aminoalkyl, -C １～４ hydroxyalkyl, -C １～４ methoxyalkyl, -(C １～４ alkyl)O(C １～４ alkyl), -C(O)(C １～４ alkyl), -C(O)OH, -C(O)O(C １～４ alkyl), -C(O)NH ２ , -C(O)NH(C １～４ alkyl), -C(O)N(C １～４ alkyl) ２ , -NH ２ , -NH(C １～４ alkyl), -NH(C ３～６ cycloalkyl), -NH(C ３～６ heterocycloalkyl), -N(C １～４ alkyl) ２ , -NHC(O)C １～４ alkyl, -NHC(O)O(C １～４ alkyl), -NHSO ２ C １～４ alkyl, -OH, -O(C １～４ alkyl), -O(C １～４ haloalkyl), -SH, -S(C １～４ alkyl), -SO(C １～４ alkyl), -S(O) ２ (C １～４ alkyl), -S(O) ２ NH ２ , -S(O ２ )NHCH ３ , or a substituted or unsubstituted C ３～６ cycloalkyl, and a substituted or unsubstituted 3- to 6-membered heterocyclyl; or two Rs Ｂ together form a carbonyl).

46. The compound according to claim 45 or a pharmaceutically acceptable salt thereof, wherein ring B is a substituted or unsubstituted pyridine or a substituted or unsubstituted pyridone.

47. Ring B is 【Chemical Formula 38】 selected from the group consisting of, the compound according to claim 45 or a pharmaceutically acceptable salt thereof.

48. Structure: 【Chemical Formula 39】 【Chemical Formula 40】 The compound according to claim 45 or a pharmaceutically acceptable salt thereof having the same.

49. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient.

50. The pharmaceutical composition according to claim 49, formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, or intranasal administration.

51. The pharmaceutical composition according to claim 49, which is in the form of tablets, pills, capsules, solutions, suspensions, dispersions, liquids, or emulsions.

52. A method of regulating the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, the method comprising administering to the mammal the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, and a composition for use in such method.

53. A composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of a disease or condition that would benefit from the regulation of prostaglandin E2 receptor 2 (EP2) activity.

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