EP2 antagonist compounds

Abstract

Disclosed herein are compounds that are EP2 antagonists, 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. In some embodiments, the compounds described herein are used to treat or prevent diseases or conditions in which EP2 activity contributes to the manifestation or progression of the disease or condition, such as, for example, inflammatory diseases or conditions. The disclosed EP2 antagonist compounds have useful pharmaceutical properties.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the earlier filing dates of U.S. Provisional Patent Applications Nos. 63 / 435,730 and 63 / 435,738, filed December 28, 2022, both of which are incorporated herein by reference in their entireties.

[0002] 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 disorders associated with EP2 activity. [Background technology]

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

[0004] The compounds described herein are antagonists of EP2. In some embodiments, the compounds described herein are used to treat or prevent diseases or conditions in which EP2 activity contributes to the onset or progression of the disease or condition, such as inflammatory diseases or conditions. The disclosed EP2 antagonist compounds have useful pharmaceutical properties. In particular, those skilled in the art will recognize, in light of the present disclosure, that the EP2 antagonist compounds disclosed herein are useful for ameliorating the pathological consequences of EP2 activation in inflammation and many other disorders. Such pathological consequences include, but are not limited to, immune cell activation, cell growth and proliferation, cell metabolism, cell signaling, cellular oxidative status and cellular stress response, cellular senescence, cell trafficking, atherosclerosis, vascular health and blood-brain barrier integrity, neuronal function, glial function, and neurodegeneration.

[0005] In another aspect, described herein is a pharmaceutical composition comprising a compound described 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 nasal administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, pill, capsule, liquid, suspension, dispersion, solution, or emulsion.

[0006] 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.

[0007] In yet another aspect, described herein are methods for treating a disease or disorder 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.

[0008] The above and other objects, features, and advantages of the present invention will become more apparent from the following detailed description of the preferred embodiments of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0009] Prostaglandins act on prostaglandin receptors such as 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.

[0010] Prostaglandin E2 (PGE2) is a metabolite of arachidonic acid synthesized by the action of cyclooxygenase and prostaglandin E synthase. Produced in almost all organs and tissues, PGE2 has various physiological functions, including mucosal protection, induction of gastric acid secretion, fever, hyperalgesia, inflammation, and immunity. The actions of PGE2 are mediated by four receptors: EP1, EP2, EP3, and EP4. PGE2 not only has affinity for all four EP receptor subtypes, but also for other prostanoid receptors, such as the PGD2 DP1 receptor.

[0011] PGE2 is a downstream product of the cyclooxygenase-2 (COX-2) pathway and a key regulator of inflammation.

[0012] At the cellular level, EP2 is activated and / or upregulated in response to various types of injury, stressors, and other disease signals, and its activation causes damage or pathology that contributes to disease symptoms (Sluter, MNet et al. EP2 Antagonists (2011-2021): A Decade's Journey from Discovery to Therapeutics. J. Med. Chem. 64, 11816-11836 (2021)).

[0013] EP2 binds to PGE2 and s EP2 is a G protein-coupled receptor that recruits proteins and initiates a signaling cascade involving adenylate cyclase (which elevates cAMP) and protein kinase A (PKA). s Upon binding to proteins, it stimulates adenylate cyclase, and their activation increases intracellular cAMP levels. This signaling pathway influences inflammation, pain, immunoregulation, mitogenesis, plasticity, and cell damage. EP2 also interacts with the β-arrestin / JNK pathway, which may influence proliferation and metastasis.

[0014] Expression of EP2 receptors has been demonstrated in a wide range of cell types and tissues, including the brain, lung, gastrointestinal tract, kidney, uterus, bone marrow, and thymus, and is associated with PGE2-mediated vasodilation and smooth muscle relaxation in the lung, gastrointestinal tract, and reproductive tract.

[0015] One of the effects of EP2 activation is the induction of inflammation, which can damage or impair the function of affected cells, tissues, and organ systems. For example, EP2 signaling has been shown to activate immune cells in aging humans and mice (Minhas, P. et al. Restoring metabolism of myeloid cells reverses cognitive decline in aging. Nature (2021) doi:10.1038 / s41586-020-03160-0), thereby contributing to the impairment of various biological functions in the aging brain, including metabolic dysfunction and inflammation, which are associated with cognitive decline. Therefore, treating EP2-mediated inflammation with these compounds is effective in treating age-related dementias such as Alzheimer's disease. Similarly, antagonizing EP2 activity as described herein reduces inflammation and modulates symptom progression. For example, antagonizing EP2 has been shown to reduce poor prognosis in mice treated with lipopolysaccharide, a rodent model of human sepsis caused by pathogen infection (Jiang, C., Caskurlu, A., Ganesh, T. & Dingledine, R. Inhibition of the prostaglandin EP2 receptor prevents long-term cognitive impairment in a model of systemic inflammation. Brain Behav. Immun. - Health 8, 100132 (2020)). Thus, the compounds disclosed in the present invention may provide therapeutic benefit in a variety of infectious or inflammatory diseases by antagonizing EP2 and modulating or attenuating the inflammatory immune response, or "cytokine storm," that is activated in response to infection with pathogens such as bacteria, viruses, or parasites (Sheppe, A.E.F. & Edelmann, M.J. Roles of Eicosanoids in Regulating Inflammation and Neutrophil Migration as an Innate Host Response to Bacterial Infections. Infect.Immun. 89, e0009521 (2021)). Because inflammation is a fundamental process in many types of chronic and acute diseases and disorders, there are many other examples in which modulation of EP2 activity as described herein has therapeutic effects, such as inflammation in cancer (Wang, D. & Dubois, RNEicosanoids and cancer. Nat. Rev. Cancer 10, 181-193 (2010)), inflammation after acute trauma and vascular injury, such as head trauma, stroke, and aneurysm (Liu, Q. et al. PGE2 signaling via the neuronal EP2 receptor increases injury in a model of cerebral ischemia. Proc. Natl. Acad. Sci. USA 116, 10019-10024 (2019); Aoki, T. et al. Prostaglandin E2-EP2-NF-κB signaling in macrophages as a potential therapeutic target for intracranial aneurysms. Sci. Signal. 10, eaah6037 (2017); Aoki, T. et al. PGE(2)-EP(2) signaling in endothelium is activated by hemodynamic stress and induces cerebral aneurysms through an amplifying loop via NF-κB. Br. J. Pharmacol. 163, 1237-1249 (2011); Li, P. et al. AH6809 decreases production of inflammatory mediators by the PGE2 - EP2 - cAMP signaling pathway in an experimentally induced pure cerebral concussion in rats. Brain Res. 1698, 11-28 (2018)), and inflammation in chronic inflammatory conditions such as endometriosis, multiple sclerosis, and amyotrophic lateral sclerosis (Noble, L. et al.Prostaglandin E2 stimulates aromatase expression in endometriosis-derived stromal cells.J.Clin.Endocrinol.Metab.82,600-606(1997);Kawahara, K., Hohjoh, H., Inazumi, T., Tsuchiya, S. & Sugimoto, Y. Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors.Biochim.Biophys.Acta 1851,414-421(2015);Liang,X.et al.The prostaglandin E2 EP2 receptor accelerates disease progression and inflammation in a model of amyotrophic lateral sclerosis.Ann.Neurol.64,304-314(2008)). .

[0016] The compounds disclosed herein have been found to have useful pharmaceutical properties. In particular, those skilled in the art will recognize, in light of this disclosure, that the EP2 modulators disclosed herein are useful for ameliorating the pathological consequences of EP2 activation in not only inflammation but also many other disorders, because EP2 regulates many other aspects of cell biology that affect disease outcome, including, but not limited to, immune cell activation, cell growth and proliferation, cell metabolism, cell signaling, cellular oxidative status and cell stress response, cell aging, cell trafficking, atherosclerosis, vascular health and blood-brain barrier integrity, neuronal function, glial function, and neurodegeneration (Sluter, M. et al. EP2 Antagonists (2011-2021): A Decade's Journey from Discovery to Therapeutics. J. Med. Chem. 64, 11816-11836 (2021)).

[0017] Thus, administration of the small molecule antagonists of EP2 disclosed in this invention has therapeutic efficacy in a wide range of diseases by affecting or ameliorating the underlying biological processes that cause the disease pathology and symptoms.

[0018] In some embodiments, the compounds described herein modulate the activity of EP2. In some embodiments, the compounds described herein inhibit or reduce the extent of inflammatory PGE2 signaling via the EP2 receptor. In particular, the compounds disclosed herein exhibit activity as prostaglandin E2 (PGE2) receptor 2 (EP2) antagonists and are useful in therapies where EP2 receptor antagonism is indicated. 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).

[0019] Abnormal EP2 expression has been observed in various types of cancer, such as colon cancer, prostate cancer, liver cancer, and breast cancer. EP2 activity (e.g., overactivity) has also been associated with cancer risk factors, such as chronic inflammation, immunomodulation, angiogenesis, metastasis, and multidrug resistance. In some embodiments, methods for 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).

[0020] More generally, the compounds of the present invention may be used to treat solid tumors, brain cancer, kidney cancer, liver cancer, adrenal gland cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, in particular colon cancer or colorectal adenoma, neck and head tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 induced diseases, ABC diffuse large intestine cancer, leukemia ... The compositions are useful for the treatment of proliferative disorders including DLBCL, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, smoldering or asymptomatic multiple myeloma, or hematopoietic malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma).

[0021] In some embodiments, the compounds described herein alleviate one or more symptoms of EP2-mediated cancer. In some embodiments, the compounds described herein alleviate 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.

[0022] In some embodiments, EP2 signaling (i.e., through activation by PGE2) contributes to inflammation by enhancing edema and leukocyte infiltration due to increased vascular permeability, thereby increasing blood or fluid flow to inflamed areas of the body. In some embodiments, modulation of EP2 function affects B lymphocyte, T lymphocyte, cytotoxic T cell function, or a combination thereof.

[0023] Activation of EP2 promotes cancer cell dissemination after needle biopsy (Kameyama et al. Cell Reports Medicine, 4, 12, 101330). Therefore, the compounds of the present invention are useful for antagonizing EP2 to suppress cancer cell dissemination after needle biopsy, tumor resection, or other tissue damage.

[0024] In certain embodiments, the compounds of the present invention are useful for the treatment of endometriosis, uterine fibroids (leiomyomas), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dysfecation, and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, breast cancer, colon cancer, familial adenomatous polyposis, colorectal adenoma, endometrial cancer, prostate cancer, lung cancer, testicular cancer, gastric cancer, macular degeneration, inflammatory and neuropathic pain, cancer pain, polycystic kidney disease, and polycystic ovary syndrome.

[0025] Particular diseases or disorders that can be treated with the compounds of the present invention include, but are not limited to, endometriosis, uterine fibroids (leiomyomas), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dysentery, and chronic pelvic pain), chronic pelvic pain syndrome, polycystic kidney disease, and polycystic ovary syndrome.

[0026] In one embodiment, the compounds of the invention are useful for treating fibrotic diseases including, but not limited to, idiopathic pulmonary fibrosis, systemic sclerosis, low-grade scarring, wound healing, uterine fibroids (leiomyomas), scleroderma, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis (necrosis due to toxins, viral hepatitis, shock, or anoxia), B viral hepatitis, non-A / non-B hepatitis, chronic hepatitis C virus (HCV) infection, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), non-alcoholic steatohepatitis (NASH), liver failure, fulminant hepatic failure, late-onset liver failure, acute exacerbation of chronic liver failure, and kidney disease (including chronic kidney disease).

[0027] In one embodiment, the compounds of the present invention are used to treat kidney diseases, including but not limited to chronic kidney failure, acute kidney injury, proteinuria, polycystic kidney disease, and the like.

[0028] More particularly, the compounds and derivatives of the present invention may be useful in the treatment of endometriosis and / or uterine fibroids (leiomyomas).

[0029] In some embodiments, disclosed herein are methods of 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 to treat or prevent inflammation-related conditions (e.g., allergies, pain, etc.).

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

[0031] In some embodiments, the compounds disclosed herein alleviate one or more symptoms of a neuroinflammatory disease or disorder, including reducing the activity of EP2 (e.g., by contacting the inflamed tissue with an EP2 antagonist disclosed herein). In some embodiments, disclosed herein are methods of alleviating 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 one embodiment, the compounds of the invention are used to treat brain aging and its effects, such as cognitive decline (Minhas, PSet al. Restoring metabolism of myeloid cells reverses cognitive decline in aging. Nature (2021) doi:10.1038 / s41586-020-03160-0).

[0033] In some embodiments, the term "dementia" includes, but is not limited to, amyotrophic lateral sclerosis (ALS), epilepsy, dementia, Alzheimer's disease, concussion, delirium, chemotherapy-associated cognitive decline, radiation-associated cognitive decline, postoperative cognitive impairment (including postoperative neurocognitive impairment, postoperative delirium, delayed neurocognitive impairment, and delayed neurocognitive recovery), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment or MCI), Binswanger dementia (subcortical arteriosclerotic encephalopathy), HIV-associated dementia (asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), HIV-associated dementia (HAD) (AIDS-associated dementia), and the like. Disclosed are compounds and methods of their use for treating neurological disorders, including neurodegenerative disorders such as dementia complex (AD), multiple system atrophy (MSA), spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), head trauma, concussion, chronic traumatic encephalopathy, intracerebral hemorrhage, hematoma, diabetic retinopathy, macular degeneration, macular edema, glaucoma, multiple sclerosis, angioedema, including edema caused by treatment with antibody therapy (e.g., ARIA-E), migraine, Huntington's disease, ALS, and neurological and neurodegenerative disorders such as Parkinson's disease.

[0034] In another embodiment, the compounds of the present invention are useful for treating disorders of the central nervous system (CNS). In one embodiment, the CNS disorder is a psychiatric, mental, mood, or affective disorder, such as a disorder selected from addiction, bipolar disorder, schizophrenia, general psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depression, e.g., treatment-resistant depression, suicidal ideation, and major depressive disorder, anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and substance abuse disorders. In certain embodiments, the CNS disorder is selected from chemobrain, levodopa-induced addictive behavior, alcoholism, narcotic addiction (including, but not limited to, amphetamine, opiate, or other substance addiction), and substance abuse.

[0035] In one embodiment, the compounds of the invention are useful for treating a CNS disorder characterized by a relative decrease in synaptic plasticity and synaptic processes, including, for example, Fragile X syndrome, Rett syndrome, Williams syndrome, Rempenning syndrome, autism spectrum disorder (ASD), autism, Asperger's syndrome, pervasive developmental disorder, or childhood disintegrative disorder.

[0036] In one embodiment, the compounds of the present invention are useful for treating diseases in which neurovascular tissue is inflamed or damaged, or the blood-brain barrier is compromised, and in some cases are accompanied by alterations in cerebral blood flow, such as impaired cerebral blood flow, alterations in diffusion or perfusion, such as impaired diffusion, or damage to associated tissues, such as white matter damage or white matter lesions. Examples of such diseases include Alzheimer's disease, vascular dementia, vascular cognitive impairment and dementia (VCID), cerebral small vessel disease, subcortical ischemic vascular disease, mixed dementia, ALS, multiple sclerosis, Parkinson's disease, and Huntington's disease. The compounds of the present invention are also useful for treating vascular injuries, such as head trauma, stroke, aneurysm, and ischemic vascular disease.

[0037] The compounds of the present invention exert anti-inflammatory and analgesic effects by modulating aspects of the prostanoid signaling pathway. Thus, the compounds of the present invention are useful as nonsteroidal anti-inflammatory drugs (NSAIDs) and can be used to treat diseases for which NSAIDs are indicated. In certain embodiments, the compounds of the present invention are useful for treating pain, including nociceptive pain and neuropathic pain. More specifically, the compounds of the present invention are useful as analgesics for treating acute pain, central pain syndromes, nerve pain (e.g., neuropathic pain, chemotherapy-induced neuropathy and neuropathic pain), diabetic neuropathy, HIV-associated neuropathy, fibromyalgia, neuralgia (e.g., postherpetic neuralgia, sciatica), neuropathic pain associated with CNS disease (e.g., multiple sclerosis), postoperative pain, tension pain, menstrual pain, osteoarthritis pain, rheumatoid arthritis pain, visceral pain, sporadic pain, migraine, chronic pain (e.g., postoperative pain), lumbosacral pain, musculoskeletal pain, headache, cluster headache, inflammation-induced pain, and cancer pain.

[0038] 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).

[0039] In certain embodiments, the compounds of the invention are used to treat genetic disorders such as Hirschsprung's disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CADASIL syndrome), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL or CARASIL syndrome), Wilson's disease, DiGeorge syndrome, and retinitis pigmentosa.

[0040] In some embodiments, the inflammatory disease is an allergic disease. In some embodiments, the inflammatory disease is asthma. In some embodiments, the inflammatory disease is anaphylaxis. In some embodiments, the inflammatory disease is chronic inflammation. In some embodiments, disclosed herein are methods of treating chronic inflammation, comprising administering to an individual in need thereof an EP2 antagonist (e.g., a compound disclosed herein).

[0041] Specific examples of inflammatory and allergic diseases that can be treated with the compounds disclosed in this invention include, but are not limited to, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, ulcerative colitis, necrotizing enterocolitis (NEC), peritonitis, gout, gouty attacks, gouty arthritis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, osteoarthritis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, and asthma.

[0042] Examples of allergic disorders that can be treated with the compounds disclosed in the present invention include asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by a pathophysiological disorder, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold-induced asthma, occupational asthma, bacterial, These include, but are not limited to, infectious asthma, early asthma, wheezy infant syndrome, bronchiolitis, cough-variant asthma, or drug-induced asthma caused by or associated with fungal, protozoal, or viral infections, allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, and sphenoid sinusitis.

[0043] In one embodiment, the compounds of the invention are used to ameliorate, treat, or prevent immunoregulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunoregulatory disorders that can be treated with the compounds of the invention include organ or tissue transplantation, transplant-induced graft-versus-host disease, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type 1 diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases (including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases), psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus, acne, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, and keratoconus. Membrane, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma, airway hyperresponsiveness, bronchitis, gastric ulcer, vascular disorders due to ischemic disease and thrombosis, ischemia Intestinal disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, and tooth substance, glomerulonephritis, and to prevent hair loss, promote hair growth, and / or promote hair growth and development. These conditions include, but are not limited to, alopecia areata due to steroid use, male pattern baldness or senile alopecia, vitiligo, muscular dystrophy, pyoderma, Sezary syndrome, Addison's disease, ischemia-reperfusion injury associated with organ preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis due to drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen or drug toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, senile macular degeneration, vitreous scarring, corneal alkali burn, erythematous dermatitis multiforme, linear IgA bulbar dermatitis, cemental dermatitis, gingivitis, periodontitis, and sepsis.

[0044] In one embodiment, the compounds of the present invention are useful for treating cytokine release syndrome (CRS), which can result from a variety of causes, including severe viral infections such as influenza, administration of antibodies used in immunotherapy, such as cancer immunotherapy, and non-protein-based cancer therapeutics, such as oxaliplatin and lenalidomide. Similarly, without being limited to a particular theory, the compounds of the present invention are useful for treating infectious diseases, for example, by modulating proinflammatory cytokines associated with severe infections. Such infections include, but are not limited to, neurocysticercosis, trypanosomiasis, cerebral malaria, viral hemorrhagic fevers (e.g., Ebola hemorrhagic fever, Marburg fever), meningitis, dengue fever, Zika fever, Nipah virus, Japanese encephalitis virus (JEV), West Nile virus (WNV), chikungunya virus, tick-borne encephalitis virus (TBEV), herpes simplex virus (HSV), human T-lymphotropic virus type 1 (HTLV-1), Naegleria fowleri, Toxoplasma gondii, listeriosis, and coronavirus infections, such as SARS, MERS, and COVID.

[0045] As noted in the preceding paragraph, the compounds disclosed herein are useful for treating diseases including, but not limited to, cancer, reproductive disorders, inflammatory disorders, pain, vascular disorders, neurological disorders, neurodegenerative disorders, and the like. In some cases, these disease states involve multifactorial disease processes, and treatment with these compounds provides therapeutic benefit by treating multiple underlying disease pathways within a single disease state or coexisting conditions. Thus, the compounds of the present invention are intended for use in treating multiple diseases mentioned in the preceding paragraph.

[0046] compound The compounds described herein (including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof) are EP2 antagonists. In some embodiments, a compound of any of the formulas described herein, or a pharmaceutically acceptable salt thereof, is an EP2 antagonist.

[0047] In one aspect, provided herein is a compound of Formula (I) or Formula (II): [ka] During the ceremony, R 1 and R 2 are independently a , -OR d , -C 1~4 haloalkyl; or R 1 and R 2 Together, Oxo, C 3~6 forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, R 3 is -CH(R b )2, -C(R b )3, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -S(O)(NR a )R d , -S(O)2N(R a )S(O)2R a , -S(O)2N(R a )S(O)NR c R c , -C(O)R d , -C(O)N(R a )C(O)R d , -C(O)OR d , -C(O)NR c R c and Ring A and Ring B are independently selected from phenyl and cycloalkyl; Each X is R b is selected from Each R A are independently halogen, -CN, -C 1~4 Alkyl, and -C 1~4 haloalkyl; Each R B are independently halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4Aminoalkyl, -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)NR c R c , -NR c R c , -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), and substituted or unsubstituted C 3~6 cycloalkyl; Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3-8 ) cycloalkyl; Each R b are independently -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , and -C(O)NR c R c is selected from the group consisting of Each R c are independently a Or, two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, which may optionally contain one or more additional heteroatoms which may be the same or different, and optionally one or more —C(O)R a and R a may be substituted with a group, Each R dare independently hydrogen, and halogen and -O(C 1~4 alkyl) optionally substituted with one, two or three groups selected from 1~6 ) alkyl; n, for each occurrence, is independently 0 to 3; The compound is not a compound disclosed in PCT / US22 / 34903.

[0048] In one embodiment of the compound of Formula (I), ring A or ring B is C 3~6 In one embodiment, ring A or ring B is C which is bicyclo[1.1.1]pentanyl. 3~6 cycloalkyl. Thus, in one embodiment, the compound of formula (I) has the formula (Ia): [ka]

[0049] In one embodiment, the compound of formula (I) may be represented by formula (Ib): [ka]

[0050] In one embodiment of the compounds according to Formula (I) and (Ib), ring A is phenyl. In one embodiment of the compounds according to Formula (I) and (Ib), ring A is unsubstituted phenyl.

[0051] In another embodiment of the compounds according to Formula (I) and (Ia), Ring B is phenyl. In certain embodiments of the compounds according to Formula (I), (Ia), and (Ib), Ring B is phenyl. B In other embodiments of the compounds according to Formula (I), (Ia) and (Ib), ring B is unsubstituted. In certain embodiments, the compounds having Formula (I), (Ia) and (Ib) contain at least one R B In certain embodiments of compounds of formula (I), (Ia) and (Ib), ring B is substituted with -CN, -C(O)(C 1~4alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl) or -C(O)NR c R c At least one R selected from B is replaced by

[0052] In more specific embodiments, compounds of formula (I), (Ia) and (Ib) contain at least one R that is —CN. B In one embodiment, the compounds according to Formula (I), (Ia) and (Ib) have the formula (Ic): [ka]

[0053] In one embodiment, the compound of Formula (I) has an unsubstituted ring B. In one embodiment, the compound of Formula (I) has an unsubstituted cycloalkyl ring B. In one embodiment, the compound with an unsubstituted cycloalkyl ring B has Formula (Id). [ka]

[0054] In one embodiment, each R A Disclosed herein are compounds of formula (II) where is independently halo. In one embodiment of a compound of formula (II), an example is that represented by formula (IIa): [ka]

[0055] A further embodiment of the compounds according to formula (II) and (IIa) has the formula (IIb): [ka]

[0056]

[0057] In certain embodiments of compounds according to Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is -CH(R b )2 and -C(R b ) 3, and in particular examples of such compounds, R 3 Each R in b are independently -OR d In certain embodiments of compounds having formula (I), (Ia), (Ib), (Ic), (Id), and (II), R 3 In other embodiments of compounds having formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is -C(OH)2CF3.

[0058] In other embodiments of compounds having formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is S(O)2R d , -S(O)(NR a )R d , -S(O)2OR d , -S(O)NR c R c , -S(O)2N(R a )S(O)2R a , and -S(O)N(R a )S(O)NR c R c In certain embodiments, in compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is S(O)NH. In other embodiments of the compounds having formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is S(O)2CH3. In certain embodiments of Formulas (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is -S(O)(NR a )Rd In still other embodiments, in compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is S(O)(NH)CH3.

[0059] In other embodiments of compounds according to Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is -C(O)R d , -C(O)N(R a )C(O)R d , -C(O)OR d , and -C(O)NR c R c In one such embodiment, such as in compounds having formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), R 3 is -C(O)OR d where R 3 is -COOH.

[0060] Specific examples of compounds of the present disclosure, including compounds according to formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), and (IIb), contain one, two, or three X substituents, where each X is independently selected from the group consisting of R b Specific examples of compounds according to formula (I), (Ia), (Ib), (Ic), and (Id) disclosed herein have a single X substituent in the ortho, meta, or para position. When such a compound has a single X in the para position, it has the structure of formula (Ie). [ka]

[0061] In one embodiment, the compounds according to Formula (I), (Ia), (Ib), (Ic), (Id), and (Ie) disclosed herein have the structure of Formula (If): [ka]

[0062] In another aspect, exemplary compounds according to Formulas (I), (Ia), (Ib), (Ic), (Id), (Ie), and (If) disclosed herein have the structure of Formula (Ig). [ka]

[0063] In yet another embodiment of the compounds disclosed herein, the compounds according to Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), and (Ig) have one or more R that is cyano. B In one aspect, in certain embodiments, such compounds are of formula (Ih): [ka]

[0064] In particular examples of compounds having formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (IIa), and (IIb), R 1 and R 2 In other examples, in compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (IIa), and (IIb), R 1 and R 2 One of them is hydrogen and the other is -CF3.

[0065] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0066] In one embodiment, the disclosed compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), IIa), and / or (IIb) include those set forth in Table (I). [Table 1-1] [Table 1-2] [Table 1-3]

[0067] compound The compounds described herein (including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof) are EP2 antagonists. In some embodiments, a compound of any of the formulas described herein, or a pharmaceutically acceptable salt thereof, is an EP2 antagonist.

[0068] In one aspect, provided herein is a compound of formula (III): [ka]

[0069] Regarding formula (III), in one embodiment, ring A is a bicyclic heterocycle having one or more nitrogen atoms, or ring A is ring A′, and each R A 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 1~4alkyl), -O(C 1~4 haloalkyl), -S(C 1~4 alkyl), -SO2C 1~4 Alkyl, -SO2NHC 1~4 Alkyl, substituted or unsubstituted C 3~6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R A together form a carbonyl, and ring A' is [ka] is selected from the group consisting of R 1 and R 2 are independently hydrogen, -C 1~4 Alkyl, -CN, C(O)NR c R c Alternatively, R 1 and R 2 Together, Oxo, C 3~6 forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, X is selected from hydrogen and halogen; R 3 and R 4 are independently hydrogen, -C 1~4 alkyl, or R 3 and R 4 together to form an oxo, or R 3 and R 4 One of them is R 5 forms a double bond with R 3 and R 4 The other is hydrogen or -C 1~4 is alkyl, R 5 is -(CH2) m -R b , -(CHR a ) m -R b , -O-(CH2) m -R b , -O-(CHR a ) m -R b, -C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b , -NHC(O)OR d , -NHC(O)NR c R c is selected from R 6 and R 7 are independently hydrogen, -C 1~4 alkyl, or R 6 and R 7 together to form oxo, Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3-8 ) cycloalkyl; Each R b are independently =O, -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , -C(O)NR c R c , and ring B [ka] wherein ring B is selected from the group consisting of C 3~6 cycloalkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl containing two or more nitrogen atoms, 9-10-membered heteroaryl; or ring B is ring B'; Each R B are independently halogen, -CN, -C 1~4 Alkyl, -C 1~4 Haloalkyl, -C 1~4 Aminoalkyl, -C 1~4 Hydroxyalkyl, -C 1~4Methoxyalkyl, -(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), -(CH2) m -N(R c )2, -(CH2) m -NHC(O)C 1~4 Alkyl, -(CH2) m -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), -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 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R B together to form a carbonyl, Each R c are independently a Or, two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, which may optionally contain one or more additional heteroatoms which may be the same or different, and optionally one or more —C(O)R a and R a may be substituted with a group, Each R dare independently hydrogen, and optionally substituted with 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl (C 1~6 ) alkyl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl are each selected from halogen, C 1~4 Alkyl, and -O(C 1~4 alkyl), l is 0 to 3; m is 0 to 3; n is 0 to 3, Ring B' is [ka] is selected from the group consisting of The compound is not a compound disclosed in PCT / US2022 / 034901.

[0070] In one embodiment of the compounds of formula (III), the EP2 antagonists disclosed herein have the formula (IV): [ka] In the formula, R A is as defined above for formula (III). In specific embodiments, at least one R of formula (IV) A is halogen. In one such embodiment, at least one R A is fluoro, for example, as in compounds according to formulae (II) and (IV) having formula (IVa). [ka] Thus, in one embodiment of the compounds according to formulas (III) and (IV), the EP2 antagonists disclosed herein have the formula (IVa):

[0071] In one embodiment of Formula (III), the EP2 antagonists disclosed herein have the formula (V): [ka] In the formula, R A is as defined above for formula (III). In specific embodiments, at least one R of formula (V) A is halogen. In one such embodiment, at least one R A is fluoro, for example, as in compounds according to formulas (III) and (V) having formula (Va). [ka] Thus, in one embodiment of the compounds according to formulas (III) and (V), the EP2 antagonists disclosed herein have the formula (Va):

[0072] In one embodiment of Formula (III), the EP2 antagonists disclosed herein have the formula (VI): [ka] In the formula, R A is as defined above for formula (III). In specific embodiments, at least one R of formula (VI) A is halogen. In one such embodiment, at least one R A is fluoro, for example, as in compounds according to formulae (III) and (VI) having formula (VIa). [ka] Thus, in one embodiment of the compounds according to formulas (III) and (VI), the EP2 antagonists disclosed herein have the formula (VIa):

[0073] In one embodiment of Formula (III), the EP2 antagonists disclosed herein have the formula (VII): [ka] In the formula, R A is as defined above for formula (III). In specific embodiments, at least one R of formula (VII) Ais halogen. In one such embodiment, at least one R A is fluoro, for example in compounds according to formulae (III) and (VII) having formula (VIIa). [ka] Thus, in one embodiment of the compounds according to formula (III) and (VII), the EP2 antagonists disclosed herein have the formula (VIIa): In a further embodiment, the compounds of formula (III) and (VII) have two or more R groups as defined above for formula (III). A In specific embodiments, compounds of formula (III) and (VII) may have two or three R A In one such embodiment, R A is halogen, such as fluoro. In one such embodiment, at least two R A is fluoro, as in compounds according to formulae (III) and (VII) having formula (VIIb). [ka] Thus, in one embodiment of the compounds according to formulas (III) and (VII), the EP2 antagonists disclosed herein have the formula (VIIb):

[0074] In one embodiment, the EP2 antagonists disclosed herein, including compounds of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), and (VIIb), are -(CH2) m -R b , -(CHR a ) m -R b , -O-(CH2) m -R b , -O-(CHR a ) m -R b , -C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a )m -R b , -NHC(O)OR d , -NHC(O)NR c R c R selected from 5 and each R b are independently =O, -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , -C(O)NR c R c , and ring B [ka] wherein ring B is selected from the group consisting of C 3~6 Alternatively, Ring B is Ring B', and Ring B' is selected from: [ka] is selected from the group consisting of:

[0075] In one embodiment, the EP2 antagonists disclosed herein, including compounds of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), and (VIIb), are -(CH2) m -R b , -(CHR a ) m -R b , -O-(CH2) m -R b , -O-(CHR a ) m -R b , -C(O)NH-(CH2) m -R b , -C(O)NH-(CHRa ) m -R b , -NHC(O)OR d , -NHC(O)NR c R c R selected from 5 and each R b are independently =O, -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , and -C(O)NR c R c is selected from the group consisting of:

[0076] In certain embodiments of compounds according to Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), and (VIIb), R 5 is -(CH2) m -R b In particular examples of compounds according to formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), and (VIIb), R 5 is -(CH2) m -R b where R b is -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , and -C(O)NR c R c is selected from.

[0077] In certain embodiments of formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), and (VIIb), R 5 teeth, [ka] is selected from.

[0078] In one embodiment, the compounds of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), and (VIIb) have the formula (VIII). [ka] Thus, in one embodiment of the compounds according to formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), and (VIIb), the EP2 antagonists disclosed herein have formula (VIII):

[0079] In one embodiment, the compounds of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), and (VIII) have the formula (VIIIa). [ka]

[0080] In one embodiment, the compounds of (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), and (VIII) have the formula (VIIIb). [ka]

[0081] In one embodiment, the compounds of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), and (VIII) have the formula (VIIIc). [ka]

[0082] In one embodiment, the compounds of (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), and (VIII) have the formula (VIIId). [ka]

[0083] In one embodiment, the compounds of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), and (VIII) have the formula (VIIIe). [ka] Thus, in certain embodiments of compounds according to (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), and (VIII), the EP2 antagonists disclosed herein have formula (VIIIa), (VIIIb), (VIIIc), (VIIId) or (VIIIe).

[0084] In one embodiment of the compounds of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), X is hydrogen. In one such embodiment, X is deuterium. In other embodiments of formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), and (VIIId), X is halogen, such as fluoro, chloro, bromo, or iodo. In certain embodiments of Formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), X is chloro. Thus, in one embodiment, the compounds disclosed herein have Formula (IIIa). [ka]

[0085] In one embodiment of the compounds disclosed herein, including compounds of formula (III), (IIIa), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), ring A is [ka] is a bicyclic heterocycle selected from the group consisting of:

[0086] In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 are independently hydrogen, -C 1~4Alkyl, -CN, C(O)NR c R c Alternatively, R 1 and R 2 Together, Oxo, C 3~6 In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 are both hydrogen. In one such embodiment, R 1 and R 2 In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 One of them is hydrogen and the other is -C 1~4 In other embodiments of compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 are both -C 1~4 In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 At least one of the following must be -C 1~4 alkyl, e.g., R 1 and R 2In other embodiments of compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), at least one of R 1 and R 2 Together, Oxo, C 3~6 In one embodiment, R 1 and R 2 In another embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 Together, C 3~6 In one embodiment, R 1 and R 2 are joined together to form a C ring such as a cyclopropyl ring or a cyclobutyl ring. 3~6 In another embodiment of compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 taken together form a 3-6 membered cycloheteroalkyl (e.g., a cycloheteroalkyl containing oxygen, nitrogen, or both). In one embodiment of Formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 1 and R 2 together to form an oxetane.

[0087] In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 3 and R 4 are independently hydrogen, -C 1~4 alkyl, or R 3 and R 4 together to form an oxo, or R 3 and R 4 One of them is R 5 forms a double bond with R 3 and R 4 The other is hydrogen or -C 1~4 In certain embodiments of Formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 3 and R 4 and are each hydrogen. In other embodiments of formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 3 and R 4 At least one of the following must be -C 1~4 alkyl and the other is hydrogen or -C 1~4 In certain embodiments of Formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 3 and R 4 are -C respectively. 1~4In other embodiments of formulas (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 3 and R 4 together to form an oxo, or R 3 and R 4 One of them is R 5 forms a double bond with R 3 and R 4 The other is hydrogen or -C 1~4 It is alkyl.

[0088] In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 6 and R 7 are independently hydrogen, -C 1~4 alkyl, or R 6 and R 7 In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 6 and R 7 In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 6 and R 7 At least one of the groups is -C such as methyl. 1~4In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 6 and R 7 are both -C 1~4 In one embodiment of the compounds of Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and (VIIIe), R 6 and R 7 together to form oxo.

[0089] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of ordinary skill in the art to provide stable moieties and compounds.

[0090] In one embodiment, the disclosed compounds according to Formula (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and / or (VIIIe) include the compounds shown in Table (II). [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12]

[0091] Additional forms of the compound In one aspect, the compounds described herein are in the form of pharmaceutically acceptable salts.In addition, the active metabolites of these compounds having the same type of activity are also included in the scope of the present disclosure.In addition, the compounds described herein can exist not only in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., but also in unsolvated form.The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0092] As used herein, "pharmaceutically acceptable" refers to a substance, such as a carrier or diluent, that does not interfere with the biological activity or properties of the compound and that is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious way with any of the components of the composition that contains it.

[0093] The term "pharmaceutically acceptable salt" refers to a form of a therapeutically active agent that consists of the cationic form of the therapeutically active agent combined with a suitable anion, or in an alternative embodiment, a form of a therapeutically active agent that consists of the anionic form of the therapeutically active agent combined with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley-VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P.H. Stahl and C.G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich: Wiley-VCH / VHCA, 2002. Pharmaceutical salts are generally more soluble in gastric and intestinal fluids and have a faster dissolution rate than non-ionic substances, making them useful in solid dosage forms. Furthermore, solubility is often a function of pH, allowing for selective dissolution across specific segments of the gastrointestinal tract, a feature that can be manipulated as an aspect of delayed- and sustained-release behavior. Additionally, salt-forming molecules can be in equilibrium with their neutral forms, allowing for tailored passage across biological membranes.

[0094] In some embodiments, a compound described herein can be reacted with an acid to obtain a pharmaceutically acceptable salt. In some embodiments, a compound described herein (i.e., a 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, metaphosphoric acid, etc. 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, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (D), and gluconic acid (D). , glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, 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, propionic 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.

[0095] 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.

[0096] In some embodiments, a pharmaceutically acceptable salt is obtained by reacting a compound described herein with a base. In some embodiments, the compounds described herein are acidic and react with a base. In such situations, the acidic proton of a compound described herein is replaced by a metal ion, such as lithium, sodium, potassium, magnesium, calcium, or aluminum ion. In some cases, the compounds described herein coordinate with organic bases such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, and tris(hydroxymethyl)methylamine. In other cases, the compounds described herein form salts with amino acids such as, but not limited to, arginine and 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, lithium hydroxide, and the like. 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.

[0097] It should be understood that a reference to a pharmaceutically acceptable salt also includes solvent addition forms. In some embodiments, solvates contain stoichiometric or non-stoichiometric amounts of solvent and are formed during the process of crystallization with a pharmaceutically acceptable solvent such as water, ethanol, etc. When the solvent is water, a hydrate is formed, and when the solvent is alcohol, an alcoholate is formed. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. Furthermore, the compounds provided herein optionally exist in unsolvated and solvated forms.

[0098] 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.

[0099] In another embodiment, the compounds described herein are labeled with an isotopic label (e.g., 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.

[0100] The compounds described herein include isotopically labeled compounds, which are identical to the compounds described in the various formulas and structures presented herein, except that one or more atoms are replaced with an atom having an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, 36Cl, and the like. In one aspect, isotopically labeled compounds described herein, e.g., compounds incorporating radioactive isotopes such as 3H and 14C, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium can confer certain therapeutic advantages, such as increased metabolic stability, increased in vivo half-life, or reduced dosage requirements.

[0101] As used herein, the term "isotopic enrichment factor" refers to the ratio of the isotopic abundance to the natural abundance of a particular isotope. It will be recognized that some variation in the natural isotopic abundance in a synthesized compound will occur depending on the origin of the chemicals used in its synthesis. Therefore, any compound preparation will inherently contain small amounts of isotopic substitution, including deuterated isotope substitution. Despite this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution in the compounds of the present disclosure. When a particular position in a compound of the present disclosure is designated as having a particular isotope, such as deuterium, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium (approximately 0.015% (mol / mol)). A position designated as a particular isotope has a minimum isotopic enrichment factor of at least 3000 (45% incorporation of the designated isotope). Thus, isotopically enriched compounds with deuterium disclosed herein will have a minimum isotopic enrichment factor of at least 3000 (45% deuterium incorporation) at each atom designated as deuterium in the compound. Such compounds may be referred to herein as "deuterated" compounds.

[0102] In other embodiments, the disclosed compounds have an isotopic enrichment factor for each designated atom of at least 3500 (52.5%). For example, if the disclosed compounds are deuterium isotope substituted, the compounds have an isotopic enrichment factor for each designated hydrogen atom of at least 3500 (52.5% deuterium incorporation at each designated atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As noted above, such compounds are also referred to as "deuterated" compounds.

[0103] In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H," it is understood that hydrogen is present at that position in approximately natural abundance isotopic composition.

[0104] The term "isotopomer" refers to a species that has the same chemical structure and formula as another compound except for its isotopic composition at one or more positions, such as H vs. D. Isotopomers therefore differ in isotopic composition.

[0105] 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.

[0106] Individual stereoisomers can be obtained, as needed, by methods such as stereoselective synthesis and / or separation of stereoisomers by chiral chromatographic columns. In certain embodiments, the compounds described herein are prepared as 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 other embodiments, diastereomers are separated by separation / resolution techniques based on differences in solubility. In other embodiments, separation of stereoisomers is carried out by chromatography, or by forming diastereomeric salts, by recrystallization, 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. term

[0107] term Unless otherwise stated, the following terms used in this application have the meanings set forth below. The use of the term "including" and other forms such as "include," "includes," and "included" is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0108] In this specification, C 1-x C 1-2 , C 1-3 ,...C 1-x For example, "C 1~4" indicates that the moiety has 1 to 4 carbon atoms, i.e., a group containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. Thus, as an example, "C 1~4 "Alkyl" indicates that the alkyl group has 1 to 4 carbon atoms, ie, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl.

[0109] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group can be branched or straight-chain. In some embodiments, an "alkyl" group can have 1 to 10 carbon atoms, i.e., C1 to C6. 10 As used herein, numerical ranges such as "1 to 10" always refer to each integer in the specified range, e.g., "1 to 10 carbon atoms" means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to 10 carbon atoms, although this definition also covers the use of the term "alkyl" when no numerical range is specified. In some embodiments, alkyl is C 1~4 C such as alkyl 1~6 In one aspect, the alkyl is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or t-butyl. Common alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl.

[0110] "Deuteroalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl have been replaced with deuterium.

[0111] The term "alkenyl" refers to a species of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group is represented by 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.

[0112] The term "alkynyl" refers to a species of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkenyl group is represented by 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.

[0113] An "alkoxy" group refers to a (alkyl)O- group, where alkyl is as defined herein.

[0114] The term "alkylamine" refers to -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.

[0115] 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. Thus, this term distinguishes carbocycle from "heterocyclic" rings or "heterocycles," which contain at least one atom other than carbon in the ring backbone. 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.

[0116] As used herein, the term "aryl" refers to an aromatic ring in which each atom 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 a C6-C 13 Aryl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0117] The term "cycloalkyl" refers to a monocyclic or polycyclic aliphatic, non-aromatic radical in which each atom 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 bicyclo[1.1.1]pentyl. In some embodiments, the cycloalkyl is a C3-C6 cycloalkyl.

[0118] The term "halo" or "halogen" or "halide" means fluoro, chloro, bromo, or iodo. In some embodiments, halo is fluoro, chloro, or bromo, e.g., fluoro or chloro.

[0119] The term "fluoroalkyl" refers to an alkyl in which one or more hydrogen atoms have been replaced with a fluorine atom. In one aspect, the fluoroalkyl is a C1-C6 fluoroalkyl.

[0120] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, such as 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.

[0121] The term "heterocycle" or "heterocyclic" refers to heteroaromatic rings (also called heteroaryls) and heterocycloalkyl rings (also called heteroalicyclic groups) containing 1 to 4 heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S, and N, and each heterocyclic group has 3 to 10 atoms in its ring system, but no ring contains two adjacent O or S atoms. Non-aromatic heterocyclic groups (also called heterocycloalkyls) 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 include 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, dithiazole ... oranyl, 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, quinolidinyl, and the like.Examples of aromatic heterocyclic groups include 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, furopyridinyl, etc. The foregoing groups may be C-attached (or C-linked) or N-attached where such is 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.

[0122] The term "heteroaryl" or "heteroaromatic" refers to an aryl group containing one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. Specific 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, heteroaryls contain zero to four N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl is a C1-C9 heteroaryl. In some embodiments, a monocyclic heteroaryl is a C1-C5 heteroaryl. In some embodiments, a monocyclic heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, a bicyclic heteroaryl is a C6-C9 heteroaryl.

[0123] 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 all ring forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. In one aspect, a heterocycloalkyl is a C 2~10 In another aspect, heterocycloalkyl is C 2~6 Heterocycloalkyl. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms, and 0-1 S atoms in the ring.

[0124] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties where the atoms joined by the bond are considered to be part of a larger substructure. In one aspect, when a group described herein is a bond, the reference group is absent, thereby allowing a bond to be formed between the remaining identified groups.

[0125] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is often recognized as a chemical substance embedded in or appended to a molecule.

[0126] The term "optionally substituted" or "substituted" means that the referenced group is individually and independently substituted with one or more additional groups 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 1~4 alkyl), -C(=O)NH2, -C(=O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, -S(O)2NH2, -S(O)2NH(C 1~4 alkyl), -S(O)N(C 1~4 Alkyl)2, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Fluoroalkyl, C 1~4 Heteroalkyl, C 1~4 Alkoxy, C 1~4 Fluoroalkoxy, -SC 1~4 Alkyl, -S(O)C 1~4 Alkyl, and -S(O)C 1~4 In some embodiments, the optional substituents are independently selected from halogen, —CN, —NH, —OH, —NH(CH), —N(CH), —CH, —CHCH, —CF, —OCH, and —OCF. In some embodiments, the substituents are substituted with one or two of the foregoing groups. In some embodiments, the optional substituents on an aliphatic carbon atom (acyclic or cyclic) include oxo (═O).

[0127] As used herein, the term "acceptable" in reference to a formulation, composition, or ingredient means having no lasting adverse effects on the general health of the subject being treated.

[0128] The term "modulate," as used herein, means to interact directly or indirectly with a target to alter the activity of the target, such as, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or prolonging the activity of the target.

[0129] As used herein, the term "modulator" refers to a molecule that interacts directly or indirectly with a target. Interactions include, but are not limited to, agonist, partial agonist, inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, the modulator is an antagonist.

[0130] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to deliver 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 of skill in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0131] As used herein, the term "co-administration" and the like is intended to encompass the administration of selected therapeutic agents to a single patient, and is intended to include treatment regimens in which the agents are administered by the same or different routes of administration or at the same or different times.

[0132] As used herein, the term "effective amount" or "therapeutically effective amount" refers to the administration of an amount of an agent or compound sufficient to relieve to some extent one or more of the symptoms of the disease or disorder being treated, resulting in reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" in therapeutic applications is the amount of a composition comprising a compound disclosed herein that is required to bring about a clinically significant alleviation of a disease symptom. An appropriate "effective" amount in any individual case can optionally be determined using techniques such as a dose escalation study.

[0133] The terms "enhance" or "enhancing," as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in contrast 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. An "enhancing-effective amount," as used herein, refers to an amount sufficient to enhance the effect of another therapeutic agent in a desired system.

[0134] As used herein, the term "pharmaceutical combination" refers to a product obtained by mixing or combining two or more active ingredients, and includes both fixed and non-fixed 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 an adjuvant are administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound described herein or a pharmaceutically acceptable salt thereof, and an adjuvant are administered to a patient simultaneously, in parallel, or sequentially as separate entities without any specific intervening time limit, such that effective levels of the two compounds are achieved in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0135] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: non-human primates such as humans, chimpanzees, 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 aspect, the mammal is a human.

[0136] As used herein, the terms "treat," "treating," or "treatment" include alleviating, relieving, or ameliorating at least one symptom of a disease or condition, preventing further symptoms, inhibiting a disease or condition, e.g., arresting the progression of a disease or condition, relieving a disease or condition, causing a disease or condition to regress, alleviating a condition caused by a disease or condition, or arresting a symptom of a disease or condition prophylactically and / or therapeutically.

[0137] 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 the active compound into a pharmaceutical preparation. The appropriate formulation depends on the selected route of administration. Overviews of the pharmaceutical compositions described herein are found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0138] In some embodiments, the compounds described herein are administered as a pharmaceutical composition, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent. Administration of the compounds and compositions described herein can be carried out by any method capable of delivering 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, such as intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intraspinal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, transdermal, transmucosal, sublingual, buccal, and topical (including epithelial, cutaneous, enema, eye drops, ear drops, intranasal, and vaginal) administration, and the most appropriate route may depend, for example, on the disease and disorder of the recipient.

[0139] 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 non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion.

[0140] Orally usable pharmaceutical compositions include tablets, push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (such as glycerol and sorbitol). Tablets may be made 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 powder or granules, optionally mixed with a binder, inert diluent, lubricant, surface active agent, or dispersing agent. Molded tablets may be made 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 within the tablet. All formulations intended for oral administration should be administered in dosages suitable for such administration. Push-fit capsules can contain the active ingredient mixed 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 suitable liquids such as fatty oils, liquid paraffin, liquid polyethylene glycol, etc. In some embodiments, stabilizers are added. The dragee core is 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. For identification or to characterize different combinations of dosages of active compounds, dyes or pigments may be added to the tablet or dragee coating.

[0141] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage forms, such as in ampoules or multi-dose containers, with an added preservative. 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, such as sealed ampoules and vials, and may be stored in powder or lyophilized (lyophilized) form, requiring only the addition of a sterile liquid carrier, such as saline or sterile, pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0142] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bactericides, and solutes that render the formulation isotonic with the recipient's blood, as well as 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, 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.

[0143] Pharmaceutical compositions can be formulated as depot preparations.This long-acting preparation can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Therefore, for example, compound can be formulated with suitable polymer or hydrophobic material (for example, as emulsion in acceptable oil) or ion exchange resin, or can be formulated as poorly soluble derivative, for example, poorly soluble salt.

[0144] Administration and Treatment Methods In one embodiment, the compounds disclosed herein are used in the preparation of a medicament for the treatment or prevention of a disease or disorder that would benefit from a reduction or suppression of EP2 activity or by a reduction or inhibition of EP2 activity. Additionally, a method of treating any of the diseases or disorders described herein in a mammal in need of such treatment comprises administering to the mammal a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (IIa), (IIb), (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId), and / or (VIIIe), or a pharmaceutically acceptable salt, active metabolite, prodrug, or solvate thereof.

[0145] In certain embodiments, compositions containing a compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially inhibit at least one symptom of the disease or condition. Amounts effective for this application will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the medication, as well as the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation clinical trials.

[0146] 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.

[0147] In certain embodiments, the dosage of the administered drug may be temporarily reduced or temporarily suspended for a period of time (ie, a "drug holiday").

[0148] Dosages used for adult treatment generally range from 0.01 mg to 5000 mg per day, or from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently present in a single dose or in divided doses.

[0149] In some cases, it may be appropriate to administer at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (IIa), (IIb), (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId) and / or (VIIIe) in combination with other therapeutic agents. In one particular embodiment, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (II), (IIa), (IIb), (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId) and / or (VIIIe) is co-administered with a second therapeutic agent, The compounds of Formula (d), (Ie), (If), (Ig), (Ih), (II), (IIa), (IIb), (III), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb), (VIIIc), (VIIId) and / or (VIIIe) and the second therapeutic agent modulate different aspects of the disease or disorder being treated, thereby providing a greater overall benefit than either therapeutic agent administered alone.

[0150] For the combination therapies described herein, the dosage of the co-administered compound will vary depending on the type of co-administered compound(s) used, the particular drug(s) used, 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 to the one or more other therapeutic agents.

[0151] When administration is simultaneous, the multiple therapeutic agents may be provided in a single, unified form or in multiple forms, by way of example only. [Example]

[0152] Example The following examples are provided for illustrative purposes only and are not intended to limit the scope of the claims provided herein.

[0153] The compounds described herein are synthesized using standard synthetic techniques or methods known in the art in combination with the methods described herein. Those skilled in the art, given this disclosure, will envision variations in the reagents and conditions to produce the molecules described herein.

[0154] The compounds are prepared using standard organic chemistry techniques, such as those described in March's Advanced Organic Chemistry, 6th Edition, John Wiley and Sons, Inc. Alternative reaction conditions for synthetic transformations may be used, such as variations in solvents, reaction temperatures, reaction times, as well as different chemical reagents and other reaction conditions that would be understood by one skilled in the art of organic synthesis. Starting materials are commercially available or readily prepared.

[0155] Preparation of 3-((4-(3-cyanobicyclo[1.1.1]pentan-1-yl)phenoxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (compound 6) [ka]

[0156] To a mixture of methyl 3-(4-{3-carbamoylbicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (80 mg, 0.167 mmol, 1 equiv.) in CHCl (2 mL) was added TFAA (70 mg, 0.334 mmol, 2 equiv.) and EtN (50.75 mg, 0.501 mmol, 3 equiv.) at 0 °C. The mixture was stirred at room temperature for 12 h. The resulting mixture was extracted with CHCl (5 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give methyl 3-(4-{3-cyanobicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (60 mg, 65.56%) as a colorless solid. LC / MS: C 27 H 28 Calculated mass of N2O5: 460.20, Measured mass: 461.15 [M+H]+

[0157] To a mixture of methyl 3-(4-{3-cyanobicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (55 mg, 0.119 mmol, 1 equiv.) in CHCN (1.5 mL) and HO (0.020 mL) was added trimethyl(sodium oxy)silane (0.18 mL, 0.002 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 6 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC under the following conditions (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: 16% B to 46% B, 46% B in 7 min, wavelength: 254 nm, RT1 (min): 5.62, run number: 0) to give 3-(4-{3-cyanobicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (24.6 mg, 44.83%) as a white solid.

[0158] LC / MS: Calculated mass for C26H26N2O5: 446.18, Found: 447.15 [M+H] + . 1 H NMR(300MHz, methanol-d4)δ 7.47-7.57(m,2H),7.08-7.20(m,2H),6.79-7.04(m,4H),3.98-4.33(m,3 H),3.85(s,3H),3.63-3.79(m,3H),2.34-2.53(m,7H),2.07-2.25(m,1H).

[0159] Preparation of 3-((4-(bicyclo[1.1.1]pentan-1-yl)phenoxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (compound 7) [ka]

[0160] To a stirred mixture of benzoyl, 4-methoxybenzoyl chloride (5 g, 29.310 mmol, 1 equiv.) and methyl pyrrolidine-3-carboxylate (4.55 g, 35.228 mmol, 1.20 equiv.) in DCM (50 mL, 786.530 mmol, 26.83 equiv.), triethylamine (8.9 g, 87.951 mmol, 3.00 equiv.) was added. The resulting mixture was extracted with CHCl (3 × 100 mL). The combined organic layers were washed with water (3 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give methyl 1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (3.6 g, 46.41%) as a colorless oil. LC / MS: C 14 H 17 Calculated mass of NO4: 263.12, Measured mass: 264.05 [M+H] + .

[0161] To a stirred mixture of methyl 3-(iodomethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (150 mg, 0.372 mmol, 1 equiv.) and 4-{bicyclo[1.1.1]pentan-1-yl}phenol (71.52 mg, 0.446 mmol, 1.2 equiv.) in DMSO was added KCO (77.12 mg, 0.558 mmol, 1.5 equiv.). The resulting mixture was stirred at 80 °C overnight. The desired product could be detected by LCMS. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give methyl 3-(4-{bicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (74 mg, 45.67%) as a colorless oil. LC / MS: Calculated mass for C14H28N2O3: 435.20, Found: 436.15 [M+H] + .

[0162] To a stirred solution of methyl 3-(4-{bicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (74 mg, 0.170 mmol, 1 equiv.) in HO (2 mL) and CHCN (2 mL) was added trimethyl(sodium oxy)silane (152.48 mg, 1.360 mmol, 8 equiv.) in portions at room temperature for 16 h. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm, Mobile phase A: water (0.05% HCl), Mobile phase B: ACN, Flow rate: 25 mL / min, Gradient: 55% B to 74% B in 7 min, Wavelength: 254 nm, RT (min): 5.25, Run number: 0) to give 3-(4-{bicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (24.6 mg, 34.31%) as a white solid. LC / MS: Calculated mass for CHNO: 421.19, Found: 422.20 [M+H]. + . 1 H NMR(300MHz,DMSO-d6)δ 7.49(m,2H),7.08(m,2H),6.97(d,J = 8.3 Hz,2H),6.93-6.69(m,2H),4.18(m,1H),4.02(m,1H),3.93(d,J = 11.5 Hz, 1H), 3.80 (s, 3H), 3.57 (m, 3H), 2.50 (s, 1H), 2.27-2.08 (m, 2H), 2.00 (s, 6H).

[0163] Preparation of 4'-((1-(4-methoxybenzoyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-3-yl)methoxy)-[1,1'-biphenyl]-4-carbonitrile (Compound 12) [ka]

[0164] To a stirred mixture of 1-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]-2,2,2-trifluoroethanol (80 mg, 0.164 mmol, 1 equiv.) and 4-cyanophenylboronic acid (28.7 mg, 0.195 mmol, 1.19 equiv.) in 2 M Na2CO3 aqueous solution (0.2 mL) and DEM (0.8 mL) was added Pd(PPh3)4 (18.9 mg, 0.016 mmol, 0.10 equiv.). The reaction was stirred at 85 °C for 16 h. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (3 × 8 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (1 mL). The crude product was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 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 85% B in 7 min, wavelength: 220 nm, RT1 (min): 6.35, run number: 0) to give 4'-{[1-(4-methoxybenzoyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (5.7 mg, 6.81%) as a white solid. LC / MS: Calculated mass for C28H25F3N2O4: 510.18, Found: 511.15 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 7.82-7.90(m,4H),7.72(s,2H),7.54(s,2H),6.98-7.12(m,4H),6.79(s,1H) ,3.96-4.23(m,3H),3.79(s,3H),3.55-3.72(m,5.1H),1.87-2.21(m,10.2H). 19 F NMR(282MHz,DMSO-d6)δ -72.034.

[0165] Preparation of (3-((4-bromophenoxy)methyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)(4-methoxyphenyl)methanone; [1-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]-2,2,2-trifluoroethanol] (Compound 14) [ka]

[0166] To a stirred mixture of methyl 3-(iodomethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (1 g, 2.480 mmol, 1 equiv.) and 4-bromophenol (514 mg, 2.971 mmol, 1.20 equiv.) in DMSO (8 mL, 112.633 mmol, 45.42 equiv.) was added K2CO3 (512 mg, 3.705 mmol, 1.49 equiv.). The reaction was stirred at 80 °C for 16 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give methyl 3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (900 mg, 80.95%) as a pale yellow oil. LC / MS: mass calculated for C21H22BrNO5: 447.07, found: 447.95 [M+H] +

[0167] To a stirred mixture of methyl 3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (720 mg, 1.606 mmol, 1 equiv.) in toluene (7 mL) was added DIBAL-H (3.3 mL, 16.265 mmol, 10.13 equiv.) portionwise at −78° C. under a nitrogen atmosphere. The reaction was stirred at −78° C. for 2 h. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water (3×10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbaldehyde (167.2 mg, 21.34%) as a pale yellow oil. LC / MS: mass calculated for CHBrNO: 417.06, found: 417.95 [M+H] +

[0168] To a stirred mixture of 3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carbaldehyde (140 mg, 0.335 mmol, 1 equiv.) and CsF (66.09 mg, 0.436 mmol, 1.30 equiv.) in DMF (2.00 mL, 25.865 mmol, 77.21 equiv.) was added TMSCF (61.87 mg, 0.436 mmol, 1.30 equiv.) portionwise at 0 °C. The reaction was stirred at room temperature for 12 h. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with water (3 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give 1-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]-2,2,2-trifluoroethanol (3.5 mg, 2.11%) as a pale yellow oil. The crude product (15 mg) was purified by preparative HPLC under the following conditions (Column: Kinetex EVO C18, 21.2*250 mm, 5 µm, Mobile phase A: water (0.05% TFA), Mobile phase B: ACN, Flow rate: 25 mL / min, Gradient: 40% B to 54% B in 15 min, Wavelength: 254 nm, RT (min): 13.5, Run number: 0) to give 1-[3-(4-bromophenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]-2,2,2-trifluoroethanol (3.5 mg, 2.11%) as a white solid. LC / MS: Calculated mass for C21H21BrF3NO4: 487.06, Found: 488.00 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ7.45(d,J = 22.5 Hz,4H),6.76-7.01(m,5H),4.25(s,1H),4.06(d,J = 10.8 Hz,1H),3.91(s,1H),3.79(s,3H),3.69(d,J = 12.3 Hz,3H),2.12(d,J = 8.7 Hz,2H). 19F NMR (282MHz, DMSO-d6) δ -71.944, -72.159, -73.446.

[0169] Preparation of 4'-((1-(4-methoxybenzoyl)-3-(2,2,2-trifluoro-1,1-dihydroxyethyl)pyrrolidin-3-yl)methoxy)-[1,1'-biphenyl]-4-carbonitrile (compound 13) [ka]

[0170] To a stirred mixture of 4'-{[1-(4-methoxybenzoyl)-3-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (60 mg, 0.118 mmol, 1 equiv.) in CHCl (1 mL) was added 1,1-bis(acetyloxy)-3-oxo-3H-1l^[5],2-benzidaoxol-1-yl acetate (99.5 mg). The reaction was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (1 mL). The crude product was purified by preparative HPLC under the following conditions (Column: Kinetex EVO C18, 21.2*250 mm, 5 μm, Mobile phase A: water (0.05% TFA), Mobile phase B: ACN, Flow rate: 25 mL / min, Gradient: 47% B to 62% B in 10 min, 62% B, Wavelength: 254 nm, RT (min): 6.87, Run number: 0) to give 4'-{[1-(4-methoxybenzoyl)-3-(2,2,2-trifluoro-1,1-dihydroxyethyl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (3.8 mg, 5.91%) as a white solid. LC / MS: Calculated mass for CHFNO: 526.17, Found: 527.10 [M+H]. + . 1H NMR(300MHz,DMSO-d6)δ 7.85-7.90(m,3H),7.74(t,J = 7.8 Hz,2H),7.51(dd,J = 8.4,18.6 Hz,2H),6.95-7.19(m,5H),4.19(s,1H),4.09(d,J = 12.3 Hz,1H),3.92(d,J = 11.4 Hz,1H),3.79(s,3H),3.70(s,3H),2.36-2.51(m,1H),1.97-2.01(m,1H). 19 F NMR(282MHz,DMSO-d6)δ -72.491,-74.626,-78.644.

[0171] Preparation of 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(4-methoxybenzoyl)-N-(methylsulfonyl)pyrrolidine-3-sulfonamide; [4'-{[3-(methanesulfonylsulfamoyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile] (Compound 10) [ka]

[0172] To a mixture of potassium (benzenesulfonyl)sulfanide (5 g, 23.549 mmol, 1 equiv.) in CHCN (50 mL, 951.209 mmol, 40.39 equiv.) was added 1-(bromomethyl)-4-methoxybenzene (3.14 g, 15.617 mmol, 0.66 equiv.). The mixture was stirred at room temperature for 1 h. The desired product could be detected by TLC. The resulting mixture was extracted with EtOAc (50 mL) and HO (50 ml). The combined organic layers were washed with water (3 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 1-methoxy-4-{[(4-methylbenzenesulfonyl)sulfanyl]methyl}benzene (3.8 g, 52.32%) as a colorless oil.

[0173] To a mixture of methyl 1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (1.7 g, 6.457 mmol, 1 equiv.) in THF (20 mL, 246.855 mmol, 38.23 equiv.) was added LiHMDS (1.62 g, 9.685 mmol, 1.5 equiv.) at −78° C. The mixture was stirred at −78° C. for 1 h. To the mixture was added 1-methoxy-4-{[(4-methylbenzenesulfonyl)sulfanyl]methyl}benzene (2.99 g, 9.685 mmol, 1.5 equiv.) at −78° C. The mixture was stirred at −78° C. for 0.5 h. The entire process was carried out under a nitrogen atmosphere. The desired product could be detected by LCMS. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (50 mL) and HO (50 ml). The combined organic layers were washed with brine (3 x 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give methyl 1-(4-hydroxybenzoyl)-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyrrolidine-3-carboxylate (1.8 g, 49.74%) as a yellow oil. LC / MS: C 22 H 25 Calculated mass of NO5S: 415.15, Measured mass: 416.05 [M+H] +

[0174] To a mixture of methyl 1-(4-methoxybenzoyl)-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyrrolidine-3-carboxylate (1.5 g, 3.610 mmol, 1 equiv.) was added trifluoroacetaldehyde (20 mL, 204.032 mmol, 56.52 equiv.). The mixture was stirred at 60° C. for 30 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give methyl 1-(4-methoxybenzoyl)-3-sulfanylpyrrolidine-3-carboxylate (1.5 g, 140.68%) as a black oil. LC / MS: calculated mass for CHNOS: 295.09, found: 296.05 [M+H]+

[0175] To a mixture of methyl 1-(4-hydroxybenzoyl)-3-sulfanylpyrrolidine-3-carboxylate (1.5 g, 5.332 mmol, 1 equiv.) in MeOH (15 mL, 370.482 mmol, 72.95 equiv.), ammonium carbamate (0.79 g, 10.158 mmol, 2 equiv.) and (acetyloxy)(phenyl)-l^[3]-iodanyl acetate (5.73 g, 17.776 mmol, 3.5 equiv.) were added. The mixture was stirred at 50°C for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (0:1) to give methyl 1-(4-methoxybenzoyl)-3-sulfamoylpyrrolidine-3-carboxylate (650 mg, 35.38%) as a pale yellow oil. LC / MS: C 14 H 18 Calculated mass of N2O6S: 342.09, Measured mass: 343.10 [M+H] +

[0176] To a mixture of methyl 1-(4-methoxybenzoyl)-3-sulfamoylpyrrolidine-3-carboxylate (640 mg, 1.869 mmol, 1 equiv.) in THF (8 mL, 98.742 mmol, 52.82 equiv.) was added LiBH4 (162.86 mg, 7.476 mmol, 4 equiv.). The mixture was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1), to give 3-(hydroxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-sulfonamide (310 mg, 50.12%) as a pale yellow oil. LC / MS: C 13 H 18 Calculated mass of N2O5S: 314.09, Measured mass: 315.00 [M+H]+

[0177] To a mixture of 3-(hydroxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-sulfonamide (20 mg, 0.064 mmol, 1 equiv.) in CHCl (2.00 mL, 31.649 mmol, 494.51 equiv.), methanesulfonyl chloride (10.93 mg, 0.096 mmol, 1.5 equiv.) and EtN (12.88 mg, 0.128 mmol, 2 equiv.) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The reaction was monitored by TLC. The mixture was concentrated under reduced pressure to give (1-(4-methoxybenzoyl)-3-(N-(methylsulfonyl)sulfamoyl)pyrrolidin-3-yl)methyl methanesulfonate (20 mg) as a brown oil.

[0178] To a mixture of (1-(4-methoxybenzoyl)-3-(N-(methylsulfonyl)sulfamoyl)pyrrolidin-3-yl)methyl methanesulfonate (20 mg, 0.051 mmol, 1 equiv.) in THF (1 mL, 12.343 mmol, 242.19 equiv.), 4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile (9.95 mg, 0.051 mmol, 1 equiv.) and TEA (10.31 mg, 0.102 mmol, 2 equiv.) were added. The mixture was stirred at 60°C for 2 hours. The desired product could be detected by LCMS. The mixture was purified by preparative HPLC under the following conditions (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 70% B, 70% B in 7 min, wavelength: 254 nm, RT1 (min): 6, run number: 0) to give 4'-{[3-(methanesulfonylsulfamoyl)-1-(4-methoxybenzoyl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (3.5 mg, 11.64%) as an off-white solid.

[0179] LC / MS:C 27 H 27 Calculated mass of N3O7S2: 569.13, Measured mass: 570.00 [M+H] +. 1 H NMR(300MHz,DMSO-d6)δ 7.79-7.98(m,6H),7.46-7.67(m,4H),6.87-7.00(m,2H),4.32-4.43(m,1H),3.91-3.91(m ,1H),3.76-3.81(m,4H),3.66-3.69(m,3H),3.03(s,3H),2.44-2.64(m,3H),1.25(s,2H).

[0180] Preparation of 4'-((1-(4-methoxybenzoyl)-3-(S-methylsulfonimidoyl)pyrrolidin-3-yl)methoxy)-[1,1'-biphenyl]-4-carbonitrile and [4'-({3-[imino(methyl)oxo-λ6-sulfanyl]-1-(4-methoxybenzoyl)pyrrolidin-3-yl}methoxy)-[1,1'-biphenyl]-4-carbonitrile] (Compound 9) [ka]

[0181] To a mixture of 1-tert-butyl 3-methylpyrrolidine-1,3-dicarboxylate (5 g, 21.808 mmol, 1 equiv.) in THF (100 mL, 1234.277 mmol, 56.60 equiv.) was added LDA (9.35 g, 87.232 mmol, 4 equiv.), and the mixture was stirred at −78° C. Dimethyl disulfide (8.22 g, 87.232 mmol, 4 equiv.) was added to the mixture at −78° C. The mixture was stirred at room temperature for 12 h. The desired product could be detected by LCMS. The reaction was quenched with saturated NH4Cl (aq.) at room temperature. The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (5:1) to give 1-tert-butyl 3-methyl 3-(methylsulfanyl)pyrrolidine-1,3-dicarboxylate (2.9 g, 45.41%) as a brown oil. LC / MS: C 12 H 21Calculated mass of NO4S: 275.12, Measured mass: 176.05 [M+H-100] +

[0182] Step 1: To a mixture of 1-tert-butyl 3-methyl 3-(methylsulfanyl)pyrrolidine-1,3-dicarboxylate (1 g, 3.632 mmol, 1 equiv.) in CHCl (6 mL, 94.384 mmol, 25.99 equiv.), TFA (6 mL, 80.778 mmol, 22.24 equiv.) was added and stirred at room temperature for 2 h. Step 2: To the residue of p-anisic acid (0.50 g, 3.269 mmol, 0.9 equiv.), SOCl (10 mL, 137.861 mmol, 37.96 equiv.) was added. The mixture was stirred at 80 °C for 2 h. Step 3: The mixture of Steps 1 and 2 was concentrated under reduced pressure. To the residue from Step 1 in DCM (15 mL, 235.959 mmol, 64.97 equiv) was added the residue from Step 2 and TEA (14.50 mL, 104.311 mmol, 28.72 equiv). The mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was extracted with CHCl (10 mL). The combined organic layers were washed with water (3×20 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give methyl 1-(4-methoxybenzoyl)-3-(methylsulfanyl)pyrrolidine-3-carboxylate (500 mg, 42.14%) as a brown oil. LC / MS: C 15 H 19 Calculated mass of NO4S: 309.10, Measured mass: 310.05 [M+H] +

[0183] To a mixture of methyl 1-(4-methoxybenzoyl)-3-(methylsulfanyl)pyrrolidine-3-carboxylate (450 mg, 1.455 mmol, 1 equiv.) in CHOH (10 mL, 246.988 mmol, 169.81 equiv.) was added LiBH (126.72 mg, 5.820 mmol, 4 equiv.). The mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (10 mL). The combined organic layers were washed with water (3×10 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure to give [1-(4-methoxybenzoyl)-3-(methylsulfanyl)pyrrolidin-3-yl]methanol (440 mg, 101.30%) as a pale yellow oil. LC / MS: C 14 H 19 Calculated mass of NO3S: 281.11, Measured mass: 282.05 [M+H] +

[0184] To a mixture of [1-(4-methoxybenzoyl)-3-(methylsulfanyl)pyrrolidin-3-yl]methanol (360 mg, 1.279 mmol, 1 equiv.) in toluene (10 mL, 0.109 mmol, 0.08 equiv.), 4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile (499.55 mg, 2.558 mmol, 2 equiv.), (NE)-N-[[(E)-(piperidin-1-yl)carbonyl]imino]piperidine-1-carboxamide (807.06 mg, 3.197 mmol, 2.5 equiv.), and tributylphosphine (647.15 mg, 3.197 mmol, 2.5 equiv.) were added. The mixture was stirred at 60°C for 2 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 4'-{[1-(4-methoxybenzoyl)-3-(methylsulfanyl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (600 mg, 97.09%) as a pale yellow oil. LC / MS: C 27 H 26Calculated mass of N2O3: 458.17, Measured mass: 459.10 [M+H] +

[0185] To a mixture of 4'-{[1-(4-methoxybenzoyl)-3-(methylsulfanyl)pyrrolidin-3-yl]methoxy}-[1,1'-biphenyl]-4-carbonitrile (100 mg, 0.218 mmol, 1 equiv.) in CHOH (2 mL, 49.398 mmol, 226.53 equiv.), (acetyloxy)(phenyl)-λ-iodanyl acetate (175.60 mg, 0.545 mmol, 2.5 equiv.) and ammonium carbamate (34.05 mg, 0.436 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 3 hours. The desired product could be detected by LCMS. The mixture was purified by preparative HPLC under the following conditions (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 70% B, 70% B in 7 min, wavelength: 254 nm, RT1 (min): 6.3, run number: 0) to give 4'-({3-[imino(methyl)oxo-λ6-sulfanyl]-1-(4-methoxybenzoyl)pyrrolidin-3-yl}methoxy)-[1,1'-biphenyl]-4-carbonitrile (6.1 mg, 5.65%) as a white solid.

[0186] LC / MS:C 27 H 27 Calculated mass of N3O4S: 489.17, Measured mass: 490.10 [M+H] + . 1 H NMR (300MHz, methanol-d4)δ 7.80(s,4H),7.70-7.72(d,2H),7.54-7.57(m,2H),7.14-7.21(m,2H),7.01(d,J = 7.8 Hz,2H),4.12-4.57(m,3H),3.66-4.12(m,6H),3.19-3.23(m,3H),2.75(br,1H),2.31-2.46(m,1H).

[0187] Preparation of 3-((4-(3-carboxybicyclo[1.1.1]pentan-1-yl)phenoxy)methyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (compound 11) [ka]

[0188] To a mixture of methyl 1-(4-methoxybenzoyl)-3-{4-[3-(methoxycarbonyl)bicyclo[1.1.1]pentan-1-yl]phenoxymethyl}pyrrolidine-3-carboxylate (70 mg, 0.142 mmol, 1 equiv.) in CHCN (2 mL, 38.048 mmol, 268.27 equiv.) and HO (0.01 mL, 0.555 mmol, 3.91 equiv.), trimethyl(sodium oxy)silane (0.245 mL, 0.002 mmol, 1.5 equiv.) was added. The mixture was stirred at room temperature for 12 h. The resulting mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC under the following conditions (Column: XBridge Shield RP18 OBD column, 19*250 mm, 10 μm, Mobile phase A: water (10 mmol / L NH4HCO3), Mobile phase B: ACN, Flow rate: 25 mL / min, Gradient: 5% B to 25% B, 25% B in 7 min, Wavelength: 254 nm, RT1 (min): 5.3 / 6.9, Run number: 0) to give 3-(4-{3-carboxybicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (20.1 mg, 30.03%) as a white solid.

[0189] LC / MS: Mass of C26H27NO7 Calculated value: 465.18, Actual value: 466.15 [M+H]+, 1H NMR (300MHz, methanol-d4)δ 7.51-7.56(m,2H),7.12-7.19(m,2H),6.99-7.01(m,2H),6.82-6.93(m,2H),4.19-4. 33(m,1H),4.11-3.99(m,2H),3.86(s,3H),3.67-3.78(m,3H),2.42(s,1H),2.25(d,J = 3.9Hz,7H).

[0190] Preparation of 3-(4-{3-carbamoylbicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (compound 8) [ka]

[0191] A mixture of methyl 3-(4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxylate (100 mg, 0.458 mmol, 1 equiv.) in MeOH (3 mL, 105.690 mmol, 230.67 equiv.) with NH3 (g) was stirred at 80 °C for 12 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-(4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxamide (95 mg, 91.81%) as a brown solid. LC / MS: mass calculated for CHNO: 203.09, found: 204.10 [M+H]

[0192] To a mixture of methyl 3-(iodomethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (237 mg, 0.588 mmol, 1 equiv.) in DMF (4 mL, 51.686 mmol, 87.94 equiv.), 3-(4-hydroxyphenyl)bicyclo[1.1.1]pentane-1-carboxamide (149.32 mg, 0.735 mmol, 1.25 equiv.) and CsCO (383.02 mg, 1.176 mmol, 2 equiv.) were added. The mixture was stirred at 80 °C for 2 h. The desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (5 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA: 0:1) to give methyl 3-(4-{3-carbamoylbicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (85 mg, 25.08%) as a light brown solid. LC / MS: mass calculated for C27H30N2O6: 478.21, found: 479.15 [M+H]+

[0193] To a mixture of methyl 3-(4-{3-carbamoylbicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylate (25 mg, 0.052 mmol, 1 equiv.) in CHCN (1 mL, 19.024 mmol, 364.16 equiv.) and HO (0.01 mL, 0.555 mmol, 10.63 equiv.), trimethyl(sodium oxy)silane (0.078 mL, 0.001 mmol, 1.5 equiv.) was added. The mixture was stirred at room temperature for 12 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture was purified by preparative HPLC under the following conditions (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: 15% B to 42% B, 42% B in 9 min, wavelength: 254 nm, RT1 (min): 7, run number: 0) to give 3-(4-{3-carbamoylbicyclo[1.1.1]pentan-1-yl}phenoxymethyl)-1-(4-methoxybenzoyl)pyrrolidine-3-carboxylic acid (3.3 mg, 13.58%) as a white solid.

[0194] LC / MS: Mass of C26H28N2O6 Calculated value: 464.19, Actual value: 465.10 [M+H]+, 1H NMR (300MHz, methanol-d4)δ 7.50-7.55(m,2H),7.12-7.19(m,2H),6.97-7.02(m,2H),6.83-6.93(m,2H),3 .93-4.32(m,3H),3.86(s,3H),3.61-3.78(m,3H),2.38-2.47(m,1H),2.24(d,J = 3.6 Hz,6H),2.14(d,J=6 Hz,1H).

[0195] Preparation of 3-(((4'-cyano-[1,1'-biphenyl]-4-yl)oxy)methyl)-1-(2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl)pyrrolidine-3-carboxylic acid (compound 2) [ka]

[0196] To a mixture of 1-tert-butyl 3-methylpyrrolidine-1,3-dicarboxylate (2 g, 8.723 mmol, 1 equiv.) in THF (100 mL, 1234.277 mmol, 141.50 equiv.) was added LDA (1.40 g, 13.085 mmol, 1.5 equiv.) at −78° C. The mixture was stirred at the same temperature under N atmosphere for 1 h. To the above mixture was added diiodomethane (3.04 g, 11.340 mmol, 1.3 equiv.) at −78° C. The mixture was stirred at room temperature for 1 h. The reaction was monitored by TLC. To the mixture was added HO (100 mL) and extracted with EtOAc (80 mL×3). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4, filtered and concentrated to give 1-tert-butyl 3-methyl 3-(iodomethyl)pyrrolidine-1,3-dicarboxylate (2 g, 62.10%) as a yellow oil.

[0197] Step 2: To a mixture of 1-tert-butyl 3-methyl 3-(iodomethyl)pyrrolidine-1,3-dicarboxylate (2 g, 5.417 mmol, 1 equiv.) and 4'-hydroxy-[1,1'-biphenyl]-4-carbonitrile (1.59 g, 8.125 mmol, 1.5 equiv.) in DMF (50 mL, 646.077 mmol, 119.27 equiv.), K2CO3 (74.87 mg, 0.542 mmol, 2 equiv.) was added. The mixture was stirred at 80 °C for 16 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc. HO (100 mL) was added to the filtrate, and the mixture was extracted with EtOAc (80 mL × 3). The combined organics were washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to give 1-tert-butyl 3-methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-1,3-dicarboxylate (2 g, 84.58%) as a brown oil. LC / MS: mass calculated for C25H28N2O5: 436.51, found: 381.15 [M-tBu] +

[0198] Step 3: To a mixture of 1-tert-butyl 3-methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-1,3-dicarboxylate (3 g, 6.873 mmol, 1 equiv.) in DCM (50 mL, 786.530 mmol, 114.44 equiv.), TFA (0.2 mL, 2.693 mmol, 117.53 equiv.) was added. The mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN (0.05% TFA) in water, 30% to 80% gradient in 30 min; detector, UV 254 nm) to give methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (1.2 g, 51.90%) as a brown, yellow oil. LC / MS: mass calculated for C20H20N2O3: 336.39; found: 337.10 [M+H]. +

[0199] Step 4: To a mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethanone (500 mg, 1.976 mmol, 1 equiv.) in i-PrOH (10 mL, 130.841 mmol, 66.21 equiv.) was added NaBH (149.52 mg, 3.952 mmol, 2 equiv.). HCl (1 M, 15 mL) was added to the mixture, which was then extracted with MTBE (10 mL x 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated to give 1-(4-bromophenyl)-2,2,2-trifluoroethanol (200 mg, 39.68%) as a colorless oil. The reaction was monitored by TLC. LC / MS: calculated mass for CHBrFO: 225.03.

[0200] Step 5: To a mixture of 1-(4-bromophenyl)-2,2,2-trifluoroethanol (30 mg, 0.118 mmol, 1 equiv.) and 2,6-lutidine (18.91 mg, 0.177 mmol, 1.5 equiv.) in DCE (1 mL, 12.633 mmol, 107.39 equiv.) was added TfO (49.78 mg, 0.177 mmol, 1.5 equiv.) at −15 °C. The mixture was stirred at room temperature for 1 h. DCM (5 mL) was added to the mixture and washed with HO, HCl (1 M), and brine. The organic layer was dried over NaSO, filtered, and concentrated to give 1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (30 mg, 65.88%) as a colorless oil. The reaction was monitored by TLC. LC / MS: Calculated mass for C9H5BrF6O3S: 387.09.

[0201] Step 6: To a mixture of methyl 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (200 mg, 0.595 mmol, 1 equiv.) and 1-(4-bromophenyl)-2,2,2-trifluoroethyl trifluoromethanesulfonate (690.43 mg, 1.785 mmol, 3 equiv.) in cyclohexane (5 mL, 0.012 mmol, 0.20 equiv.), DMAP (72.64 mg, 0.595 mmol, 1 equiv.) and K2CO3 (164.34 mg, 1.190 mmol, 2 equiv.) were added. The mixture was stirred at 75 °C for 16 h. The desired product could be detected by LCMS. DCM (10 mL) was added to the mixture, which was washed with HO and brine, dried over Na2SO4, and concentrated. The residue was purified by reverse flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.05% TFA) in water, 50% to 100% gradient in 20 min; detector, UV 254 nm) to give methyl 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (40 mg, 11.73%) as a colorless oil. LC / MS: mass calculated for CHBrFNO: 572.09; found: 573.20 [M+H]. + .

[0202] Step 7: To a mixture of methyl 1-[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]pyrrolidine-3-carboxylate (25 mg, 0.044 mmol, 1 equiv.) in MeOH (1 mL, 24.699 mmol, 566.50 equiv.), NaOMe (4.71 mg, 0.088 mmol, 2 equiv.), di-tert-butyl[2', 4',6'-Tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane, {2'-amino-[1,1'-biphenyl]-2-yl}paradiomethanesulfonic acid (3.46 mg, 0.004 mmol, 0.1 equiv.) and di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (1.85 mg, 0.004 mmol, 0.1 equiv.) were added. The mixture was stirred at 100°C for 16 hours. The desired product could be detected by LCMS. The mixture was purified by preparative HPLC under the following conditions (Column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm, Mobile phase A: water (0.05% TFA), Mobile phase B: ACN, Flow rate: 25 mL / min, Gradient: 50% B to 80% B in 7 min, Wavelength: 254 nm, RT (min): 6, Run number: 0) to give 3-[({4'-cyano-[1,1'-biphenyl]-4-yl}oxy)methyl]-1-[2,2,2-trifluoro-1-(4-methoxyphenyl)ethyl]pyrrolidine-3-carboxylic acid, trifluoroacetic acid (2.6 mg, 9.46%) as a white solid.

[0203] LC / MS:C 30 H 26 Calculated mass of F6N2O6: 510.18, Measured mass: 511.20 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ 7.80-7.93(m,4H),7.70(d,J = 9.0 Hz,2H),7.40 - 7.25(m,2H),7.13-7.01(m,2H),7.00 - 6.90(m,2H),4.37-4.22(m,1H),4.12(s,2H),3.77(d,J = 3.0 Hz,3H),3.05-2.56(m,4H),2.25 - 2.12(m,1H),1.93 - 1.77(m,1H). 19 F NMR (282 MHz, methanol-d4) δ -68.112, -74.071.

[0204] 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]oxazepine [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.158 mmol, 1 equiv.) and 1,5-dimethylpyrazole-4-carbaldehyde (40 mg, 0.316 mmol, 2 equiv.) in CHCl (1 mL) was added NaBH(OAc) (70 mg, 0.316 mmol, 2 equiv.) and AcOH (40 μL) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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, Run number: 0) 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, 21.42%) as a white solid. LC / MS:C 23H 23 Calculated mass of ClFNO: 424.2, Found: 425.1 [M+H] + . 1 H NMR(300MHz, methanol-d4)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 = 3.3 Hz,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, methanol-d4) δ −126.0.

[0205] 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]oxazepine [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, 0.080 mmol, 1 equiv.) in CHCl (2 mL) was added TFA (0.4 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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: 45% B to 75% B, 75% B in 7 min, Wavelength: 254 nm, RT1 (min): 5, Run number: 0) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-(1H-pyrazol-4-ylmethyl)-3,5-dihydro-2H-1,4-benzoxazepine (7.2 mg, 22.22%) as a white solid. LC / MS:C 21 H 18 Calculated mass of ClFNO: 396.1, Found: 397.0 [M+H] + . 1 H NMR(300MHz,methanol-d4)δ 7.59-7.62(br,2H),7.51(d,J = 2.7 Hz,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 = 3.3 Hz, 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, methanol-d4) δ −126.2.

[0206] 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 [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, 0.130 mmol, 1 equiv.) and 5-fluoro-1H-pyrrolo[2,3-b]pyridine (27 mg, 0.195 mmol, 1.5 equiv.) in dioxane (2 mL) was added trans-cyclohexane-1,2-diamine (7 mg, 0.065 mmol, 0.5 equiv.), CuI (7 mg, 0.039 mmol, 0.3 equiv.), and KPO (83 mg, 0.390 mmol, 3 equiv.) under a nitrogen atmosphere. The resulting mixture was stirred overnight at 110 °C under a nitrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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; run number: 0) 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, 8.76%) as a white solid. LC / MS:C 22 H 19 Calculated mass of ClFN5O2: 439.1, Found: 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 = 2.7 Hz,1H),6.74(d,J = 3.7 Hz,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.

[0207] 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 [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, 0.114 mmol, 1 equivalent). The resulting mixture was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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; run number: 0) 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, 10.26%) as a white solid. LC / MS:C 21 H 17 Calculated mass of ClFN5O2: 425.1, Found: 426.0. [M+H] + . 1 H NMR(400MHz,methanol-d4)δ 8.25-8.31(m,3H),7.77-7.85(m,3H),7.57(d,J = 2.8 Hz,1H),6.70(d,J = 3.6 Hz,1H),4.19-4.21(m,2H),3.98(s,2H),3.59(s,2H),3.22-3.24(m,2H). 19F NMR (376 MHz, methanol-d4) δ −140.0.

[0208] 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, 0.130 mmol, 1 equiv.) and 1-benzothiophen-3-ylboronic acid (35 mg, 0.195 mmol, 1.5 equiv.) in THF (0.8 mL) and HO (0.2 mL) was added KCO (36 mg, 0.260 mmol, 2 equiv.) and Pd(PPh) (15 mg, 0.013 mmol, 0.1 equiv.). The mixture was stirred at 80 °C under a nitrogen atmosphere for 16 h. The desired product could be detected by LCMS. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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, run number: 0) 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, 10.34%) as an off-white solid. LC / MS:C 23 H 20 Calculated mass of ClN3O2: 437.1, Found: 438.1 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ 8.54(s,2H),8.08(d,J = 6.0 Hz,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).

[0209] 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 [ka] A solution of 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (50 mg, 0.130 mmol, 1 equiv.) in toluene (1.5 mL) was treated with 6-fluoro-1,2,3,4-tetrahydroquinoline (24 mg, 0.156 mmol, 1.2 equiv.), Pd(OAc) (1 mg, 0.004 mmol, 0.03 equiv.), tri-tert-butylphosphonium tetrafluoroboranide (2 mg, 0.008 mmol, 0.06 equiv.), and t-BuONa (25 mg, 0.260 mmol, 2 equiv.) under a nitrogen atmosphere at 110 °C for 16 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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, Run number: 0) 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, 12.23%) as a white solid. LC / MS:C 24 H 24Calculated mass of ClFN4O2: 454.2, Found: 455.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 8.49(s,2H),7.15(d,J = 2.4 Hz,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 = 5.7 Hz,2H),3.02-3.03(m,2H),2.75(t,J = 5.7 Hz,2H),1.85-1.93(m,2H). 19 F(282MHz,DMSO-d6)δ -125.5.

[0210] 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 [ka] To a stirred solution of 1,3-oxazol-5-ylmethyl methanesulfonate (56 mg, 0.316 mmol, 2 equiv.) and 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.158 mmol, 1.00 equiv.) in THF (1 mL) was added EtN (35 mg, 0.316 mmol, 2 equiv.). The resulting mixture was stirred at 70° C. for 16 hours. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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 in 7 min, Wavelength: 254 nm, RT1 (min): 6, Run number: 0) 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, 6.59%) as a white solid. LC / MS:C 21 H 17 Calculated mass of ClFN3O2: 397.1, Measured mass: 398.0 [M+H] + . 1 H NMR(300MHz,methanol-d4)δ 8.20(s,1H),7.50(d,J = 2.7 Hz,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, methanol-d4) δ −126.1.

[0211] 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 [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, 0.048 mmol, 1 equiv.) in DMF (2 mL) was added pyridine hydrobromide (50 mg, 0.288 mmol, 6 equiv.). The mixture was stirred at 60° C. for 24 hours. The desired product could be detected by LCMS. The mixture was purified by preparative HPLC under the following conditions (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; run number: 0) 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-white solid. LC / MS:C 24 H 16 Calculated mass of ClF4N3O3: 505.1, Measured mass: 506.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.55(br,1H),8.10(d,J = 4.0 Hz,1H),7.82 - 7.88(m,2H),7.40 - 7.55(m,3H),7.11(m,1H),6.74(d,J = 4.0 Hz,1H),6.44(s,1H),6.32(d,J = 8.0 Hz,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.

[0212] 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-carboxamide [f][1,4]oxazepine [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, 0.077 mmol, 1 equiv.) and CH3NH2·HCl (11 mg, 0.154 mmol, 2 equiv.) in DMF (1 mL) was added HATU (45 mg, 0.115 mmol, 1.5 equiv.) and DIEA (25 mg, 0.193 mmol, 2.5 equiv.). The resulting mixture was stirred at room temperature for an additional 2 h. The desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified using the following conditions (column: XBridge Prep OBD C 18 Purification by preparative HPLC using a 30*150 mm, 5 μm column, 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, run number: 0) gave 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, 9.16%) as a white solid. LC / MS:C 26 H 29 Calculated mass of ClFN3O2: 469.1, Found: 469.9 [M+H] + 1H 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 = 7.8 Hz,2H)2.13-2.18(m,1H),1.75-1.76(m,1H),1.40-1.67(m,8H). 19 F NMR (400 MHz, methanol-d4) δ −126.1.

[0213] 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]oxazepine [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, 0.109 mmol, 1 equiv.) in CHCl (1 mL), CHNHHCl (15 mg, 0.218 mmol, 2 equiv.), PyBOP (86 mg, 0.164 mmol, 1.5 equiv.), and DIEA (30 mg, 0.218 mmol, 2 equiv.) were added. The mixture was stirred at room temperature for 16 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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 in 7 min; wavelength: 254 nm; RT1 (min): 6; run number: 0) 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, 29.05%) as a white solid. LC / MS:C 26 H 29 Calculated mass of ClFN3O2: 469.1, Found: 469.9 [M+H] + 1 H NMR(300MHz,DMSO-d6)δ 7.72(d,J = 3.2 Hz,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 = 6.9 Hz,2H),2.01-2.08(m,1H),1.68-1.78(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, methanol-d4) δ -123.5.

[0214] 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 [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, 0.113 mmol, 1 equiv.) and acetohydroxamic acid (25 mg, 0.339 mmol, 3 equiv.) in DMSO (1 mL) was added KCO (80 mg, 0.565 mmol, 5 equiv.). The resulting mixture was stirred at 80 °C overnight. The desired product could be detected by LCMS. The solid was filtered. The filtrate was purified by preparative HPLC under the following conditions (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; run number: 0) 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, 16.30%) as a white solid.

[0215] LC / MS:C 22 H 18 Calculated mass of ClFN4O2: 424.1, Measured mass: 425.0 [M+H] + .

[0216] 1H NMR(300MHz,DMSO-d6)δ 12.07(s,1H),7.98(d,J = 2.4 Hz,1H),7.71(d,J = 3.0 Hz,1H),7.60(d,J = 2.7 Hz,1H),7.54(d,J = 9.0 Hz,1H),7.39 - 7.45(m,3H),7.07(t,J = 9.1 Hz,1H),6.69(d,J = 3.3 Hz,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.

[0217] 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 [ka] The title compound was prepared according to Method D. However, the crude product was purified by preparative HPLC under the following conditions (Column: Xselect CSH C18 OBD column 30*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, Run number: 0) 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, 7.35%) as a pale yellow solid. LC / MS:C 20 H 17 Calculated mass of ClN6O2: 408.1, Found: 409.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.58(d,J = 2.6 Hz,1H),8.24 - 8.41(m,4H),8.14(s,1H),7.93(s,1H),6.98(d,J = 4.0 Hz,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.

[0218] Method N: 4'-chloro-5-fluoro-1'-[(2-methoxypyridin-4-yl)methyl]-1,6'-biindole [ka] To a stirred mixture of 6-bromo-4-chloro-1-[(2-methoxypyridin-4-yl)methyl]indole (210 mg, 0.597 mmol, 1 equiv.) and 5-fluoro-1H-indole (160 mg, 1.194 mmol, 2 equiv.) in dioxane (6 mL), KCO (165 mg, 1.194 mmol, 2 equiv.), CuI (6 mg, 0.030 mmol, 0.05 equiv.), and DMEDA (11 mg, 0.119 mmol, 0.2 equiv.) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (10:1) to give 4'-chloro-5-fluoro-1'-[(2-methoxypyridin-4-yl)methyl]-1,6'-biindole (170 mg, 67.76%) as a white solid. LC / MS:C 23 H 17 Calculated mass of ClFNO: 405.1, Found: 406.0 [M+H] + . 1H NMR(400MHz,methanol-d4)δ 8.06(d,J = 5.4 Hz,1H),7.52(d,J = 3.2 Hz,1H),7.46(d,J = 3.2 Hz,1H),7.34-7.43(m,1H),7.25 - 7.27(m,2H),7.19(s,1H),6.86(t,J = 9.1 Hz,1H),6.70 - 6.71(m,2H),6.61(s,1H),6.52(s,1H),5.48(s,2H),3.87(s,3H). 19 F NMR (400 MHz, methanol-d4) δ −126.53.

[0219] Method R: Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.158 mmol, 1 equiv.) in THF (3 mL) was added 5-(chloromethyl)-4-methoxypyrimidine (273 mg, 0.474 mmol, 3.00 equiv.) and EtN (32 mg, 0.316 mmol, 2 equiv.) in portions at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). The crude product was purified by preparative HPLC under the following conditions (Column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n, Mobile phase A: water (0.1% FA), 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, Run number: 0) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (2.2 mg, 3.14%) as an off-white solid.

[0220] LC / MS:C 23 H 20 Calculated mass of ClFN4O2: 438.13, Measured mass: 439.05 [M+Na] + . 1 H NMR(300MHz,DMSO-d6)δ 8.71(s,1H),8.48(s,1H),7.72(d,J = 3.3 Hz,1H),7.63(d,J = 2.7 Hz,1H),7.49-7.53(m,1H),7.41-7.46(m,2H),7.01-7.08(m,1H),6.69(d,J = 3.3 Hz,1H),4.18-4.21(m,2H),3.98(s,2H),3.90(s,3H),3.65(s,2H),3.08-3.11(m,2H). 19 F NMR (282 MHz, methanol-d4) δ -126.14.

[0221] Method P: Preparation of 9-chloro-7-(5-fluoroindazol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine [ka] To a mixture of 9-chloro-7-(5-fluoroindazol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.157 mmol, 1 equiv.) and 2-methoxypyrimidine-5-carbaldehyde (43 mg, 0.314 mmol, 2 equiv.) in MeOH (3 mL) was added NaBHCN (3 mg, 0.048 mmol, 3 equiv.). The mixture was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The mixture was filtered. The filtrate was purified by preparative HPLC under the following conditions (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: 40% B to 70% B, 70% B in 10 min; Wavelength: 254 nm; RT1 (min): 8.89; Run number: 0) to give 9-chloro-7-(5-fluoroindazol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (4.2 mg, 6.05%) as a pale yellow solid. LC / MS:C 22 H 19 Calculated mass of ClFN5O2: 439.1, Measured mass: 440.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 8.53(s,2H),8.37(d,J = 3.0 Hz,1H),7.80 - 7.90(m,1H),7.76(d,J = 3.0 Hz,1H),7.62 - 7.70(m,1H),7.58(d,J = 3.0 Hz,1H),7.31 - 7.41(m,1H),4.14 - 4.22(m,2H),4.00(s,2H),3.90(s,3H),3.67(s,2H),3.05(s,2H). 19 F NMR (282MHz, DMSO-d6)δ -119.1.

[0222] Method Q: Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4-[(4-methylpyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine [ka] To a mixture of 9-chloro-7-(5-fluoroindol-1-yl)-4-[(tributylstannyl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.161 mmol, 1 equiv.), Aphos (10 mg, 0.016 mmol, 0.10 equiv.), and Aphos PdG (4 mg, 0.015 mmol, 0.09 equiv.) in DMF (3 mL) was added 5-bromo-4-methylpyrimidine (42 mg, 0.241 mmol, 1.5 equiv.). The mixture was stirred at 100 °C under a nitrogen atmosphere for 16 h. The desired product could be detected by LCMS. The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel, mobile phase: MeCN (0.05% NH4HCO3) in water, 10% to 50% gradient in 15 min, detector: UV 254 nm. The crude product was purified by preparative HPLC under the following conditions: column: Xselect CSH C18 OBD column 30*150 mm 5 μm, mobile phase A: water (0.1% FA), mobile phase B: ACN, flow rate: 60 mL / min, gradient: 50% B to 80% B in 7 min, wavelength: 254 nm, RT (min): 5.87 to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(4-methylpyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (3.9 mg, 5.60%) as a white solid. LC / MS:C 23 H 20 Calculated mass for ClFNO: 422.1, found: 423.1 [M+H]. 1H NMR(300MHz,DMSO-d6)δ 8.92(s,1H),8.51(s,1H),7.71(d,J = 3.3 Hz,1H),7.64(d,J = 2.6 Hz,1H),7.53(d,J = 9.0,4.4 Hz,1H),7.44-7.40(m,2H),7.05(t,J = 9.2 Hz,1H),6.69(d,J = 3.2 Hz,1H),4.21(d,J = 5.7,2.9 Hz, 2H), 3.98 (s, 2H), 3.70 (s, 2H), 3.36 (s, 1H), 3.05-3.03 (m, 2H). 19 F NMR (282MHz, DMSO-d6)δ -123.62.

[0223] Characterization data for exemplary compounds prepared according to the above method are shown in Table (III). [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11]

[0224] Preparation of N-(5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidin-2-yl)methanesulfonamide [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, 1 equiv.) in CHCl (1 mL) was added methanesulfonyl chloride (20 μL, 0.236 mmol, 2.00 equiv.) and EtN (33 μL, 0.236 mmol, 2 equiv.) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LCMS. After concentration, the residue was purified by preparative HPLC under the following conditions (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 9 min, Wavelength: 254 nm, RT1 (min): 8.23, Run number: 0) 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, 7.43%) as a white solid. LC / MS:C 23 H 21 Calculated mass of ClFN5O3S: 501.1, Measured mass: 502.1 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ 11.31(s,1H),8.50(s,2H),7.72(d,J = 3.3 Hz,1H),7.64(d,J = 2.6 Hz,1H),7.49-7.53(m 1H),7.42-7.45(m,2H),7.02-7.14(m,1H),6.69(d,J = 3.2 Hz,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.

[0225] Preparation of 9-chloro-7-(6-fluoro-4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-4-((2-methoxypyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [ka] Methyl 2-[(5-fluoro-2-nitrophenyl)(methyl)amino]acetate To a stirred mixture of 2,4-difluoro-1-nitro (2 g, 12.571 mmol, 1 equiv.) and methyl 2-(methylamino)acetate hydrochloride (1.75 g, 12.571 mmol, 1 equiv.) in DMF (25 mL) was added DIEA (2.44 g, 18.857 mmol, 1.5 equiv.) at 0 °C. The resulting mixture was stirred at 0 °C for an additional 6 h and allowed to warm to room temperature. The mixture was stirred at room temperature overnight. To the mixture was added HO (30 mL), and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with water (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (10:1) to give methyl 2-[(5-fluoro-2-nitrophenyl)(methyl)amino]acetate (1.6 g, 52.55%) as a white solid.

[0226] 6-Fluoro-4-methyl-1,3-dihydroquinoxalin-2-one To a stirred mixture of methyl 2-[(5-fluoro-2-nitrophenyl)(methyl)amino]acetate (1 g, 4.129 mmol, 1 equiv.) and NH4Cl (2.21 g, 41.290 mmol, 10 equiv.) in EtOH (20 mL) was added HO (15 mL). To the above mixture, iron powder (2.31 g, 41.290 mmol, 10 equiv.) was added portionwise with stirring at 80 °C. The resulting mixture was stirred at 80 °C for 1 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (4 × 50 mL). The filtrate was concentrated to dryness under reduced pressure. The residue was triturated with EtOAc (50 mL) and filtered. The filter cake was washed with EtOAc (50 mL). The combined filtrate was concentrated under reduced pressure. Crude 6-fluoro-4-methyl-1,3-dihydroquinoxalin-2-one (0.75 g, 101%) was obtained as a white solid, which was used in the next step without further purification.

[0227] 7-Fluoro-1-methyl-3,4-dihydro-2H-quinoxaline To a stirred mixture of 6-fluoro-4-methyl-1,3-dihydroquinoxalin-2-one (500 mg, 2.775 mmol, 1 equiv.) and THF (15 mL) was added 1 M BH3 in THF (14 mL, 13.875 mmol, 5.0 equiv.) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 3 h under a nitrogen atmosphere. To the above mixture, 2 M aqueous HCl (12 mL) was added dropwise over 2 min at 70 °C. The resulting mixture was stirred at 70 °C for 20 min. The resulting mixture was cooled to room temperature and neutralized with aqueous Na2CO3. The resulting mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 7-fluoro-1-methyl-3,4-dihydro-2H-quinoxaline (180 mg, 39.03%) as a brown solid. Because the crude product was not stable, it was used in the next step without further purification.

[0228] 9-chloro-7-(6-fluoro-4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-4-((2-methoxypyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane To a stirred mixture of 7-fluoro-1-methyl-3,4-dihydro-2H-quinoxaline (36 mg, 0.217 mmol, 1 equiv.) and 7-bromo-9-chloro-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (100 mg, 0.260 mmol, 1.2 equiv.) in dioxane (2 mL), Cphos pdG (18 mg, 0.022 mmol, 0.1 equiv.), Cphos (10 mg, 0.022 mmol, 0.1 equiv.), and CsCO (141 mg, 0.434 mmol, 2 equiv.) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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): 5.87, Run number: 0) 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, 3.32%) as a white solid. LC / MS:C 24 H 25 Calculated mass of ClFN5O2: 469.2, Measured mass: 470.1 [M+H] + . 1H NMR(300MHz,DMSO-d6)δ 8.49(s,2H),7.03(d,J = 3.0 Hz,1H),6.80(d,J = 3.0 Hz,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 = 6.0 Hz, 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.

[0229] Preparation of bis(5-cyclopropyl-1H-indole) [ka]

[0230] tert-Butyl 5-cyclopropylindole-1-carboxylate To a mixture of tert-butyl 5-bromoindole-1-carboxylate (500 mg, 1.688 mmol, 1 equiv.) and cyclopropylboronic acid (188 mg, 2.194 mmol, 1.3 equiv.) in toluene (10 mL), Pd(OAc) (19 mg, 0.084 mmol, 0.05 equiv.), tricyclohexylphosphane (47 mg, 0.169 mmol, 0.1 equiv.), KPO (895 mg, 4.220 mmol, 2.5 equiv.), and HO (0.5 mL) were added. The mixture was stirred at 100 °C under a nitrogen atmosphere for 3 h. The desired product could be detected by LCMS. HO (20 mL) was added to the mixture, which was then extracted with EtOAc (3 × 15 mL). The organic layers were combined, washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (10:1) to give tert-butyl 5-cyclopropylindole-1-carboxylate (300 mg, 69.05%) as a red oil.

[0231] Bis(5-cyclopropyl-1H-indole) To a mixture of bis(tert-butyl 5-cyclopropylindole-1-carboxylate) (500 mg, 0.972 mmol, 1 equiv.) in CHCl (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 1 h. The desired product could be detected by LCMS. After concentration, the mixture was diluted with CHCl (20 mL) and washed with saturated aqueous NaHCO (20 mL) and brine (20 mL). The organic layer was dried over MgSO, filtered, and concentrated to give bis(5-cyclopropyl-1H-indole) (300 mg, 98.21%) as a yellow oil. The crude product was used in the next step without further purification.

[0232] Preparation of 4-((2-(1H-pyrazol-1-yl)pyrimidin-5-yl)methyl)-9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [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, 0.113 mmol, 1 eq.) and pyrazole (15 mg, 0.226 mmol, 2 eq.) in DMF was added KCO (31 mg, 0.226 mmol, 2 eq.). The resulting mixture was stirred at 140 °C overnight. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filtrate was purified by preparative HPLC under the following conditions: 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 78% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.23; Run number: 0) 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, 21.45%) as a white solid. LC / MS:C 25 H 20 Calculated mass of ClFNO: 474.1, Found: 475.1 [M+H] + 1 H NMR(300MHz,DMSO-d6)δ 8.79(s,2H),8.66(d,J = 2.1 Hz,1H),7.85(s,1H),7.70(d,J = 3.3 Hz,1H),7.63(d,J = 2.4 Hz,1H),7.51(d,J = 9.0 Hz,1H),7.42 - 7.44(m,2H),7.05(t,J = 9.3 Hz,1H),6.66(d,J = 3.3 Hz,1H),6.59(d,J = 2.7 Hz,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.

[0233] Preparation of 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4-((2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane [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, 0.113 mmol, 1 equiv.) and 1-methylpyrazol-4-ylboronic acid (28 mg, 0.226 mmol, 2 equiv.) in 1,4-dioxane (1 mL) and water (0.2 mL) was added KCO (31 mg, 0.226 mmol, 2 equiv.) and Pd(PPh) (13 mg, 0.011 mmol, 0.1 equiv.). The resulting mixture was stirred overnight at 80 °C under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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: 58% B to 88% B in 7 min, Wavelength: 254 nm, RT1 (min): 5.98, Run number: 0) 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, 25.50%) as a white solid. LC / MS:C 26 H 22 Calculated mass of 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 = 0.6 Hz,1H),7.71(d,J = 3.3 Hz,1H),7.62(d,J = 2.4 Hz,1H),7.50(d,J = 9.0 Hz,1H),7.42(d,J = 7.5 Hz,2H),7.02(t,J = 6.9 Hz,1H),6.68(d,J = 2.7 Hz,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.

[0234] Preparation of N-(5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidin-2-yl)acetamide [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, 0.120 mmol, 1 equiv.) in acetic anhydride (1 mL) was stirred at 140 °C overnight. After concentration, aqueous NH 3 ·H 2 O (2 mL) was added to the residue. The resulting mixture was stirred at room temperature for another 1 h. The desired product could be detected by LCMS. The aqueous layer was extracted with CHCl (3 × 2 mL). The combined organic layers were washed with brine (2 mL) and dried over anhydrous NaSO 4 . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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 9 min, Wavelength: 254 nm, RT1 (min): 8.23, Run number: 0) to give N-(5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidin-2-yl)acetamide (9.0 mg, 13.56%) as a white solid. LC / MS:C 24 H 21 Calculated mass of ClFN5O2: 465.1, Found: 466.0 [M+H] + 1 H NMR(300MHz,DMSO-d6)δ 10.54(s,1H),8.57(s,2H),7.71(d,J = 3.3 Hz,1H),7.63(d,J = 2.6 Hz,1H),7.51(d,J = 9.0 Hz,1H),7.47-7.37(m,2H),7.07(t,J = 9.2 Hz,1H),6.69(d,J = 3.2 Hz,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.

[0235] Preparation of methyl 5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)picolinate [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, 0.105 mmol, 1 equiv.) in THF (1 mL) was added 1 M aqueous LiOH (0.5 mL, 0.5 mmol, 5 equiv.) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The mixture was acidified to pH 6 with 1 M aqueous HCl. The aqueous layer was extracted with CHCl (3 × 2 mL). The combined organic layers were washed with brine (2 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC under the following conditions (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: 27% B to 57% B, 57% B in 7 min, Wavelength: 254 nm, RT1 (min): 5.87, Run number: 0) 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, 14.91%) as a white solid. LC / MS:C 24 H 19 Calculated mass of ClFN3O3: 451.1, Measured mass: 452.1 [M+H] + 1H NMR(300MHz,DMSO-d6)δ 8.57(s,1H),7.97(d,J = 8.0 Hz,1H),7.85(d,J = 8.1 Hz,1H),7.72(d,J = 3.3 Hz,1H),7.64(d,J = 2.6 Hz,1H),7.39-7.51(m,2H),7.35(d,J = 2.7 Hz,1H),7.14-7.02(m,1H),6.68(d,J = 3.3 Hz,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.

[0236] Preparation of 4-((2-(1H-tetrazol-5-yl)pyrimidin-5-yl)methyl)-9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [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, 0.115 mmol, 1 equiv.) and NaN (22 mg, 0.345 mmol, 3 equiv.) in water (2 mL), ZnCl (47 mg, 0.345 mmol, 3 equiv.) and 2-(trimethylazaniumyl)acetate (2 mg, 0.012 mmol, 0.1 equiv.) were added. The resulting mixture was stirred at room temperature for 3 days. The desired product could be detected by LCMS. The precipitated solid was collected by filtration and washed with water (3 × 2 mL). The crude product (30 mg) was purified by preparative HPLC under the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 25% B to 55% B in 7 min; wavelength: 254 nm; RT1 (min): 5.87; run number: 0) 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, 6.44%) as a pale yellow solid. LC / MS:C 23 H 18 Calculated mass of ClFNO: 476.1, Found: 477.1 [M+H] + 1 H NMR(300MHz,DMSO-d6)δ 8.76(s,2H),7.69(d,J = 3.2 Hz,1H),7.61(d,J = 2.6 Hz,1H),7.51(d,J = 9.0 Hz,1H),7.41(d,J = 9.4 Hz,2H),7.08(t,J = 9.2 Hz,1H),6.68(d,J = 3.4 Hz,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.

[0237] Preparation of 2-(5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidin-2-yl)acetonitrile [ka]

[0238] 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, 0.226 mmol, 1 equiv.) in DMF (2 mL) was added 2-(trimethylsilyl)acetonitrile (38 mg, 0.339 mmol, 1.5 equiv.), Xantphos (5 mg, 0.009 mmol, 0.04 equiv.), Pd2(dba)3 (4 mg, 0.005 mmol, 0.02 equiv.), and zinc fluoride (14 mg, 0.136 mmol, 0.6 equiv.). The final reaction mixture was microwaved at 140 °C under a nitrogen atmosphere for 0.5 h. The desired product could be detected by LCMS. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The mixture was purified by preparative HPLC under the following conditions: column: XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water; column: XBridge Prep Phenyl OBD column, 19 × 250 mm, 5 μm; mobile phase A: water (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; run number: 0) 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, 3.21%) as a white solid. LC / MS:C 24 H 19 Calculated mass of ClFNO: 447.1, Found: 448.0 [M+H] + 1 H NMR(300MHz,DMSO-d6)δ 8.77(s,2H),7.71(d,J = 3.3 Hz,1H),7.64(d,J = 2.7 Hz,1H),7.54 - 7.59(m,1H),7.41 -7.45(m,2H),7.03 - 7.10(m,1H),6.69(d,J = 3.3 Hz,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.

[0239] Preparation of 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4-((2-(S-methylsulfonimidoyl)pyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [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, 0.226 mmol, 1 equiv.) in DMF (3 mL) was added (methylsulfanyl)sodium (32 mg, 0.452 mmol, 2 equiv.). The mixture was stirred at 80° C. for 12 hours. The desired product could be detected by LCMS. The mixture was directly purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 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, 57.53%) as a pale yellow oil.

[0240] 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4-((2-(S-methylsulfonimidoyl)pyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane 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, 0.132 mmol, 1 equiv.) in MeOH (1.5 mL) was added (NH4)2CO3 (25 mg, 0.264 mmol, 2 equiv.) and (acetyloxy)(phenyl)-λ3-iodanyl acetate (148.68 mg, 0.462 mmol, 3.5 equiv.). The mixture was stirred at 50 °C for 3 h. The desired product could be detected by LCMS. The mixture was directly purified by preparative HPLC under the following conditions: 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: 35% B to 65% B in 10 min; wavelength: 254 nm; RT1 (min): 8.25; run number: 0) 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-λ6-sulfanone (9.1 mg, 13.55%) as an off-white solid. LC / MS:C 23 H 21 Calculated mass of ClFN5O2S: 485.1, Measured mass: 486.0 [M+H] + 1 H NMR(300MHz,DMSO-d6)δ 8.95(s,2H),7.72(d,J = 3.3 Hz,1H),7.65(d,J = 2.7 Hz,1H),7.42- 7.55(m,3H),7.01 - 7.13(m,1H),6.69(d,J = 3.3 Hz,1H),4.59(s,1H),4.19-4.22(m,2H),4.04(s,2H),3.84(s,2H),3.29(d,J =2.7 Hz,3H),3.09-3.12(m,2H). 19 F NMR (282MHz, DMSO-d6) δ-123.5.

[0241] Preparation of 2-amino-5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidin-4(3H)-one [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (30 mg, 0.095 mmol, 1 equiv.) and 2-amino-4-oxo-3H-pyrimidine-5-carbaldehyde (20 mg, 0.143 mmol, 1.5 equiv.) in MeOH (1 mL) was added NaBHCN (12 mg, 0.190 mmol, 2 equiv.). The reaction was stirred at room temperature for 12 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. The crude product was directly purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD column, 19*250 mm, 10 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 9 min, wavelength: 254 nm, RT1 (min): 8.23, run number: 0) 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, 2.56%) as a white solid. LC / MS:C 22 H 19 Calculated mass of ClFN5O2: 439.1, Measured mass: 424.1 [M+H] + 1H NMR(300MHz,DMSO-d6)δ 10.89(s,1H),7.73(d,J = 3.3 Hz,1H),7.48-7.67(m,3H),7.38-7.48(m,2H),7.00-7.13(m,1H),6.68(d,J = 3.3 Hz,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.

[0242] 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 [ka]

[0243] tert-Butyl N-(tert-butoxycarbonyl)-N-(5-chloropyridazin-3-yl)carbamate To a stirred mixture of 5-chloropyridazin-3-amine (500 mg, 3.860 mmol, 1 equiv.) and BocO (1.26 g, 5.790 mmol, 1.5 equiv.) in CHCl (10 mL) was added EtN (590 mg, 5.790 mmol, 1.5 equiv.) and DMAP (47 mg, 0.386 mmol, 0.1 equiv.). The reaction was stirred at 40 °C for 2 h. The desired product could be detected by LCMS. Water (50 mL) was added to the above mixture and extracted with CHCl (3 × 50 mL). The combined organic layers were washed with water (10 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (20:1). The fractions were combined and concentrated to give tert-butyl N-(tert-butoxycarbonyl)-N-(5-chloropyridazin-3-yl)carbamate (350 mg, 39.49%) as a white solid.

[0244] 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, 0.910 mmol, 1 equiv.) in toluene (3 mL), tributyl(vinyl)stannane (763 mg, 1.820 mmol, 2 equiv.) and Pd(pph3)2Cl2 (64 mg, 0.091 mmol, 0.1 equiv.) were added. The reaction was stirred at 110 °C under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL). The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with petroleum ether / ethyl acetate (5:1). The fractions were combined and concentrated to give tert-butyl N-(tert-butoxycarbonyl)-N-(5-ethenylpyridazin-3-yl)carbamate (280 mg, 90.99%) as a pale yellow oil.

[0245] 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, 0.840 mmol, 1 equiv) in THF (2.5 mL) and HO (2.5 mL) was added OsO (22 mg, 0.084 mmol, 0.10 equiv) at room temperature. The reaction was stirred at room temperature for 2 minutes. To the above mixture was added NaIO (361 mg, 1.688 mmol, 2.01 equiv) over 2 minutes at room temperature. The resulting mixture was stirred at room temperature for an additional 5 hours. To the above mixture was added NaBH (81 mg, 2.142 mmol, 2.55 equiv) at 0 °C. The resulting mixture was stirred at room temperature for an additional 15 minutes. The desired product could be detected by LCMS. Water (30 mL) was added to the residue and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with petroleum ether / ethyl acetate (5:1). The combined fractions were concentrated to give tert-butyl N-(tert-butoxycarbonyl)-N-[5-(hydroxymethyl)pyridazin-3-yl]carbamate (160 mg, 52.68%) as a yellow oil.

[0246] 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, 0.307 mmol, 1 equiv.) in CHCl (2 mL) was added SOCl (44 mg, 0.370 mmol, 1.20 equiv.) at 0 °C. The reaction was stirred at room temperature for 1 h. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo to give tert-butyl N-(tert-butoxycarbonyl)-N-[5-(chloromethyl)pyridazin-3-yl]carbamate (100 mg, 85.17%) as a pale yellow oil. The crude product was used in the next step without further purification.

[0247] 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, 0.221 mmol, 1 equiv.) in THF (1 mL) was added tert-butyl N-(tert-butoxycarbonyl)-N-[5-(chloromethyl)pyridazin-3-yl]carbamate (76 mg, 0.221 mmol, 1 equiv.), EtN (45 mg, 0.442 mmol, 2 equiv.), and NaI (66 mg, 0.442 mmol, 2 equiv.). The reaction was stirred at 70° C. for 2 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.05% NH4HCO3) in water, 20% to 100% gradient in 10 min; detector, UV 254 nm. The combined fractions were concentrated in vacuo 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, 51.66%) as a pale yellow solid.

[0248] Preparation of 2-(6-fluoro-1-benzothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0249] 3-chloro-6-fluoro-1-benzothiophene To a stirred mixture of 3-chloro-6-fluoro-1-benzothiophene-2-carboxylic acid (400 mg, 1.734 mmol, 1 equiv.) in DMSO (5 mL) was added CuI (99 mg, 0.520 mmol, 0.30 equiv.). The resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 16 h. The resulting mixture was diluted with HO (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 3-chloro-6-fluoro-1-benzothiophene (240 mg, 74.15%) as a white solid.

[0250] 2-(6-fluoro-1-benzothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a mixture of 3-chloro-6-fluoro-1-benzothiophene (300 mg, 1.607 mmol, 1 equiv.) and bis(pinacolato)diboron (816 mg, 3.214 mmol, 2 equiv.) in dioxane (5.22 mL), KOAc (473 mg, 4.821 mmol, 3 equiv.) and [2-(2-aminoethyl)phenyl](chloro)palladium dicyclohexyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane (237 mg, 0.321 mmol, 0.2 equiv.) were added. The resulting mixture was stirred at 70 °C for 16 h under a nitrogen atmosphere. The desired product could be detected by TLC (PE). The residue was purified by preparative TLC (PE) to give 2-(6-fluoro-1-benzothiophen-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 44.73%) as a yellow solid.

[0251] Preparation of 9-chloro-4-((2-(4,5-dihydro-1H-imidazol-2-yl)pyrimidin-5-yl)methyl)-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [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, 0.115 mmol, 1 equiv.) and ethylenediamine (10.39 mg, 0.173 mmol, 1.5 equiv.) in toluene (3 mL), [(2-hydroxy-2-phenylacetyl)oxy]cuprio-2-hydroxy-2-phenylacetic acid (5 mg, 0.012 mmol, 0.1 equiv.) and NaOAc (3 mg, 0.035 mmol, 0.3 equiv.) were added. The resulting mixture was stirred at 90 °C overnight. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. The crude product (50 mg) was purified by preparative HPLC under the following conditions (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: 22% B to 52% B in 7 min, wavelength: 254 nm, RT1 (min): 5.76.8) to give 9-chloro-4-{[2-(4,5-dihydro-1H-imidazol-2-yl)pyrimidin-5-yl]methyl}-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine (19.9 mg, 34.02%) as a white solid. LC / MS:C 25 H 22 Calculated mass for ClFNO: 476.15, found: 477.15 [M+H]. 1 H NMR(300MHz,DMSO-d6)δ 8.90(s,2H),7.68(m,2H),7.32-7.56(m,3H),7.08(t,J = 8.8 Hz,1H),6.69(d,J = 3.3 Hz,1H),4.22 - 4.23(m,2H),4.00(s,2H),3.89(s,2H),3.75 - 3.83(m,4H),3.12 - 3.13(m,2H). 19F NMR(282MHz,DMSO-d6)δ -123.58.

[0252] Preparation of 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4-((2-(oxazol-2-yl)pyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [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, 1 equiv.) and 2-(tributylstannyl)-1,3-oxazole (10 mg, 0.028 mmol, 1.2 equiv.) in DMF (3 mL) was added XPhos Pd G3 (4 mg, 0.005 mmol, 0.2 equiv.) and ZnCl2 (3 mg, 0.023 mmol, 1 equiv.) in portions. The final reaction mixture was irradiated in a microwave oven at 110 °C for 2 h. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (30 mg) was purified by preparative HPLC under the following conditions (column: XBridge Shield RP18 OBD 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: 43% B to 73% B in 7 min, wavelength: 254 nm, RT1 (min): 6, run number: 0) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-{[2-(1,3-oxazol-2-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (2.1 mg, 19.11%) as a white solid. LC / MS:C 25 H 19Calculated mass of ClFN5O2: 474.9, found: 476.0 [M+H]+. 1 H NMR(300MHz,methanol-d4)δ 8.94(s,2H),8.18(d,J = 0.8 Hz,1H),7.55(d,J = 2.6 Hz,1H),7.51-7.39(m,3H),7.35-7.22(m,2H),6.99(t,J = 9.1 Hz,1H),6.64(d,J = 3.3 Hz,1H),4.30-4.21(m,2H),4.01(s,2H),3.91(s,2H),3.25(d,J = 5.1 Hz,2H). 19 F NMR (282MHz, DMSO-d6)δ -123.62.

[0253] Preparation of 4-((2-(1H-tetrazol-5-yl)pyrimidin-5-yl)methyl)-9-chloro-7-(4,5-difluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [ka]

[0254] 5-{[9-chloro-7-(4,5-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carbonitrile To a stirred mixture of 9-chloro-7-(4,5-difluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.299 mmol, 1 equiv.) and 5-formylpyrimidine-2-carbonitrile (60 mg, 0.449 mmol, 1.5 equiv.) in DCM (2 mL) was added NaBH(OAc) (127 mg, 0.598 mmol, 2 equiv.) and AcOH (0.2 mL). The reaction was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 3 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 10% to 100% gradient in 20 min; detector: UV 254 nm. The combined fractions were concentrated to give 5-{[9-chloro-7-(4,5-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carbonitrile (50 mg, 35.19%) as a pale yellow oil. LC / MS:C 23 H 16 Calculated mass for ClF2N5O: 451.10, found: 452.05 [M+H]+.

[0255] 4-((2-(1H-tetrazol-5-yl)pyrimidin-5-yl)methyl)-9-chloro-7-(4,5-difluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine To a stirred mixture of 5-{[9-chloro-7-(5,6-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carbonitrile (50 mg, 0.111 mmol, 1 equiv.) and NaN (22 mg, 0.333 mmol, 3 equiv.) in water, ZnCl (46 mg, 0.333 mmol, 3 equiv.) and 2-(trimethylazaniumyl)acetate (13 mg, 0.111 mmol, 1 equiv.) were added. The resulting mixture was stirred at 80 °C for 16 h. The desired product could be detected by LCMS. The precipitated solid was collected by filtration. The crude product (50 mg) was purified by preparative HPLC under the following conditions: 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: 28% B to 58% B in 7 min; wavelength: 254 nm; RT1 (min): 6.23; run number: 0) to give 4-((2-(1H-tetrazol-5-yl)pyrimidin-5-yl)methyl)-9-chloro-7-(4,5-difluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (2.6 mg, 4.70%) as an off-white solid.

[0256] LC / MS:C 23 H 17 Calculated mass for ClF2N8O: 494.10, found: 495.10 [M+H]+.

[0257] 1 H NMR(300MHz,DMSO-d6)δ 8.80(s,2H),7.78(d,J = 3.4 Hz,1H),7.67(d,J = 2.5 Hz,1H),7.44(d,J = 2.7 Hz,1H),7.21 - 7.34(m,2H),7.15(br,1H),6.82(d,J = 3.3 Hz,1H),4.21 - 4.22(m,2H),4.01(s,2H),3.79(s,2H),3.12 - 3.13(m,2H). 19F NMR(282MHz,DMSO-d6)δ 148.52,148.26.

[0258] Method R: Preparation of 9-chloro-7-(5-fluoro-1H-indol-1-yl)-4-((4-methoxypyrimidin-5-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (50 mg, 0.158 mmol, 1 equiv.) in THF (3 mL) was added 5-(chloromethyl)-4-methoxypyrimidine (273 mg, 0.474 mmol, 3.00 equiv.) and EtN (32 mg, 0.316 mmol, 2 equiv.) in portions at room temperature. The resulting mixture was stirred at 70 °C for 16 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). The crude product was purified by preparative HPLC under the following conditions (Column: Xselect CSH C18 OBD column 30*150 mm 5 μm, n, Mobile phase A: water (0.1% FA), 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, Run number: 0) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(2-methoxypyrimidin-5-yl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (2.2 mg, 3.14%) as an off-white solid. LC / MS:C 23 H 20 Calculated mass of ClFN4O2: 438.13, Measured mass: 439.05 [M+Na] + . 1H NMR(300MHz,DMSO-d6)δ 8.71(s,1H),8.48(s,1H),7.72(d,J = 3.3 Hz,1H),7.63(d,J = 2.7 Hz,1H),7.49-7.53(m,1H),7.41-7.46(m,2H),7.01-7.08(m,1H),6.69(d,J = 3.3 Hz,1H),4.18-4.21(m,2H),3.98(s,2H),3.90(s,3H),3.65(s,2H),3.08-3.11(m,2H). 19 F NMR (282 MHz, methanol-d4) δ -126.14.

[0259] Preparation of 9-chloro-7-(5-fluoroindol-1-yl)-4,5-dihydro-2H-spiro[1,4-benzoxazepine-3,1'-cyclopropane] [ka]

[0260] (2-chloro-4,6-dimethylpyrimidin-5-yl)methanol To a stirred mixture of ethyl 2-chloro-4,6-dimethylpyrimidine-5-carboxylate (300 mg, 1.398 mmol, 1 equiv.) in THF (12 mL) was added LiBH (60.88 mg, 2.796 mmol, 2 equiv.) portionwise at 0 °C under an air atmosphere. The resulting mixture was further stirred at 60 °C overnight. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The reaction was quenched by adding sodium sulfate decahydrate (3 g) at 0 °C. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in (2-chloro-4,6-dimethylpyrimidin-5-yl)methanol (300 mg, 124.36%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0261] (2-chloro-4,6-dimethylpyrimidin-5-yl)methyl methanesulfonate

[0262] To a stirred mixture of (2-chloro-4,6-dimethylpyrimidin-5-yl)methanol (100 mg, 0.579 mmol, 1 equiv.) in CHCl (5 mL), EtN (176 mg, 1.737 mmol, 3 equiv.) and MsCl (133 mg, 1.158 mmol, 2 equiv.) were added dropwise under air at 0° C. The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. As a result, (2-chloro-4,6-dimethylpyrimidin-5-yl)methyl methanesulfonate (145 mg, 99.83%) was obtained as a brown oil. The crude product was used directly in the next step without further purification.

[0263] Preparation of 5-(chloromethyl)-4-methoxypyrimidine [ka]

[0264] (4-Methoxypyrimidin-5-yl)methanol To a stirred mixture of 4-methoxypyrimidine-5-carboxylic acid (500 mg, 3.244 mmol, 1 equiv.) in THF (15 mL), 2-methylpropyl carbonochloridate (665 mg, 4.866 mmol, 1.5 equiv.) and N-methylmorpholine (493 mg, 4.866 mmol, 1.5 equiv.) were added dropwise at −10° C. under an air atmosphere. The resulting mixture was stirred at −10° C. for an additional 30 minutes. The reaction was monitored by TLC. To the above mixture, NaBH4 (615 mg, 16.220 mmol, 5 equiv.) was added portionwise over 3 minutes at −10° C. The resulting mixture was further stirred at room temperature overnight. The reaction was monitored by LCMS. The desired product could be detected by LCMS. To the resulting mixture, water (20 mL) was added. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (4-methoxypyrimidin-5-yl)methanol (825 mg, 181.46%) as a yellow oil. The crude product was used directly in the next step without further purification.

[0265] 5-(chloromethyl)-4-methoxypyrimidine To a stirred mixture of (4-methoxypyrimidin-5-yl)methanol (200 mg, 1.427 mmol, 1 equiv.) in CHCl (5 mL) was added SOCl (849 mg, 7.135 mmol, 5 equiv.) dropwise at room temperature under an air atmosphere. The resulting mixture was stirred at room temperature for another 1 h. The reaction was monitored by LCMS. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CHCl (5 mL). The resulting mixture was concentrated under reduced pressure. As a result, 5-(chloromethyl)-4-methoxypyrimidine (269 mg, 118.63%) was obtained as a yellow oil. The crude product was used directly in the next step without further purification.

[0266] Preparation of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylic acid [ka]

[0267] 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 (150 mg, 0.338 mmol, 1 equiv.) in MeOH (2 mL) and DMF (0.4 mL) was added Pd(dppf)Cl (37 mg, 0.051 mmol, 0.15 equiv.) and EtN (103 mg, 1.018 mmol, 3.01 equiv.) at 120 °C under a carbon monoxide (3 MPa) atmosphere. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 5 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (3 mL). The residue was purified by reverse-phase flash chromatography under the following conditions: column: C18 silica gel; mobile phase: MeCN (0.1% TFA) in water, 20% to 100% gradient in 10 min; detector: UV 254 nm. The fractions were concentrated in vacuo to give methyl 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate (100 mg, 60.13%) as a pale yellow oil.

[0268] 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 (100 mg, 0.214 mmol, 1 equiv.) in THF (2 mL) was added 2 M LiOH (0.54 mL). The reaction was stirred at room temperature for 2 h. The desired product could be detected by LCMS. Water (10 mL) was added to the above mixture and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with water (5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylic acid (80 mg, 78.35%) as a pale yellow oil.

[0269]

[0270] Preparation of 4-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [ka]

[0271] 5-Iodo-2-methylpyridazin-3-one To a stirred mixture of 5-iodo-2H-pyridazin-3-one (500 mg, 2.252 mmol, 1 equiv.) and K2CO3 (623 mg, 4.504 mmol, 2 equiv.) in DMF (10.00 mL) was added methyl iodide (639 mg, 4.504 mmol, 2 equiv.) dropwise over 16 h at 80 °C under an air atmosphere. The desired product could be detected by LCMS. Water (50 mL) was added to the residue and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 5-iodo-2-methylpyridazin-3-one (0.6 g, 112.87%) as a white solid.

[0272] 5-ethenyl-2-methylpyridazin-3-one To a stirred mixture of 5-iodo-2-methylpyridazin-3-one (570 mg, 2.415 mmol, 1 equiv.) and tributyl(ethenyl)stannane (1532 mg, 4.830 mmol, 2 equiv.) in toluene (10 mL) was added Pd(pph3)2Cl2 (169 mg, 0.242 mmol, 0.1 equiv.) dropwise over 2 h at 110 °C under a nitrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (2:1) to give 5-ethenyl-2-methylpyridazin-3-one (280 mg, 85.15%) as an off-white solid.

[0273] tert-Butyl N-(tert-butoxycarbonyl)-N-[5-(hydroxymethyl)pyridazin-3-yl]carbamate To a stirred mixture of 5-ethenyl-2-methylpyridazin-3-one (250 mg, 1.836 mmol, 1 equiv) in THF (1.5 mL) and HO (1.5 mL) was added OsO (52 mg, 0.202 mmol, 0.11 equiv). The reaction was stirred at room temperature for 2 min. NaIO (789 mg, 3.690 mmol, 2.01 equiv) was added. The reaction was stirred at room temperature for 5 h. To the above mixture was added NaBH (140 mg, 3.709 mmol, 2.02 equiv) at 0 °C. The resulting mixture was stirred at room temperature for an additional 15 min. The desired product could be detected by LCMS. To the above mixture was added water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give 5-(hydroxymethyl)-2-methylpyridazin-3-one (220 mg, 81.22%) as a brown oil.

[0274] 5-(chloromethyl)-2-methylpyridazin-3-one To a stirred mixture of 5-(hydroxymethyl)-2-methylpyridazin-3-one (100 mg, 0.714 mmol, 1 equiv.) in DCM (1.5 mL) was added SOCl (127 mg, 1.071 mmol, 1.5 equiv.) in DCM (0.5 mL) at 0 °C. The reaction was stirred at room temperature for 1 h. The desired product could be detected by TLC (PE / EA 2:1, Rf = 0.4). The resulting mixture was concentrated in vacuo to give 5-(chloromethyl)-2-methylpyridazin-3-one (100 mg, 79.53%) as a light brown oil.

[0275] 4-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (70 mg, 0.221 mmol, 1 equiv.) and 5-(chloromethyl)-2-methylpyridazin-3-one (70 mg, 0.442 mmol, 2 equiv.) in THF (1 mL) was added EtN (45 mg, 0.442 mmol, 2 equiv.) and NaI (66 mg, 0.442 mmol, 2 equiv.). The reaction was stirred at 70 °C for 12 h. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was dissolved in MeOH (1 mL). The crude product was purified by preparative HPLC under the following conditions: column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 55% B to 85% B in 7 min; wavelength: 254 nm; RT (min): 5.25; run number: 0. The combined fractions were lyophilized to give 4-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine (19.3 mg, 19.84%) as an off-white solid. LC / MS:C 23 H 20 Calculated mass of ClFN4O2: 438.1, Measured mass: 439.1 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 7.87(d,J = 2.0 Hz,1H),7.71(d,J = 3.3 Hz,1H),7.63(d,J = 2.6 Hz,1H),7.48-7.57(m,1H),7.38-7.47(m,2H),7.13-7.00(m,1H),6.81(s,1H),6.69(d,J = 3.2 Hz, 1H), 4.15-4.21 (m, 2H), 3.97 (s, 2H), 3.58-3.65 (m, 5H), 3.10-3.16 (m, 2H). 19 F NMR(282MHz,DMSO-d6)δ -123.6.

[0276] Preparation of 5-((9-chloro-7-(4,5-difluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidine-2-carboxylic acid [ka] To a stirred mixture of ethyl 5-{[9-chloro-7-(4,5-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylate (100 mg, 0.200 mmol, 1 equiv.) in THF (2 mL) was added 2 M LiOH.HO (2 mL, 0.200 mmol). The reaction was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The mixture was neutralized to pH 7 with 2 M HCl (aq). The resulting mixture was concentrated in vacuo. The residue was dissolved in DMSO (2 mL). The crude product was purified by preparative HPLC under the following conditions: Column: XBridge Prep OBD C18 column, 19*250 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO); Mobile phase B: ACN; Flow rate: 25 mL / min; Gradient: 30% B to 60% B in 7 min; Wavelength: 254 nm; RT1 (min): 6.12; Run number: 0. The combined fractions were lyophilized to give 5-{[9-chloro-7-(4,5-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carboxylic acid (31.7 mg, 33.15%) as an off-white solid. LC / MS:C 23 H 17 Calculated mass of ClF2N4O3: 470.1, Measured mass: 471.0 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 8.75(s,2H),7.78(d,J = 3.4 Hz,1H),7.67(d,J = 2.6 Hz,1H),7.43(d,J = 2.7 Hz,1H),7.19-7.34(m,2H),6.83(d,J = 3.3 Hz,1H),4.17-4.23(m,2H),3.98(s,2H),3.77(s,2H),3.07-3.13(m,2H). 19 F NMR (282MHz, DMSO-d6)δ -148.596,151.2.

[0277] Preparation of 4-((2-(1H-tetrazol-5-yl)pyrimidin-5-yl)methyl)-9-chloro-7-(6-fluorobenzofuran-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine [ka]

[0278] 5-{[9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carbonitrile To a stirred mixture of 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (60 mg, 0.189 mmol, 1 equiv.) and 5-formylpyrimidine-2-carbonitrile (38 mg, 0.283 mmol, 1.5 equiv.) in CHCl (2 mL) was added NaBH(OAc) (80 mg, 0.378 mmol, 2 equiv.) and AcOH (0.08 mg, 0.001 mmol, 0.01 equiv.). The reaction was stirred at room temperature for 3 hours. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 3 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (1 mL). The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 100% gradient in 20 min; detector, UV 254 nm. The fractions were combined and concentrated to give 5-{[9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carbonitrile (60 mg, 69.41%) as a pale yellow oil.

[0279] 4-((2-(1H-tetrazol-5-yl)pyrimidin-5-yl)methyl)-9-chloro-7-(6-fluorobenzofuran-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepane

[0280] To a stirred mixture of 5-{[9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidine-2-carbonitrile (60 mg, 0.138 mmol, 1 equiv.) in HO (1 mL) was added NaN (27 mg, 0.414 mmol, 3 equiv.), ZnCl (37 mg, 0.276 mmol, 2 equiv.), and betaine (16 mg, 0.138 mmol, 1 equiv.). The reaction was stirred at 80 °C for 36 h. The desired product could be detected by LCMS. The precipitated solid was collected by filtration and washed with water (3 × 2 mL). The filtrate was dissolved in DMSO (3 mL). The crude product was purified by preparative HPLC under the following conditions (column: XBridge Prep Phenyl OBD column, 19*100 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): 6.55, injection volume: 1900 mL, run number: 3) to give 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-4-{[2-(1H-1,2,3,4-tetrazol-5-yl)pyrimidin-5-yl]methyl}-3,5-dihydro-2H-1,4-benzoxazepine (10.6 mg, 16.00%) as a white solid. LC / MS:C 23 H 17 Calculated mass of ClFN7O2: 477.1, Measured mass: 478.0 [M+H-56] + 1H NMR(300MHz,DMSO-d6)δ 8.79(s,2H),8.43(s,1H),7.86-7.97(m,1H),7.74(d,J = 2.1 Hz,1H),7.59-7.68(m,1H),7.51(d,J = 2.2 Hz,1H),7.22-7.34(m,1H),7.17-7.21(m,1H),4.17-4.23(m,2H),4.01(s,2H),3.78(s,2H),3.09-3.14(s,2H). 19 F NMR (282MHz, DMSO-d6)δ -116.8.

[0281] Preparation of N-(5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyridazin-3-yl)methanesulfonamide [ka] To a stirred mixture of 5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridazin-3-amine (15 mg, 0.035 mmol, 1 equiv.) in CHCl (1 mL) was added EtN (7 mg, 0.070 mmol, 2 equiv.) and MsCl (8 mg, 0.070 mmol, 2 equiv.) dropwise at −20° C. The reaction was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was dissolved in DMF (1 mL). The crude product was purified by preparative HPLC under the following conditions: column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3); mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 55% B to 85% B in 7 min; wavelength: 254 nm; RT (min): 5.25; run number: 0. The combined fractions were lyophilized to give N-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyridazin-3-yl)methanesulfonamide (1.5 mg, 8.14%) as an off-white solid. LC / MS:C 23 H 21 Calculated mass of ClFN5O3S: 501.1, Measured mass: 502.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.29(s,1H),7.72(d,J = 3.3 Hz,1H),7.63(d,J = 2.6 Hz,1H),7.48-7.55(m,1H),7.38-7.46(m,2H),7.02-7.12(m,1H),6.68(d,J = 3.3 Hz,1H),6.54(s,1H),4.15-4.21(m,2H),3.96(s,2H),3.70(s,2H),3.10-3.16(m,2H),2.89(s,3H). 19 F NMR(376MHz,DMSO-d6)δ -123.6.

[0282] Preparation of 9-chloro-7-(4,5-difluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine [ka]

[0283] tert-Butyl 9-chloro-7-(4,5-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a stirred mixture of tert-butyl 7-bromo-9-chloro-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (600 mg, 1.654 mmol, 1 equiv.) and 4,5-difluoro-1H-indole (0.38 g, 2.481 mmol, 1.5 equiv.) in 1,4-dioxane (6 mL), CuI (0.09 g, 0.496 mmol, 0.3 equiv.), KPO (1.23 g, 5.789 mmol, 3.5 equiv.), and (1R,2R)-cyclohexane-1,2-diamine (0.09 g, 0.827 mmol, 0.5 equiv.) were added. The reaction was stirred at 100 °C for 2 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with 1,4-dioxane (3 × 5 mL). The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel, mobile phase, MeCN (0.1% TFA) in water, 10% to 100% gradient over 20 min, detector, UV 254 nm. The combined fractions were concentrated to give tert-butyl 9-chloro-7-(4,5-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (400 mg, 52.82%) as a pale yellow solid.

[0284] 9-chloro-7-(4,5-difluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine

[0285] To a stirred mixture of tert-butyl 9-chloro-7-(4,5-difluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (400 mg, 0.920 mmol, 1 equiv.) in CHCl (5.00 mL) was added TFA (1.00 ml). The reaction was stirred at room temperature for 2 hours. The desired product could be detected by LCMS. The mixture was neutralized to pH 7 with saturated NaHCO (aq.). The resulting mixture was extracted with CHCl (3 × 15 mL). The combined organic layers were washed with water (2 × 7 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 9-chloro-7-(4,5-difluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (300 mg, 92.56%) as a tan oil.

[0286] Preparation of 1-(5-((9-chloro-7-(5-fluoro-1H-indol-1-yl)-2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl)methyl)pyrimidin-2-yl)ethanone [319-3] [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 (20 mg, 0.046 mmol, 1 equiv.) in THF (1 mL) was added (methyl)magnesium bromide (7 mg, 0.055 mmol, 1.2 equiv.) dropwise at −78° C. under a nitrogen atmosphere. The reaction was stirred at −78° C. under a nitrogen atmosphere for 3 hours. The desired product could be detected by LCMS. The reaction was quenched with saturated NH4Cl (aq.) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (1 mL). The crude product was purified by preparative HPLC under the following conditions: Column: XBridge Prep Phenyl OBD column, 19*100 mm, 5 μm; Mobile phase A: water (10 mmol / L NH4HCO3 + 0.1% NH3.HO); Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 42% B to 72% B in 7 min; Wavelength: 254 nm; RT (min): 6; Run number: 0. The combined fractions were lyophilized to give 1-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)ethanone (20 mg, 91.79%) as an off-white oil. LC / MS:C 24 H 20 Calculated mass of ClFN4O2: 450.13, Found: 451.05 [M+H] + . 1 H NMR(300MHz,DMSO-d6)δ 8.94(s,2H),7.71(d,J = 3.3 Hz,1H),7.65(d,J = 2.6 Hz,1H),7.47-7.57(m,1H),7.38-7.47(m,2H),7.00-7.12(m,1H),6.65-6.73(m,1H),4.1 8-4.23(m,2H),4.01(s,2H),3.84(s,2H),3.34(s,32H),3.08-3.14(m,2H),2.67(s,3H). 19F NMR(282MHz,DMSO-d6)δ -123.6.

[0287] Preparation of 1-(5-{[9-chloro-7-(5-fluoroindol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepin-4-yl]methyl}pyrimidin-2-yl)ethanone [ka]

[0288] 6-Fluoro-2,3-dihydro-1-benzofuran-3-yl trifluoromethanesulfonate To a stirred mixture of 6-fluoro-2H-1-benzofuran-3-one (500 mg, 3.287 mmol, 1 equiv.) in CHCl (5 mL) was added DIEA (849 mg, 6.574 mmol, 2 equiv.) dropwise at room temperature under an air atmosphere. TfO (1066 mg, 3.780 mmol, 1.15 equiv.) was added dropwise to the above mixture at 0 °C. The resulting mixture was stirred at room temperature for an additional 10 min. The reaction was monitored by TLC (PE / EA = 5:1, Rf = 0.3). The resulting mixture was diluted with water (10 mL). The aqueous layer was extracted with CHCl (3 × 10 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 6-fluoro-2,3-dihydro-1-benzofuran-3-yl trifluoromethanesulfonate (500 mg, 53.15%) as a colorless oil.

[0289] tert-Butyl 8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-2H-1,3-benzoxazepine-3-carboxylate To a stirred mixture of tert-butyl 6-bromo-8-chloro-4,5-dihydro-2H-1,3-benzoxazepine-3-carboxylate (500 mg, 1.379 mmol, 1.00 equiv.) in 1,4-dioxane (5 mL) was added KOAc (406 mg, 4.137 mmol, 3 equiv.) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (385 mg, 1.517 mmol, 1.1 equiv.) in 1,4-dioxane (5 mL) at room temperature under an air atmosphere. The resulting mixture was stirred overnight at 90 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give tert-butyl 8-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-2H-1,3-benzoxazepine-3-carboxylate) (460 mg, 81.43%) as a white solid.

[0290] tert-Butyl 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a stirred mixture of tert-butyl 9-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (350 mg, 0.854 mmol, 1 equiv.) and 6-fluoro-1-benzofuran-3-yl trifluoromethanesulfonate (437 mg, 1.537 mmol, 1.8 equiv.) in toluene (3 mL), EtOH (1.5 mL), and HO (1.5 mL), NaCO (163 mg, 1.537 mmol, 1.8 equiv.) and Pd(pph) (49 mg, 0.043 mmol, 0.05 equiv.) were added. The reaction was stirred at 95 °C under a nitrogen atmosphere for 12 hours. The desired product could be detected by LCMS. The resulting mixture was extracted with toluene (3 × 30 mL). The combined organic layers were washed with water (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give tert-butyl 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (340 mg, 90.49%) as a pale yellow oil.

[0291] 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine To a stirred mixture of tert-butyl 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (330 mg, 0.790 mmol, 1 equiv.) in DCM (3 mL) was added TFA (0.6 mL). The reaction was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The mixture was neutralized to pH 7 with saturated NaHCO (aq.). Water (30 ml) was added to the above mixture. The resulting mixture was extracted with CHCl (3 × 30 mL). The combined organic layers were washed with brine (1 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (260 mg, 93.25%) as a pale yellow oil.

[0292] Preparation of 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine [ka]

[0293] 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine

[0294] To a stirred mixture of 9-chloro-7-(6-fluoro-1-benzofuran-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.315 mmol, 1 equiv.) and 2-chloropyrimidine-5-carbaldehyde (67 mg, 0.473 mmol, 1.5 equiv.) in CHCl (1 mL) was added NaBH(OAc) (133 mg, 0.630 mmol, 2 equiv.) and AcOH (0.08 mg, 0.001 mmol). The reaction was stirred at room temperature for 2 h. The desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with CHCl (3 × 3 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (2 mL). The residue was purified by reverse-phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, MeCN (0.1% TFA) in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. The combined fractions were concentrated to give 9-chloro-4-[(2-chloropyrimidin-5-yl)methyl]-7-(6-fluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine (80 mg, 54.35%) as an off-white solid.

[0295] Preparation of 9-chloro-7-(5-fluoroindazol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine

[0296] [ka]

[0297] 9-chloro-7-(5-fluoroindazol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate

[0298] To a mixture of 4-(tert-butoxycarbonyl)-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-7-ylboronic acid (300 mg, 0.916 mmol, 1 equiv.) and 5-fluoro-1H-indazole (124 mg, 0.916 mmol, 1 equiv.) in CHCl (5 mL) was added copper(II) acetate (332 mg, 1.832 mmol, 2 equiv.) and pyridine (289 mg, 3.664 mmol, 4 equiv.). The mixture was stirred at room temperature under an O atmosphere for 16 hours. The desired product could be detected by LCMS. HO (5 mL) was added to the mixture, which was then extracted with EtOAc (5 mL x 3). The organic layers were combined, washed with brine (15 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 9-chloro-7-(5-fluoroindazol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (150 mg, 39.20%) as a yellow oil.

[0299] 9-chloro-7-(5-fluoroindazol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine To a mixture of tert-butyl 9-chloro-7-(5-fluoroindazol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (150 mg, 0.359 mmol, 1 equiv.) in CHCl (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to give 9-chloro-7-(5-fluoroindazol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 87.67%) as a brown oil.

[0300] Preparation of 9-chloro-7-(5-fluoro-1,3-benzodiazol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine [ka]

[0301] 4-(tert-Butoxycarbonyl)-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-7-ylboronic acid To a stirred mixture of tert-butyl 7-bromo-9-chloro-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (1 g, 2.757 mmol, 1 equiv.) and triisopropyl borate (674 mg, 3.584 mmol, 1.3 equiv.) in THF (20 mL) was added 2.5 M n-butyllithium in hexane (1.4 mL) portionwise at −78° C. under a nitrogen atmosphere. The mixture was stirred at −78° C. for 1 hour. The desired product could be detected by LCMS. To the mixture was added HO (10 mL). The mixture was stirred at room temperature for 12 hours. The resulting mixture was extracted with EtOAc (50 mL×3) and HO (50 mL). The combined organic layers were washed with brine (2×30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with EtO (3 mL) and PE (5 mL). The precipitated solid was collected by filtration and washed with PE (3 × 10 mL) to give 4-(tert-butoxycarbonyl)-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-7-ylboronic acid (270 mg, 20.92%) as a gray solid.

[0302] tert-Butyl 9-chloro-7-(5-fluoro-1,3-benzodiazol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a mixture of 4-(tert-butoxycarbonyl)-9-chloro-3,5-dihydro-2H-1,4-benzoxazepin-7-ylboronic acid (150 mg, 0.458 mmol, 1 equiv.), 5-fluoro-1H-1,3-benzodiazole (62 mg, 0.458 mmol, 1 equiv.), and cupric acetate (166 mg, 0.916 mmol, 2 equiv.) in CHCl (5 mL) was added pyridine (10 mg, 0.124 mmol, 4 equiv.). The mixture was stirred at room temperature under an O atmosphere for 16 hours. The desired product could be detected by LCMS. HO (10 mL) was added to the mixture, which was then extracted with DCM (5 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with CH2Cl2 / MeOH (10:1) to give tert-butyl 9-chloro-7-(5-fluoro-1,3-benzodiazol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (50 mg, 26.13%) as a yellow oil.

[0303] 9-chloro-7-(5-fluoro-1,3-benzodiazol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine To a mixture of tert-butyl 9-chloro-7-(5-fluoro-1,3-benzodiazol-1-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (100 mg, 0.239 mmol, 1 equiv.) in CHCl (5.00 mL) was added TFA (1.00 mL). The mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to give 9-chloro-7-(5-fluoro-1,3-benzodiazol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (60 mg, 78.91%) as a yellow oil.

[0304] Preparation of tert-butyl 6-bromoimidazo[4,5-b]pyridine-3-carboxylate [ka]

[0305] tert-Butyl 6-bromoimidazo[4,5-b]pyridine-3-carboxylate To a mixture of 6-bromo-3H-imidazo[4,5-b]pyridine (200 mg, 1.010 mmol, 1 equiv.) in THF (5 mL) was added BocO (264 mg, 1.212 mmol, 1.2 equiv.) and TEA (204 mg, 2.020 mmol, 2 equiv.). The mixture was stirred at room temperature for 16 h. The desired product could be detected by LCMS. The mixture was concentrated under reduced pressure to give tert-butyl 6-bromoimidazo[4,5-b]pyridine-3-carboxylate (100 mg, 33.21%) as a white solid.

[0306] Preparation of tert-butyl 9-chloro-7-(5-fluoroindol-1-yl)-4-[(tributylstannyl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine [ka] To a stirred mixture of 9-chloro-7-(5-fluoroindol-1-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (100 mg, 0.316 mmol, 1 equiv.) in THF (2 mL) was added NaH (38 mg, 1.579 mmol, 5.00 equiv.) portionwise over 30 min at 0 °C. To the above mixture was added tributyl(iodomethyl)stannane (680 mg, 1.578 mmol, 5.00 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature for an additional 24 h. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA 1:1) to give 9-chloro-7-(5-fluoroindol-1-yl)-4-[(tributylstannyl)methyl]-3,5-dihydro-2H-1,4-benzoxazepine (120 mg, 50.16%) as a white oil.

[0307] Preparation of 9-chloro-7-(6,7-difluoro-1-benzofuran-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine [ka]

[0308] 1-(2,2-diethoxyethoxy)-2,3-difluorobenzene To a mixture of 2,3-difluorophenol (5 g, 38.434 mmol, 1 equiv.) in DMSO (200 mL) was added 2-bromo-1,1-diethoxyethane (8.33 g, 42.277 mmol, 1.1 equiv.) and K2CO3 (7.97 g, 57.651 mmol, 1.5 equiv.). The mixture was stirred at 95 °C for 16 h. The mixture was diluted with EtOAc (300 mL) and filtered. The filtrate was washed with HO (500 mL), dried over Na2SO4, filtered, and concentrated to give 1-(2,2-diethoxyethoxy)-2,3-difluorobenzene (8 g, 84.53%) as a yellow oil.

[0309] 6,7-Difluoro-1-benzofuran To a mixture of 1-(2,2-diethoxyethoxy)-2,3-difluorobenzene (5 g, 20.304 mmol, 1 equiv.) in toluene (100 mL) was added polyphosphoric acid (9.63 g, 98.219 mmol, 4.84 equiv.). The mixture was stirred at 100 °C for 6 h. The mixture was cooled to room temperature. The mixture was poured into HO (300 mL). The HO layer was extracted with EtOAc (200 mL × 3). The organic layers were combined, washed with brine (500 mL), dried over NaSO, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give 6,7-difluoro-1-benzofuran (500 mg, 15.98%) as a yellow oil.

[0310] 3-Bromo-6,7-difluoro-1-benzofuran To a mixture of 6,7-difluoro-1-benzofuran (100 mg, 0.649 mmol, 1 equiv) in CHCl (3 mL) was added Br (114 mg, 0.714 mmol, 1.1 equiv) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. The mixture was quenched with saturated aqueous NaSO (10 mL) and extracted with CHCl (5 mL × 3). The organic layer was washed with brine (10 mL), dried over MgSO, filtered, and concentrated. The residue was dissolved in THF (2 mL). To the mixture was added KOH (36 mg, 0.649 mmol, 1 equiv) in MeOH (1 mL). The mixture was stirred at room temperature for 1 h. To the mixture was added HO (10 mL) and extracted with DCM (5 mL × 3). The organic layer was washed with brine (10 mL), dried over MgSO, filtered, and concentrated. The residue was purified by preparative TLC (PE) to give 3-bromo-6,7-difluoro-1-benzofuran (50 mg, 33.07%) as a white solid.

[0311] tert-Butyl 9-chloro-7-(6,7-difluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate To a mixture of tert-butyl 9-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (40 mg, 0.098 mmol, 1 equiv.) and 3-bromo-6,7-difluoro-1-benzofuran (34 mg, 0.147 mmol, 1.5 equiv.) in toluene (1 mL), EtOH (0.5 mL), HO (0.5 mL), NaCO (20 mg, 0.196 mmol, 2 equiv.), and Pd(PPh) (11 mg, 0.010 mmol, 0.1 equiv.) were added. The mixture was stirred at 95 °C for 16 h. The desired product could be detected by LCMS. The mixture was cooled to room temperature. The HO layer was extracted with toluene (3 mL × 3). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and concentrated. The residue was purified by preparative TLC (PE) to give tert-butyl 9-chloro-7-(6,7-difluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (20 mg, 47.00%) as a yellow oil.

[0312] 9-chloro-7-(6,7-difluoro-1-benzofuran-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine To a mixture of tert-butyl 9-chloro-7-(6,7-difluoro-1-benzofuran-3-yl)-3,5-dihydro-2H-1,4-benzoxazepine-4-carboxylate (30 mg, 0.069 mmol, 1 equiv.) in CHCl (1 mL) was added TFA (0.2 mL). The mixture was stirred at room temperature for 1 hour. The desired product could be detected by TLC. The mixture was concentrated under reduced pressure to give 9-chloro-7-(6,7-difluoro-1-benzofuran-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (20 mg, 86.55%) as a white solid.

[0313] biological activity Example B1: EP2 Potency Assay: Compounds of the present disclosure are effective in inhibiting half-maximal inhibitory concentrations (IC50 ) values ​​less than 25 μM. Compound potency was measured in the cAMP TR-FRET assay.

[0314] CHO-K1 cells (ATCC) were seeded at a density of 9.75 x 10 cells per 6 cm plate. The next day, the cell culture medium was replaced with Opti-Mem I reduced serum medium (Gibco) and transfected with a plasmid for expression of the EP2 receptor (target receptor) using FuGENE 6 Transfection Reagent (Promega). After 6 hours of culture, the cell culture medium was replaced with F12 medium supplemented with 10% FBS and 100 U / ml Pen-Strep. 24 hours after transfection, the cells were harvested and seeded at a density of 3000 cells per well in a 384-well plate. cAMP assays were performed using the LANCE Ultra cAMP Assay Kit (PerkinElmer).

[0315] For each test compound of interest, 10 nL of serially diluted test compound was added to each well, creating a 10-step compound concentration range from 10,000 nM to 0.038 nM, with duplicate wells for each concentration. The plate was then centrifuged at 1,000 rpm for 1 minute, agitated at 600 rpm for 2 minutes at room temperature, and then incubated at 25°C for 5 minutes. The control agonist, prostaglandin E2 (MCE), was added to each well at the appropriate concentration to achieve the 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.

[0316] 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 incubated 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, emission wavelength = 615 and 665 nm). Dose-response curves were generated by plotting the percent inhibition versus the concentration of each compound, and then curve fitting was performed to determine the IC. 50 IC by extrapolating the concentration 50 was calculated. Exemplary compounds disclosed herein exhibit potent EP2 antagonist activity. IC50 results for selected compounds are shown in Tables (IV) and (V), with "--" indicating data unavailable. 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). [Table 4-1] [Table 4-2] [Table 4-3] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12]

[0317] Specific Embodiments This disclosure contemplates, inter alia, the following numbered embodiments: 1. [ka] A compound having the formula: During the ceremony, R 1 and R 2 are independently a , -OR d , -C 1~4 haloalkyl; or R 1 and R 2 Together, Oxo, C 3~6 forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, R 3 is -CH(R b )2, -C(R b )3, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -S(O)(NRa )R d , -S(O)2N(R a )S(O)2R a , -S(O)2N(R a )S(O)NR c R c , -C(O)R d , -C(O)N(R a )C(O)R d , -C(O)OR d , -C(O)NR c R c and Ring A and Ring B are independently selected from phenyl and cycloalkyl; X is hydrogen and R b is selected from Each R A are independently halogen, -CN, -C 1~4 Alkyl, and -C 1~4 haloalkyl; Each R B are independently 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)NR c R c , -NR c R c , -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), and substituted or unsubstituted C 3~6 cycloalkyl; Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3~8 ) cycloalkyl; Each R b are independently -ORd , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , and -C(O)NR c R c is selected from the group consisting of Each R c are independently a Or, two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, which may optionally contain one or more additional heteroatoms which may be the same or different, and optionally one or more —C(O)R a and R a may be substituted with a group, Each R d are independently hydrogen, and halogen and -O(C 1~4 alkyl) optionally substituted with one, two or three groups selected from 1~6 ) alkyl; n, for each occurrence, is independently 0 to 3; The compound is not a compound disclosed in PCT / US22 / 34903. 2. Ring A or ring B is C 3~6 The compound of embodiment 1, wherein the compound is cycloalkyl. 3. [ka] 2. The compound of embodiment 1, having the structure: 4. [ka] 2. The compound of embodiment 1, having the structure: 5. [ka] 2. The compound of embodiment 1, having the structure: 6.R B -CN, --C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl) or -C(O)NR c R c The compound of any one of embodiments 1 to 4, wherein: 7.R 3 is -CH(R b )2 and -C(R b 6. The compound of any one of embodiments 1 to 5, wherein the compound is selected from: 8.R 3 Each R in b are independently -OR d 8. The compound of embodiment 7, wherein the compound is selected from: —OCF2H, —OCF3, and —CF3. 9.R 3 is —CH(OH)CF 3 . 10.R 3 The compound of embodiment 7, wherein is —C(OH) 2 CF 3 . 11.R 3 is S(O)2R d , -S(O)(NR a )R d , -S(O)2OR d , -S(O)NR c R c , -S(O)2N(R a )S(O)2R a , and -S(O)N(R a )S(O)NR c R c 6. The compound of any one of embodiments 1 to 5, selected from: 12.R 3 is -C(O)R d , -C(O)N(R a )C(O)R d , -C(O)OR d , and -C(O)NR c Rc 6. The compound of any one of embodiments 1 to 5, selected from: 13.R 3 The compound of any one of embodiments 1-5, wherein is —COOH. 14.R 3 The compound of any one of embodiments 1-5, wherein is S(O)2NH2. 15.R 3 The compound of any one of embodiments 1-5, wherein is S(O)2CH3. 16.R 3 is -S(O)(NR a )R d The compound of any one of embodiments 1 to 5, wherein 17.R 3 The compound of any one of embodiments 1-5, wherein is —S(O)(NH)CH 3 . 18.R 1 and R 2 The compound of any one of embodiments 1-17, wherein together form oxo. 19.R 1 and R 2 The compound of any one of embodiments 1-17, wherein one of is hydrogen and the other is -CF3. 20. At least one R B The compound of any one of embodiments 1-19, wherein is —CN. twenty one. [ka] 21. The compound of any one of embodiments 1-20, having the structure: twenty two. [ka] 22. The compound of any one of embodiments 1-21, having the structure: twenty three. [ka] 23. The compound of any one of embodiments 1-22, having the structure: twenty four. [ka] 24. The compound of any one of embodiments 1-23, having the structure: twenty five. [ka] wherein each R A is independently halo. 26. [ka] [ka] [ka] A compound. 27. The compound according to any one of embodiments 1-26, in the form of a pharmaceutically acceptable salt. 28. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 27 and a pharmaceutically acceptable excipient. 29. A method for inhibiting the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal an effective amount of a compound according to any one of embodiments 1 to 27 or a pharmaceutical composition according to embodiment 28. 30. A method for treating a disease or disorder that would benefit from modulation of prostaglandin E2 receptor 2 (EP2) activity, comprising administering to a mammal an effective amount of a compound according to any one of embodiments 1-27 or a pharmaceutical composition according to embodiment 28. 31. A method for modulating prostaglandin E2 receptor 2 (EP2), comprising contacting said EP2 with a compound according to any one of embodiments 1 to 27 or a pharmaceutical composition according to embodiment 28. 32. The method of embodiment 31, wherein said contacting is carried out in vitro. 33. The method of embodiment 31, wherein said contacting is performed in vivo. 34. A method for treating a disease or disorder selected from a neurological disorder, an inflammatory disorder, an autoimmune disorder, a fibrotic disorder, an allergic disorder, and a combination thereof, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28. 35. Amyotrophic lateral sclerosis (ALS), epilepsy, dementia, Alzheimer's disease, concussion, delirium, chemotherapy-associated cognitive decline, radiation-associated cognitive decline, postoperative cognitive impairment (including postoperative neurocognitive impairment, postoperative delirium, delayed neurocognitive impairment, and delayed neurocognitive recovery), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment or MCI), Binswanger dementia (subcortical arteriosclerotic encephalopathy), HIV-associated dementia (including asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy)) 28. A method of treating a neurological disorder selected from: encephalopathy, including encephalopathy, multiple system atrophy (MSA), spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), head trauma, concussion, chronic traumatic encephalopathy, intracerebral hemorrhage, hematoma, diabetic retinopathy, macular degeneration, macular edema, glaucoma, multiple sclerosis, angioedema, including edema caused by treatment with antibody therapy (e.g., ARIA-E), migraine, Huntington's disease, ALS, and Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28. 36. Systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, hyperimmunoglobulin D and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, ulcerative colitis, necrotizing enterocolitis (NEC), peritonitis, gout, gouty attacks, gouty arthritis, bullous pemphigoid , sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, asthma, atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, 28. A method for treating an inflammatory or allergic disease selected from emotion-induced asthma, extrinsic asthma caused by environmental factors, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infection, early asthma, wheezy infant syndrome, bronchiolitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, and sphenoid sinusitis, comprising administering an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28 to a subject in need thereof. 37. Tissue or organ transplantation, graft-versus-host disease caused by transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type 1 diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus, acne, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular blepharitis ulcer, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma, airway hyperresponsiveness, bronchitis, gastric ulcer, vascular disorders due to ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuropathy neuritis), mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, and dentin, glomerulonephritis, alopecia areata by preventing hair loss, promoting hair growth, and / or promoting hair growth and development, male pattern baldness or senile alopecia, vitiligo, and muscular dystrophy 28. A method for treating an immune dysregulation disorder selected from the group consisting of erythroderma, pyoderma, Sezary syndrome, Addison's disease, ischemia-reperfusion injury associated with organ preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen- or drug-induced toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, corneal alkali burn, erythematous dermatitis multiforme, linear IgA bulbar dermatitis, cemental dermatitis, gingivitis, periodontitis, and sepsis, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28. 38. Solid tumors, brain cancer, kidney cancer, liver cancer, adrenal gland cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, tumors of the neck and head, epidermal hyperproliferation, psoriasis, prostate Hypertrophy, tumorigenesis, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-induced disease, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin's lymphoma 28. A method of treating a proliferative disorder selected from lymphoma, primary cutaneous T-cell lymphoma, smoldering or asymptomatic multiple myeloma, or a hematopoietic malignancy (including leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma), comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28. 39. A method for treating a fibrotic disease selected from idiopathic pulmonary fibrosis, systemic sclerosis, uterine leiomyoma, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis due to toxins, viral hepatitis, shock, or anoxia, B viral hepatitis, non-A / non-B hepatitis, chronic hepatitis C virus (HCV) infection, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), non-alcoholic steatohepatitis (NASH), liver failure, fulminant hepatic failure, delayed liver failure, acute exacerbation of chronic liver failure, kidney disease, and chronic kidney disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28. 40. A method for treating cytokine release syndrome, comprising administering an effective amount of a compound according to any one of embodiments 1-27 or a pharmaceutical composition according to embodiment 28 to a subject in need thereof. 41. A method for treating a disease selected from endometriosis, uterine fibroids (leiomyoma), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dysfecation, and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, breast cancer, colon cancer, familial adenomatous polyposis, colorectal adenoma, endometrial cancer, prostate cancer, lung cancer, testicular cancer, gastric cancer, macular degeneration, inflammatory and neuropathic pain, migraine, headache, cluster headache, inflammation-induced pain, cancer pain, polycystic kidney disease, and polycystic ovary syndrome, comprising administering an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28 to a subject in need thereof. 42. A method for treating a vascular disorder, comprising administering an effective amount of a compound according to any one of embodiments 1-27 or a pharmaceutical composition according to embodiment 28 to a subject in need thereof. 43. The method of embodiment 42, wherein the vascular disorder is selected from head trauma, stroke, aneurysm, vascular dementia, vascular cognitive impairment and dementia (VCID), cerebral small vessel disease, subcortical ischemic vascular disease, mixed dementia, and ischemic vascular disease. 44. A method for treating a disease selected from Alzheimer's disease, ALS, multiple sclerosis, Parkinson's disease, and Huntington's disease, comprising administering an effective amount of a compound of any one of embodiments 1-27 or a pharmaceutical composition of embodiment 28 to a subject in need thereof.

[0318] This disclosure contemplates, inter alia, the following numbered embodiments: 1. [ka] A compound having the formula: During the ceremony, R 1 and R 2are independently a , -OR d , -C 1~4 haloalkyl; or R 1 and R 2 Together, Oxo, C 3~6 forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, R 3 is -CH(R b )2, -C(R b )3, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -S(O)(NR a )R d , -S(O)2N(R a )S(O)2R a , -S(O)2N(R a )S(O)NR c R c , -C(O)R d , -C(O)N(R a )C(O)R d , -C(O)OR d , -C(O)NR c R c and Ring A and Ring B are independently selected from phenyl and cycloalkyl; X is hydrogen and R b is selected from Each R A are independently halogen, -CN, -C 1~4 Alkyl, and -C 1~4 haloalkyl; Each R B are independently 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(C1~4 alkyl), -C(O)NR c R c , -NR c R c , -NH(C 3~6 cycloalkyl), -NH(C 3~6 heterocycloalkyl), and substituted or unsubstituted C 3~6 cycloalkyl; Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3~8 ) cycloalkyl; Each R b are independently -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , -C(O)NR c R c is selected from the group consisting of Each R c are independently a Or, two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, which may optionally contain one or more additional heteroatoms which may be the same or different, and optionally one or more —C(O)R a and R a may be substituted with a group, Each R d are independently hydrogen, and halogen and -O(C 1~4 alkyl) optionally substituted with one, two or three groups selected from 1~6 ) alkyl; n, for each occurrence, is independently 0 to 3; The compound is not a compound disclosed in PCT / US22 / 34903. 2. The compound of embodiment 1, wherein ring A or ring B, or both, are bicyclic. 3. The compound of embodiment 1 or embodiment 2, wherein ring A or ring B, or both, is a bridged bicyclic ring. 4. The compound of embodiment 1 or embodiment 2, wherein ring A or ring B, or both, is a bridged bicyclic cycloalkyl. 5. The compound of embodiment 1 or embodiment 2, wherein ring A is a bridged cycloalkyl. 6. The compound of embodiment 1 or embodiment 2, wherein ring B is a bridged cycloalkyl. 7. Ring A or ring B is C 3~6 The compound of embodiment 1, wherein the compound is cycloalkyl. 8. [ka] 2. The compound of embodiment 1, having the structure: 9. [ka] 2. The compound of embodiment 1, having the structure: 10. [ka] 2. The compound of embodiment 1, having the structure: 11.R B -CN, --C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C 1~4 alkyl) or -C(O)NR c R c The compound of any one of embodiments 1 to 10, wherein 12.R 3 is -CH(R b )2 and -C(R b 11. The compound of any one of embodiments 1 to 10, wherein the compound is selected from: 13.R3 Each R in b are independently -OR d , —OCF2H, —OCF3, and —CF3. 14.R 3 The compound of embodiment 12, wherein is —CH(OH)CF 3 . 15.R 3 The compound of embodiment 12, wherein is —C(OH) 2 CF 3 . 16.R 3 is S(O)2R d , -S(O)(NR a )R d , -S(O)2OR d , -S(O)NR c R c , -S(O)2N(R a )S(O)2R a , and -S(O)N(R a )S(O)NR c R c 11. The compound of any one of embodiments 1 to 10, selected from: 17.R 3 is -C(O)R d , -C(O)N(R a )C(O)R d , -C(O)OR d , and -C(O)NR c R c 11. The compound of any one of embodiments 1 to 10, selected from: 18.R 3 The compound of any one of embodiments 1-10, wherein is —COOH. 19.R 3 The compound of any one of embodiments 1-10, wherein is S(O)2NH2. 20.R 3 The compound of any one of embodiments 1-10, wherein is S(O)2CH3. 21.R 3 is -S(O)(NR a )R d The compound of any one of embodiments 1 to 10, wherein 22.R 3The compound of any one of embodiments 1-10, wherein is —S(O)(NH)CH 3 . 23.R 1 and R 2 The compound of any one of embodiments 1-22, wherein together form oxo. 24.R 1 and R 2 The compound of any one of embodiments 1-22, wherein one of is hydrogen and the other is -CF3. 25. At least one R B The compound of any one of embodiments 1-24, wherein is —CN. 26. [ka] 26. The compound of any one of embodiments 1-25, having the structure: 27. [ka] 26. The compound of any one of embodiments 1-25, having the structure: 28. [ka] 26. The compound of any one of embodiments 1-25, having the structure: 29. [ka] 26. The compound of any one of embodiments 1-25, having the structure: 30. [ka] wherein each R A is independently halo. 31. The compound of any one of embodiments 1-30, in the form of a pharmaceutically acceptable salt. 32. A pharmaceutical composition comprising a compound according to any one of embodiments 1-31 and a pharmaceutically acceptable excipient. 33. A method for inhibiting the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal an effective amount of a compound according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 32. 34. A method for treating a disease or disorder that benefits from modulation of prostaglandin E2 receptor 2 (EP2) activity, comprising administering to a mammal an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32. 35. A method for modulating prostaglandin E2 receptor 2 (EP2), comprising contacting said EP2 with a compound according to any one of embodiments 1 to 31 or a pharmaceutical composition according to embodiment 32. 36. The method of embodiment 35, wherein said contacting is carried out in vitro. 37. The method of embodiment 35, wherein said contacting is performed in vivo. 38. A method for treating a disease or disorder selected from a neurological disorder, an inflammatory disorder, an autoimmune disorder, a fibrotic disorder, an allergic disorder, and a combination thereof, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32. 39. Amyotrophic lateral sclerosis (ALS), epilepsy, dementia, Alzheimer's disease, concussion, delirium, chemotherapy-associated cognitive decline, radiation-associated cognitive decline, postoperative cognitive impairment (including postoperative neurocognitive impairment, postoperative delirium, delayed neurocognitive impairment, and delayed neurocognitive recovery), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment or MCI), Binswanger dementia (subcortical arteriosclerotic encephalopathy), HIV-associated dementia (including asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy)) 32. A method of treating a neurological disorder selected from: encephalopathy, including encephalopathy, multiple system atrophy (MSA), spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), head trauma, concussion, chronic traumatic encephalopathy, intracerebral hemorrhage, hematoma, diabetic retinopathy, macular degeneration, macular edema, glaucoma, multiple sclerosis, angioedema, including edema caused by treatment with antibody therapy (e.g., ARIA-E), migraine, Huntington's disease, ALS, and Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32. 40. Systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, hyperimmunoglobulin D and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, ulcerative colitis, necrotizing enterocolitis (NEC), peritonitis, gout, gouty attacks, gouty arthritis, bullous pemphigoid , sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, asthma, atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, 32. A method for treating an inflammatory or allergic disease selected from emotion-induced asthma, extrinsic asthma caused by environmental factors, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infection, early asthma, wheezy infant syndrome, bronchiolitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, and sphenoid sinusitis, comprising administering an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32 to a subject in need thereof. 41. Tissue or organ transplantation, graft-versus-host disease caused by transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type 1 diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus, acne, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular blepharitis ulcer, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma, airway hyperresponsiveness, bronchitis, gastric ulcer, vascular disorders due to ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuropathy neuritis), mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, and dentin, glomerulonephritis, alopecia areata by preventing hair loss, promoting hair growth, and / or promoting hair growth and development, male pattern baldness or senile alopecia, vitiligo, and muscular dystrophy 32. A method for treating an immune dysregulation disorder selected from the group consisting of erythroderma, pyoderma, Sezary syndrome, Addison's disease, ischemia-reperfusion injury associated with organ preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen- or drug-induced toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, corneal alkali burn, erythematous dermatitis multiforme, linear IgA bulbar dermatitis, cemental dermatitis, gingivitis, periodontitis, and sepsis, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32. 42. Solid tumors, brain cancer, kidney cancer, liver cancer, adrenal gland cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, tumors of the neck and head, epidermal hyperproliferation, psoriasis, prostate Hypertrophy, tumorigenesis, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-induced disease, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin's lymphoma 32. A method of treating a proliferative disorder selected from lymphoma, primary cutaneous T-cell lymphoma, smoldering or asymptomatic multiple myeloma, or a hematopoietic malignancy (including leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma), comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32. 43. A method for treating a fibrotic disease selected from idiopathic pulmonary fibrosis, systemic sclerosis, uterine leiomyoma, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis due to toxins, viral hepatitis, shock, or anoxia, B viral hepatitis, non-A / non-B hepatitis, chronic hepatitis C virus (HCV) infection, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), non-alcoholic steatohepatitis (NASH), liver failure, fulminant hepatic failure, delayed liver failure, acute exacerbation of chronic liver failure, kidney disease, and chronic kidney disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32. 44. A method for treating cytokine release syndrome, comprising administering an effective amount of a compound according to any one of embodiments 1-31 or a pharmaceutical composition according to embodiment 32 to a subject in need thereof. 45. A method for treating a disease selected from endometriosis, uterine fibroids (leiomyoma), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dysfecation, and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, breast cancer, colon cancer, familial adenomatous polyposis, colorectal adenoma, endometrial cancer, prostate cancer, lung cancer, testicular cancer, gastric cancer, macular degeneration, inflammatory and neuropathic pain, migraine, headache, cluster headache, inflammation-induced pain, cancer pain, polycystic kidney disease, and polycystic ovary syndrome, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32. 46. ​​A method for treating a vascular disorder, comprising administering to a subject in need thereof an effective amount of a compound according to any one of embodiments 1-31 or a pharmaceutical composition according to embodiment 32. 47. The method of embodiment 46, wherein the vascular disorder is selected from head trauma, stroke, aneurysm, vascular dementia, vascular cognitive impairment and dementia (VCID), cerebral small vessel disease, subcortical ischemic vascular disease, mixed dementia, and ischemic vascular disease. 48. A method for treating a disease selected from Alzheimer's disease, ALS, multiple sclerosis, Parkinson's disease, and Huntington's disease, comprising administering an effective amount of a compound of any one of embodiments 1-31 or a pharmaceutical composition of embodiment 32 to a subject in need thereof.

[0319] This disclosure contemplates, inter alia, the following numbered embodiments: 1.Formula (III) [ka] A compound having the structure During the ceremony, Ring A is a bicyclic heterocycle having one or more nitrogen atoms, or ring A is ring A'; Each R A 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 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R A together to form a carbonyl, Ring A' is [ka] is selected from the group consisting of R 1 and R 2 are independently hydrogen, -C 1~4 Alkyl, -CN, C(O)NR c R c Alternatively, R 1 and R 2 Together, Oxo, C 3~6 forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, X is selected from hydrogen and halogen; R 3 and R 4 are independently hydrogen, -C 1~4 alkyl, or R 3 and R 4together to form an oxo, or R 3 and R 4 One of them is R 5 forms a double bond with R 3 and R 4 The other is hydrogen or -C 1~4 is alkyl, R 5 is -(CH2) m -R b , -(CHR a ) m -R b , -O-(CH2) m -R b , -O-(CHR a ) m -R b , -C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b , -NHC(O)OR d , -NHC(O)NR c R c is selected from R 6 and R 7 are independently hydrogen, -C 1~4 alkyl, or R 6 and R 7 together to form oxo, Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3~8 ) cycloalkyl; Each R b are independently =O, -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , -C(O)NR c R c, and ring B [ka] is selected from the group consisting of Ring B is C 3~6 cycloalkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl containing two or more nitrogen atoms, 9-10-membered heteroaryl, or ring B is ring B'; Each R B are independently 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), --(CH2) m -N(R c )2, -(CH2) m -NHC(O)C 1~4 Alkyl, -(CH2) m -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), -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 3~6cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R B together to form a carbonyl, Each R c are independently a Or, two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, which may optionally contain one or more additional heteroatoms which may be the same or different, and optionally one or more —C(O)R a and R a may be substituted with a group, Each R d are independently hydrogen, and optionally substituted with 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl (C 1~6 ) alkyl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl are each selected from halogen, C 1~4 Alkyl, and -O(C 1~4 alkyl), l is 0 to 3; m is 0 to 3; n is 0 to 3, Ring B' is [ka] is selected from the group consisting of The compound is not a compound disclosed in PCT / US2022 / 034901. 2.Formula (IIIa) [ka] 2. The compound of embodiment 1, having the formula: 3. Ring A is [ka] 3. The compound of embodiment 1 or embodiment 2, wherein 4. Ring A is 1 to 3 Rs (optional) A replaced with [ka] 3. The compound of embodiment 1 or embodiment 2, wherein 5. Ring A is [ka] and X is a halogen. 6. Ring A is [ka] 5. The compound of embodiment 4, wherein 7. Ring A is [ka] 6. The compound of embodiment 5, wherein 8. Ring A is 1 to 3 Rs (optional) A replaced with [ka] 3. The compound of embodiment 1 or embodiment 2, wherein 9. Ring A is [ka] and X is a halogen. 10. Ring A is [ka] 10. The compound of embodiment 9, wherein: 11. Ring A is [ka] and X is a halogen. 12. Ring A is [ka] 12. The compound of embodiment 11, wherein: 13. Ring A is [ka] 12. The compound of embodiment 11, wherein: 14.R 3 and R 4 The compound of any one of embodiments 1-13, wherein together form an oxo group. 15.R 5 is -(CH2) m -R b , -(CHR a ) m -R b , -O-(CH2) m -R b , -O-(CHR a ) m -R b , -C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b , -NHC(O)OR d , -NHC(O)NR c R c is selected from Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3~8 ) cycloalkyl; Each R b are independently =O, -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)OR d , and -C(O)NRc R c The compound of embodiment 1 or embodiment 2, selected from the group consisting of: 16. Ring A is [ka] The compound of embodiment 15, wherein the compound is a bicyclic heterocycle selected from the group consisting of: 17. Ring A is [ka] and each optionally contains 1 to 3 R A The compound of embodiment 15, wherein the compound is substituted with 18. Expression [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Compound. 19. The compound of any one of embodiments 1-18, in the form of a pharmaceutically acceptable salt. 20. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 19 and a pharmaceutically acceptable excipient. 21. A method for inhibiting the activity of prostaglandin E2 receptor 2 (EP2) in a mammal, comprising administering to the mammal an effective amount of a compound according to any one of embodiments 1 to 19 or a pharmaceutical composition according to embodiment 20. 22. A method for treating a disease or disorder that benefits from modulation of prostaglandin E2 receptor 2 (EP2) activity, comprising administering to a mammal an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20. 23. A method for treating a disease or disorder selected from a neurological disorder, an inflammatory disorder, an autoimmune disorder, a fibrotic disorder, an allergic disorder, and a combination thereof, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20. 24. Amyotrophic lateral sclerosis (ALS), epilepsy, dementia, Alzheimer's disease, concussion, delirium, chemotherapy-associated cognitive decline, radiation-associated cognitive decline, postoperative cognitive impairment (including postoperative neurocognitive impairment, postoperative delirium, delayed neurocognitive impairment, and delayed neurocognitive recovery), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment or MCI), Binswanger dementia (subcortical arteriosclerotic encephalopathy), HIV-associated dementia (including asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy)) 20. A method of treating a neurological disorder selected from: encephalopathy, including encephalopathy, multiple system atrophy (MSA), spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), head trauma, concussion, chronic traumatic encephalopathy, intracerebral hemorrhage, hematoma, diabetic retinopathy, macular degeneration, macular edema, glaucoma, multiple sclerosis, angioedema, including edema caused by treatment with antibody therapy (e.g., ARIA-E), migraine, Huntington's disease, ALS, and Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20. 25. Systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, hyperimmunoglobulin D and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, ulcerative colitis, necrotizing enterocolitis (NEC), peritonitis, gout, gouty attacks, gouty arthritis, bullous pemphigoid , sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, asthma, atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, 20. A method for treating an inflammatory or allergic disease selected from emotion-induced asthma, extrinsic asthma caused by environmental factors, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan, or viral infection, early asthma, wheezy infant syndrome, bronchiolitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, and sphenoid sinusitis, comprising administering an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20 to a subject in need thereof. 26. Tissue or organ transplantation, graft-versus-host disease caused by transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type 1 diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus, acne, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular blepharitis ulcer, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma, airway hyperresponsiveness, bronchitis, gastric ulcer, vascular disorders due to ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuropathy neuritis), mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, and dentin, glomerulonephritis, alopecia areata by preventing hair loss, promoting hair growth, and / or promoting hair growth and development, male pattern baldness or senile alopecia, vitiligo, and muscular dystrophy 20. A method for treating an immune dysregulation disorder selected from the group consisting of erythroderma, pyoderma, Sezary syndrome, Addison's disease, ischemia-reperfusion injury associated with organ preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen- or drug-induced toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, corneal alkali burn, erythematous dermatitis multiforme, linear IgA bulbar dermatitis, cemental dermatitis, gingivitis, periodontitis, and sepsis, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20. 27. Solid tumors, brain cancer, kidney cancer, liver cancer, adrenal gland cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, tumors of the neck and head, epidermal hyperproliferation, psoriasis, prostate Hypertrophy, tumorigenesis, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-induced disease, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin's lymphoma 20. A method of treating a proliferative disorder selected from lymphoma, primary cutaneous T-cell lymphoma, smoldering or asymptomatic multiple myeloma, or a hematopoietic malignancy (including leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma), comprising administering an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20 to a subject in need thereof. 28. A method for treating a fibrotic disease selected from idiopathic pulmonary fibrosis, systemic sclerosis, uterine leiomyoma, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis due to toxins, viral hepatitis, shock, or anoxia, B viral hepatitis, non-A / non-B hepatitis, chronic hepatitis C virus (HCV) infection, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), non-alcoholic steatohepatitis (NASH), liver failure, fulminant hepatic failure, delayed liver failure, acute exacerbation of chronic liver failure, kidney disease, and chronic kidney disease, comprising administering an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20 to a subject in need thereof. 29. A method for treating cytokine release syndrome, comprising administering an effective amount of a compound according to any one of embodiments 1-19 or a pharmaceutical composition according to embodiment 20 to a subject in need thereof. 30. A method for treating a disease selected from endometriosis, uterine fibroids (leiomyoma), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dysfecation, and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, breast cancer, colon cancer, familial adenomatous polyposis, colorectal adenoma, endometrial cancer, prostate cancer, lung cancer, testicular cancer, gastric cancer, macular degeneration, inflammatory and neuropathic pain, migraine, headache, cluster headache, inflammation-induced pain, cancer pain, polycystic kidney disease, and polycystic ovary syndrome, comprising administering an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20 to a subject in need thereof. 31. A method for treating a vascular disorder, comprising administering an effective amount of a compound according to any one of embodiments 1-19 or a pharmaceutical composition according to embodiment 20 to a subject in need thereof. 32. The method of embodiment 31, wherein the vascular disorder is selected from head trauma, stroke, aneurysm, vascular dementia, vascular cognitive impairment and dementia (VCID), cerebral small vessel disease, subcortical ischemic vascular disease, mixed dementia, and ischemic vascular disease. 33. A method for treating a disease selected from Alzheimer's disease, ALS, multiple sclerosis, Parkinson's disease, and Huntington's disease, comprising administering an effective amount of a compound of any one of embodiments 1-19 or a pharmaceutical composition of embodiment 20 to a subject in need thereof.

[0320] This disclosure contemplates, inter alia, the following numbered embodiments: 1. [ka] A compound having the structure (Wherein, ring A is 1 to 3 R Aoptionally replaced with [ka] 1 to 3 R A optionally replaced with [ka] [ka] is selected from the group consisting of Each R A 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 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R A together to form a carbonyl, R 1 and R 2 are independently hydrogen, -C 1~4 Alkyl, -CN, -C(O)NR c R c Alternatively, R 1 and R 2 Together, Oxo, C 3~6 forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, X is selected from hydrogen and halogen; R 3 and R 4 are independently hydrogen, -C 1~4 alkyl, or R 3 and R 4 together to form an oxo, or R 3 and R 4 One of them is R 5 forms a double bond with R 3 and R 4 The other is hydrogen or -C 1~4 is alkyl, R 5 is -(CH2) m -R b , -(CHR a ) m -R b , -O-(CH2) m -R b , -O-(CHR a ) m -R b , -C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b is selected from R 6 and R 7 are independently hydrogen, -C 1~4 alkyl, or R 6 and R 7 together to form oxo, Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3~8 ) cycloalkyl; Each R b are independently =O, -OR d , -OCF2H, -OCF3, -NR c R c , halogen, -CF3, -CN, -S(O)2R d , -S(O)2OR d , -S(O)NR c R c , -C(O)R d , -C(O)ORd , -C(O)NR c R c , and ring B [ka] is selected from the group consisting of Ring B is C 3~6 cycloalkyl, phenyl, 5-membered heteroaryl, 6-membered heteroaryl containing two or more nitrogen atoms, 9-10-membered heteroaryl, or ring B is ring B', and ring B is [ka] Instead, Each R B are independently 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), -(CH2) m -N(R c )2, -(CH2) m -NHC(O)C 1~4 Alkyl, -(CH2) m -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), -S(O)(C 1~4alkyl), -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 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R B together to form a carbonyl, Each R c are independently a Or, two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, which may optionally contain one or more additional heteroatoms which may be the same or different, and optionally one or more —C(O)R a and R a may be substituted with a group, Each R d are independently hydrogen, and optionally substituted with 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl (C 1~6 ) alkyl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl are each selected from halogen, C 1~4 Alkyl, and -O(C 1~4 alkyl), m is 0 to 3; n is 0 to 3). 2.R b n R B are respectively replaced by [ka] [ka] 2. The compound of embodiment 1, selected from: 3.Each R B is -C(O)(C 1~4 alkyl), -C(O)OH, -C(O)O(C1~4 alkyl), -C(O)NH2, -C(O)NH(C 1~4 alkyl), -C(O)N(C 1~4 alkyl)2, -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, -S(O)2(C 6~13 aryl), and -S(O)2NHS(O)2(C 1~4 2. The compound of embodiment 1, wherein the compound is selected from: 4.R 5 is -(CH2) m -R b and R b teeth, [ka] The compound of embodiment 1, selected from the group consisting of: 5.R B is -S(O)2(C 1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, and -S(O)2(C 6~13 5. The compound of any one of embodiments 1-4, wherein the compound is selected from: 6.R b teeth, [ka] 2. The compound of embodiment 1, wherein 7.R b teeth, [ka] 2. The compound of embodiment 1, wherein 8. Ring A is [ka] The compound of any one of embodiments 1 to 7, wherein: 9. The compound of any one of embodiments 1-8, in the form of a pharmaceutically acceptable salt. 10. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 9 and a pharmaceutically acceptable excipient. 11. A method for modulating prostaglandin E2 receptor 2 (EP2), comprising contacting said EP2 with a compound according to any one of embodiments 1 to 9 or a pharmaceutical composition according to embodiment 10. 12. The method of embodiment 11, wherein said contacting is effected in vitro. 13. The method of embodiment 11, wherein said contacting occurs in vivo. 14. A method for treating a disease or disorder that benefits from modulation of the prostaglandin E2 receptor 2 (EP2), comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10. 15. A method for treating a disease or disorder selected from a neurological disorder, an inflammatory disorder, an autoimmune disorder, a fibrotic disorder, an allergic disorder, and a combination thereof, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10. 16. Amyotrophic lateral sclerosis (ALS), epilepsy, dementia, Alzheimer's disease, concussion, delirium, chemotherapy-associated cognitive decline, radiation-associated cognitive decline, postoperative cognitive impairment (including postoperative neurocognitive impairment, postoperative delirium, delayed neurocognitive impairment, and delayed neurocognitive recovery), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment or MCI), Binswanger dementia (subcortical arteriosclerotic encephalopathy), HIV-associated dementia (including asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), and HIV-associated dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy)) 10. A method of treating a neurological disorder selected from: encephalopathy, including encephalopathy, multiple system atrophy (MSA), spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), head trauma, concussion, chronic traumatic encephalopathy, intracerebral hemorrhage, hematoma, diabetic retinopathy, macular degeneration, macular edema, glaucoma, multiple sclerosis, angioedema, including edema caused by treatment with antibody therapy (e.g., ARIA-E), migraine, Huntington's disease, ALS, and Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10. 17. Systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, hyperimmunoglobulin D and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, ulcerative colitis, necrotizing enterocolitis (NEC), peritonitis, gout, gouty attacks, gouty arthritis, bullous pemphigoid , sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, asthma, atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, 13. A method for treating an inflammatory or allergic disease selected from emotion-induced asthma, extrinsic asthma caused by environmental factors, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infection, early asthma, wheezy infant syndrome, bronchiolitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, and sphenoid sinusitis, comprising administering an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10 to a subject in need thereof. 18. Tissue or organ transplantation, graft-versus-host disease caused by transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type 1 diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus, acne, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular blepharitis ulcer, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma, airway hyperresponsiveness, bronchitis, gastric ulcer, vascular disorders due to ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuropathy neuritis), mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, and dentin, glomerulonephritis, alopecia areata by preventing hair loss, promoting hair growth, and / or promoting hair growth and development, male pattern baldness or senile alopecia, vitiligo, and muscular dystrophy 10. A method for treating an immune dysregulation disorder selected from the group consisting of erythroderma, pyoderma, Sezary syndrome, Addison's disease, ischemia-reperfusion injury associated with organ preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen- or drug-induced toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, corneal alkali burn, erythematous dermatitis multiforme, linear IgA bulbar dermatitis, cemental dermatitis, gingivitis, periodontitis, and sepsis, comprising administering an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10 to a subject in need thereof. 19. Solid tumors, brain cancer, kidney cancer, liver cancer, adrenal gland cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, tumors of the neck and head, epidermal hyperproliferation, psoriasis, prostate cancer Glandular hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-induced diseases, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin's lymphoma 10. A method of treating a proliferative disorder selected from lymphoma, primary cutaneous T-cell lymphoma, smoldering or asymptomatic multiple myeloma, or a hematopoietic malignancy (including leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma), comprising administering an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10 to a subject in need thereof. 20. A method of treating a fibrotic disease selected from idiopathic pulmonary fibrosis, systemic sclerosis, uterine leiomyoma, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis due to toxins, viral hepatitis, shock, or anoxia, B viral hepatitis, non-A / non-B hepatitis, chronic hepatitis C virus (HCV) infection, liver cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), non-alcoholic steatohepatitis (NASH), liver failure, fulminant liver failure, delayed liver failure, acute exacerbation of chronic liver failure, kidney disease, and chronic kidney disease, comprising administering an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10 to a subject in need thereof. 21. A method for treating cytokine release syndrome, comprising administering an effective amount of a compound according to any one of embodiments 1-9 or a pharmaceutical composition according to embodiment 10 to a subject in need thereof. 22. A method for treating a disease selected from endometriosis, uterine fibroids (leiomyoma), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dysfecation, and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, breast cancer, colon cancer, familial adenomatous polyposis, colorectal adenoma, endometrial cancer, prostate cancer, lung cancer, testicular cancer, gastric cancer, macular degeneration, inflammatory and neuropathic pain, migraine, headache, cluster headache, inflammation-induced pain, cancer pain, polycystic kidney disease, and polycystic ovary syndrome, comprising administering an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10 to a subject in need thereof. 23. A method for treating a vascular disorder, comprising administering an effective amount of a compound according to any one of embodiments 1-9 or a pharmaceutical composition according to embodiment 10 to a subject in need thereof. 24. The method of embodiment 23, wherein the vascular disorder is selected from head trauma, stroke, aneurysm, vascular dementia, vascular cognitive impairment and dementia (VCID), cerebral small vessel disease, subcortical ischemic vascular disease, mixed dementia, and ischemic vascular disease. 25. A method for treating a disease selected from Alzheimer's disease, ALS, multiple sclerosis, Parkinson's disease, and Huntington's disease, comprising administering an effective amount of a compound of any one of embodiments 1-9 or a pharmaceutical composition of embodiment 10 to a subject in need thereof.

[0321] This disclosure contemplates, inter alia, the following numbered embodiments: 1.Formula (III) [ka] A compound having the structure (In the formula, Ring A is a bicyclic heterocycle having one or more nitrogen atoms, or ring A is ring A'; Each R A 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 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two R A together to form a carbonyl, Ring A' is [ka] is selected from the group consisting of R 1 and R 2 are independently hydrogen, -C 1~4 Alkyl, -CN, C(O)NR c R c Alternatively, R 1 and R 2 Together, Oxo, C 3~6 forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, X is selected from hydrogen and halogen; R 3 and R 4 are independently hydrogen, -C 1~4 alkyl, or R 3 and R 4together to form an oxo, or R 3 and R 4 One of them is R 5 forms a double bond with R 3 and R 4 The other is hydrogen or -C 1~4 is alkyl, R 5 is -(CH2) m -R b , -(CHR a ) m -R b , -O-(CH2) m -R b , -O-(CHR a ) m -R b , -C(O)NH-(CH2) m -R b , -C(O)NH-(CHR a ) m -R b is selected from R 6 and R 7 are independently hydrogen, -C 1~4 alkyl, or R 6 and R 7 together to form oxo, Each R a are independently hydrogen, (C 1~6 ) alkyl and (C 3~8 ) cycloalkyl; R b teeth, [ka] is selected from Each R B is -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, -S(O)(C 1~4 alkyl), -S(O)(NH)(C 1~4 alkyl), -S(O)2(C1~4 alkyl), -S(O)2NH2, -S(O2)NHCH3, -S(O)2(C 6~13 aryl), and -S(O)2NHS(O)2(C 1~4 alkyl), Each R c are independently a Or, two R c together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, whic...

Claims

1. Formula (III) 【Chemistry 161】 A compound having the structure During the ceremony, Ring A is a bicyclic heterocycle having one or more nitrogen atoms, or Ring A is Ring A'; Each R Ａ 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)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 R Ａ together to form a carbonyl, Ring A' is 【Chemistry 162】 is selected from the group consisting of R １ and R ２ are independently hydrogen, —C １～４ Alkyl, —CN, —C(O)NR ｃ R ｃ Alternatively, R １ and R ２ Together, Oxo, C ３～６ forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, X is selected from hydrogen and halogen; R ３ and R ４ are independently hydrogen, —C １～４ alkyl, or R ３ and R ４ together form an oxo, or R ３ and R ４ One of them is R ５ forms a double bond with R ３ and R ４ The other is hydrogen or —C １～４ is alkyl, R ５ is -(CH ２ ) ｍ -R ｂ , -(CHR ａ ) ｍ -R ｂ , —O—(CH ２ ) ｍ -R ｂ , —O—(CHR ａ ) ｍ -R ｂ , -C(O)NH-(CH ２ ) ｍ -R ｂ , -C(O)NH-(CHR ａ ) ｍ -R ｂ is selected from R ６ and R ７ are independently hydrogen, —C １～４ alkyl, or R ６ and R ７ together to form oxo, Each R ａ are independently hydrogen, (C １～６ ) alkyl and (C ３～８ ) cycloalkyl; R ｂ teeth, 【Chemical 163】 is selected from Each R Ｂ is -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 , -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 , -S(O) ２ (C ６～１３ aryl), and —S(O) ２ NHS (O) ２ (C １～４ alkyl), Each R ｃ are independently R ａ or two R ｃ together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, said 5- to 8-membered cycloheteroalkyl or 5-membered heteroaryl optionally containing one or more additional heteroatoms which may be the same or different, and optionally containing one or more —C(O)R ａ and R ａ may be substituted with a group, Each R ｄ are independently hydrogen and optionally substituted with 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl (C １～６ ) alkyl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl are each selected from halogen, C １～４ Alkyl, and —O(C １～４ alkyl), l is 0 to 3; m is 0 to 3; The compound, wherein n is 0 to 3.

2. R Ｂ is -S(O) ２ (C １～４ alkyl), -S(O) ２ NH ２ , -S(O ２ ) NHCH ３ , and -S(O) ２ (C ６～１３ 2. The compound of claim 1, wherein the aryl is selected from the group consisting of aryl, ...

3. R ｂ teeth, 【Chemistry 164】 2. The compound of claim 1, wherein:

4. Rb is 【Chemistry 165】 2. The compound of claim 1, wherein:

5. Ring A is 【Chemistry 166】 2. The compound of claim 1, wherein: 【Request Item 6】 【Chemistry 167】 A compound having the structure In the formula, ring A is 1 to 3 R Ａ optionally replaced with 【Chemical 168】 1 to 3 R Ａ optionally replaced with 【Chemistry 169】 【Chemistry 170】 is selected from the group consisting of Each R Ａ 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)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 R Ａ together to form a carbonyl, R １ and R ２ are independently hydrogen, —C １～４ Alkyl, —CN, C(O)NR ｃ R ｃ Alternatively, R １ and R ２ Together, Oxo, C ３～６ forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, X is selected from hydrogen and halogen; R ３ and R ４ are independently hydrogen, —C １～４ alkyl, or R ３ and R ４ together form an oxo, or R ３ and R ４ One of them is R ５ forms a double bond with R ３ and R ４ The other is hydrogen or —C １～４ is alkyl, R ５ is -(CH ２ ) ｍ -R ｂ , -(CHR ａ ) ｍ -R ｂ , —O—(CH ２ ) ｍ -R ｂ , —O—(CHR ａ ) ｍ -R ｂ , -C(O)NH-(CH ２ ) ｍ -R ｂ , -C(O)NH-(CHR ａ ) ｍ -R ｂ is selected from R ６ and R ７ are independently hydrogen, —C １～４ alkyl, or R ６ and R ７ together to form oxo, Each R ａ are independently hydrogen, (C １～６ ) alkyl and (C ３～８ ) cycloalkyl; R ｂ teeth, 【Chemistry 171】 is selected from Each R Ｂ is -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 , -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 , -S(O) ２ (C ６～１３ aryl), and —S(O) ２ NHS (O) ２ (C １～４ alkyl), Each R ｃ are independently R ａ or two R ｃ together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, said 5- to 8-membered cycloheteroalkyl or 5-membered heteroaryl optionally containing one or more additional heteroatoms which may be the same or different, and optionally containing one or more —C(O)R ａ and R ａ may be substituted with a group, Each R ｄ are independently hydrogen and optionally substituted with 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl (C １～６ ) alkyl, wherein the 5-membered heteroaryl, 6-membered heteroaryl, and 6-membered aryl are each selected from halogen, C １～４ Alkyl, and —O(C １～４ alkyl), m is 0 to 3; The compound wherein n is 0 to 3. 【Request Item 7】 【Chemistry 172】 A compound having the structure: 【Request Item 8】 【Chemistry 173】 A compound having the structure: 【Request Item 9】 【Chemistry 174】 A compound having the structure: 【Request Item 10】 【Chemistry 175】 A compound having the structure: 【Request Item 11】 【Chemistry 176】 A compound having the structure: 【Request Item 12】 【Chemistry 177】 A compound having the structure: 【Request Item 13】 【Chemistry 178-1】 【Chemistry 178-2】 【Chemistry 178-3】 【Chemistry 178-4】 【Chemistry 178-5】 【Chemistry 178-6】 【Chemistry 178-7】 【Chemistry 178-8】 【Chemistry 178-9】 A compound selected from: 【Request Item 14】 【Chemistry 179】 A compound having the formula: During the ceremony, R １ and R ２ are independently R ａ , -OR ｄ , -C １～４ haloalkyl; or R １ and R ２ Together, Oxo, C ３～６ forming a 3- to 6-membered cycloalkyl or a 3- to 6-membered cycloheteroalkyl, R ３ は、-CH(R ｂ ) ２ 、-C(R ｂ ) ３ 、-S(O) ２ R ｄ 、-S(O) ２ OR ｄ 、-S(O) ２ NR ｃ R ｃ 、-S(O)(NR ａ )R ｄ 、-S(O) ２ N(R ａ )S(O) ２ R ａ 、-S(O) ２ N(R ａ )S(O) ２ NR ｃ R ｃ 、-C(O)R ｄ 、-C(O)N(R ａ )C(O)R ｄ 、-C(O)OR ｄ 、-C(O)NR ｃ R ｃ であり、 Ring A and Ring B are independently selected from phenyl and cycloalkyl; X is hydrogen and R ｂ is selected from Each R Ａ are independently halogen, —CN, —C １～４ Alkyl, and -C １～４ haloalkyl; Each R Ｂ are independently 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)NR ｃ R ｃ , -NR ｃ R ｃ , —NH(C ３～６ cycloalkyl), -NH(C ３～６ heterocycloalkyl), and substituted or unsubstituted C ３～６ cycloalkyl; Each R ａ are independently hydrogen, (C １～６ ) alkyl and (C ３～８ ) cycloalkyl; Each R ｂ are independently -OR ｄ , -OCF ２ H, -OCF ３ , -NR ｃ R ｃ , halogen, -CF ３ , -CN, -S(O) ２ R ｄ , -S(O) ２ OR ｄ , -S(O) ２ NR ｃ R ｃ , -C(O)R ｄ , -C(O)OR ｄ , —C(O)NR ｃ R ｃ is selected from the group consisting of Each R ｃ are independently R ａ or two R ｃ together with the nitrogen atom to which they are attached form a 5- to 8-membered cycloheteroalkyl or a 5-membered heteroaryl, said 5- to 8-membered cycloheteroalkyl or 5-membered heteroaryl optionally containing one or more additional heteroatoms which may be the same or different, and optionally containing one or more —C(O)R ａ and R ａ may be substituted with a group, Each R ｄ are independently selected from hydrogen, halogen and —O(C １～４ (C alkyl) optionally substituted with one, two or three groups selected from １～６ ) alkyl; n, at each occurrence, is independently 0 to 3; The compound is not a compound disclosed in PCT / US22 / 34903.

15. 15. The compound of claim 14, wherein ring A or ring B, or both, are bicyclic.

16. 16. The compound of claim 14 or 15, wherein ring A or ring B, or both, are bridged bicyclic.

17. 16. The compound of claim 14 or 15, wherein ring A or ring B, or both, is a bridged bicyclic cycloalkyl.

18. 16. The compound of claim 14 or 15, wherein ring A is a bridged cycloalkyl.

19. 16. The compound of claim 14 or 15, wherein Ring B is a bridged cycloalkyl.

20. Ring A or ring B is C ３～６ 15. The compound of claim 14, which is cycloalkyl. 【Request Item 21】 【Chemistry 180】 15. The compound of claim 14 having the structure: 【Request Item 22】 【Chemistry 181】 15. The compound of claim 14 having the structure: 【Request Item 23】 【Chemistry 182】 15. The compound of claim 14 having the structure:

24. R Ｂ is -CN, -C(O)(C １～４ alkyl), —C(O)OH, —C(O)O(C １～４ alkyl) or —C(O)NR ｃ R ｃ The compound according to any one of claims 14 to 23,

25. R ３ is -CH(R ｂ ) ２ and -C(R ｂ ) ３ The compound according to any one of claims 14 to 23, selected from:

26. R ３ Each R in ｂ are independently -OR ｄ , -OCF ２ H, -OCF ３ , and -CF ３ 26. The compound of claim 25, selected from:

27. R ３ is -CH(OH)CF ３ 26. The compound of claim 25, wherein:

28. R ３ is -C(OH) ２ CF ３ 26. The compound of claim 25, wherein:

29. R ３ is S(O) ２ R ｄ , -S(O)(NR ａ ) R ｄ , -S(O) ２ OR ｄ , -S(O) ２ NR ｃ R ｃ , -S(O) ２ N (R ａ ) S (O) ２ R ａ , and -S(O) ２ N (R ａ ) S (O) ２ NR ｃ R ｃ The compound according to any one of claims 14 to 23, selected from:

30. R ３ is -C(O)R ｄ , -C(O)N(R ａ ) C(O)R ｄ , -C(O)OR ｄ and —C(O)NR ｃ R ｃ The compound according to any one of claims 14 to 23, selected from:

31. R ３ The compound according to any one of claims 14 to 23, wherein is -COOH.

32. R ３ is S(O) ２ NH ２ The compound according to any one of claims 14 to 23,

33. R ３ is S(O) ２ CH ３ The compound according to any one of claims 14 to 23,

34. R ３ is -S(O)(NR ａ ) R ｄ The compound according to any one of claims 14 to 23,

35. R ３ is -S(O)(NH)CH ３ The compound according to any one of claims 14 to 23,

36. R １ and R ２ The compound of any one of claims 14 to 23, wherein together form oxo.

37. R １ and R ２ One of the groups is hydrogen and the other is —CF ３ The compound according to any one of claims 14 to 23,

38. At least one R Ｂ The compound according to any one of claims 14 to 36, wherein is -CN. 【Request Item 39】 【Chemistry 183】 The compound of any one of claims 14 to 38, having the structure: 【Request Item 40】 【Chemistry 184】 The compound of any one of claims 14 to 37, having the structure: 【Request Item 41】 【Chemistry 185】 The compound of any one of claims 14 to 40, having the structure: 【Request Item 42】 【Chemistry 186】 The compound of any one of claims 14 to 41, having the structure: 【Request Item 43】 【Chemistry 187】 wherein each R Ａ is independently halo. 【Request Item 44】 【Chemistry 188-1】 【Chemistry 188-2】 【Chemistry 188-3】 A compound.

45. 44. The compound of any one of claims 1 to 43 in the form of a pharmaceutically acceptable salt.

46. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46 and a pharmaceutically acceptable excipient.

47. 47. A method of modulating prostaglandin E2 receptor 2 (EP2), comprising contacting said EP2 with a compound according to any one of claims 1 to 45 or a composition according to claim 46.

48. 48. The method of claim 47, wherein said contacting is carried out in vitro.

49. 48. The method of claim 47, wherein said contacting occurs in vivo.

50. 47. A method for treating a disease or disorder that would benefit from modulation of the prostaglandin E2 receptor 2 (EP2), comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

51. 47. A method for treating a disease or disorder selected from a neurological disorder, an inflammatory disorder, an autoimmune disorder, a fibrotic disorder, an allergic disorder, and combinations thereof, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

52. amyotrophic lateral sclerosis (ALS), epilepsy, dementia, Alzheimer's disease, concussion, delirium, chemotherapy-associated cognitive decline, radiation-associated cognitive decline, postoperative cognitive impairment (including postoperative neurocognitive impairment, postoperative delirium, delayed neurocognitive impairment, and delayed neurocognitive recovery), vascular dementia, frontotemporal dementia, dementia with Lewy bodies, presenile dementia (mild cognitive impairment or MCI), Binswanger dementia (subcortical arteriosclerotic encephalopathy), HIV-associated dementia (asymptomatic neurocognitive impairment (ANI), mild neurocognitive impairment (MND), HIV-associated dementia (HAD) (also known as AIDS dementia complex [ADC] or HIV encephalopathy) 47. A method of treating a neurological disorder selected from the group consisting of encephalopathy, multiple system atrophy (MSA), spinocerebellar ataxia, Steele-Richardson-Olszewski disease (progressive supranuclear palsy), head trauma, concussion, chronic traumatic encephalopathy, intracerebral hemorrhage, hematoma, diabetic retinopathy, macular degeneration, macular edema, glaucoma, multiple sclerosis, angioedema including edema caused by treatment with antibody therapy (e.g., ARIA-E), migraine, Huntington's disease, ALS, and Parkinson's disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-45 or a composition of claim 46.

53. Systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, hyperimmunoglobulin D and periodic fever syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, ulcerative colitis, necrotizing enterocolitis (NEC), peritonitis, gout, gouty attacks, gouty arthritis, bullous pemphigoid, and sarcopenia. Lucoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, asthma, atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, essential asthma of unknown or unclear cause, emphysematous asthma, exercise-induced asthma, 47. A method for treating an inflammatory or allergic disease selected from emotion-induced asthma, extrinsic asthma caused by environmental factors, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoal, or viral infection, incipient asthma, wheezy infant syndrome, bronchiolitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, ethmoid sinusitis, frontal sinusitis, maxillary sinusitis, and sphenoid sinusitis, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

54. Tissue or organ transplantation, graft-versus-host disease caused by transplantation, rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes mellitus, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus, acne, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma, airway hyperresponsiveness, bronchitis, gastric ulcer, vascular disorders due to ischemic disease and thrombosis, ischemic bowel disease, inflammatory bowel disease, Necrotizing enterocolitis, intestinal lesions associated with burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic hypersensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy, scleroderma, Wegener's granulomatosis, Sjogren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, and dentin, glomerulonephritis, and alopecia areata by preventing hair loss, promoting hair growth, and / or promoting hair growth and development, and male pattern baldness or senile alopecia, vitiligo, and muscular dystrophy 47. A method for treating an immunoregulatory disorder selected from the group consisting of erythematosus, pyoderma, Sezary syndrome, Addison's disease, ischemia-reperfusion injury associated with organ preservation, transplantation, or ischemic disease, endotoxin shock, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen- or drug-induced toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, age-related macular degeneration, vitreous scarring, corneal alkali burn, dermatitis multiforme, linear IgA globulosa, cemental dermatitis, gingivitis, periodontitis, and sepsis, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

55. Solid tumors, brain cancer, kidney cancer, liver cancer, adrenal gland cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, neck and head tumors, epidermal hyperproliferation, psoriasis, prostate hyperplasia, tumors Tumor formation, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 induced diseases, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary epithelial tumors 47. A method of treating a proliferative disorder selected from: cutaneous T-cell lymphoma, or chronic lymphocytic leukemia), smoldering or asymptomatic multiple myeloma, or a hematopoietic malignancy (including leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma), comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-45 or a composition of claim 46.

56. 47. A method of treating a fibrotic disease selected from idiopathic pulmonary fibrosis, systemic sclerosis, uterine leiomyoma, scleroderma, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis due to toxins, viral hepatitis, shock, or anoxia, B viral hepatitis, non-A / non-B hepatitis, chronic hepatitis C virus (HCV) infection, cirrhosis, alcoholic liver disease (including alcoholic cirrhosis), non-alcoholic steatohepatitis (NASH), liver failure, fulminant hepatic failure, delayed onset liver failure, acute exacerbation of chronic liver failure, kidney disease, and chronic kidney disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-45 or a composition of claim 46.

57. 47. A method for treating cytokine release syndrome, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

58. 47. A method for treating a disease selected from endometriosis, uterine fibroids (leiomyoma), menorrhagia, adenomyosis, primary and secondary dysmenorrhea (including symptoms of dyspareunia, dysentery, and chronic pelvic pain), chronic pelvic pain syndrome, precocious puberty, cervical ripening, breast cancer, colon cancer, familial adenomatous polyposis, colorectal adenoma, endometrial cancer, prostate cancer, lung cancer, testicular cancer, gastric cancer, macular degeneration, inflammatory and neuropathic pain, migraine, headache, cluster headache, inflammation-induced pain, cancer pain, polycystic kidney disease, and polycystic ovary syndrome, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

59. 47. A method for treating a vascular disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

60. 60. The method of claim 59, wherein the vascular disorder is selected from head trauma, stroke, aneurysm, vascular dementia, vascular cognitive impairment and dementia (VCID), cerebral small vessel disease, subcortical ischemic vascular disease, mixed dementia, and ischemic vascular disease.

61. 47. A method for treating a disease selected from Alzheimer's disease, ALS, multiple sclerosis, Parkinson's disease, and Huntington's disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

62. 47. A method for treating a CNS disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

63. 63. The method of claim 62, wherein the CNS disorder is selected from addiction, bipolar disorder, schizophrenia, general psychosis, drug-induced psychosis, delusional disorder, schizoaffective disorder, obsessive-compulsive disorder (OCD), depression, including treatment-resistant depression, suicidal ideation, and major depressive disorder, anxiety disorder, panic disorder, post-traumatic stress disorder (PTSD), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), substance abuse disorder, chemobrain, levodopa-induced addictive behavior, alcoholism, and narcotic addiction.

64. 47. A method of treating dementia, delirium, chemotherapy-associated cognitive decline, radiation-associated cognitive decline, postoperative cognitive impairment including postoperative neurocognitive impairment, postoperative delirium, delayed neurocognitive impairment, delayed neurocognitive recovery, vascular dementia, frontotemporal dementia, dementia with Lewy bodies, presenile dementia, Binswanger dementia, and HIV-associated dementia, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 45 or a composition of claim 46.

65. 47. A method for treating pain, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 45 or a composition according to claim 46.

66. 66. The method of claim 65, wherein the pain comprises nociceptive pain or neuropathic pain.

67. 66. The method of claim 65, wherein the pain comprises pain selected from acute pain, central pain syndromes, nerve pain (e.g., neuropathic pain, chemotherapy-induced neuropathy and neuropathic pain), diabetic neuropathy, HIV-associated neuropathy, fibromyalgia, neuralgia, postherpetic neuralgia, sciatica, neuropathic pain associated with CNS disease, post-operative pain, tension pain, menstrual pain, osteoarthritis pain, rheumatoid arthritis pain, visceral pain, sporadic pain, migraine, chronic pain, post-operative pain, lumbosacral pain, musculoskeletal pain, headache, cluster headache, inflammation-induced pain, and cancer pain.

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