HK1258849B - Tricyclic pi3k inhibitor compounds and methods of use - Google Patents

Description

Tricyclic PI3K inhibitor compounds and methods of use

Cross-reference to related applications

This nonprovisional application, filed pursuant to 37 CFR §1.53(b), claims the benefit of International Application No. PCT/CN2015/089121, filed on September 8, 2015, and International Application No. PCT/CN2016/076126, filed on March 11, 2016, under 35 U.S.C. §119(e) and §365, which are incorporated herein by reference in their entireties.

Technical Field

The present invention generally relates to tricyclic PI3K inhibitor compounds having activity against hyperproliferative disorders such as cancer. The invention also relates to methods of using the compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells or related pathological disorders.

Background Art

Upregulation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is a common feature of most cancers (Yuan and Cantley (2008) Oncogene 27:5497-510). Genetic variations in the pathway have been detected in a variety of human cancers (Osaka et al. (2004) Apoptosis 9:667-76) and primarily stimulate cell proliferation, migration, and survival. Activation of the pathway occurs after point mutations or amplification of the PIK3CA gene, which activates the p110α PI3K isoform (Hennessy et al. (2005) Nat. Rev. Drug Discov. 4:988-1004). Genetic deletions or loss of function mutations in the tumor suppressor PTEN (a phosphatase with functions opposite to PI3K) also increase PI3K pathway signaling (Zhang and Yu (2010) Clin. Cancer Res. 16:4325-30). These aberrations increase downstream signaling through kinases such as Akt and mTOR, and increased activity of the PI3K pathway has been proposed as a hallmark of resistance to cancer therapy (Opel et al. (2007) Cancer Res. 67:735-45; Razis et al. (2011) Breast Cancer Res. Treat. 128:447-56).

Phosphatidylinositol-3-kinase (PI3K) is the main signaling node of key survival and growth signals of lymphoma and is opposed by the activity of phosphatase PTEN. The phosphatidylinositol-3-dependent kinase (PI3K) signaling pathway is the most severely dysregulated pathway in hormone receptor positive breast cancer (HR ⁺ BC). The PI3K pathway is dysregulated in aggressive forms of lymphoma (Abubaker (2007) Leukemia 21:2368-2370). 8% of DLBCL (diffuse large B cell lymphoma) cancers have PI3CA (phosphatidylinositol-3-kinase catalytic subunit α) missense mutations and 37% are PTEN negative by immunohistochemistry.

Phosphatidylinositol is one of the multiple phospholipids found in cell membrane and participates in intracellular signal transduction. Cell signal transduction via 3'-phosphorylated phosphoinositides involves multiple cellular processes such as malignant transformation, growth factor signal transduction, inflammation and immunity (Rameh et al. (1999) J.Biol Chem. 274:8347-8350). The enzyme responsible for generating these phosphorylation signal transduction products, i.e., phosphatidylinositol -3- kinase (also referred to as PI3 kinase or PI3K), was initially identified as having activity related to viral oncoproteins and growth factor receptor tyrosine kinases, and it phosphorylates phosphatidylinositol (PI) and its 3'- hydroxyl at the inositol ring (Panayotou et al. (1992) Trends Cell Biol 2:358-60). Phosphoinositide -3- kinase (PI3K) is a lipid kinase (Whitman et al. (1988) Nature, 332:664) that phosphorylates lipids at the 3'- hydroxyl at the inositol ring. 3-Phospholipids (PIP3) generated by PI3 kinase act as second messengers that recruit kinases with lipid-binding domains including a pleckstrin homology (PH) region, such as Akt and PDK1 (phosphoinositide-dependent kinase-1) (Vivanco et al. (2002) Nature Rev. Cancer 2:489; Phillips et al. (1998) Cancer 83:41).

The PI3 kinase family includes at least 15 different enzymes that are subdivided by structural homology and are divided into three classes based on sequence homology and the products formed by enzyme catalysis. Class I PI3 kinases are composed of two subunits: a 110 kd catalytic subunit and an 85 kd regulatory subunit. The regulatory subunit contains an SH2 domain and binds to tyrosine residues phosphorylated by growth factor receptors or oncogene products with tyrosine kinase activity, thereby inducing the PI3K activity of the p110 catalytic subunit, which phosphorylates its lipid substrates. Class I PI3 kinases are involved in important signaling events downstream of cytokines, integrins, growth factors, and immune receptors, suggesting that controlling this pathway may lead to important therapeutic effects such as regulating cell proliferation and carcinogenesis. Class I PI3Ks phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-bisphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-bisphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ks phosphorylate both PI and phosphatidylinositol-4-phosphate. Class III PI3Ks phosphorylate only PI. As shown by recurrent oncogene mutations in p110α, the key PI3 kinase isoform in cancer is class I PI3 kinase p110α (Samuels et al. (2004) Science 304:554; US Pat. No. 5,824,492; No. 5,846,824; No. 6,274,327). Other isoforms may be important in cancer and are also implicated in cardiovascular and immunoinflammatory diseases (Workman P (2004) Biochem Soc Trans 32:393-396; Patel et al. (2004) Proc. Am. Assoc. of Cancer Res. (Abstract LB-247) 95th Annual Meeting, March 27-31, Orlando, Florida, USA; Ahmadi K and Waterfield MD (2004) "Phosphoinositide 3-Kinase: Function and Mechanisms" Encyclopedia of Biological Chemistry (Lennarz WJ, Lane MD eds) Elsevier/Academic Press). Oncogene mutations of p110α have been found very frequently in solid tumors of the colon, breast, brain, liver, ovary, stomach, lung, and head and neck. Approximately 35-40% of hormone receptor-positive (HR ⁺ ) breast cancer tumors have PIK3CA mutations. PTEN abnormalities have been found in glioblastoma, melanoma, prostate cancer, endometrial cancer, ovarian cancer, breast cancer, lung cancer, head and neck cancer, hepatocellular carcinoma, and thyroid cancer.

PI3 kinase (PI3K) is a heterodimer composed of p85 and p110 subunits (Otsu et al. (1991) Cell 65:91-104; Hiles et al. (1992) Cell 70:419-29). Four different class I PI3Ks have been identified, designated PI3Kα, β, δ, and γ, each composed of a different 110 kDa catalytic subunit and a regulatory subunit. Three of the catalytic subunits, p110α, p110β, and p110δ, each interact with the same regulatory subunit, p85; whereas p110γ interacts with a different regulatory subunit, p101. The expression patterns of each of these PI3Ks in human cells and tissues are different. In each of the PI3K α, β, and δ isoforms, the p85 subunit localizes PI3 kinase to the plasma membrane by interacting through its SH2 domain with phosphorylated tyrosine residues in target proteins (present in the appropriate sequence context) (Rameh et al. (1995) Cell, 83:821-30; Volinia et al. (1992) Oncogene, 7:789-93).

The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drug development because such drugs are expected to inhibit cell proliferation, suppress signals from stromal cells that maintain cancer cell survival and chemoresistance, reverse the suppression of apoptosis, and overcome the intrinsic resistance of cancer cells to cytotoxic agents. PI3K is activated by receptor tyrosine kinase signaling and by mutations in the p110 catalytic subunit that activates PI3K, by loss of the tumor suppressor PTEN, or by rare activating mutations in AKT.

Summary of the Invention

The present invention generally relates to tricyclic compounds having the structure of Formula I or stereoisomers, tautomers, and pharmaceutically acceptable salts thereof that are active in modulating PI3K, including modulating mutant forms of the PI3Kα isoform:

Various substituents are defined throughout this application.

Another aspect of the present invention is a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, glidant, diluent or excipient.

Another aspect of the present invention is a process for preparing the pharmaceutical composition.

Another aspect of the present invention is a method of treating cancer in a patient having cancer, comprising administering to the patient a therapeutically effective amount of a compound of Formula I, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer. The patient may be administered a therapeutic agent selected from the group consisting of 5-FU, docetaxel, eribulin, gemcitabine, cobimetinib, ipatasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, palbociclib, bevacizumab, pertuzumab, trastuzumab emtansine, trastuzumab, and letrozole.

Another aspect of the invention is a kit for the therapeutic treatment of breast cancer comprising:

a) a first pharmaceutical composition comprising a compound of formula I; and

b) instructions for use in the therapeutic treatment of breast cancer.

DETAILED DESCRIPTION

Certain embodiments of the present invention will now be described in detail, examples of which are illustrated in the accompanying structures and formulas. When describing the present invention in conjunction with the listed embodiments, it should be understood that the embodiments are not intended to limit the present invention to these embodiments. On the contrary, the present invention is intended to include all optional forms, modifications and equivalent forms that may be included within the scope of the present invention as defined in the claims. Those skilled in the art will recognize that a variety of methods and materials similar to or equivalent to the methods and materials described in this application can be used to implement the present invention. The present invention is in no way limited to the methods and materials described. If one or more of the documents, patents and similar materials introduced are different from or contradictory to the present application (including but not limited to defined terms, term usage, described technology, etc.), the present application shall prevail. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as those generally understood by those skilled in the art to which this application belongs. Although methods and materials similar to or equivalent to those methods and materials described in this application can be used to implement or test the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned in this application are fully incorporated into this application by reference. Unless otherwise indicated, the nomenclature used in this application is based on the IUPAC systematic nomenclature.

definition

When specifying the number of substituents, the term "one or more" refers to one substituent to the maximum possible number of substitutions, i.e., replacing one hydrogen to replacing all hydrogens with substituents. The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on the parent molecule. The term "substituted" means that the specified group carries one or more substituents. When any group can carry multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and need not be the same. The term "unsubstituted" means that the specified group does not carry a substituent. The term "optionally substituted" means that the specified group is unsubstituted or substituted by one or more substituents independently selected from the possible substituents. When specifying the number of substituents, the term "one or more" refers to one substituent to the maximum possible number of substitutions, i.e., replacing one hydrogen to replacing all hydrogens with substituents.

As used herein, the term "alkyl" refers to a saturated linear or branched monovalent hydrocarbon radical having 1 to 12 carbon atoms (C ₁ -C ₁₂ ), wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. In another embodiment, the alkyl radical has 1 to 8 carbon atoms (C ₁ -C ₈ ) or 1 to 6 carbon atoms (C ₁ -C ₆ ). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, isopropyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, isobutyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, sec-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH ₃ )CH 2 CH ₂ CH _{3 ) ,} CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH(CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ , 1-heptyl, 1-octyl, and the like.

The terms "carbocycle,""carbocyclyl,""carbocycle," and "cycloalkyl" refer to monovalent, non-aromatic, saturated or partially unsaturated rings having 3-12 carbon atoms ( _C3 - _C12 ) in a monocyclic form or having 7-12 carbon atoms in a bicyclic form. Bicyclic carbocycles with 7-12 atoms can be arranged, for example, as a bicyclic [4,5] system, a bicyclic [5,5] system, a bicyclic [5,6] system, or a bicyclic [6,6] system, and bicyclic carbocycles with 9 or 10 ring atoms can be arranged as a bicyclic [5,6] system or a bicyclic [6,6] system or as a bridged system such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane. Spirocarbocyclyl moieties are also included within the scope of this definition. Examples of spirocarbocyclyl moieties include [2.2] pentyl, [2.3] hexyl, and [2.4] heptyl. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Carbocyclyl groups are optionally substituted independently with one or more substituents described herein.

"Aryl" refers to a monovalent aromatic hydrocarbon radical having 6-20 carbon atoms ( _C6 - _C20 ) derived by removing one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented as "Ar" in the exemplary structures. Aryl groups include bicyclic radicals containing an aromatic ring fused to a saturated ring, a partially unsaturated ring, or an aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthalene, and the like. Aryl groups may be optionally substituted independently with one or more substituents described herein.

The terms "heterocycle," "heterocyclyl," and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated (i.e., having one or more double and/or triple bonds in the ring) carbocyclic group having from 3 to about 20 ring atoms, wherein at least one ring atom is a heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur, and the remaining ring atoms are C, wherein one or more ring atoms are optionally substituted independently with one or more substituents described below. The heterocycle may be a monocyclic ring having 3-7 ring members (2-6 carbon atoms and 1-4 heteroatoms selected from N, O, P, and S) or a bicyclic ring having 7-10 ring members (4-9 carbon atoms and 1-6 heteroatoms selected from N, O, P, and S), such as a bicyclic [4,5] system, a bicyclic [5,5] system, a bicyclic [5,6] system, or a bicyclic [6,6] system. Heterocycles are described in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968) (particularly Chapters 1, 3, 4, 6, 7, and 9); "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present) (particularly Volumes 13, 14, 16, 19, and 28); and J. Am. Chem. Soc. (1960) 82:5566. "Heterocyclic" also includes groups in which a heterocyclic group is fused to a saturated ring, a partially unsaturated ring, an aromatic carbocyclic ring, or an aromatic heterocyclic ring. Examples of heterocycles include, but are not limited to, morpholin-4-yl, piperidin-1-yl, piperazinyl, piperazin-4-yl-2-one, piperazin-4-yl-3-one, pyrrolidine -1-yl, thiomorpholin-4-yl, S,S-dioxothiomorpholin-4-yl, azocan-1-yl, azetidin-1-yl, octahydropyrido[1,2-a]pyrazin-2-yl, [1,4]diazepan-1-yl, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thiooxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxadiazinyl 1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-indolyl, quinolizinyl, and N-pyridylurea groups. Spiroheterocyclyl moieties are also included within the scope of this definition. Examples of spiroheterocyclyl moieties include azaspiro[2.5]octyl and azaspiro[2.4]heptyl.Examples of heterocyclyl groups wherein 2 ring atoms are substituted with oxo (=0) moieties are pyrimidinone and 1,1-dioxo-thiomorpholinyl.

The term "heteroaryl" refers to a monovalent aromatic group in the form of a 5-, 6-, or 7-membered ring containing one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur and includes fused ring systems having 5-20 atoms, wherein at least one ring is aromatic. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothienyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

The terms "treat" and "treat" refer to therapeutic treatments, wherein the purpose is to slow down (mitigate) the development or spread of undesirable physiological changes or obstacles such as arthritis or cancer. For the purposes of this application, useful or desired clinical results include but are not limited to alleviating symptoms, reducing the degree of disease, stabilizing the disease state (i.e., not worsening), delaying or slowing the course of the disease, improving or alleviating the disease state and alleviating (whether partially or completely), whether detectable or undetectable. "Treatment" can also refer to extending survival compared to the survival expected when not receiving treatment. Those in need of treatment include those suffering from a disease or obstacle.

The phrase "therapeutically effective amount" refers to an amount of a compound of the invention that (i) treats a specific disease, condition, or disorder; (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop to some extent) cancer cell infiltration into surrounding organs; inhibit (i.e., slow down and preferably stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and/or alleviate to some extent one or more symptoms associated with cancer. A drug can prevent cancer cell growth and/or kill existing cancer cells to some extent, and it can be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by evaluating the time to disease progression (TTP) and/or determining the response rate (RR).

The term "cancer" refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinomas, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. More specific examples of the above cancers include squamous cell carcinomas (e.g., epithelial squamous cell carcinomas); lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), lung adenocarcinoma, and lung squamous cell carcinoma; peritoneal cancer; hepatocellular carcinoma; stomach cancer or gastric cancer, including gastrointestinal cancer; pancreatic cancer; glioblastoma; cervical cancer; ovarian cancer; liver cancer; bladder cancer; hepatoma; breast cancer; colon cancer; rectal cancer; colorectal cancer; endometrial cancer or uterine cancer; salivary gland cancer; kidney cancer or renal cancer; prostate cancer; vulvar cancer; thyroid cancer; hepatocarcinoma; anal cancer; penile cancer; and head and neck cancer.

"Hematologic malignancies" are types of cancer that affect the blood, bone marrow, and lymph nodes. Because these three are closely related through the immune system, diseases that affect one will often affect the others: although lymphoma is a disease of the lymph nodes, it often spreads to the bone marrow, affecting the blood. Hematologic malignancies are malignant tumors ("cancers") and are typically treated by specialists in hematology and/or oncology. "Hematology/Oncology" is a subspecialty within internal medicine at some centers, while at other centers it is considered a separate department (which also includes surgical and radiation oncologists). Not all hematologic diseases are malignant ("cancerous"); these other blood diseases can also be managed by hematologists. Hematologic malignancies can arise from two major blood cell lineages: the myeloid and lymphoid lineages. The myeloid lineage typically produces granulocytes, red blood cells, platelets, macrophages, and mast cells; the lymphoid lineage produces B cells, T cells, NK cells, and plasma cells. Lymphomas, lymphocytic leukemias, and myelomas arise from the lymphoid cell lineage, while acute and chronic myeloid leukemias, myelodysplastic syndromes, and myeloproliferative disorders arise from myeloid cells. Leukemias include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMOL), and small lymphocytic lymphoma (SLL). Lymphomas include Hodgkin lymphoma (all four subtypes) and non-Hodgkin lymphoma (NHL, all subtypes).

A "chemotherapeutic agent" is a compound useful in the treatment of cancer, regardless of its mechanism of action. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle-toxic plant alkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapies" and conventional chemotherapy. Examples of chemotherapeutic agents include: ibrutinib (IMBRUVICA ^™ , APCI-32765, Pharmacyclics Inc./Janssen Biotech Inc.; CAS Reg. No. 936563-96-1, US7514444), idelalisib (formerly CAL-101, GS 1101, GS-1101, Gilead Sciences Inc.; CAS Reg. No. 1146702-54-6), erlotinib (Genentech/OSI Pharm.), docetaxel (Sanofi-Aventis), 5-FU (fluorouracil, 5-fluorouracil, CAS No. 51-21-8), gemcitabine (Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), cisplatin ((SP-4-2)-diaminedichloroplatinum(II), cis-diaminedichloroplatinum(II), CAS No. 15663-27-1), carboplatin (CAS No. 41575-94-4), paclitaxel (Bristol-Myers Squibb Oncology, Princeton, NJ), trastuzumab (Genentech), temozolomide (4-methyl-5-oxo-2,3,4,6,8-pentaazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, Schering Plough), tamoxifen ((Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine), doxorubicin (CAS No. 23214-92-8), Akti-1/2, HPPD, and rapamycin.

Chemotherapeutic agents include inhibitors of B cell receptor targets such as BTK, Bcl-2, and JAK inhibitors.

More examples of chemotherapeutic agents include oxaliplatin (Sanofi), bortezomib (Millennium Pharm.), sunitinib (SU11248, Pfizer), letrozole (Novartis), imatinib mesylate (Novartis), XL-518 (MEK inhibitor, Exelixis, WO2007/044515), ARRY-886 (Mek inhibitor, AZD6244, Array BioPharma, Astra Zeneca), SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787/ZK 222584 (Novartis), fulvestrant ( AstraZeneca), leucovorin, folinic acid, rapamycin (sirolimus, Wyeth), lapatinib (GSK572016, Glaxo Smith Kline), lonafarnib (SARASAR ^™ , SCH 66336, Schering Plough), sorafenib (BAY43-9006, Bayer Labs), gefitinib (AstraZeneca), irinotecan (CPT-11, Pfizer), tipifarnib (ZARNESTRA ^™ , Johnson & Johnson), ABRAXANE ^™ (without Cremophor), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceuticals Partners, Schaumberg, IL), vandetanib (rINN, ZD6474, AstraZeneca), chloranmbucil, AG1478, AG1571 (SU 5271; Sugen), temsirolimus (Wyeth), pazopanib (GlaxoSmithKline), canfosfamide (Telik), thiotepa, and cyclosphosphamide alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altrexam; tamine), triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylomelamine; annona lactones (especially bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, and chlorambucil. hydrochloride), melphalan, novembichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitroureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicins, including calicheamicin gamma and calicheamicin omega (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicins, including dynemicin A; bisphosphonates, such as clodronate; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores. chromophore), aclacinomysins, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, and mitomycin antifungal agents such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and 5-fluorouracil; terin and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, and daptomycin; propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids, such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazine; procarbazine; polysaccharide complex (JHS Natural Products, Eugene, OR; razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; cytarabine ("Ara-C");cyclophosphamide;thiotepa;6-thioguanine;mercaptopurine;methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (novantrone); teniposide; edatrexate; daunomycin; aminopterin; capecitabine (Roche); ibandronate; CPT-11; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

The following are also included within the definition of "chemotherapeutic agent": (i) antihormonal drugs used to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and toremifine citrate, and selective estrogen receptor modulators (SERDs) such as fulvestrant (Astra Zeneca); (ii) aromatase inhibitors that inhibit aromatase (the enzyme in the adrenal glands that regulates the production of estrogen), such as 4(5)-imidazoles, aminoglutethimide, megestrol acetate, and dapoxetine. (iii) antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors such as MEK inhibitors such as cobimetinib (WO2007/044515); (v) lipid kinase inhibitors such as taselisib (GDC-0032, Genentech Inc.); (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, for example, PKC-α, Ralf and H-Ras, such as oblimersen (Genta Inc.); (vii) ribozymes, such as VEGF expression inhibitors (for example) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, for example, and topoisomerase 1 inhibitors, such as and (ix) anti-angiogenic drugs, such as bevacizumab (Genentech); and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

Also included within the definition of "chemotherapeutic agent" are therapeutic antibodies, such as alemtuzumab (Campath), bevacizumab (Genentech); cetuximab (Imclone); panitumumab (Amgen), rituximab (Genentech/Biogen Idec), pertuzumab (PERJETA ^™ , 2C4, Genentech), trastuzumab (Genentech), trastuzumab emtansine (Genentech Inc.), and tositumomab (BEXXAR, Corixia).

"Metabolites" are products produced by the in vivo metabolism of a particular compound or its salt. Metabolites of a compound can be identified using conventional techniques known in the art and their activity can be determined using the tests described herein. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound. Therefore, the present invention includes metabolites of the compounds of the present invention, including compounds produced by the following methods, comprising contacting a compound of Formula I of the present invention with a mammal for a period of time sufficient to produce its metabolic products.

The term "package insert" refers to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or precautions concerning the use of such therapeutic products.

The term "chiral" refers to molecules that have the property of non-superimposability of their mirror image counterparts, while the term "achiral" refers to molecules that are superimposable on their mirror image counterparts.

The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

"Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereoisomers can be separated by high-resolution analytical procedures such as electrophoresis and chromatography.

"Enantiomers" refers to two stereoisomers of a compound that are non-superimposable mirror images of one another.

The stereochemical definitions and common sense used herein are generally in accordance with S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. The present invention is intended to include all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers, and mixtures thereof, such as racemic mixtures, which form a part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to specify the sign by which a compound rotates plane polarized light, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are right-handed. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers may also be referred to as enantiomers, and mixtures of these isomers are often referred to as mixtures of enantiomers. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur when a chemical reaction or process does not have stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric substances that are optically inactive. Enantiomers can be separated from the racemic mixture by chiral separation methods such as supercritical fluid chromatography (SFC). Configurational assignments at chiral centers in separated enantiomers may be tentative and are depicted in the structures of Table 1 for illustrative purposes, whereas stereochemistry is definitively established, such as from X-ray crystallographic data.

The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions such as keto-enol isomerization and imine-enamine isomerization via migration of a proton. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

The term "pharmaceutically acceptable salts" refers to salts that are not biologically or otherwise undesirable. Pharmaceutically acceptable salts include acid and base addition salts. The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the formulation and/or the mammal to be treated therewith.

The term "pharmaceutically acceptable acid addition salts" refers to those with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and organic acids selected from the aliphatic, alicyclic, aromatic, aryl-aliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, pamoic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

The term "pharmaceutical base addition salt" refers to a pharmaceutical salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, amine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

"Solvate" refers to an association or complex of one or more solvent molecules with a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term " _EC50 " is half maximal effective concentration and represents the plasma concentration of a particular compound required to obtain 50% of the maximum specific effect in vivo.

The term "Ki" is the inhibition constant and represents the absolute binding affinity of a particular inhibitor to a receptor. In the absence of a competing ligand (e.g., a radioligand), it is measured using a competitive binding assay and is equal to the concentration at which 50% of the receptors are occupied by the particular inhibitor. Ki values can be logarithmically converted to pKi values (-log Ki), where higher values exponentially represent greater potency.

The term " _IC50 " is the half-maximal inhibitory concentration and represents the concentration of a particular compound required to achieve 50% inhibition of an in vitro biological process. _IC50 values can be converted logarithmically to _pIC50 values (-log _IC50 ), where higher values represent exponentially greater potency. _IC50 values are not absolute values, but rather depend on experimental conditions, such as the concentration used, and can be converted to an absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22:3099). Other percentage inhibition parameters such as _IC70 , _IC90 , etc. can be calculated.

The terms "compounds of the present application," "compounds of the present invention," and "compounds of Formula I" include compounds of Formula I and stereoisomers, geometric isomers, tautomers, solvates, metabolites, pharmaceutically acceptable salts, and prodrugs thereof.

Any formula or structure given herein (including compounds of Formula I) is also intended to represent hydrates, solvates, and polymorphs of such compounds, and mixtures thereof.

Any formula or structure (including formula I compound) provided herein is also intended to represent the unlabeled form and the isotopically labeled form of the compound. Isotopically labeled compounds have the structure described by the chemical formula provided herein, except that one or more atoms are replaced by the atom with selected atomic weight or mass number. The example of the isotope that can be incorporated into the compounds of this invention includes isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine such as but not limited to ² H (deuterium, D), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. The present invention includes various isotopically labeled compounds of this invention, for example radioactive isotopes such as ³ H, ¹³ C and ¹⁴ C are incorporated into those compounds of this invention therein. The above-mentioned isotopically labeled compounds can be used for metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution determinations or radiotherapy of patients. Deuterium-labeled or substituted therapeutic compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetics) properties, including absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium can provide some therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) due to better metabolic stability. ¹⁸ F-labeled compounds can be used for PET or SPECT studies. Isotopically labeled compounds of the present invention and their prodrugs can generally be prepared by carrying out the procedures disclosed in the following schemes or examples and preparations and substituting readily available isotopically labeled reagents for non-isotopically labeled reagents. In addition, the substitution with heavier isotopes, particularly deuterium (i.e. ² H or D), can provide some therapeutic advantages (e.g., an increase in half-life in vivo or a reduction in dosage requirements or an improvement in therapeutic index) due to better metabolic stability. It should be understood that deuterium in this application is considered to be a substituent in the compound of formula (I). The concentration of the above-mentioned heavier isotopes, particularly deuterium, can be defined by the isotopic enrichment factor. In the compounds of the present invention, any atom not specifically designated as a specific isotope is intended to represent any stable isotope of the atom. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", it should be understood that the position has a concentration of hydrogen at the natural abundance isotope composition of hydrogen. Therefore, in the compounds of the present invention, any atom specifically designated as deuterium (D) is intended to represent deuterium.

Tricyclic PI3K inhibitor compounds

The present invention provides a tricyclic inhibitor compound of formula I or its stereoisomers, tautomers and pharmaceutically acceptable salts and pharmaceutical preparations thereof, which can be potentially used to treat cancer and has the following structure:

in

Dashed/solid lines indicate single or double bonds;

^Xa is ^CRa , N, ^NRb , O or S;

^Xb is C or N;

^Xc is C or N;

^Xd is ^CR2 or N;

wherein at least one of X ^a , X ^b and X ^c is N, O or S;

R ^a is selected from H, C ₁ -C ₆ alkyl, -CN and F;

R ^b is selected from H and C ₁ -C ₆ alkyl;

R ¹ is selected from Br, Cl, I, C ₂ -C ₂₀ heterocyclyl, C ₁ -C ₂₀ heteroaryl, -NR ³ R ⁴ and -OR ⁵ ;

R ² is selected from H, F, Cl, C ₁ -C ₆ alkyl and -O(C ₁ -C ₆ alkyl);

R ³ is selected from H and C ₁ -C ₆ alkyl;

R ⁴ is selected from H, C ₁ -C ₆ alkyl, C ₂ -C ₂₀ heterocyclyl and C ₁ -C ₂₀ heteroaryl;

or R ³ and R ⁴ form a 4-membered, 5-membered or 6-membered heterocyclyl ring;

R ⁵ is selected from C ₁ -C ₆ alkyl, C ₂ -C ₂₀ heterocyclyl and C ₁ -C ₂₀ heteroaryl;

R ⁶ is independently selected from H, C ₁ -C ₄ alkyl and F;

or two geminal or ortho R ⁶ groups may form a 3-, 4-, or 5-membered carbocyclic ring;

p is 2, 3, or 4;

A is selected from C ₆ -C ₂₀ aryl, -(C ₆ -C ₂₀ aryl)-(C ₆ -C ₂₀ aryl), -(C ₆ -C ₂₀ aryl)-(C ₁ -C ₂₀ heteroaryl), -(C ₆ -C ₂₀ aryl)-(C ₂ -C ₂₀ heterocyclyl), -(C ₁ -C ₂₀ heteroaryl)-(C ₂ -C ₂₀ heterocyclyl), -(C ₁ -C ₂₀ heteroaryl)-(C ₁ -C ₂₀ heteroaryl), C ₂ -C ₂₀ heterocyclyl, and C ₁ -C ₂₀ heteroaryl; and

wherein the alkyl, aryl, heterocyclyl and heteroaryl groups are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, -CN, _-CH3 , _-CH2CH3 , -CH( _CH3 ) _{2 ,} C( _CH3 ) ₃ , _{-CH2CH ( CH3 ) 2} , _-CH2OH , -CH2OCH3, -CH2CH2OH, -C _{( CH3 ) 2OH ,} -CH( _OH )CH( _{CH3 ) 2 ,} -C( _CH3 ) _2CH2OH , _{-CH2CH2SO2CH3} , _-CH2OP (O) ₍ OH) _{2 ,} -CH2F, _-CHF2 , _{-CH2NH2 , -CH2NHSO2CH3} , _-CH2NHCH3 , _{-CH2N ( CH3 )} ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH _3. -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , ＝O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O) ₍ OH) ₂ , -S(O) 2 N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, cyclopentyl, tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, and tetrahydropyranyl.

Exemplary embodiments of the present invention include compounds of Formulas Ia-If:

Exemplary embodiments of the present invention include compounds of Formula Ig:

Exemplary embodiments of the present invention include compounds of Formula Ih-j:

Exemplary embodiments of the present invention include compounds of formula Ik-m:

Exemplary embodiments of the present invention include compounds of the formula In-p:

wherein Y is O or NR ³ ; and

R ⁷ is selected from H, cyclopropyl, cyclobutyl and C ₁ -C ₆ alkyl, which is optionally substituted with F, Cl, -OCH ₃ or -OH; or R ³ and R ⁷ form a 4-membered, 5-membered or 6-membered heterocyclyl ring.

Exemplary compounds of Formula Ij-1 include those wherein Y is NH.

Exemplary compounds of Formula Ij-1 include those wherein Y is NR ³ and R ³ and R ⁷ form a pyrrolidinyl ring.

Exemplary compounds of Formula Ij-1 include those wherein Y is O.

Exemplary compounds of Formula I include those wherein R ¹ is Br or substituted pyrazolyl.

Exemplary compounds of Formula I include those wherein R ¹ is selected from:

The wavy lines indicate the sites of connection.

Exemplary compounds of Formula I include those wherein A is substituted benzo[d]oxazolyl or substituted benzothiazolyl.

Exemplary compounds of Formula I include those wherein A is selected from the following structures:

The wavy lines indicate the sites of connection.

Exemplary embodiments of compounds of Formula I include the compounds in Table 1.

The compounds of Formula I of the present invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and mixtures thereof such as racemic mixtures, form part of the present invention. In some cases, stereochemistry has not been determined or has been tentatively assigned.

Furthermore, the present invention includes all diastereomers, including cis-trans (geometric) and conformational isomers. For example, if a compound of Formula I contains a double bond or a fused ring, the cis- and trans-forms and mixtures thereof are included within the scope of the present invention.

In the structures shown in this application, if the stereochemistry of any particular chiral atom is not specified, the compounds of the invention are intended to include all stereoisomers. If stereochemistry is specified by a solid wedge or dashed line representing a specific configuration, then that stereoisomer is so specified and defined.

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the present invention embrace both solvated and unsolvated forms.

The compounds of the present invention may also exist in different tautomeric forms and all such forms are included within the scope of the present invention. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions through reorganization of some of the bonding electrons.

The invention as described in this application.

Biological evaluation

The relative effectiveness of the compounds of Formula I as inhibitors of enzyme activity (or other biological activity) can be determined as follows: determine the concentration at which each compound inhibits the activity to a predetermined degree and then compare the results. Generally, it is preferred to determine the concentration that inhibits 50% of the activity in a biochemical assay, i.e., the 50% inhibitory concentration or " _IC50 ". Conventional techniques known in the art can be used to determine the _IC50 value. Generally, _IC50 can be determined by measuring the activity of a given enzyme in the presence of a certain concentration range of the inhibitor under study. The enzyme activity values obtained in the experiment are then plotted relative to the inhibitor concentration used. The inhibitor concentration that shows 50% enzyme activity (compared to the activity in the absence of any inhibitor) is used as the _IC50 value. Similarly, other inhibitory concentrations can be defined by appropriate activity determinations. For example, in some cases, it may be necessary to determine a 90% inhibitory concentration, i.e., _IC90 , etc.

The ability of compounds of the invention to act as inhibitors of PI3Kα was determined using the method of Example 901. Representative compounds of the invention exhibited potent activity against PI3Kα isoforms.

The exemplary compounds of Formula I in Tables 1 and 2 were prepared, characterized, and tested for binding to PI3Kα according to the methods of the present invention and have the following structures, corresponding names (ChemBioDraw, Version 14.0.0, CambridgeSoft Corp., Cambridge MA) and biological activities. When more than one name is associated with a compound of Formula I or an intermediate, the chemical structure should be used to qualify the compound.

Table 1. Compounds of Formula I

Table 2. Compounds of Formula I

Administration of compounds of formula I

The compounds of this invention can be used by any approach suitable for the condition to be treated. Suitable approaches include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal and epidural), transdermal, rectal, nasal, local (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary and intranasal. For local immunosuppressive therapy, the compound can be used by intralesional administration (including perfusion or contacting the graft with an inhibitor before transplantation). It should be understood that preferred approaches can vary with, for example, the situation of the recipient. When the compound is orally administered, it can be formulated into pills, capsules, tablets, etc. together with a pharmaceutical carrier or excipient. When the compound is administered parenterally, it can be formulated into a unit dose injection form together with a pharmaceutical parenteral vehicle as described below.

The dosage for treating human patients can be from about 1 mg to about 1000 mg of the compound of formula I. A typical dosage can be from about 10 mg to about 300 mg of the compound. The dosage can be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of the specific compound, including absorption, distribution, metabolism, and excretion. In addition, toxic factors can affect the dosage and administration regimen. When administered orally, a pill, capsule, or tablet can be taken daily or at a lower frequency for a specified period of time. The regimen can be repeated for multiple treatment cycles.

Methods of treatment using compounds of formula I

The compounds of Formula I of the present invention can be used to treat human or animal patients suffering from diseases or conditions such as cancer caused by abnormal cell growth, function or behavior associated with PI3K, and can therefore be treated by a method comprising administering the compounds of the present application as defined above. Human or animal patients suffering from cancer can also be treated by a method comprising administering the compounds of the present invention as defined above. The patient's condition can thereby be improved or alleviated.

The methods of the present invention also include treating a cancer selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell carcinoma, oral cancer, nasopharyngeal cancer. , pharyngeal cancer, lip cancer, tongue cancer, oral cancer, small intestine cancer, colon-rectum cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, Hodgkin cancer, leukemia, bronchial cancer, thyroid cancer, liver cancer and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer and renal pelvis cancer, bladder cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral cancer and pharyngeal cancer, non-Hodgkin lymphoma, melanoma and villous colon adenoma.

The present invention also encompasses the use of the compounds described herein as therapeutically active substances.

The present invention also includes the use of the compounds described herein for treating cancer selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell carcinoma, oral cancer, ovarian ... Cavity cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, oral cancer, small intestine cancer, colon-rectum cancer, large intestine cancer, rectal cancer, brain cancer and central nervous system cancer, Hodgkin cancer, leukemia, bronchial cancer, thyroid cancer, liver cancer and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer and renal pelvis cancer, bladder cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral cancer and pharyngeal cancer, non-Hodgkin lymphoma, melanoma and villous colon adenoma.

The present invention also includes the use of the compounds described herein in the preparation of a medicament for the treatment of cancer selected from the group consisting of breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer and biliary tract cancer, renal cancer, pancreatic cancer, myeloid disorders, lymphoma, capillary Cancers of the brain and central nervous system include: Hodgkin's cancer, leukemia, bronchial cancer, thyroid cancer, liver cancer and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer and renal pelvis cancer, bladder cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral and pharyngeal cancer, non-Hodgkin's lymphoma, melanoma, and villous colon adenoma.

The present invention also includes compounds described herein for use in the treatment of cancer selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, Follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract cancer, kidney cancer, pancreatic cancer, myeloid disorders, lymphoma, hairy cell carcinoma, oral cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, mouth cancer, small intestine cancer, colon-rectum cancer, large intestine cancer, rectum cancer, brain cancer and central nervous system cancer, Hodgkin cancer, leukemia, bronchial cancer, thyroid cancer, liver cancer and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer and renal pelvis cancer, bladder cancer, uterine corpus cancer, cervical cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, oral cancer and pharyngeal cancer, non-Hodgkin lymphoma, melanoma and villous colon adenoma.

Based on expression analysis, immunohistochemistry, and cell line distribution, malignancies of the colon, breast, cervix, stomach, lung, and multiple myeloma are most likely to be responsive to PI3K modulators or inhibitors.

pharmaceutical preparations

In order to use the compounds of the invention for the therapeutic treatment of mammals (including humans), they are typically formulated into pharmaceutical compositions according to standard pharmaceutical practice.This aspect of the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable diluent or carrier.

Typical preparations are prepared by mixing the compounds of this invention with carriers, diluents or excipients. Suitable carriers, diluents, additives and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water. The specific carrier, diluent or excipient used will depend on the means and purpose of administering the compounds of this invention. Solvents are generally selected based on those skilled in the art who believe that they are safe solvents (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300) and mixtures thereof. The preparation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, glidants, processing aids, colorants, sweeteners, aromas, flavorings and other known additives to give the drug (i.e., the compound of the present application or its pharmaceutical composition) a high-quality appearance or to facilitate the manufacture of pharmaceutical products (i.e., medicines).

The formulations can be prepared using conventional dissolution and mixing procedures. For example, bulk drug substance (i.e., a compound of the invention or a stabilized form of the compound (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned excipients. The compounds of the invention are typically formulated into pharmaceutical dosage forms to provide easily controllable drug dosages and enable patients to comply with prescribed regimens.

The pharmaceutical composition (or preparation) for administration can be packaged in a variety of ways depending on the method of administering the drug. Typically, the product for distribution includes a container in which a pharmaceutical preparation in a suitable form is stored. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders, etc. The container may also include a pry-proof device to prevent inadvertent access to the package contents. In addition, the container may have a label describing the container contents. The label may also include suitable warning information.

Pharmaceutical preparations of the present invention can be prepared for various routes of administration and types. For example, the compound of formula I with the desired purity can be optionally mixed with a pharmaceutical diluent, carrier, excipient or stabilizer into a lyophilized preparation, ground powder or aqueous solution form (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. editor). Preparation can be carried out as follows: at ambient temperature at a suitable pH with a suitable purity and a physiologically acceptable carrier, i.e., a carrier that is nontoxic to the recipient at the dosage and concentration used. The pH of the preparation depends primarily on the specific use and compound concentration, but can be from about 3 to about 8. Preparations in acetate buffer at a pH of 5 are suitable embodiments.

The drug can generally be stored in the form of a solid composition, a lyophilized formulation or an aqueous solution.

The pharmaceutical compositions of the present invention will be formulated, dosed, and administered in a manner consistent with good medical practice (i.e., dosage, concentration, time schedule, course of treatment, vehicle, and route). Factors to be considered in this context include the specific condition being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the condition, the site of drug delivery, the method of administration, the time schedule of administration, and other factors known to medical practitioners. A "therapeutically effective amount" of the compound to be administered will depend on the above-mentioned factors considered and is the minimum amount required to improve or treat a hyperproliferative condition.

As a general suggestion, the initial pharmaceutically effective amount of the inhibitor per parenteral dose will be about 0.01-100 mg/kg, ie, about 0.1-20 mg/kg, of patient body weight per day, with a typical initial range of 0.3 to 15 mg/kg/day of compound used.

Acceptable diluents, carriers, excipients, and stabilizers are nontoxic to recipients at the dosages and concentrations employed and include buffers such as phosphates, citrates, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl alcohol, or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as TWEEN ^™ , PLURONICS ^™ or polyethylene glycol (PEG). The active pharmaceutical ingredient can also be entrapped in microcapsules prepared by, for example, coacervation techniques or interfacial polymerization, such as hydroxymethylcellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules) or macroemulsions. Such techniques are described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980).

Sustained-release formulations of the compound of formula I can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compound of formula I, in the form of shaped articles such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (US3773919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT ^™ (microspheres for injection consisting of lactic acid-glycolic acid copolymer and leuprorelin acetate), and poly-D-(-)-3-hydroxybutyric acid.

Formulations include those suitable for the routes of administration described herein. Formulations can be suitably provided in unit dosage form and can be prepared by any method known in the pharmaceutical art. Techniques and formulations are generally described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). The above methods include the step of combining the active ingredient with a carrier that serves as one or more auxiliary ingredients. Typically, the formulation is prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely dispersed solid carrier, or both, and then molding the product as needed.

Formulations of compounds of Formula I suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of a compound of Formula I. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, in a suitable machine. Molded tablets can be prepared by molding a mixture of the powdered active ingredient moistened with an inert liquid diluent in a suitable machine. The tablets can optionally be coated or scored and optionally formulated to provide slow or controlled release of the active ingredient therefrom. Tablets, lozenges, troches, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules such as gelatin capsules, syrups, or elixirs can be prepared for oral administration. Formulations of compounds of Formula I intended for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more substances including sweeteners, flavorings, coloring agents, and preservatives to provide a palatable formulation. Tablets containing the active ingredient mixed with non-toxic physiologically acceptable excipients suitable for preparing tablets are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained effect over a longer period of time. For example, a time delay substance such as glyceryl monostearate or glyceryl distearate, alone or in combination with a wax, may be used.

For treatment of the eye or other external tissues such as the mouth and skin, the formulation may preferably be applied in the form of a topical ointment or cream containing, for example, 0.075 to 20% w/w of the active ingredient. When formulated as an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may contain a polyol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, and polyethylene glycol (including PEG 400), and mixtures thereof. Topical formulations may contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other area of action, as desired. Examples of the above-mentioned skin penetration enhancers include dimethyl sulfoxide and related analogs. The oil phase of the emulsion of the present application may be composed of known ingredients in a known manner. While the phase may comprise only an emulsifier, it may comprise, as required, a mixture of at least one emulsifier with a fat or oil, or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included with the lipophilic emulsifier as a stabilizer. It is also preferred to include both an oil and a fat. In addition, the emulsifier, with or without a stabilizer, constitutes a so-called emulsifying wax, and the wax, together with the oil and fat, constitutes a so-called emulsifying cream base, which forms the oily dispersed phase of the cream. Emulsifiers and emulsion stabilizers suitable for the present formulations include cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

Aqueous suspensions of the compound of formula I contain a mixture of the active substance and excipients suitable for preparing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, cross-linked carboxymethylcellulose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinyl pyrrolidone, gum tragacanth, and gum arabic; and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain fatty alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners such as sucrose or saccharin.

The pharmaceutical composition of the compound of formula I may be in the form of a sterile injection such as a sterile aqueous or oily suspension for injection. The suspension may be prepared using the above-mentioned suitable dispersants or wetting agents and suspending agents according to methods known in the art. Sterile injections may also be sterile injection solutions or suspensions in non-toxic parenteral-acceptable diluents or solvents such as solutions in 1,3-butanediol or prepared as lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils can generally be used as solvents or suspending media. For this purpose, any mild fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may also be used to prepare injections.

The amount of active ingredient that can be combined with a carrier material to prepare a single dosage form will vary depending on the host being treated and the specific mode of administration. For example, a timed-release formulation intended for oral administration to humans may contain about 1 to 1000 mg of the active compound and a suitable and appropriate amount of a carrier material that can account for about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions can be prepared to provide an easily measurable dosage. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution, thereby enabling infusion of a suitable volume to be performed at a rate of about 30 mL/hr.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration have, for example, a particle size of 0.1 to 500 microns (inclusive between 0.1 and 500 microns and in increments such as 0.5, 1, 30, 35 microns, etc.) and are administered by rapid inhalation through the nasal passages or inhalation through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents, such as compounds heretofore used to treat or prevent the conditions described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Preparation can be packaged in unit dose or multidose container such as sealed ampoule or bottle and can be stored under freeze drying (lyophilization) state, and it only needs to add sterile liquid carrier such as water for injection before use. Instant injection solution and suspension are prepared by sterile powder, granule and tablet of the above-mentioned kind. Preferred unit dose preparation is those preparations containing the active ingredient of the above-mentioned daily dose of the application or unit daily subdose or its suitable fraction.

The present invention also provides veterinary compositions comprising at least one active ingredient as described above and a veterinary carrier. A veterinary carrier is a substance useful for the purpose of administering the composition and can be a solid, liquid, or gaseous substance that is inert or acceptable in veterinary medicine and compatible with the active ingredient. These veterinary compositions can be administered parenterally, orally, or by any other desired route.

Combination therapy

Formula I compound can be used alone or in combination with other therapeutic agents for treating diseases or conditions described herein, such as inflammation or hyperproliferative conditions (e.g., cancer). In some embodiments, Formula I compound is combined with an additional second therapeutic compound having anti-inflammatory or anti-hyperproliferative properties or can be used to treat inflammation, immune response disorders, or hyperproliferative conditions (e.g., cancer) in a pharmaceutical combination formulation or as a combination therapy administration regimen. Additional therapeutic agents can be Bcl-2 inhibitors, JAK inhibitors, anti-inflammatory agents, immunomodulators, chemotherapeutic agents, apoptosis enhancers, neurotrophic factors, cardiovascular disease therapeutic agents, liver disease therapeutic agents, antiviral agents, blood disorder therapeutic agents, diabetes therapeutic agents, and immunodeficiency disorder therapeutic agents. The second therapeutic agent can be an NSAID anti-inflammatory agent. The second therapeutic agent can be a chemotherapeutic agent. The second compound in the pharmaceutical combination formulation or administration regimen preferably has an activity complementary to the Formula I compound so that they do not adversely affect each other. The above compounds are suitably present in an effective amount combination for the intended purpose. In one embodiment, the composition of the present application comprises a compound of Formula I or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof in combination with a therapeutic agent such as an NSAID.

Combination therapy can be administered in a simultaneous or sequential manner. When administered sequentially, the combination can be administered in two or more administrations. Administration in combination includes co-administration using separate formulations or a single pharmaceutical formulation and sequential administration in any order, wherein preferably there is a period of time during which both (or all) active agents simultaneously exert their biological activities.

Suitable dosages for any of the above co-administered drugs are those currently used and may be lowered due to the combined action (synergy) of the newly identified drug and other therapeutic agents or treatments.

Combination therapy can provide and be demonstrated to be "synergistic," i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects achieved when the compounds are used separately. Synergy can be achieved when the active ingredients are: (1) co-formulated in a combined unit dosage formulation and administered or delivered simultaneously; (2) delivered in separate formulations in alternation or parallel; or (3) administered by some other regimen. When delivered in alternation therapy, synergy can be achieved when the compounds are administered or delivered sequentially, for example, by separate injections in different syringes, separate pills or capsules, or separate infusions. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

In a specific embodiment of the therapy, the compound of formula I or its stereoisomers, tautomers, solvates, metabolites or pharmaceutically acceptable salts or prodrugs can be combined with other therapeutic agents, hormone drugs or antibody drugs such as those described herein and in combination with surgical therapy and radiotherapy. The combination therapy of the present invention thus includes administering at least one compound of formula I or its stereoisomers, tautomers, solvates, metabolites or pharmaceutically acceptable salts or prodrugs and using at least one other cancer treatment method. The amount of the compound of formula I and other pharmaceutically active therapeutic agents and the associated administration schedule will be selected so as to achieve the desired combined therapeutic effect.

Additional therapeutic agents for use in combination with compounds of Formula I include 5-FU, docetaxel, eribulin, gemcitabine, cobimetinib, ipatasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, palbociclib, bevacizumab, pertuzumab, trastuzumab-emtansine conjugate, trastuzumab, and letrozole.

Metabolites of compounds of formula I

The in vivo metabolic products of Formula I described herein also fall within the scope of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like of the administered compound. Thus, the present invention includes metabolites of compounds of Formula I, including compounds produced by a process comprising contacting a compound of the invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

Metabolites are typically identified by preparing a radiolabeled (e.g., ¹⁴ C or ³ H) isotope of a compound of the invention, administering it parenterally to an animal such as a rat, mouse, guinea pig, monkey, or to a human at a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (usually about 30 seconds to 30 hours), and separating its conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are separated by using antibodies that can bind to antigenic epitopes that survive in the metabolites). Metabolite structures are determined in a conventional manner, for example, by MS, LC/MS, or NMR analysis. Typically, analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. Metabolites can be used for diagnostic determination of therapeutic doses of the compounds of the invention, as long as they are not otherwise present in vivo.

Products

Another embodiment of the present invention provides an article or "kit" containing materials that can be used to treat the above-mentioned diseases and conditions. In one embodiment, the kit comprises a container containing a compound of Formula I or its stereoisomers, tautomers, solvates, metabolites, or pharmaceutically acceptable salts or prodrugs. The kit may also include a label or package insert on or associated with the container. The term "package insert" is used to refer to instructions typically included in commercial packaging of therapeutic products, which contain information about the indications, usage, dosage, administration, contraindications and/or precautions involved in using the above-mentioned therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container can be formed from a variety of materials such as glass or plastic. The container can hold a compound of Formula I or its formulation that can effectively treat the condition and can have a sterile interface (for example, the container can be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is a compound of Formula I. The label or package insert indicates that the composition is used to treat a selected condition, such as cancer. In addition, the label or package insert may indicate that the patient to be treated is a patient suffering from a disease such as a hyperproliferative disease, neurodegeneration, cardiac hypertrophy, pain, migraine or neurotraumatic disease or event. In one embodiment, the label or package insert indicates that the composition comprising the compound of Formula I can be used to treat a disease caused by abnormal cell growth. The label or package insert may also indicate that the composition can be used to treat other diseases. Alternatively or additionally, the product may further include a second container comprising a pharmaceutical buffer such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may also include other substances desired from a commercial and user perspective, including other buffers, diluents, filters, needles and syringes.

The kit may further comprise instructions for administering the compound of Formula I and the second pharmaceutical formulation (if present). For example, if the kit comprises a first composition comprising a compound of Formula I and a second pharmaceutical formulation, the kit may further comprise instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or separately to a patient in need thereof.

In another embodiment, the kit is suitable for delivering a solid oral form of a compound of formula I, such as a tablet or capsule. The kit preferably comprises a plurality of unit doses. The kit may comprise a card with doses arranged in the order in which they are intended to be used. An example of a kit is a "blister pack". Blister packs are known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. A memory aid may be provided as needed, for example in the form of numbers, letters or other markings or with a calendar indicating the days on which administration may be performed in the treatment schedule.

According to one embodiment, the kit may comprise (a) a first container containing a compound of Formula I therein; and optionally (b) a second container containing a second pharmaceutical formulation therein, wherein the second pharmaceutical formulation comprises a second compound having anti-hyperproliferative activity. Alternatively or additionally, the kit may further comprise a third container comprising a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and glucose solution. It may also comprise other substances desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

In some other embodiments where the kit comprises a composition of Formula I and a second therapeutic agent, the kit may comprise containers such as separate bottles or separate foil packages for accommodating the separate compositions, but the separate compositions may also be contained in a single, unseparated container. Typically, the kit comprises instructions for administering the separate components. The kit format is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral) or at different dosage intervals, or when the attending physician needs to titrate the combined components.

Preparation of compounds of formula I

The compounds of formula I can be synthesized by the following synthetic routes, which include methods similar to those known in the chemical art and particularly those referenced in the present specification, as well as those for other heterocycles, such as those described in Comprehensive Heterocyclic Chemistry II, edited by Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958);

Arzneimittel-Forschung, 40(12):1328-31, (1990), each of which is expressly incorporated by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or readily prepared using methods known to those skilled in the art (e.g., by methods outlined in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 editions) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin (including supplements) (also available from the Beilstein online database)).

Synthetic chemistry transformations and protecting group methodology (protection and deprotection) and the necessary reagents and intermediates that can be used to synthesize compounds of Formula I are known in the art and are described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions.

The examples provide exemplary methods for preparing compounds of Formula I. Those skilled in the art will recognize that other synthetic routes can be used to synthesize compounds of Formula I. Although specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, the various exemplary compounds prepared by the methods described can be further modified based on the present disclosure using conventional chemical methods known to those skilled in the art.

When preparing compound of formula I, it may be necessary to protect the long-range functional group (such as primary amine or secondary amine) of intermediate. The needs of above-mentioned protection will change along with the property of long-range functional group and the condition of preparation method. Suitable amino protecting group comprises acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The needs of above-mentioned protection are easily determined by those skilled in the art. About the general description of protecting group and its use referring to T.W.Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

In the process for preparing the compound of formula I, it may be advantageous to separate the reaction products from each other and/or from the starting materials. The desired product of each step or steps is separated and/or purified to the desired uniformity by conventional techniques in the art. Typically, the separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve a variety of methods, including, for example: reverse phase and normal phase chromatography; size exclusion chromatography; ion exchange chromatography; high, medium, and low pressure liquid chromatography methods and apparatus; small-scale analytical chromatography; simulated moving bed (SMB) and preparative thin or thick layer chromatography and small-scale thin layer and flash chromatography.

Another type of separation method involves treating the mixture with a reagent selected to bind to or otherwise separable the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent may be an acid (in the case of a basic substance), a base (in the case of an acidic substance), a binding agent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid ion extraction reagent (LIX), etc. The choice of an appropriate separation method depends on the properties of the substances involved, such as boiling point and molecular weight (in distillation and sublimation), the presence or absence of polar functional groups (in chromatography), the stability of the substance in acidic and basic media (in multiphase extraction), etc.

Diastereomeric mixtures can be separated into their individual diastereomers based on their physicochemical differences by methods known to those skilled in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers, and then converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. In addition, some compounds of the present invention may be atropisomers (e.g., substituted biaryl compounds) and are considered part of the present invention. Enantiomers can also be separated by using a chiral HPLC column.

Individual stereoisomers, such as enantiomers, that are substantially free of their stereoisomers can be obtained by resolution of the racemic mixture using, for example, an optically active resolving agent to form diastereomers (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of the chiral compounds of the present invention can be separated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of the diastereomers and conversion to pure stereoisomers; and (3) direct separation of the substantially pure or enriched stereoisomers under chiral conditions. See "Drug Stereochemistry, Analytical Methods and Pharmacology", edited by Irving W. Wainer, Marcel Dekker, Inc., New York (1993).

In method (1), diastereomeric salts can be formed by reacting an enantiomerically pure chiral base such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine) or the like with an asymmetric compound having an acidic functional group such as a carboxylic acid or sulfonic acid. The diastereomeric salts can be separated by fractional crystallization or ion chromatography. To separate the optical isomers of an amino compound, the addition of a chiral carboxylic acid or sulfonic acid such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid can result in the formation of diastereomeric salts.

Alternatively, the substrate to be resolved is reacted with one enantiomer of a chiral compound by method (2) to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting an asymmetric compound with an enantiomerically pure derivatizing agent such as a menthyl derivative, followed by separation and hydrolysis of the diastereomers to yield the pure or enriched enantiomer. Methods for determining optical purity involve preparing a chiral ester of the racemic mixture, such as a menthyl ester, e.g., (-) menthyl chloroformate or Mosher ester, α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem., (1982) 47: 4165), in the presence of a base and analyzing the ¹ H NMR spectrum for the presence of two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal and reverse phase chromatography followed by methods for separating atropisomeric naphthyl-isoquinolines (WO96/15111). In method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) WJ Lough, ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). The enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

The compounds of the present invention were prepared as shown in General Schemes 1 to 10.

Solution 1

a) bromine, acetic acid; b) potassium carbonate, potassium iodide, 3-bromo-1,1-dimethoxypropane, 80°C; c) ammonium chloride, iron powder, methanol, water, 90°C; d) trifluoroacetic acid, triethylsilane, DCM, 0-20°C; e) A-COCl, triethylamine, THF; f) A-CO ₂ H, DIPEA, HATU, DMF; g) acetic acid, 90°C; h) Ar-B(OR) ₂ , Pd(dppf)Cl ₂ , sodium carbonate, 1,4-dioxane, water, 100°C.

As shown in Scheme 1, 2-amino-3-nitrophenol is brominated to give compound 2. Alkylation affords compound 3. Reduction of the nitro group with iron, followed by cyclization, affords compound 5. Acylation of compound 5, followed by cyclization in acetic acid, affords compound 6. Palladium-catalyzed cross-coupling with a boronate ester affords compound 7.

Option 2

i) HNR ³ -CH(R ⁷ )-CO ₂ H, copper(I) iodide, potassium phosphate, DMSO, 100-120° C.; j) ammonium chloride, HATU, DIPEA, DMSO or DMF.

Compound 6 can be converted to compound 8 via copper-mediated cross-coupling with amino acids as shown in Scheme 2. Conversion of acid 8 to primary amide 9 is achieved by reaction with ammonium chloride and HATU.

Option 3

k) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane), Pd(dppf)Cl ₂ , potassium acetate, 1,4-dioxane, 80° C.; l) acetic acid, water, hydrogen peroxide; m) CH ₃ CO ₂ -CH(R)-O-p-toluenesulfonyl, potassium carbonate, DMSO; n) lithium hydroxide, methanol, water; o) ammonium chloride, HATU, DIPEA, DMF.

As shown in Scheme 3, aryl bromide 6 was converted to the pinacol boronic acid ester followed by oxidation to afford compound 10. Alkylation with an activated α-hydroxy ester followed by ester hydrolysis afforded compound 11. Conversion of acid 11 to primary amide 12 was achieved by reaction with ammonium chloride and HATU.

Option 4

p) thiophosgene, triethylamine, THF, 0°C; q) iodomethane, potassium carbonate, acetone; r) 3-chloroperbenzoic acid, DCM; s) HNR ₂ , DIPEA, 2-propanol, irradiation 150°C.

As shown in Scheme 4, cyclization of compound 5 can be carried out with thiophosgene to give compound 13. S-methylation followed by oxidation to sulfone affords compound 14. Reaction with amines under microwave heating affords compound 15.

Option 5

t) triethyl orthoformate, p-toluenesulfonic acid, 100°C; u) lithium diisopropylamide, N-iodosuccinimide or N-chlorosuccinimide, THF, -78°C; v) HNR ₂ , irradiation, 140°C; w) AB(OR) ₂ , Pd(dppf)Cl ₂ , potassium acetate, sodium carbonate, water, acetonitrile, heating.

As shown in Scheme 5, compound 5 can be cyclized with triethyl orthoformate followed by halogenation to afford compound 16 as a chloride or iodide. Heating with an amine under microwave irradiation affords compound 6. Alternatively, palladium-catalyzed Suzuki coupling with an aryl boronic acid ester affords compound 6.

Option 6

a) 3,3-diethoxypropanol, NaH, DMF; b) 1,1,1-trimethylhydrazine iodide, KOtBu, DMSO; c) iron, ammonium chloride, methanol, water, 90°C; d) TFA, triethylsilane, DCM; e) similar steps as shown in Schemes 1-5.

As shown in Scheme 6, substituted alcohols can replace the fluorine atom in 17 to provide aryl ether 18. Amination can be carried out using 1,1,1-trimethylhydrazine iodide in the presence of a base. Reduction of the nitro group with iron, followed by cyclization under acidic conditions, can provide compound 21. Conversion to general compound 22 can be carried out using similar procedures as shown in Schemes 1-5.

Option 7

f) 1,1,1-trimethylhydrazine iodide, KOtBu, DMSO; g) iron, ammonium chloride, THF, ethanol, water, 100°C; h) trimethyl orthoformate, p-toluenesulfonic acid, 100°C; i) boron tribromide, DCM, 40°C; j) 1,4-dibromobutane, potassium carbonate, DMF, 100°C; k) similar steps as shown in Schemes 1-5.

As shown in Scheme 7, amination of compound 23 can be carried out using 1,1,1-trimethylhydrazine iodide in the presence of a base to provide compound 24. Reduction of the nitro group with iron followed by cyclization in trimethyl orthoformate can provide compound 26. Demethylation using boron tribromide followed by dialkylation with 1,4-dibromobutane can provide compound 28. Conversion to general compound 29 can be carried out using similar procedures as shown in Schemes 1-5.

Option 8

l) 1,2-dibromoethane, KOH, DMF, 140°C; m) a similar procedure as shown in Scheme 1-5; n) aqueous HBr solution, sodium nitrite, copper (II) bromide, 0-100°C; o) substituted alcohol, triphenylphosphine, diisopropyl azodicarboxylate, THF; p) i. HCl, dioxane, 50°C, ii. potassium carbonate, DMF, 90°C.

As shown in Scheme 8, compound 2 can be cyclized with 1,2-dibromoethane in the presence of a base to provide compound 30. Conversion to general compound 31 can be performed using similar procedures as shown in Schemes 1-5. Alternatively, compound 2 can be converted to dibromo compound 32 using Sandmeyer conditions. Mitsunobu conditions allow alkylation of the phenol to provide compound 33 with defined stereochemistry. Boc deprotection and cyclization can provide compound 34, which can be converted to general compound 31 using similar procedures as shown in Schemes 1-5.

Option 9

q) methyl 4-bromobutyrate, potassium iodide, potassium carbonate, acetone, reflux; r) lithium hydroxide, methanol, water, 60°C; s) i. thionyl chloride, DCM, ii. aluminum chloride, DCM, 0°C; t) R-NHNH ₂ , pyridine, 60°C; u) analogous procedure from Schemes 1-5; v) hydrazine, diglyme, 120°C; w) ArBr, copper(II) acetate, pyridine, 90°C.

As shown in Scheme 9, compound 35 can be alkylated and the methyl ester can be saponified to provide compound 36. The resulting acid chloride, followed by treatment with aluminum chloride, can provide a mixture of compounds 37 and 38. Compound 37 can be treated with a substituted hydrazine to provide compound 39, which can be converted to the general compound 40 using similar procedures as shown in Schemes 1-5. Alternatively, compound 37 can be cyclized with hydrazine to provide compound 41. Copper-catalyzed coupling with an aryl bromide can provide a mixture of compounds 42 and 43; when isolated, compound 43 can be converted to the general compound 44 using similar procedures as shown in Schemes 1-5.

Plan 10

v) 2-(3-chloropropyl)-1,3-dioxolane, potassium carbonate, sodium iodide, DMF, 80°C; w) TFA, triethylsilane, DCM, 0-25°C; x) iron, ammonium chloride, methanol, water; y) trimethyl orthoformate, p-toluenesulfonic acid, 100°C; z) lithium diisopropylamide, N-iodosuccinimide, THF, -78°C; aa) Analogous steps from Schemes 1-5.

As shown in Scheme 10, compound 2 can be alkylated to give compound 45. Treatment with TFA and triethylsilane can provide compound 46. Reduction of the nitro group with iron, followed by cyclization with trimethyl orthoformate, can provide compound 48. Treatment with lithium diisopropylamide followed by N-iodosuccinimide can provide compound 49. Conversion to general compound 50 can be carried out using similar procedures as shown in Schemes 1-5.

Example

abbreviation

DCM dichloromethane

DIPEA N,N-Diisopropylethylamine

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

ESI electrospray ionization

h hour

HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium

3-oxide hexafluorophosphate

HPLC High-pressure liquid chromatography

LCMS liquid chromatography mass spectrometry

LDA lithium diisopropylamide

min

N equivalent concentration

NMR Nuclear Magnetic Resonance

_RT retention time

SFC Supercritical Fluid Chromatography

THF Tetrahydrofuran

TFA trifluoroacetic acid

LCMS method

LCMS Method A: Experiments were performed on a Waters Micromass ZQ2000 quadrupole mass spectrometer connected to a Waters Acquity UPLC system with a PDA UV detector. The mass spectrometer had an electrospray source operating in positive and negative ion modes. The system used either an Acquity BEH C18 1.7 μm 100×2.1 mm column maintained at 40°C or an Acquity BEH Shield RP18 1.7 μm 100×2.1 mm column maintained at 40°C and a flow rate of 0.4 mL/min. The initial solvent system was 95% water (solvent A) containing 0.1% formic acid and 5% acetonitrile (solvent B) containing 0.1% formic acid for the first 0.4 minutes, followed by a gradient increase to 5% solvent A and 95% solvent B over the next 5.6 minutes. This was held for 0.8 minutes, then returned to 95% solvent A and 5% solvent B over the next 0.2 minutes. The total run time was 8 minutes.

LCMS Method B: Experiments were performed on an Agilent 1100 HPLC coupled to an Agilent MSD mass spectrometer using ESI as the ionization source. LC separations were performed using a Phenomenex XB-C18, 1.7 mm, 50 x 2.1 mm column at a flow rate of 0.4 mL/min. Solvent A was water containing 0.1% formic acid, and solvent B was acetonitrile containing 0.1% formic acid. The gradient was 2-98% solvent B over 7 minutes, followed by a 1.5-minute equilibration and a 1.5-minute hold at 97% solvent B. The LC column temperature was 40°C. UV absorbance was collected at 220 nm and 254 nm, and full-scan mass spectra were used for all experiments.

LCMS Method C: Experiments were performed on a Shimadzu 2020 HPLC system coupled to a Shimadzu MSD mass spectrometer using ESI as the ionization source. LC separations were performed using a Shim-Pack XR-ODS-C18, 50 x 3.0 mm column, at a flow rate of 1 mL/min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient was 5-100% solvent B over 2.2 minutes, with a hold of 100% B for 1 minute. The LC column temperature was 40°C. UV absorbance was collected from 190 nm to 400 nm, and full mass scans were used for all experiments.

LCMS Method D: Experiments were performed on a Shimadzu 2020 HPLC system coupled to a Shimadzu MSD mass spectrometer using ESI as the ionization source. LC separations were performed using a Gemini-NX 3μ C18 110A, 50 × 3.0 mm column at a flow rate of 1.2 mL/min. Solvent A was water containing 0.4% _{NH₄HCO₃ ,} and solvent B was acetonitrile. The gradient was 10-50% solvent B over 4 minutes, with a hold of 50% B for 1.2 minutes. The LC column temperature was 40°C. UV absorbance was collected from 190 nm to 400 nm, and full mass scans were used for all experiments.

LCMS Method E: Experiments were performed on a Shimadzu UFLC-MS 2010EV coupled to a Shimadzu MSD mass spectrometer using ESI as the ionization source. LC separations were performed using a Shim-Pack XR-ODS-C18, 50 x 3.0 mm column, at a flow rate of 1 mL/min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient was 5-100% solvent B over 2.2 minutes, with a hold of 100% B for 1 minute. The LC column temperature was 40°C. UV absorbance was collected from 190 nm to 400 nm, and full mass scans were used for all experiments.

LCMS Method F: Experiments were performed on a Shimadzu LCMS-2020 coupled to a Shimadzu MSD mass spectrometer using ESI as the ionization source. LC separations were performed using an Ascentis Express C18, 50 × 2.1 mm column at a flow rate of 1 mL/min. Solvent A was water containing 0.05% TFA, and solvent B was acetonitrile containing 0.05% TFA. The gradient was 5–95% solvent B over 2.0 minutes, with a hold of 95% B for 0.7 minutes. The LC column temperature was 40°C. UV absorbance was collected from 190 nm to 400 nm, and full mass scans were used for all experiments.

LCMS Method G: Experiments were performed on a Shimadzu LCMS-2020 coupled to a Shimadzu MSD mass spectrometer using ESI as the ionization source. LC separations were performed using a Gemini-NX 3μ C18 110A, 50 × 3.0 mm column at a flow rate of 1.2 mL/min. Solvent A was water containing 0.05% _{NH₄HCO₃ ,} and solvent B was acetonitrile. The gradient was 95% solvent B over 2.2 minutes and held at 95% B for 1 minute. The LC column temperature was 45°C. UV absorbance was collected from 190 nm to 400 nm, and full mass scans were used for all experiments.

Example 101 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine 101

Step 1: 2-Amino-5-bromo-3-nitrophenol

Bromine (51.9 g, 324 mmol) was added dropwise to a solution of 2-amino-3-nitrophenol (50.0 g, 324 mmol) in acetic acid at 25°C, and the reaction mixture was stirred at 25°C overnight. The solid was collected by filtration to give the crude title compound (84 g, 80% purity (LCMS), 89.1%) as a red solid and used without further purification. LCMS (ESI): [M+H] ⁺ = 233/235.

Step 2: 4-Bromo-2-(3,3-dimethoxypropoxy)-6-nitroaniline

A mixture of 2-amino-5-bromo-3-nitrophenol (93g, 399mmol), potassium carbonate (110g, 797mmol), potassium iodide (13.0g, 78.3mmol) and 3-bromo-1,1-dimethoxypropane (87.4g, 478mmol) in DMF (600mL) was stirred at 80 ° C for 4h. The reaction mixture was then cooled to room temperature and the resulting solid was filtered. The filtrate was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, then dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-10% ethyl acetate/petroleum ether) to give 110g (82.7%) of the title compound as a yellow solid.

¹ H NMR (400MHz, DMSO-d ₆ ) δ7.44 (d, J = 2.4Hz, 1H), 7.24 (s, 2H), 7.21 (d, J＝2.0Hz,1H),4.71-4.68(m,1H),4.11-4.08(m,2H),3.27(s,6H),2.08-2.03(m,2H).

Step 3: 5-Bromo-3-(3,3-dimethoxypropoxy)benzene-1,2-diamine

A mixture of 4-bromo-2-(3,3-dimethoxypropoxy)-6-nitroaniline (30.0 g, 89.6 mmol), ammonium chloride (43.0 g, 811 mmol) and iron powder (30.0 g, 436 mmol) in methanol/water (150 mL/150 mL) was stirred at 90 ° C for 2 h. The solution was cooled to room temperature and the resulting solid was filtered. The filtrate was diluted with water and extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 22 g (81.4%) of the title compound as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ6.40 (d, J = 2.0 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 4.79 (s, 2H), 4.66-4.63 (m, 1H), 4.13 (s, 2H), 3.92-3.89(m,2H),3.26(s,6H),1.99-1.94(m,2H).

Step 4: 8-Bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine

Trifluoroacetic acid (20mL) and triethylsilane (3.20g, 27.6mmol) are added dropwise to a solution of 5-bromo-3-(3,3-dimethoxypropoxy)benzene-1,2-diamine (1.70g, 5.57mmol) in DCM (20mL) at 0°C while maintaining an inert nitrogen atmosphere. The resulting solution is stirred at 0°C for 10min and then stirred at room temperature for another 2h. The reaction mixture is evaporated in vacuo. The mixture is adjusted to pH 10 with aqueous sodium bicarbonate solution and then extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue is purified via flash chromatography on silica gel (solvent gradient: 0-20% ethyl acetate/petroleum ether) to give 0.6g (44.4%) of the title compound as a pale white solid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 6.46 (d, J = 2.4Hz, 1H), 6.26 (d, J = 2.4Hz, 1H), 5.01 (s, 2H), 4.37 (br, 1H), 3.98-3.94(m,2H),3.09-3.04(m,2H),1.87-1.79(m,2H).

Step 5: 4-Hydroxy-3-nitrobenzoyl chloride

A mixture of 4-hydroxy-3-nitrobenzoic acid (1.83 g, 9.99 mmol) and thionyl chloride (1.1 mL, 15.2 mmol) in 1,2-dimethoxyethane (20 mL) was stirred overnight at 80° C. The reaction mixture was evaporated in vacuo to give the crude title compound which was used without further purification.

Step 6: N-(8-Bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)-4-hydroxy-3-nitrobenzamide

4-Hydroxy-3-nitrobenzoyl chloride (2.01 g crude product) in THF (20 mL) was added dropwise to a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine (2.42 g, 9.96 mmol) and triethylamine (1.21 g, 12.0 mmol) in THF (100 mL) at 0 ° C. The resulting solution was stirred at room temperature for 1 h and then quenched by adding water. The resulting solution was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-30% ethyl acetate/petroleum ether) to give 3.0 g (73.8%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =408/410.

Step 7: 4-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-2-nitrophenol

A mixture of N-(8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)-4-hydroxy-3-nitrobenzamide (3 g, 7.35 mmol) in acetic acid (50 mL) was stirred at 90°C for 2 h. The resulting mixture was evaporated in vacuo to give 2.9 g of the crude title compound, which was used without further purification. LCMS (ESI): [M+H] ⁺ = 390/392.

Step 8: 2-amino-4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)phenol

A mixture of 4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2-nitrophenol (130 mg, 0.330 mmol) and iron powder (93.0 mg, 1.66 mmol) in AcOH (10 mL) was stirred at 50 ° C for 2 h. The resulting solid was removed by filtration. The filtrate was evaporated in vacuo to give 250 mg of the crude title compound as a black solid and used without further purification. LCMS (ESI):

[M+H] ⁺ =360/362.

Step 9: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine

A mixture of 2-amino-4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)phenol (250 mg, crude) and cyanogen bromide (147 mg, 1.39 mmol) in methanol/water (15 mL/5 mL) was stirred at room temperature for 2 h. The reaction mixture was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified via silica gel flash chromatography (solvent gradient: 0-5% methanol/DCM) to give 98 mg (76.5% over two steps) of 101 as a yellow solid. LCMS (ESI):

_RT (min) = 2.69, [M+H] ⁺ = 385/387, method = D; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.59-7.57 (m, 3H), 7.51-7.36 (m, 3H), 6.89 (s, 1H), 4.45-4.42 (m, 2H), 4.33-4.29 (m, 2H), 2.38-2.25 (m, 2H).

Example 102 4-Bromo-1-(2-methyloxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene 102

102 was prepared following the procedure of this application. [M+H] ⁺ = 385.10

Example 103 1-(1-(2-methylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 103. [M+H] ⁺ =418.18

103 was prepared following the procedures of this application. [M+H] ⁺ = 385

Example 104 (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 104

Step 1: (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxylic acid

A mixture of 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine (50.0 mg, 0.130 mmol), (S)-pyrrolidine-2-carboxylic acid (75.0 mg, 0.651 mmol), copper(I) iodide (8.00 mg, 0.0420 mmol), and potassium phosphate (193 mg, 0.909 mmol) in DMSO (2 mL) was heated at 120° C. under microwave irradiation for 90 min. The solid was removed by filtration, and the brown filtrate was used without purification. LCMS (ESI): [M+H] ⁺ = 420.

Step 2: (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide

A mixture of (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxylic acid (crude), ammonium chloride (135 mg, 2.52 mmol), HATU (193 mg, 0.508 mmol) and DIPEA (707 mg, 5.47 mmol) in DMSO (2 mL) was stirred at room temperature for 2 h. The reaction solution was diluted with water and then extracted with ethyl acetate. The organic extracts were combined and evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to afford 9.9 mg (18.2% over two steps) of 104 as a white solid. LCMS (ESI): _RT (min) = 2.00, [M+H] ⁺ = 419, method = C; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.56-7.54 (m, 3H), 7.47 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.02 (s, 1H), 6.36 (s, 1H), 6.07 (s, 1H), 4.36-4.34 (m, 2H), 4.25-4.22 (m, 2H), 3.85-3.83 (m, 1H), 3.60-3.57 (m, 1H), 3.25-3.10 (m, 1H), 2.26-2.19(m,3H),2.03-1.92(m,3H).

Example 105 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide 105

Step 1: (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanoic acid and (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanoic acid

The title compound (200 mg, crude) was prepared as a mixture of major (S) and minor (R) stereoisomers from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine (300 mg, 0.779 mmol) and (S)-2-aminopropanoic acid (347 mg, 3.89 mmol) from Example 101 following a procedure analogous to Step 1 of Example 104. LCMS (ESI): [M+H] ⁺ = 394.

Step 2: (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide and (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide

The title compound 95 mg (31% over two steps) of (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanoic acid (200 mg crude) was prepared following a procedure similar to that in Step 2 of Example 104. d]azulen-4-yl)amino)propanamide 105 and 40 mg (13.1% over two steps) (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide 107 (Example 107) and the two stereoisomers were separated by chiral HPLC. 105: LCMS (ESI): R _T (min) = 1.99, [M+H] ⁺ = 393, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.55 (s, 2H), 7.51 (s, 1H), 7.45 (d, J = 8.1Hz, 1H),7.32(d,J＝8.1Hz,1H),7.29(s,1H),6.94(s,1H),6.37(s,1H),6.20(s,1H), 5.42(d,J＝7.5Hz,1H),4.33-4.31(m,2H),4.21-4.18(m,2H),3.75-3.70(m,1H), 2.17-2.32(m,2H),1.31(d,J＝6.9Hz,3H).

Example 106 (S)-2-((1-phenyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)propanamide 106

Step 1: (S)-2-(4-amino-3-(3,3-dimethoxypropoxy)-5-nitrophenylamino)propanoic acid

A mixture of 4-bromo-2-(3,3-dimethoxypropoxy)-6-nitroaniline (2 g, 5.97 mmol), copper (I) iodide (340 mg, 1.79 mmol), potassium phosphate (7.59 g, 35.8 mmol) and (S)-2-aminopropionic acid (2.66 g, 29.9 mmol) in DMSO (20 mL) was placed in a tube and the mixture was degassed with nitrogen under ultrasonic conditions. The tube was sealed and stirred at 90 ° C for 16 h. The resulting solid was filtered and the brown filtrate was used without purification. LCMS (ESI): [M+H] ⁺ = 344.

Step 2: (S)-2-(4-amino-3-(3,3-dimethoxypropoxy)-5-nitrophenylamino)propionamide

A mixture of (S)-2-(4-amino-3-(3,3-dimethoxypropoxy)-5-nitrophenylamino)propanoic acid (crude), ammonium chloride (4.62 g, 86.4 mmol), HATU (4.42 g, 11.6 mmol), and DIPEA (15.0 g, 116 mmol) in DMSO (20 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-5% methanol/DCM) to give 800 mg (39.2% over two steps) of the title compound as a red solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.39 (s, 1H), 6.99 (s, 1H), 6.73-6.69(m,3H),6.53(s,1H),5.57-5.55(m,1H),4.69(t,J＝5.6Hz,1H),4. 01-3.98(m,2H),3.71-3.68(m,1H),3.28(s,6H),2.09-2.05(m,2H),1.27(d, J=6.8Hz,3H).

Step 3: (S)-2-(6-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-ylamino)propanamide

Trifluoroacetic acid (5 mL, 67.3 mmol) and triethylsilane (676 mg, 5.81 mmol) were added dropwise to a solution of (S)-2-(4-amino-3-(3,3-dimethoxypropoxy)-5-nitrophenylamino)propionamide (400 mg, 1.17 mmol) in DCM (20 mL) at 0 ° C and the reaction mixture was stirred at 0 ° C for 10 min. The mixture was evaporated in vacuo and the pH value was adjusted to 8 with aqueous sodium bicarbonate solution and the resulting solution was extracted with ethyl acetate. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated in vacuo to give 140 mg of the crude title compound as a purple solid and used without further purification. ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.48-7.46(m,1H),7.39(s,1H),6.99(s,1H),6.78(s,1H),6.65(s,1H), 5.74(d,J＝7.2Hz,1H),4.17-4.06(m,2H),3.68-3.52(m,1H),3.49-3.32(m,2H), 2.03-1.95(m,2H),1.25(d,J＝6.8Hz,3H).

Step 4: (S)-2-(6-amino-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-ylamino)propanamide

Pd (10 mg, 10 wt% on carbon) was added to a solution of (S)-2-(6-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-ylamino)propanamide (70.0 mg, 0.250 mmol) in ethanol (20 mL) and the reaction mixture was stirred under a hydrogen balloon at room temperature for 16 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to give 62 mg of the crude title compound, which was used without further purification. LCMS (ESI):

[M+H] ⁺ =251.

Step 5: (S)-N-(8-(1-amino-1-oxopropan-2-ylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)benzamide

Benzoyl chloride (34.8 mg, 0.248 mmol) in THF (1 mL) was added dropwise to a solution of crude (S)-2-(6-amino-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-8-ylamino)propanamide (62 mg, 0.248 mmol) and triethylamine (74.8 mg, 0.739 mmol) in THF (20 mL) at 0°C. The reaction mixture was stirred at 0°C for 10 min and then evaporated in vacuo to give 87 mg of the crude title compound, which was used without purification. LCMS (ESI): [M+H] ⁺ = 355.

Step 6: (S)-2-((1-phenyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide

A mixture of crude (S)-N-(8-(1-amino-1-oxopropan-2-ylamino)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)benzamide (87 mg) and acetic acid (5 mL) was stirred at 90° C. for 2 h. The reaction mixture was evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to afford 13.8 mg (16.2% over three steps) of 106 as an off-white solid. LCMS (ESI): _RT (min) = 1.23, [M+H] ⁺ = 337, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.76-7.73 (m, 2H), 7.57-7.49 (m, 3H), 7.28 (s, 1H), 6.94 (s, 1H), 6.38 (s, 1H), 6.22 (s, 1H), 5.45 (d, J = 7.2 Hz, 1H), 4.33-4.31 (m, 2H), 4.22-4.19 (m, 2H), 3.77-3.68 (m, 1H), 2.30-2.17 (m, 2H), 1.32 (d, J = 6.9 Hz, 3H).

Example 107 (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide 107

107 was prepared following the procedure of Example 105. LCMS (ESI): R _T (min) = 1.22, [M+H] ⁺ = 393, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.55 (s, 2H), 7.51 (s, 1H), 7.45 (d, J＝8.1Hz,1H),7.32(d,J＝8.1Hz,1H),7.29(s,1H),6.94(s,1H),6.37(s,1H),6.20(s, 1H), 5.42 (d, J = 7.5Hz, 1H), 4.33-4.31 (m, 2H), 4.21-4.18 (m, 2H), 3.75-3.70 (m, 1H), 2.17-2.32 (m, 2H), 1.31 (d, J = 6.9Hz, 3H).

Example 108 (S)-2-((1-(pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)propanamide 108

108 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.83, [M+H] ⁺ = 338, method = G; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 8.20-8.16 (m, 1H), 7.59-7.54 (m, 1H), 7.29 (s, 1H), 6.94 (s, 1H), 6.40 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.49 (d, J = 4.5 Hz, 1H), 4.35-4.32 (m, 2H), 4.27-4.24 (m, 2H), 3.78-3.68 (m, 1H), 2.35-2.20 (m, 2H), 1.32 (d, J = 6.8Hz, 3H).

Example 109 (S)-2-((1-(pyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)propanamide 109

109 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.79, [M+H] ⁺ = 339.1, method = D; ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.31 (s, 1H), 8.94 (d, J = 5.2 Hz, 1H), 8.26 (d, J = 6.8 Hz, 1H), 7.34 (s, 1H), 6.96 (s, 1H), 6.40 (s, 1H), 6.36 (s, 1H), 5.66 (d, J = 7.2 Hz, 1H), 4.87-4.76 (m, 2H), 4.44-4.35 (m, 2H), 3.77-3.73 (m, 1H), 2.20-2.40 (m, 2H), 1.32 (d, J = 6.8 Hz, 3H).

Example 110 (S)-2-((1-(5-cyanopyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)propanamide 110

110 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.18, [M+H] ⁺ = 363.1, method = D; ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.21 (s, 1H), 8.44-8.39 (m, 2H), 7.33 (s, 1H), 6.96 (s, 1H), 6.44 (s, 1H), 6.40 (s, 1H), 5.64 (d, J = 7.2 Hz, 1H), 4.81-4.78 (m, 2H), 4.45-4.36 (m, 2H), 3.78-3.71 (m, 1H), 2.20-2.40 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H).

Example 111 (S)-2-((1-(6-methoxypyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)propanamide 111

111 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.96, [M+H] ⁺ = 368, method = D; ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.55 (s, 1H), 8.09 (d, J = 10.8 Hz, 1H), 7.28 (s, 1H), 6.99-6.93 (m, 2H), 6.37 (s, 1H), 6.22 (s, 1H), 5.45 (d, J = 7.2 Hz, 1H), 4.33-4.31 (m, 2H), 4.27-4.17 (m, 2H), 3.93 (s, 3H), 3.75-3.69 (m, 1H), 2.15-2.35 (m, 2H), 1.31 (d, J = 6.8 Hz, 3H).

Example 112 (S)-2-((1-(pyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)propanamide 112

112 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.13, [M+H] ⁺ = 338, method = E; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (d, J = 4.2 Hz, 1H), 8.20 (d, J = 7.8 Hz, 1H), 7.99-7.36 (m, 1H), 7.50-7.45 (m, 1H), 7.31 (s, 1H), 6.95 (s, 1H), 6.39 (d, J = 2.1 Hz, 1H), 6.26 (d, J = 1.8 Hz, 1H), 5.52 (d, J = 7.2 Hz, 1H), 4.77-4.73 (m, 2H), 4.35-4.32(m,2H),3.78-3.69(m,1H),2.20-2.40(m,2H),1.31(d,J＝6.9Hz,3H).

Example 113 (S)-2-cyclopropyl-2-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 113

113 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.55, [M+H] ⁺ = 443, method = C; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.82 (s, 1H), 7.66-7.54 (m, 2H), 7.34 (s, 1H), 6.96 (s, 1H), 6.38 (s, 1H), 6.27 (s, 1H), 5.51 (d, J = 7.4 Hz, 1H), 4.34-4.31 (m, 2H), 4.23-4.20 (m, 2H), 3.16-3.12 (m, 1H), 2.15-2.35 (m, 2H), 1.13-1.08 (m, 1H), 0.58-0.42 (m, 3H), 0.36-0.26 (m, 1H).

Example 114 (S)-2-((1-(Benzo[d][1,3]dioxol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 114

114 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.55, [M+H] ⁺ = 407, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.33 (s, 1H), 7.29 (s, 1H), 7.25-7.22 (d, J = 9.6 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.96 (s, 1H), 6.36 (s, 1H), 6.23 (s, 1H), 6.13 (s, 2H), 5.45 (d, J = 7.4 Hz, 1H), 4.32-4.30 (m, 2H), 4.20-4.17 (m, 2H), 3.16-3.12 (m, 1H),2.15-2.30(m,2H),1.13-1.08(m,1H),0.52-0.46(m,3H),0.32-0.29(m,1H).

Example 115 (S)-2-Cyclopropyl-2-((1-(3-oxoisoindolin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 115

115 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.16, [M+H] ⁺ = 418, method = E; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.72 (s, 1H), 8.01-7.97 (m, 2H), 7.77-7.74 (d, J = 8.4 Hz, 1H), 7.35 (s, 1H), 6.97 (s, 1H), 6.41 (d, J = 1.8 Hz, 1H), 6.28 (d, J = 2.1 Hz, 1H), 5.50 (d, J = 7.5 Hz, 1H), 4.49 (s, 2H), 4.37-4.34 (m, 2H), 4.27-4.24 (m, 2H),3.19-3.15(m,1H),2.15-2.35(m,2H),1.17-1.09(m,1H),0.54-0.45(m,3H), 0.36-0.30(m,1H).

Example 116 (S)-2-Cyclopropyl-2-((1-(quinazolin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 116

Step 1: Methyl quinazoline-7-carboxylate

Carbon monoxide was passed through a solution of 7-bromoquinazoline (250 mg, 1.20 mmol), sodium carbonate (320 mg, 2.96 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (90.0 mg, 0.120 mmol) in methanol (10 ml). The reaction mixture was stirred at 60 ° C for 2.5 h and then evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 180 mg (80%) of the title compound as an off-white solid. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 9.44 (s, 1H), 8.55 (s, 1H), 8.35-8.32 (d, J = 8.4Hz, 1H), 8.25-8.22 (d, J = 8.7Hz, 1H), 3.98 (s, 3H).

Step 2: Quinazoline-7-carboxylic acid

A mixture of quinazoline-7-carboxylic acid methyl ester (180 mg, 0.900 mmol), lithium hydroxide (70.0 mg, 2.70 mmol), water (5 mL) and THF (15 mL) was stirred at room temperature for 2 h. The reaction mixture was evaporated in vacuo. The residue was dissolved in water (10 mL) and the pH was adjusted to 2 with acetic acid. The resulting precipitate was collected by filtration to give 150 mg (98%) of the title compound as an off-white solid. LCMS (ESI): [MH] ⁻ = 173.

Step 3: N-(8-Bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)quinazoline-7-carboxamide

The title compound (crude) was prepared from 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-amine from Example 101 (188 mg, 0.770 mmol) and quinazoline-7-carboxylic acid (150 mg, 0.860 mmol) following a procedure analogous to Example 125, Step 1. LCMS (ESI): [M+H] ⁺ =399/401.

Step 4: 4-Bromo-1-(quinazolin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (160 mg, 54% yield over 2 steps) was prepared from N-(8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)quinazoline-7-carboxamide (crude) following a procedure similar to that described in Example 125, Step 2. LCMS (ESI): [M+H] ⁺ = 381/383.

Step 5: (S)-2-Cyclopropyl-2-((1-(quinazolin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (50.3 mg, 36% yield) was prepared from 4-bromo-1-(quinazolin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (140 mg, 0.370 mmol) following procedures similar to those in Steps 3-4 of Example 125. 116: LCMS (ESI): _RT (min) = 1.98, [M+H] ⁺ = 415, Method = D;

¹ H NMR (400MHz, DMSO-d ₆ ) δ9.72(s,1H),9.39(s,1H),8.38(s,1H),8.31(d, J＝8.4Hz,1H),8.20(d,J＝8.0Hz,1H),7.37(s,1H),6.98(s,1H),6.43(s,1H),6.33(s, 1H),5.57(d,J＝7.2Hz,1H),4.39-4.38(m,4H),3.19-3.15(m,1H),2.40-2.20(m, 2H),1.24-1.11(m,1H),0.58-0.43(m,3H),0.37-0.25(m,1H).

Example 117 (S)-2-Cyclopropyl-2-((1-(quinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 117

117 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.21, [M+H] ⁺ = 415, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.05-9.03 (m, 2H), 8.47 (d, J = 1.5 Hz, 1H), 8.30-8.22 (m, 2H), 7.36 (s, 1H), 6.98 (s, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.31 (d, J = 2.1 Hz, 1H), 5.55 (d, J = 7.2 Hz, 1H), 4.39-4.36 (m, 4H), 3.19-3.19-3.14 (m, 1H), 2.20-2.40(m,2H),1.15-1.08(m,1H),0.54-0.50(m,3H),0.36-0.27(m,1H).

Example 118 (S)-2-((1-(3-cyanophenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 118

118 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.36, [M+H] ⁺ = 388, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 8.12-8.10 (m, 1H), 8.01-7.98 (m, 1H), 7.78-7.74 (m, 1H), 7.35 (s, 1H), 6.97 (s, 1H), 6.39 (s, 1H), 6.29 (s, 1H), 5.54 (d, J = 7.6 Hz, 1H), 4.35-4.32 (m, 2H), 4.27-4.23 (m, 3H), 3.17-3.13 (m, 1H),2.29-2.26(m,2H),1.13-1.10(m,1H),0.52-0.47(m,3H),0.33-0.30(m,1H).

Example 119 (S)-2-Cyclopropyl-2-((1-(quinazolin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 119

119 was prepared following the procedure of Example 116. LCMS (ESI): _RT (min) = 1.95, [M+H] ⁺ = 415, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 9.38 (s, 1H), 8.62 (s, 1H), 8.46-8.43 (d, J = 9.0 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.36 (s, 1H), 6.98 (s, 1H), 6.42 (d, J = 2.0 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.55 (d, J = 7.4 Hz, 1H), 4.45-4.30 (m, 4H), 3.18-3.13(m,1H),2.31-2.30(m,2H),1.16-1.09(m,1H),0.60-0.40(m,3H), 0.34-0.29(m,1H).

Example 120 (S)-2-Cyclopropyl-2-((1-(quinazolin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 120

120 was prepared following the procedure of Example 116. LCMS (ESI): _RT (min) = 1.11, [M+H] ⁺ = 430, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.21 (s, 1H), 8.22 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.34 (s, 1H), 7.07 (s, 2H), 6.96 (s, 1H), 6.38 (s, 1H), 6.25 (s, 1H), 5.49 (d, J = 7.4 Hz, 1H), 4.36-4.30 (m, 4H), 3.17-3.11 (m, 1H), 2.38-2.20(m,2H),1.12-1.10(m,1H),0.53-0.47(m,3H),0.33-0.31(m,1H).

Example 121 (S)-2-cyclopropyl-2-((1-(2-methoxy-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 121

121 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.22, [M+H] ⁺ = 409, method = C; ¹ H NMR (300 MHz, DMSO-d ₆ ): δ 7.80 (s, 1H), 7.36 (br, 1H), 6.97 (br, 1H), 6.38-6.35 (m, 2H), 5.65 (d, J = 7.2 Hz, 1H), 4.86-4.82 (m, 2H), 4.39-4.30 (m, 2H), 3.97 (s, 3H), 3.15-3.10 (m, 1H), 2.49 (s, 3H), 2.34-2.30 (m, 2H), 1.16-1.08 (m, 1H), 0.58-0.41 (m, 3H), 0.37-0.24 (m, 1H).

Example 122 (S)-2-cyclopropyl-2-((1-(4-methylpyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 122

122 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.15, [M+H] ⁺ = 378, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.58-8.56 (m, 2H), 7.44 (d, J = 5.1 Hz, 1H), 7.34 (s, 1H), 6.96 (s, 1H), 6.38 (d, J = 1.9 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 5.51 (d, J = 7.4 Hz, 1H), 4.34-4.25 (m, 2H), 3.92-3.82 (m, 2H), 3.14-3.11 (m, 1H), 2.35-2.15(m,5H),1.15-1.07(m,1H),0.59-0.40(m,3H),0.33-0.26(m,1H).

Example 123 (S)-2-Cyclopropyl-2-((1-(2-(hydroxymethyl)-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 123

Step 1: 2-(Methoxymethyl)-6-methylpyrimidin-4(3H)-one

A mixture of sodium (1.84 g, 80.0 mmol) in ethanol (80 mL) was stirred under an inert nitrogen atmosphere until the sodium disappeared. Ethyl 3-oxobutanoate (5.20 g, 40.0 mmol) and 2-methoxyacetamidine hydrochloride (5.00 g, 40.1 mmol) were added to the resulting mixture. The resulting solution was stirred at 80 ° C for 18 h and then concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 5 with concentrated hydrochloric acid (37%, 12 M) and extracted with ethyl acetate. The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo to give 2.8 g (45%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =155.

Step 2: 4-chloro-2-(methoxymethyl)-6-methylpyrimidine

A mixture of 2-(methoxymethyl)-6-methylpyrimidin-4(3H)-one (2.80 g, 18.1 mmol) in phosphoryl trichloride (25 mL) was stirred at 80 ° C for 1 h. The reaction mixture was evaporated in vacuo and then quenched with cold ammonia water. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 1.9 g (crude) of the title compound as a red oil that was used without purification. LCMS (ESI): [M+H] ⁺ = 173.

Step 3: 2-(Methoxymethyl)-6-methylpyrimidine-4-carboxylic acid

A mixture of 4-chloro-2-(methoxymethyl)-6-methylpyrimidine (500 mg, 3.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (211 mg, 0.288 mmol), and sodium carbonate (766 mg, 7.23 mmol) in ethanol (20 mL) was stirred at 80° C. for 14 h while maintaining a carbon monoxide atmosphere. The solid was filtered off and the filtrate was evaporated in vacuo to give 180 mg (crude) of the title compound as a red solid, which was used without purification. LCMS (ESI): [M+H] ⁺ = 183.

Step 4: N-(8-Bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)-2-(methoxymethyl)-6-methylpyrimidine-4-carboxamide

The title compound (crude) was prepared using a procedure analogous to that described in Step 1 of Example 125 from 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-amine from Example 101 (232 mg, 0.954 mmol) and 2-(methoxymethyl)-6-methylpyrimidine-4-carboxylic acid (350 mg, crude). The crude product was used without purification. LCMS (ESI): [M+H] ⁺ = 407/409.

Step 5: 4-Bromo-1-(2-(methoxymethyl)-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (350 mg, 81%) was prepared from N-(8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)-2-(methoxymethyl)-6-methylpyrimidine-4-carboxamide (450 mg, 1.11 mmol) following a procedure similar to that described in Example 125, Step 2. LCMS (ESI): [M+H] ⁺ = 389/391.

Step 6: (4-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-6-methylpyrimidin-2-yl)methanol

A mixture of 4-bromo-1-(2-(methoxymethyl)-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (350 mg, 0.899 mmol) in hydrobromic acid (48 wt% in water, 9 mL) was stirred at 90 ° C in an oil bath for 3 h. The pH was adjusted to 8 with aqueous sodium bicarbonate solution. The resulting solution was extracted with DCM and the organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 269 mg (79.8%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =375/377.

Step 7: (S)-2-Cyclopropyl-2-((1-(2-(hydroxymethyl)-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid

The title compound (60 mg, 21% yield) was prepared from (4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-6-methylpyrimidin-2-yl)methanol (260 mg, 0.693 mmol) and (S)-2-amino-2-cyclopropylacetic acid (399 mg, 3.47 mmol) following a procedure similar to that described in Step 3 of Example 125. LCMS (ESI): [M+H] ⁺ = 410.

Step 8: (S)-2-Cyclopropyl-2-((1-(2-(hydroxymethyl)-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (16 mg, 27% yield) was prepared from (S)-2-cyclopropyl-2-((1-(2-(hydroxymethyl)-6-methylpyrimidin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid (60 mg, 0.147 mmol) following a procedure analogous to that described in Step 4 of Example 125. 123: LCMS (ESI): _RT (min) = 1.83, [M+H] ⁺ = 409, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.00 (s, 1H), 7.36 (s, 1H), 6.97 (s, 1H), 6.38-6.35 (m, 2H), 5.65 (d, J = 7.2 Hz, 1H), 5.33 (br, 1H), 4.90-4.86 (m, 2H), 4.64 (s, 2H), 4.35-4.32 (m, 2H), 3.15-3.10 (m, 1H), 2.55 (s, 3H),2.31-2.30(m,2H),1.14-1.08(m,1H),0.54-0.48(m,3H),0.30-0.20(m,1H).

Example 124 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide 124

Step 1: Methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 5.15 mmol), methyl 2-bromo-2-methylpropanoate (1.12 g, 6.19 mmol) and potassium carbonate (2.14 g, 15.5 mmol) in DMF (10 mL) was stirred at 90 ° C overnight. The resulting solution was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-20% ethyl acetate/petroleum ether) to give the title compound 0.77 g (51%) as a white solid. LCMS (ESI): [M+H] ⁺ = 295.

Step 2: Methyl 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-methylpropanoate

A mixture of 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine from Example 101 (270 mg, 0.701 mmol), methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (247 mg, 0.841 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (51.3 mg, 0.07 mmol), sodium carbonate (223 mg, 2.10 mmol), water (2 mL) and 1,4-dioxane (6 mL) was heated in a sealed tube under microwave irradiation at 100° C. for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-3% methanol/DCM) to afford 240 mg (72%) of the title compound as a yellow solid. LCMS: [M+H] ⁺ =473.

Step 3: 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-methylpropanamide

A mixture of methyl 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-methylpropanoate (200 mg, 0.423 mmol), formamide (0.500 mL, 11.1 mmol) and sodium methoxide (68.6 mg, 1.27 mmol) in DMF (2 mL) was heated at 80 ° C. for 30 min under microwave irradiation. The solid was filtered off and the filtrate was purified by reverse phase HPLC and lyophilized to afford 89.7 mg (46%) of 124 as an off-white solid. LCMS: R _T (min) = 1.25, [M+H] ⁺ = 458, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 7.96 (s, 1H), 7.58-7.55(m,4H),7.50(d,J＝8.1Hz,1H),7.39(d,J＝8.4Hz,1H),7.18(s,1H), 7.09(s,1H),6.78(s,1H),4.43-4.40(m,2H),4.31-4.28(m,2H),2.40-2.22(m,2H),1.74(s,6H).

Example 125 (S)-2-Cyclopropyl-2-((1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 125

Step 1: N-(8-Bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)pyridazine-4-carboxamide

A mixture of 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine (200 mg, 0.823 mmol) from Example 101, pyridazine-4-carboxylic acid (103 mg, 0.830 mmol), DIPEA (540 mg, 4.178 mmol) and HATU (628 mg, 1.65 mmol) in DMF (20 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 520 mg of the crude title compound, which was used without purification. LCMS (ESI): [M+H] ⁺ =349/351.

Step 2: 4-Bromo-1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of crude N-(8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)pyridazine-4-carboxamide (520 mg) and acetic acid (10 mL) was heated at 80° C. for 0.5 h. The reaction mixture was evaporated in vacuo. The resulting residue was purified via silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) to afford 150 mg (55% over 2 steps) of the title compound as a light brown solid. LCMS (ESI): [M+H] ⁺ = 331/333.

Step 3: (S)-2-Cyclopropyl-2-((1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid

A mixture of 4-bromo-1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (130 mg, 0.393 mmol), (S)-2-amino-2-cyclopropylacetic acid (240 mg, 2.09 mmol), copper(I) iodide (40 mg, 0.210 mmol), and potassium phosphate (430 mg, 2.03 mmol) in DMSO (10 mL) was microwaved in a sealed tube at 120° C. for 1.5 h. The solid was removed by filtration, and the brown filtrate was used without purification. LCMS (ESI): [M+H] ⁺ = 366.

Step 4: (S)-2-Cyclopropyl-2-((1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

A mixture of (S)-2-cyclopropyl-2-((1-(pyridazin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetic acid (crude), DIPEA (1.20 g, 9.29 mmol), ammonium chloride (390 mg, 7.29 mmol) and HATU (276 mg, 0.726 mmol) in DMSO (10 mL) was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified via reverse phase HPLC and lyophilized to afford 14.0 mg (9.7% over 2 steps) of 125 as a yellow solid. LCMS (ESI): R _T (min) = 1.64, [M+H] ⁺ = 365, method = C; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 9.40 (d, J＝5.2Hz,1H),8.11-8.09(m,1H),7.37(s,1H),6.98(s,1H),6.41(s,1H),6.36(s, 1H),5.64(d,J＝7.6Hz,1H),4.41-4.37(m,4H),3.18-3.14(m,1H),2.31-2.30(m, 2H),1.15-1.08(m,1H),0.54-0.48(m,3H),0.35-0.25(m,1H).

Example 126 (S)-2-Cyclopropyl-2-[1-(4-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino]acetamide 126

Step 1: 4-Bromo-8,9-dihydro-2H,7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-thione

A solution of thiophosgene (0.74 mL, 20.1 mmol) in THF (5.0 mL) was added to a solution of 8- bromo-2,3,4,5- tetrahydrobenzo [b] [1,4] oxazepine-6-amine (1.97 g, 8.09 mmol) and triethylamine (2.8 mL, 20.1 mmol) in THF (40 mL) at 0 ° C over 15 minutes. The reaction mixture was stirred at 0 ° C for 15 min, then at room temperature for 30 min, and then evaporated in vacuo. The residual solid was washed with water and then dried in a vacuum oven at 40 ° C to give 2.35 g (quantitative) of the title compound as a white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ12.96 (br s, 1H), 6.91 (d, J = 1.8Hz, 1H), 6.86 (d, J = 1.8Hz, 1H), 4.39-4.37 (m, 2H), 4.12-4.09 (m, 2H), 2.34-2.28(m,2H).

Step 2: 4-Bromo-1-methylsulfanyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

Methyl iodide (1.0 mL, 16.2 mmol) is added to a suspension of 4-bromo-8,9-dihydro-2H,7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-thione (2.35 g, 8.09 mmol) and potassium carbonate (3.35 g, 24.3 mmol) in acetone (35 mL). The reaction mixture is stirred at room temperature for 16 h, then filtered through celite and the filtrate is evaporated in vacuo. The residue is purified by flash chromatography on silica gel (solvent gradient: 20-40% ethyl acetate/toluene) to give 1.83 g (76%) of the title compound as a beige solid. ¹ H NMR (400MHz, CDCl ₃ ) δ7.43 (d, J = 1.7 Hz, 1H), 6.90 (d, J = 1.7 Hz, 1H), 4.35-4.33 (m, 2H), 4.05-4.02 (m, 2H), 2.79 (s, 3H), 2.43-2.37 (m, 2H).

Step 3: 4-Bromo-1-methanesulfonyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A solution of 3-chloroperoxybenzoic acid (3.39 g, about 77 wt%, about 15.1 mmol) in DCM (20 mL) was added to an ice-cooled solution of 4-bromo-1-methylsulfanyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (1.81 g, 6.05 mmol) in DCM (50 mL) over 10 min. Stirring was continued at room temperature for 16 h. The reaction mixture was diluted with DCM and washed with an aqueous solution of sodium metabisulfite. The aqueous phase was extracted with DCM and the combined organic extracts were washed with an aqueous solution of sodium bicarbonate, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 5-25% ethyl acetate/toluene) to give 1.49 g (74%) of the title compound as a colorless foam. ¹ H NMR (400MHz, CDCl ₃ ) δ7.58 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 1.7 Hz, 1H), 4.69-4.66 (m, 2H), 4.42-4.40 (m, 2H), 3.57 (s, 3H), 2.49-2.44 (m, 2H).

Step 4: [1-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidin-4-yl]methanol

A mixture of 4-bromo-1-methanesulfonyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (0.35 g, 1.06 mmol), 4-(hydroxymethyl)piperidine (0.30 g, 2.64 mmol) and DIPEA (0.37 mL, 2.11 mmol) in propan-2-ol (2.0 mL) was heated at 150 ° C for 17 h in a sealed vial under microwave irradiation. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 25-100% ethyl acetate/toluene, then 50-100% methyl acetate/ethyl acetate) to give 0.15 g (39%) of the title compound as a white solid. LCMS(ESI): [M+H] ⁺ =366/368.

Step 5: (S)-cyclopropyl-[1-(4-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ylamino]acetic acid

A mixture of [1-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidin-4-yl]methanol (40 mg, 0.11 mmol), L-cyclopropylglycine (31.5 mg, 0.27 mmol), cuprous iodide (4.2 mg, 0.022 mmol) and potassium phosphate (92.5 mg, 0.436 mmol) in DMSO (0.7 mL) was heated at 100 ° C. for 16 h in a sealed vial. The cooled reaction mixture was diluted with DCM (20 mL) and purified via silica gel flash chromatography (solvent gradient: 5-50% (2N ammonia/methanol)/DCM) to give 28.6 mg (66%) of the title compound as a beige solid. LCMS (ESI): [M+H] ⁺ =401.

Step 6: (S)-2-Cyclopropyl-2-[1-(4-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ylamino]acetamide

To a mixture of (S)-cyclopropyl-[1-(4-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ylamino]acetic acid (28.6 mg, 0.071 mmol), ammonium chloride (7.6 mg, 0.142 mmol), and DIPEA (50 μL, 0.285 mmol) in DMF (0.5 mL) was added HATU (54.3 mg, 0.142 mmol) portionwise over 5 minutes, and the reaction mixture was stirred at room temperature for 10 minutes. The resulting mixture was diluted with DCM (10 mL) and purified via silica gel flash chromatography (solvent gradient: 2-12% (2N ammonia/methanol)/DCM) to afford 11.8 mg (41%) of 126 as a colorless foam. LCMS (ESI): _RT (min) = 2.17, [M+H] ⁺ = 400.2, method = A; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ especially 7.27 (br s, 1H), 6.91 (br s, 1H), 6.21 (d, J = 2.0 Hz, 1H), 6.02 (d, J = 2.0 Hz, 1H), 5.24 (d, J = 7.4 Hz, 1H), 4.49 (t, J = 5.3 Hz, 1H), 4.25-4.23 (m, 2H), 3.89-3.86 (m, 2H), 3.46-3.42 (m, 2H), 3.07 (t, J = 7.7 Hz, 1H), 2.82-2.75 (m, 2H), 2.20-2.15 (m, 2H), 1.76-1.72(m,2H),1.59-1.49(m,1H),1.36-1.26(m,2H),1.12-1.04(m,1H), 0.50-0.42(m,3H),0.30-0.25(m,1H).

Example 127 (S)-2-Cyclopropyl-2-(1-piperidin-1-yl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino)acetamide 127

Step 1: 4-Bromo-1-piperidin-1-yl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of 4-bromo-1-methanesulfonyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (0.35 g, 1.06 mmol) and piperidine (5.0 mL) was heated at 150 ° C for 5 h in a sealed vial under microwave irradiation. The reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 10-40% ethyl acetate/toluene) to give 0.27 g (77%) of the title compound as a colorless solid. LCMS (ESI): [M+H] ⁺ =336/338.

127 was prepared following the procedure of Example 126. LCMS (ESI): _RT (min) = 2.50, [M+H] ⁺ = 370.1, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ) δ esp 7.27 (br s, 1H), 6.91 (br s, 1H), 6.21 (d, J = 2.0 Hz, 1H), 6.02 (d, J = 2.0 Hz, 1H), 5.24 (d, J = 7.5 Hz, 1H), 4.25-4.23 (m, 2H), 3.89-3.87 (m, 2H), 3.10-3.07 (m, 4H), 2.20-2.15 (m, 2H), 1.67-1.62(m,4H),1.59-1.53(m,2H),1.12-1.04(m,1H),0.50-0.42(m,3H), 0.30-0.25(m,1H).

Example 128 (S)-2-cyclopropyl-2-((1-(2-methoxypyrimidin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 128

128 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.55, [M+H] ⁺ = 395, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 7.33 (s, 1H), 6.95 (s, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.28 (d, J = 1.9 Hz, 1H), 5.51 (d, J = 7.4 Hz, 1H), 4.39-4.30 (m, 2H), 4.30-4.20 (m, 2H), 4.01 (s, 2H), 3.15 (t, J = 7.7 Hz, 1H), 2.31-2.22 (m, 2H), 1.18-1.04(m,1H),0.57-0.41(m,3H),0.35-0.25(m,1H).

Example 129 (S)-2-Cyclopropyl-2-((1-(1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 129

129 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.89, [M+H] ⁺ = 395, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.15 (d, J = 10.0 Hz, 1H), 7.34 (s, 1H), 7.06 (d, J = 9.8 Hz, 1H), 6.95 (s, 1H), 6.34 (dd, J = 21.7, 2.1 Hz, 2H), 5.59 (d, J = 7.2 Hz, 1H), 4.59 (t, J = 5.7 Hz, 2H), 4.34 (t, J = 4.6 Hz, 2H), 3.76 (s, 3H), 3.13 (t, J = 7.7 Hz, 1H),2.34-2.25(m,2H),1.18-1.04(m,1H),0.57-0.43(m,3H),0.40-0.25(m,1H).

Example 130 (S)-2-((1-(5-chloro-6-methoxypyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 130

130 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 3.15, [M+H] ⁺ = 428, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 7.33 (s, 1H), 6.95 (s, 1H), 6.37 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 1.9 Hz, 1H), 5.50 (d, J = 7.4 Hz, 1H), 4.32 (t, J = 4.7 Hz, 2H), 4.29-4.17 (m, 2H), 4.03 (s, 2H), 3.28 (s, 1H), 3.14(t,J＝7.7Hz,1H),2.30-2.22(m,2H),1.18-1.04(m,1H),0.57-0.42(m,3H), 0.35-0.25(m,1H).

Example 131 (S)-2-Cyclopropyl-2-((1-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 131

Step 1: 4-Bromo-1-(2-(chloromethyl)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

2-Chloro-1,1,1-triethoxyethane (0.53 g, 2.71 mmol) was added to a solution of 2-amino-4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)phenol (0.800 g, 2.22 mmol) in acetic acid (10 mL). The reaction mixture was heated at 120 ° C for 3 h. The solid was filtered off and the filtrate was evaporated in vacuo. The residue was dissolved in ethyl acetate and then diluted with petroleum ether. The precipitated solid was collected by filtration to give the crude title compound, which was used without purification. ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.25(s, 1H),8.00(d,J＝8.3Hz,1H),7.80(d,J＝8.5Hz,1H),7.50(s,1H),6.95(s,1H),5.15(s, 2H),4.50-4.44(m,2H),4.40-4.33(m,2H),2.40-2.30(m,2H).

Step 2: 6-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one

Lithium hydroxide (0.040 g, 0.950 mmol) was added to a solution of 4-bromo-1-(2-(chloromethyl)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (200 mg, 0.480 mmol) in THF (10 mL) and water (2 mL). The resulting mixture was stirred at 25 ° C for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 80 mg (42%) of the title compound as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 10.89 (s, 1H), 7.43 (s, 1H), 7.38-7.33 (m, 2H), 7.11 (d, J = 8.1Hz, 1H), 6.90 (s, 1H), 4.68(s,2H),4.45-4.42(m,2H),4.31-4.27(m,2H),2.31-2.20(m,2H).

Step 3: (S)-2-Cyclopropyl-2-((1-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 131

A mixture of 6-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (150 mg, 0.380 mmol), (S)-2-amino-2-cyclopropylacetic acid (216 mg, 1.88 mmol), copper(I) iodide (36.0 mg, 0.190 mmol) and potassium phosphate (477 mg, 2.25 mmol) in DMSO (6 mL) was degassed with nitrogen under ultrasonic conditions. The reaction mixture was heated at 100 ° C for 2 hours and then cooled to room temperature. The solid was removed by filtration and the filtrate was diluted with DMSO (2 mL). Ammonium chloride (370 mg, 6.92 mmol), HATU (263 mg, 0.690 mmol) and DIPEA (1.12 g, 8.63 mmol) were added and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to give 11.9 mg (8%) of 131 as a white solid. LCMS (ESI): R _T (min) = 1.23, [M+H] ⁺ = 434, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.84 (s, 1H), 7.37-7.26 (m, 3H), 7.12-7.03 (m, 1H), 6.95 (d, J = 2.3Hz, 1H),6.35(d,J＝2.0Hz,1H),6.23(d,J＝2.0Hz,1H),5.47(d,J＝7.4Hz,1H),4.66(s, 2H),4.37-4.27(m,2H),4.20-4.16(m,2H),3.16-3.10(m,1H),2.23-2.12(m,2H), 1.11-1.09(m,1H),0.58-0.39(m,3H),0.31-0.28(m,1H).

Example 132 (S)-2-((1-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 132

132 was prepared following the procedure of Example 116. LCMS (ESI): _RT (min) = 1.25, [M+H] ⁺ = 404, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.09-9.07 (d, J = 7.2 Hz, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 7.61 (d, J = 6.9 Hz, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 6.41 (d, J = 2.8 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 5.57 (d, J = 7.5 Hz, 1H), 4.40-4.35 (m, 4H), 3.19-3.14 (m, 1H), 2.40-2.20(m,2H),1.19-1.02(m,1H),0.52-0.47(m,3H),0.31-0.30(m,1H).

Example 133 (S)-2-((1-(1H-indazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 133

133 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.39, [M+H] ⁺ = 403, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 13.33 (s, 1H), 8.20 (d, J = 8.4 Hz, 2H), 7.76-7.67 (m, 2H), 7.36 (s, 1H), 6.98 (s, 1H), 6.38 (s, 1H), 6.27 (s, 1H), 5.59 (br, 1H), 4.45-4.30 (m, 2H), 4.29-4.15 (m, 2H), 3.17-3.12 (m, 1H), 2.35-2.18 (m, 2H), 1.14-1.08(m,1H),0.51-0.44(m,3H),0.35-0.25(m,1H).

Example 134 (S)-2-Cyclopropyl-2-((1-(pyrimidin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 134

134 was prepared following the procedure of Example 125. LCMS (ESI): R _T (min) = 1.59, [M+H] ⁺ = 365, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 9.21 (s, 2H), 7.35 (s, 1H), 6.97(s,1H),6.39(d,J＝2.0Hz,1H),6.31(d,J＝2.0Hz,1H),5.58(d,J＝7.4Hz,1H), 4.33-4.32(m,4H),3.16-3.11(m,1H),2.35-2.15(m,2H),1.13-1.07(m,1H), 0.52-0.44(m,3H),0.38-0.25(m,1H).

Example 135 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 135

135 was prepared following the procedure of Example 104. LCMS (ESI): _RT (min) = 2.04, [M+H] ⁺ = 419, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.55 (s, 2H), 7.51 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.34-7.30 (m, 2H), 6.96 (s, 1H), 6.36 (d, J = 1.8 Hz, 1H), 6.22 (d, J = 1.8 Hz, 1H), 5.44 (d, J = 7.2 Hz, 1H), 4.33-4.30 (m, 2H), 4.20-4.10 (m, 2H), 3.16-3.11(m,1H),2.35-2.15(m,2H),1.13-1.08(m,1H),0.52-0.46(m,3H), 0.40-0.25(m,1H).

Example 136 (S)-2-Cyclopropyl-2-((1-(thiazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 136

136 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.83, [M+H] ⁺ = 370.0, method = D; ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.26 (s, 1H), 8.45 (s, 1H), 7.36 (s, 1H), 6.97 (s, 1H), 6.35 (s, 1H), 6.28 (s, 1H), 5.63 (br s, 1H), 4.45-4.43 (m, 2H), 4.37-4.34 (m, 2H), 3.20-3.11 (m, 1H), 2.40-2.30 (m, 2H), 1.18-1.05 (m, 1H), 0.58-0.43 (m, 3H), 0.33-0.28 (m, 1H).

Example 137 (S)-2-Cyclopropyl-2-((1-(4-(methylsulfonyl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 137

Step 1: 4-Bromo-1-(4-(methylsulfonyl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

To a mixture of 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine (176.7 mg, 0.7269 mmol) from Example 101, 4-methylsulfonylbenzoic acid (151.8 mg, 0.7582 mmol), DIPEA (0.35 mL, 2.0 mmol), and DMF (3.0 mL, 39 mmol) was added HATU (374.1 mg, 0.964 mmol). The reaction mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with ethyl acetate, washed with water (3×) and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The resulting residue was dissolved in acetic acid (2.0 mL, 35 mmol) and heated at 90°C for 1 h. The reaction mixture was cooled to room temperature, and the acetic acid was removed under vacuum. The resulting residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield 243.6 mg (82%) of the title compound. LCMS (ESI): [M+H] ⁺ =406.95; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ, inter alia, 8.19-8.04 (m, 4H), 7.51 (d, J=1.8 Hz, 1H), 6.96 (d, J=1.8 Hz, 1H), 4.53-4.42 (m, 2H), 4.40-4.32 (m, 2H), 2.39-2.28 (m, 2H).

Step 2: (S)-2-Cyclopropyl-2-((1-(4-(methylsulfonyl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

To a mixture of 4-bromo-1-(4-(methylsulfonyl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (242.6 mg, 0.5956 mmol), (2S)-2-amino-2-cyclopropyl-acetic acid (141 mg, 1.22 mmol), potassium phosphate (398 mg, 1.8375 mmol), and DMSO (2.0 mL, 28 mmol) was added copper (I) iodide (67.9 mg, 0.357 mmol). The reaction mixture was heated at 120° C. under microwave irradiation for 2 h. To the crude reaction mixture were added triethylamine (0.35 mL, 2.5 mmol), ammonium chloride (130.3 mg, 2.44 mmol), and HATU (933 mg, 2.40 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, washed with water (2x) and brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (12 g silica gel, solvent gradient: 0-10% methanol/DCM) and further purified by preparative HPLC and lyophilized to afford 17.1 mg (6.5%) of 137. LCMS (ESI): R _T (min) = 2.74, [M+H] ⁺ = 441.2, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.13-7.98(m,4H),7.34(d,J＝2.5Hz,1H),6.95(d,J＝2.4Hz,1H),6.40(d,J＝2.0Hz, 1H),6.30(d,J＝2.0Hz,1H),5.54(d,J＝7.4Hz,1H),4.35(t,J＝4.7Hz,2H), 4.31-4.21(m,2H),3.30(s,3H),3.15(t,J＝7.8Hz,1H),2.31-2.19(m,2H), 1.16-1.05(m,1H),0.56-0.41(m,3H),0.35-0.24(m,1H).

Example 138 (S)-2-Cyclopropyl-2-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 138

Step 1: 4-Bromo-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

To a solution of 8-bromo-2,3,4,5-tetrahydro-1,5-benzoxazepine-6-amine (120.4 mg, 0.495 mmol), 2,3-dihydro-1,4-benzodioxine-6-carboxylic acid (80.0 mg, 0.431 mmol), and DIPEA (111.3 mg, 0.861 mmol) in DMF (4 mL) was added HATU (334.2 mg, 0.861 mmol). The reaction was sealed in a vial under nitrogen and stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and evaporated in vacuo. The resulting residue was purified by flash chromatography (solvent gradient: 0-80% ethyl acetate/heptane) to give 120 mg (72%) of the title compound. LCMS (ESI): [M+H] ⁺ = 387.

Step 2: (S)-2-Cyclopropyl-2-((1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

To a suspension of 4-bromo-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (42 mg, 0.109 mmol), potassium phosphate (118 mg, 0.54 mmol), and (2S)-2-amino-2-cyclopropyl-acetic acid (49.95 mg, 0.434 mmol) in DMSO (1.00 mL) was added cuprous iodide (12.4 mg, 0.065 mmol). The reaction was sealed in a vial under nitrogen and heated at 120° C. under microwave irradiation for 2 h. The resulting mixture was treated with 5 mL of DMSO, followed by triethylamine (110 mg, 1.09 mmol), ammonium chloride (58.0 mg, 1.09 mmol), and HATU (421 mg, 1.09 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic fractions were washed with water and brine, then dried over magnesium sulfate, filtered, and evaporated in vacuo. The resulting crude residue was purified via silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) to afford 9.2 mg (20%) of 138. LCMS (ESI): R _T (min) = 2.98, [M+H] ⁺ = 421.2, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.31 (s, 1H), 7.25-7.17 (m, 2H), 6.99 (d, J = 8.2Hz, 1H), 6.94(s,1H),6.34(d,J＝2.0Hz,1H),6.22(d,J＝1.9Hz,1H),5.43(d,J＝7.3Hz,1H), 4.36-4.26(m,6H),4.24-4.12(m,2H),3.13(t,J＝7.7Hz,1H),2.28-2.18(m,2H), 1.17-1.04(m,1H),0.56-0.41(m,3H),0.35-0.24(m,1H).

Example 139 (S)-2-[1-((R)-3-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino]propanamide 139

Step 1: [(R)-1-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidin-3-yl]methanol

A mixture of 4-bromo-1-methanesulfonyl-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (0.305 g, 0.92 mmol), (R)-1-piperidin-3-ylmethanol (0.212 g, 1.84 mmol) and N,N-diisopropylethylamine (0.319 mL, 1.84 mmol) in propan-2-ol (2.0 mL) was heated at 150 ° C for 17 hours in a sealed vial under microwave irradiation. The reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 25-100% ethyl acetate/toluene, then 50-100% methyl acetate/ethyl acetate) to give 71 mg (21%) of the title compound as a white solid. LCMS(ESI): [M+H] ⁺ =366/368.

Step 2: (S)-2-[1-((R)-3-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ylamino]propanoic acid

A mixture of [(R)-1-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidin-3-yl]methanol (51 mg, 0.139 mmol), L-alanine (31.1 mg, 0.349 mmol), cuprous iodide (5.4 mg, 0.028 mmol) and potassium phosphate (118 mg, 0.556 mmol) in dimethyl sulfoxide (0.5 mL) was heated at 100 ° C. for 3 hours in a sealed vial. The cooled reaction mixture was diluted with dichloromethane (10 mL) and purified via silica gel flash chromatography (solvent gradient: 5-50% (2N ammonia/methanol)/dichloromethane) to give the title compound (quantitative) as a beige solid. LCMS (ESI): [M+H] ⁺ = 375.

Step 3: (S)-2-[1-((R)-3-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ylamino]propanamide

To a mixture of (S)-2-[1-((R)-3-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ylamino]propanoic acid (0.139 mmol), ammonium chloride (14.9 mg, 0.278 mmol) and N,N-diisopropylethylamine (96.4 μL, 0.556 mmol) in N,N-dimethylformamide (0.75 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (105.6 mg, 0.278 mmol) portionwise over 5 minutes and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with dichloromethane (15 mL) and purified via silica gel flash chromatography (solvent gradient: 2-12% (2N ammonia/methanol)/dichloromethane) to afford 39 mg (75% over 2 steps) of a colorless foam. This partially epimerized material was separated into the pure diastereomers by SFC (Amylose-C and methanol/ _CO₂ as eluents). The later-eluting diastereomer was 139 (24.6 mg). LCMS (ESI): R _T (min) = 2.01, [M+H] ⁺ = 374.2, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.22 (br s, 1H), 6.89 (br s, 1H), 6.21 (d, J = 2.0Hz, 1H), 6.00 (d, J = 2.0Hz, 1H),5.23(d,J＝7.4Hz,1H),4.53(t,J＝5.3Hz,1H),4.26-4.24(m,2H),3.94-3.84(m, 2H),3.65(pent,J=7.1Hz,1H),3.46-3.42(m,1H),3.39-3.29(m,2H),2.82-2.76(m, 1H), 2.64-2.59 (m, 1H), 2.21-2.16 (m, 2H), 1.83-1.58 (m, 4H), 1.28 (d, J = 6.9Hz, 3H), 1.18-1.08 (m, 1H).

Example 140 (S)-2-[1-(4-hydroxymethylpiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino]propanamide 140

140 was prepared following the procedure of Example 139. LCMS (ESI): _RT (min) = 1.94, [M+H] ⁺ = 374.2, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ) δ esp 7.21 (br s, 1H), 6.89 (br s, 1H), 6.21 (d, J = 2.0 Hz, 1H), 6.00 (d, J = 2.0 Hz, 1H), 5.23 (d, J = 7.4 Hz, 1H), 4.49 (t, J = 5.3 Hz, 1H), 4.26-4.24 (m, 2H), 3.90-3.87 (m, 2H), 3.65 (pent, J = 7.1 Hz, 1H),3.47-3.42(m,2H),2.83-2.75(m,2H),2.21-2.16(m,2H),1.76-1.71(m,2H), 1.60-1.50(m,1H),1.36-1.27(m,1H),1.28(d,J＝6.9Hz,3H).

Example 141 (S)-2-cyclopropyl-2-((1-morpholino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 141

Step 1: 4-Bromo-1-morpholino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (500mg, 1.32mmol) and morpholine (2.30g, 26.39mmol) in DMF (15mL) was heated at 140 ° C for 2h in a sealed tube under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 110mg (25%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =338/340.

Step 2: (S)-2-Cyclopropyl-2-((1-morpholino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid

The title compound (110 mg, 50%) was prepared from 4-bromo-1-morpholino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (200 mg, 0.590 mmol) following a procedure similar to that of Example 125, Step 3. LCMS (ESI): [M+H] ⁺ =373.

Step 3: (S)-2-Cyclopropyl-2-((1-morpholino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (21.9 mg, 22%) was prepared from (S)-2-cyclopropyl-2-((1-morpholino-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid (100 mg, 0.27 mmol) following a procedure analogous to that of Example 125, step 4. 141: LCMS (ESI): R _T (min) = 1.61, [M+H] ⁺ = 372, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.29 (s, 1H), 6.93 (s, 1H), 6.23 (d, J = 1.8Hz, 1H),6.05(d,J＝1.8Hz,1H),5.29(d,J＝7.2Hz,1H),4.27-4.24(m,2H),3.95-3.91(m, 2H),3.75-3.72(m,4H),3.14-3.05(m,5H),2.22-2.10(m,2H),1.11-1.05(m,1H), 0.51-0.44(m,3H),0.39-0.19(m,1H).

Example 142 (S)-2-cyclopropyl-2-((1-(oxazol-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 142

142 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.16, [M+H] ⁺ = 354, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.36 (s, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 6.98 (s, 1H), 6.38-6.35 (m, 2H), 5.65 (d, J = 7.2 Hz, 1H), 4.72-4.68 (m, 2H), 4.35-4.32 (m, 2H), 3.16-3.11 (m, 1H), 2.33-2.27 (m, 2H), 1.14-1.11 (m, 1H), 0.53-0.50 (m, 3H), 0.35-0.24 (m, 1H).

Example 143 (S)-2-Cyclopropyl-2-((1-(3-(difluoromethoxy)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 143

143 was prepared following the procedure of Example 125. LCMS (ESI): R _T (min) = 1.54, [M+H] ⁺ = 429, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.65-7.10 (m, 6H), 6.95 (s, 1H), 6.38 (d, J＝1.8Hz,1H),6.27(d,J＝1.8Hz,1H),5.50(d,J＝7.5Hz,1H),4.34-4.31(m,2H), 4.30-4.15(m,2H),3.17-3.12(m,1H),2.35-2.15(m,2H),1.14-1.08(m,1H), 0.53-0.47(m,3H),0.35-0.25(m,1H).

Example 144 (S)-2-Cyclopropyl-2-((1-(2-fluoro-4-methoxyphenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 144

144 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.46, [M+H] ⁺ = 411, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.54-7.52 (m, 1H), 7.34 (s, 1H), 7.06-7.02 (m, 1H), 6.97-6.95 (m, 2H), 6.38 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 5.49 (d, J = 7.5 Hz, 1H), 4.35-4.28 (m, 2H), 4.01-3.93 (m, 2H), 3.86 (s, 3H), 3.17-3.13(m,1H),2.23-2.22(m,2H),1.15-1.09(m,1H),0.53-0.45(m,3H), 0.34-0.30(m,1H).

Example 145 (S)-2-Cyclopropyl-2-((1-(2,4-difluorophenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 145

145 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.78, [M+H] ⁺ = 399, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.72-7.66 (m, 1H), 7.54-7.46 (m, 1H), 7.34-7.26 (m, 2H), 6.96 (s, 1H), 6.38 (d, J = 1.8 Hz, 1H), 6.29 (d, J = 2.1 Hz, 1H), 5.52 (d, J = 7.5 Hz, 1H), 4.33-4.30 (m, 2H), 3.99-3.95 (m, 2H), 3.17-3.12 (m, 1H), 2.35-2.15(m,2H),1.14-1.17(m,1H),0.53-0.49(m,3H),0.33-0.29(m,1H).

Example 146 (S)-3-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzamide 146

146 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 0.713, [M+H] ⁺ = 406, method = F; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 8.13 (s, 1H), 8.04-8.01 (m, 1H), 7.93-7.90 (m, 1H), 7.66-7.61 (m, 1H), 7.50 (s, 1H), 7.35 (s, 1H), 6.97 (s, 1H), 6.40 (s, 1H), 6.28 (s, 1H), 5.50 (d, J = 7.5 Hz, 1H), 4.36-4.34 (m, 2H), 4.29-4.24(m,2H),3.19-3.14(m,1H),2.27-2.25(m,2H),1.16-1.07(m,1H), 0.55-0.45(m,3H),0.33-0.31(m,1H).

Example 147 (S)-2-Cyclopropyl-2-((1-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 147

147 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.45, [M+H] ⁺ = 394, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 7.67 (s, 1H), 7.32 (s, 1H), 6.95 (s, 1H), 6.37 (s, 1H), 6.26 (s, 1H), 5.50 (s, 1H), 4.52-4.45 (m, 2H), 4.36-4.26 (m, 4H), 4.26-4.15 (m, 2H), 3.14 (t, J = 7.7 Hz, 1H), 2.30-2.20 (m, 2H), 1.18-1.04 (m, 1H),0.57-0.41(m,3H),0.35-0.25(m,1H).

Example 148 (S)-2-Cyclopropyl-2-((1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 148

148 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.65, [M+H] ⁺ = 422, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 7.67 (s, 1H), 7.32 (s, 1H), 6.95 (s, 1H), 6.37 (s, 1H), 6.26 (s, 1H), 5.50 (s, 1H), 4.52-4.45 (m, 2H), 4.36-4.26 (m, 4H), 4.26-4.15 (m, 2H), 3.14 (t, J = 7.7 Hz, 1H), 2.30-2.20 (m, 2H), 1.18-1.04 (m, 1H),0.57-0.41(m,3H),0.35-0.25(m,1H).

Example 149 (S)-2-((1-(2-amino-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 149

149 was prepared following the procedure of Example 161. LCMS (ESI): _RT (min) = 1.89, [M+H] ⁺ = 421, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.22 (s, 1H), 7.27 (s, 1H), 6.91 (s, 1H), 6.66 (s, 2H), 6.18 (s, 1H), 5.96 (s, 1H), 5.23-5.21 (d, J = 7.2 Hz, 1H), 4.75 (s, 2H), 4.67 (s, 2H), 4.28-4.25 (m, 2H), 4.15-4.05 (m, 2H), 3.10-3.05 (m, 1H), 2.35-2.15 (m, 2H),1.14-1.04(m,1H),0.50-0.46(m,3H),0.44-0.42(m,1H).

Example 150 (S)-2-Cyclopropyl-2-((1-(4-(difluoromethoxy)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 150

Step 1: 4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

4-Methylbenzenesulfonic acid (354 mg, 2.06 mmol) was added to a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-amine (5.00 g, 20.6 mmol) from Example 101 in triethyl orthoformate (60 mL) and the reaction mixture was heated at 100° C. for 16 h. The reaction mixture was evaporated in vacuo and the resulting residue was purified by silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) to give 4.20 g (81%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =253/255; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.27 (s, 1H), 7.43 (d, J = 1.8Hz, 1H), 6.89 (d, J = 1.8Hz, 1H),4.40-4.31(m,4H),2.35-2.28(m,2H).

Step 2: 4-Bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

Lithium diisopropylamide (LDA) (2M, 16 mL, 32 mmol) in anhydrous THF was added dropwise to a solution of 4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (4.00 g, 15.8 mmol) in anhydrous THF at -78 ° C and the reaction mixture was stirred at -78 ° C for 1 h. N-iodosuccinimide (5.33 g, 23.7 mmol) was added to the mixture at -78 ° C and the resulting mixture was stirred at -78 ° C for 1 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the filtrate was evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-25% ethyl acetate/petroleum ether) to give 3.68 g (62%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 379/381; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.38-7.37 (d, J = 1.8Hz, 1H), 6.89 (d, J = 1.8Hz, 1H), 4.40-4.37 (m, 2H), 4.22-4.18 (m, 2H), 2.40-2.34(m,2H).

Step 3: 4-Bromo-1-(4-(difluoromethoxy)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (500 mg, 1.3 mmol), 4-(difluoromethoxy)phenylboronic acid (250 mg, 1.33 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (100 mg, 0.13 mmol), potassium acetate (2M aqueous solution, 2.50 mL, 5.00 mmol) and sodium carbonate (2M aqueous solution, 2.5 mL, 5.00 mmol) in acetonitrile (10 mL) was heated at 80 ° C for 20 min under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 160 mg (31%) of the title compound as an off-white solid. LCMS(ESI): [M+H] ^{+ =} 395/397.

Step 4: (S)-2-Cyclopropyl-2-((1-(4-(difluoromethoxy)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (25.5 mg, 16%) was prepared from 4-bromo-1-(4-(difluoromethoxy)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (150 mg, 0.380 mmol) following procedures similar to those in Example 125, Steps 3-4. 150: LCMS (ESI): R _T (min) = 1.65, [M+H] ⁺ = 429, method = D; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.84-7.81 (m, 2H), 7.56-7.19 (m, 4H), 6.96 (s, 1H), 6.38(d,J＝2.0Hz,1H),6.26(d,J＝2.0Hz,1H),5.49(d,J＝7.4Hz,1H),4.37-4.30(m, 2H),4.23-4.19(m,2H),3.33-3.13(m,1H),2.27-2.24(m,2H),1.18-1.05(m,1H), 0.58-0.43(m,3H),0.36-0.26(m,1H).

Example 151 (S)-4-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)pyridine-2-carboxamide 151

151 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.12, [M+H] ⁺ = 407, method = E; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.79 (d, J = 5.2 Hz, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 8.01-7.99 (d, J = 5.2 Hz, 1H), 7.78 (s, 1H), 7.35 (s, 1H), 6.96 (s, 1H), 6.42 (d, J = 2.0 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H), 5.58 (d, J = 7.2 Hz, 1H), 4.45-4.25 (m, 4H),3.19-3.15(m,1H),2.34-2.30(m,2H),1.15-1.10(m,1H),0.54-0.50(m,3H), 0.35-0.25(m,1H).

Example 152 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)ethanol 152

152 was prepared following the procedure of Example 124. LCMS (ESI): _RT (min) = 2.41, [M+H] ⁺ = 417, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.14 (s, 1H), 7.88 (s, 1H), 7.58 (app s 3H), 7.51-7.47 (m, 2H), 7.40-7.37 (m, 1H), 7.00 (s, 1H), 4.93 (br, 1H), 4.50-4.35 (m, 2H), 4.31-4.28 (m, 2H), 4.17-4.13 (m, 2H), 3.79-3.76 (m, 2H), 2.40-2.25 (m, 2H).

Example 153 5-(4-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine 153

153 was prepared following the procedure of Example 124. LCMS (ESI): _RT (min) = 2.38, [M+H] ⁺ = 387, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.11 (s, 1H), 7.85 (s, 1H), 7.57 (app. s, 3H), 7.50-7.45 (m, 2H), 7.39-7.37 (d, J = 8.1 Hz, 1H), 6.99 (s, 1H), 4.42-4.39 (m, 2H), 4.30-4.27 (m, 2H), 3.85 (s, 3H), 2.37-2.24 (m, 2H).

Example 154 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)-1H-pyrazol-1-yl)-N,2-dimethylpropanamide 154

154 was prepared following the procedure of Example 124. LCMS (ESI): _RT (min) = 1.34, [M+H] ⁺ = 472, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.31 (s, 1H), 7.96 (s, 1H), 7.58-7.55 (m, 4H), 7.49 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.29-7.28 (m, 1H), 7.09 (s, 1H), 4.46-4.37 (m, 2H), 4.32-4.28 (m, 2H), 2.57 (d, J = 4.5 Hz, 3H), 2.40-2.20 (m, 2H), 1.73 (s, 6H).

Example 155 (S)-2-Cyclopropyl-2-((1-(2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 155

155 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.74, [M+H] ⁺ = 420, method = C; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 11.76 (br, 1H), 7.59 (s, 1H), 7.50-7.48 (m, 1H), 7.35 (s, 1H), 7.16 (d, J = 8.1 Hz, 1H), 6.94 (s, 1H), 6.36 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.44 (d, J = 7.4 Hz, 1H), 4.33-4.31 (m, 2H), 4.25-4.18 (m, 2H), 3.17-3.13(m,1H),2.34-2.25(m,2H),1.14-1.09(m,1H),0.57-0.42(m,3H), 0.35-0.25(m,1H).

Example 157 (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2-fluorobenzamide 157

157 was prepared following the procedure of Example 164. LCMS (ESI): _RT (min) = 1.24, [M+H] ⁺ = 424, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.00-7.98 (m, 1H), 7.90-7.86 (m, 2H), 7.74 (s, 1H), 7.48-7.42 (m, 1H), 7.33 (s, 1H), 6.96 (s, 1H), 6.38 (d, J = 1.8 Hz, 1H), 6.26 (d, J = 2.1 Hz, 1H), 5.49 (d, J = 7.2 Hz, 1H), 4.34-4.33 (m, 2H), 4.22-4.20 (m, 2H), 3.19-3.10(m,1H),2.35-2.15(m,2H),1.14-1.08(m,1H),0.53-0.47(m,3H), 0.31-0.29(m,1H).

Example 158 (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2-methoxybenzoic acid methyl ester 158

Step 1: Methyl 5-bromo-2-methoxybenzoate

Trimethylsilyldiazomethane (2M solution in hexanes, 40 mL, 80.0 mmol) was added to a solution of 5-bromo-2-methoxybenzoic acid (5.00 g, 21.6 mmol) in methanol (100 mL) at 0°C and the resulting solution was stirred at room temperature for 4 h. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel flash chromatography (solvent gradient: 0-20% ethyl acetate/petroleum ether) to give 5.26 g (99%) of the title compound as a white solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.58-7.54 (d, J=9.0 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 3.90 (s, 6H).

Step 2: Methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A mixture of methyl 5-bromo-2-methoxybenzoate (2.09 g, 8.53 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.10 g, 12.2 mmol), potassium acetate (2.59 g, 26.4 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (600 mg, 0.820 mmol) in 1,4-dioxane (40 mL) was stirred at 80 ° C under a nitrogen atmosphere for 2.5 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% ethyl acetate/petroleum ether) to give 2.20 g (88.3%) of the title compound as a yellow solid. ¹ H NMR (300MHz, CDCl ₃ ) δ 8.23 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 1.35 (s, 12H).

Step 3: Methyl 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-2-methoxybenzoate

The title compound (241 mg, 49%) was prepared from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (450 mg, 1.19 mmol) and methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (418 mg, 1.43 mmol) following a procedure similar to that described in Step 3 of Example 150. LCMS (ESI): [M+H] ⁺ = 417/419.

Step 4: (S)-2-cyclopropyl-2-((1-(4-methoxy-3-(methoxycarbonyl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid

A mixture of methyl 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2-methoxybenzoate (340 mg, 0.815 mmol), (S)-2-amino-2-cyclopropylacetic acid (460 mg, 3.99 mmol), copper(I) iodide (193 mg, 1.01 mmol), and potassium phosphate (1.02 g, 4.81 mmol) in DMSO (10 ml) was heated in a sealed tube at 110° C. under a nitrogen atmosphere for 2 h under microwave irradiation. The reaction mixture was filtered and the filtrate was purified via reverse phase flash chromatography (solvent gradient: 0-100% methanol/water) to give 310 mg (84.2%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 452.

Step 5: (S)-methyl 5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-2-methoxybenzoate

Ammonium chloride (729 mg, 13.6 mmol) was added to a solution of (S)-2-cyclopropyl-2-((1-(4-methoxy-3-(methoxycarbonyl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetic acid (310 mg, 0.687 mmol), DIPEA (2.22 g, 17.2 mmol) and HATU (522 mg, 1.373 mmol) in DMF (15 mL) and the resulting mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and the filtrate evaporated in vacuo. The residue was purified via reverse phase HPLC and lyophilized to give 9.0 mg (3%) of 158 as a white solid. LCMS (ESI): _RT (min) = 2.378, [M+H] ⁺ = 451, method = C; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.37-7.29 (m, 2H), 6.95 (s, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.48 (d, J = 7.4 Hz, 1H), 4.35-4.33 (m, 2H), 4.22-4.21 (m, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.17-3.13 (m, 1H), 2.27-2.26(m,2H),1.14-1.09(m,1H),0.53-0.45(m,3H),0.34-0.29(m,1H).

Example 159 (S)-2-Cyclopropyl-2-((1-(2-(methylsulfonyl)pyridin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 159

Following the procedure of Example 125, 159 was prepared. LCMS (ESI): _RT (min) = 1.32, [M+H] ⁺ = 442, method = C; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (d, J = 6.8 Hz, 1H), 8.41 (s, 1H), 8.17 (d, J = 5.1 Hz, 1H), 7.37 (s, 1H), 6.98 (s, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.36 (d, J = 2.1 Hz, 1H), 5.63 (d, J = 9.6 Hz, 1H), 4.43-4.37 (m, 4H), 3.37 (s, 3H), 3.20-3.15 (m, 1H),2.40-2.25(m,2H),1.16-1.10(m,1H),0.55-0.46(m,3H),0.33-0.32(m,1H).

Example 160 (S)-2-cyclopropyl-2-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino]acetamide 160

Step 1: (6-Amino-8-bromo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)(1,3-dimethyl-1H-pyrazol-4-yl)methanone and N-(8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide

To a mixture of 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (231 mg, 1.65 mmol) and DIPEA (0.32 mL, 1.82 mmol) in DCM (6.0 mL) was added methanesulfonyl chloride (0.14 mL, 1.82 mmol) at 0 ° C under nitrogen and the resulting mixture was stirred at 0 ° C for 15 min. Another portion of DIPEA (0.32 mL, 1.82 mmol) was added at 0 ° C, and the resulting mixture was then added to a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine (365 mg, 1.50 mmol) from Example 101 in DCM (6.0 mL) at 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C for 30 min and then diluted with water. The organic extract was dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel flash chromatography (solvent gradient: 0-5% methanol/DCM) to give 458 mg (84%, approximately 2:1 mixture of isomers) of the title compound as a beige foam. LCMS (ESI): [M+H] ⁺ =365/367.

Step 2: 4-Bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of (6-amino-8-bromo-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)(1,3-dimethyl-1H-pyrazol-4-yl)methanone and N-(8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)-1,3-dimethyl-1H-pyrazole-4-carboxamide (348 mg, 0.95 mmol) in acetic acid (3.0 mL) was heated at 120° C. for 15 min under microwave irradiation. The reaction mixture was evaporated in vacuo and the crude residue was purified via silica gel flash chromatography (solvent gradient: 0-8% methanol/DCM) to give 237 mg (72%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 347/349.

Step 3: (S)-2-Cyclopropyl-2-[1-(1,3-dimethyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ylamino]acetamide

A mixture of 4-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (100 mg, 0.58 mmol), L-cyclopropylglycine (66 mg, 0.58 mmol), cuprous iodide (11 mg, 0.06 mmol) and potassium phosphate (123 mg, 0.58 mmol) in DMSO (1.0 mL) was degassed with argon under ultrasonic conditions. The reaction mixture was heated at 100 ° C for 18 h and then cooled to room temperature. Ammonium chloride (93 mg, 1.16 mmol) and triethylamine (404 μL, 2.90 mmol) were added to the resulting mixture, followed by portion-wise addition of HATU (441 mg, 1.16 mmol) and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with aqueous ammonium hydroxide solution and extracted with DCM. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified by silica gel flash chromatography (solvent gradient: 0-15% methanol/DCM) to afford 20 mg (18%) of 160 as an off-white solid. LCMS (ESI): _RT (min) = 2.29, [M+H] ⁺ = 381.2, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 7.32 (s, 1H), 6.94 (s, 1H), 6.33 (d, J = 2.0 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 5.40 (br s, 1H), 4.31 (t, J = 4.5 Hz, 2H), 4.16 (t, J = 5.4 Hz, 2H), 3.84 (s, 3H), 3.13(t,J=7.7Hz,1H),2.34(s,3H),2.29-2.21(m,2H),1.13-1.07(m,1H),0.53-0.44(m,3H),0.33-0.26(m,1H).

Example 161 (S)-2-Cyclopropyl-2-((1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 161

Step 1: 4-Bromo-1-chloro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

LDA (2M in THF, 0.75mL, 1.5mmol) was added dropwise to a solution of 4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (200mg, 0.790mmol) in anhydrous THF (6mL) from Example 150 at -78°C and the mixture was stirred at -78°C for 1h. A solution of N-chlorosuccinimide (211mg, 1.58mmol) in THF was added dropwise at -78°C. The reaction mixture was warmed to 20°C and stirred for another 1h. The reactant was then quenched by adding an aqueous ammonium chloride solution. The resulting solution was extracted with DCM and the organic extracts were combined and dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-5% methanol/DCM) to give 100mg (44%) of the title compound as a white solid. LCMS(ESI): [M+H] ⁺ =287/289.

Step 2: 4-Bromo-1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of 4-bromo-1-chloro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (200 mg, 0.696 mmol) and 5,6,7,7a-tetrahydro-4H-imidazo[4,5-c]pyridine (867 mg, 6.99 mmol) in DMSO (4 mL) was heated at 140 ° C. for 2 h under microwave irradiation. The reaction mixture was purified by reverse phase flash chromatography (solvent gradient: 0-95% methanol/water) to give 220 mg (84%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 375/377.

Step 3: (S)-2-Cyclopropyl-2-((1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid

The title compound (240 mg, 69% yield) was prepared from 4-bromo-1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (320 mg, 0.853 mmol) following a procedure similar to that described in Step 3 of Example 125. LCMS (ESI): [M+H] ⁺ = 410.

Step 4: (S)-2-Cyclopropyl-2-((1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (130 mg, 57% yield) was prepared from (S)-2-cyclopropyl-2-((1-(5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid (230 mg, 0.562 mmol) following a procedure analogous to that of Example 125, step 4. 161: LCMS (ESI): R _T (min) = 2.10, [M+H] ⁺ = 409, method = C; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.98 (s, 1H), 7.29 (s, 1H), 6.92 (s, 1H), 6.24 (d, J = 2.0Hz, 1H), 6.10 (d, J＝2.0Hz,1H),5.33(d,J＝7.2Hz,1H),4.55(s,2H),4.39-4.22(m,4H),4.12-3.92(m, 2H),3.82-3.64(m,2H),3.17-3.01(m,1H),2.23-2.15(m,2H),1.13-1.04(m,1H), 0.52-0.40(m,3H),0.32-0.21(m,1H).

Example 162 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanamide 162

Step 1: 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine

A mixture of 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine from Example 101 (1.5 g, 3.89 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.98 g, 7.80 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride complex with dichloromethane (1.59 g, 1.95 mmol), potassium acetate (1.53 g, 15.6 mmol), and 1,4-dioxane (20 mL) was degassed with nitrogen under ultrasonication. The resulting solution was stirred at 80°C for 15 h. The solid was filtered off, and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-100% ethyl acetate/petroleum ether) to give 750 mg (45%) of the title compound as a black solid. LCMS: [M+H] ⁺ =433.

Step 2: 1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol

A mixture of 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine (800 mg, 1.85 mmol), acetic acid (3 mL), water (3 mL) and hydrogen peroxide (1.5 mL) was stirred at 25 ° C for 1 h. The reaction was quenched by adding aqueous sodium bisulfite. The precipitate was collected by filtration to give 420 mg (70%) of the title compound as a yellow solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.54 (br, 1H), 7.69 (s, 2H), 7.63 (s, 1H), 7.54 (d, J = 8.0Hz, 1H), 7.43 (d, J = 8.0Hz, 1H), 6.66 (s, 1H), 6.41 (s, 1H),4.46-4.40(m,2H),4.36-4.30(m,2H),2.40-2.25(m,2H).

Step 3: (S)-methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoate

A mixture of 1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ol (450 mg, 1.40 mmol), (R)-methyl 2-(tosyloxy)propanoate (540 mg, 2.09 mmol) and potassium carbonate (771 mg, 5.58 mmol) in DMSO (8 mL) was stirred at 35 ° C for 24 h. The solid was removed by filtration and the filtrate was purified by reverse phase flash chromatography (solvent gradient: 0-100% methanol/water) to give 500 mg (88%) of the title compound as a yellow solid. LCMS: [M+H] ⁺ = 409.

Step 4: (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoic acid

Lithium hydroxide (53.0 mg, 2.21 mmol) in water (2 mL) was added to a solution of (S)-methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoate (600 mg, 1.47 mmol) in methanol (8 mL), and the resulting solution was stirred at 25° C. for 3 h. The pH was adjusted to 5 with acetic acid and evaporated in vacuo. The residue was purified by reverse phase flash chromatography (solvent gradient: 0-95% methanol/water) to give 350 mg (60%) of the title compound as a white solid. LCMS: [M+H] ⁺ = 395.

Step 5: (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanamide

A mixture of (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoic acid (330 mg, 0.837 mmol), DIPEA (3 mL, 38.765 mmol), ammonium chloride (452 mg, 8.45 mmol), and HATU (636 mg, 1.67 mmol) in DMF (3 mL) was stirred at room temperature for 20 min. The solid was filtered off and the filtrate was purified via reverse phase HPLC and lyophilized to afford 160 mg (49%) of 162 as a white solid. LCMS (ESI): _RT (min) = 2.41, [M+H] ⁺ = 394, method = C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.62-7.52 (m, 3H), 7.50-7.42 (m, 2H), 7.38-7.30 (m, 1H), 7.19 (s, 1H), 6.76 (s, 1H), 6.41 (s, 1H), 4.68-4.54 (m, 1H), 4.45-4.30 (m, 2H), 4.30-4.17 (m, 2H), 2.15-2.25 (m, 2H), 1.42 (d, J = 6.8 Hz, 3H).

Example 163 (S)-2-Cyclopropyl-2-((1-(3-(difluoromethoxy)-4-methoxyphenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 163

163 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.57, [M+H] ⁺ = 459, method = G; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.64 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 2.0 Hz, 1H), 7.40-7.00 (m, 3H), 6.96 (s, 1H), 6.37 (d, J = 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 5.47 (d, J = 7.4 Hz, 1H), 4.34-4.32 (m, 2H), 4.25-4.21 (m, 2H), 3.92 (s, 3H), 3.16-3.12(m,1H),2.35-2.20(m,2H),1.12-1.09(m,1H),0.58-0.42(m,3H), 0.36-0.26(m,1H).

Example 164 (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2-methoxybenzamide 164

A mixture of (S)-methyl 5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2-methoxybenzoate (120 mg, 0.266 mmol) from Example 158 and a saturated solution of ammonia in methanol (10 mL) was stirred in a sealed tube at room temperature for 24 h. The reaction mixture was evaporated in vacuo. The residue was purified via reverse phase HPLC and lyophilized to afford 15.6 mg (13%) of 164 as a light yellow solid. LCMS (ESI): _RT (min) = 1.614, [M+H] ⁺ = 436, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.74-7.68 (m, 2H), 7.37 (m, 2H), 6.99 (s, 1H), 6.33 (m, 2H), 5.76 (br, 1H), 4.50-4.35 (m, 2H), 4.32-4.15 (m, 2H), 3.98 (s, 3H), 3.19-3.15 (m, 1H), 2.29-2.27 (m, 2H),1.13-1.11(m,1H),0.52-0.48(m,3H),0.35-0.27(m,1H).

Example 165 (S)-2-Cyclopropyl-2-((1-(pyridin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 165

165 was prepared following the procedure of Example 150. LCMS (ESI): _RT (min) = 1.17, [M+H] ⁺ = 364, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.74 (d, J = 4.5 Hz, 2H), 7.78 (d, J = 4.5 Hz, 2H), 7.34 (s, 1H), 6.96 (s, 1H), 6.39 (d, J = 2.0 Hz, 1H), 6.30 (d, J = 2.0 Hz, 1H), 5.55 (d, J = 7.4 Hz, 1H), 4.39-4.23 (m, 4H), 3.17-3.12 (m, 1H), 2.34-2.22 (m, 2H), 1.20-1.02(m,1H),0.59-0.40(m,3H),0.35-0.20(m,1H).

Example 166 (S)-2-Cyclopropyl-2-[1-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino]acetamide 166

166 was prepared following the procedure of Example 160. LCMS (ESI): _RT (min) = 2.22, [M+H] ⁺ = 380.2, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 8.16 (s, 0.6H), 7.94 (d, J = 0.8 Hz, 1H), 7.33 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 2.0 Hz, 1H), 6.16 (d, J = 2.0 Hz, 1H), 5.39 (br s, 1H), 4.34-4.24 (m, 4H), 3.92 (s, 3H), 3.11 (d, J = 8.2Hz, 1H), 2.34-2.25 (m, 2H), 1.14-1.04 (m, 1H), 0.53-0.41 (m, 3H), 0.33-0.22 (m, 1H).

Example 167 (S)-2-Cyclopropyl-2-((1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 167

167 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.87, [M+H] ⁺ = 421, method = B; ^1H NMR (400 MHz, DMSO-d6) δ 7.76 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.33 (br s, 1H), 6.95 (br s, 1H), 6.35 (d, J = 2.0 Hz, 1H), 6.26 (d, J = 2.0 Hz, 1H), 5.50 (d, J = 7.3 Hz, 1H), 4.67 (t, J = 5.6 Hz, 2H), 4.51-4.44 (m, 2H), 4.37-4.27 (m, 4H), 3.13(t,J＝7.7Hz,1H),2.30-2.24(m,2H),1.19-1.03(m,1H),0.56-0.45(m,3H), 0.30(dt,J＝9.8,4.2Hz,1H).

Example 168 (5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-yl)methanol 168

Step 1: (5-bromobenzo[d]oxazol-2-yl)methyl acetate

A mixture of 5-bromo-2-(chloromethyl)benzo[d]oxazole (1.40 g, 5.71 mmol) and cesium acetate (2.20 g, 11.52 mmol) in DMF (30 mL) was stirred at room temperature for 10 hours. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 1.2 g (78%) of the title compound as an off-white solid. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.91 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 5.36 (s, 2H), 2.24 (s, 3H).

Step 2: (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)methyl acetate

A mixture of (5-bromobenzo [d] oxazol-2-yl) methyl acetate (600 mg, 2.23 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (678 mg, 2.66 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium chloride (II) (100 mg, 0.130 mmol) and potassium acetate (652 mg, 6.66 mmol) in 1,4-dioxane (10 mL) was heated at 80 ° C for 30 min in a sealed tube under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 600 mg (85%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =318.

Step 3: (5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-yl)methyl acetate

A mixture of 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (900 mg, 2.37 mmol), (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-yl)methyl acetate (600 mg, 1.89 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (138 mg, 0.190 mmol), potassium acetate (2N aqueous solution, 1.8 mL, 3.60 mmol) and sodium carbonate (2N aqueous solution, 1.8 mL, 3.60 mmol) in acetonitrile (7.2 mL) was heated at 80 ° C. for 20 min under microwave irradiation. The reaction mixture was diluted with water and extracted with DCM. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 201 mg (24%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ = 442/444; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.23-8.15 (m, 1H), 8.02-7.87 (m, 1H), 7.87-7.72 (m, 1H), 7.48 (d, J=1.8 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 5.43 (d, J=2.8 Hz, 2H), 4.49-4.40 (m, 2H), 4.38-4.28 (m, 2H), 2.38-2.28 (m, 2H), 2.17 (s, 3H).

Step 4: (5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-yl)methanol

A mixture of 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-yl)methyl acetate (150 mg, 0.340 mmol) and potassium carbonate (11.8 mg, 0.090 mmol) in methanol (2 mL) was stirred at room temperature for 2 h. The mixture was evaporated in vacuo and the residue was purified by reverse phase HPLC and lyophilized to afford 25.8 mg (19%) of 168 as a white solid. LCMS (ESI): R _T (min) = 1.49, [M+H] ⁺ = 400/402, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.15 (s, 1H), 7.93-7.90(d,J＝8.4Hz,1H),7.83-7.80(d,J＝8.4Hz,1H),7.47(d,J＝1.8Hz,1H), 6.92(d,J＝1.8Hz,1H),5.97-5.92(m,1H),4.76(d,J＝6.3Hz,2H),4.46-4.32(m,2H), 4.39-4.28(m,2H),2.33-2.07(m,2H).

Example 169 (S)-2-((1-(1H-pyrazolo[3,4-b]pyridin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 169

169 was prepared following the procedure of Example 164. LCMS (ESI): _RT (min) = 1.65, [M+H] ⁺ = 404, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 13.89 (br, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.32 (s, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.39 (s, 1H), 6.99 (s, 1H), 6.48 (d, J = 1.9 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 5.61 (d, J = 7.4 Hz, 1H), 4.44-4.29 (m, 4H), 3.21-3.16 (m, 1H), 2.35-2.20(m,2H),1.13-1.09(m,1H),0.54-0.48(m,3H),0.39-0.29(m,1H).

Example 170 (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 170

170 was prepared following the procedure of Example 164. LCMS (ESI): _RT (min) = 1.25, [M+H] ⁺ = 435, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.07 (s, 1H), 7.69 (s, 2H), 7.60 (d, J = 8.2, 1H), 7.44 (d, J = 8.3 Hz, 1H), 7.34 (s, 1H), 6.96 (s, 1H), 6.37 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 5.45 (d, J = 7.3 Hz, 1H), 4.37-4.29 (m, 2H), 4.24-4.15 (m, 2H), 3.16-3.12(m,1H),2.26-2.25(m,2H),1.13-1.09(m,1H),0.51-0.45(m,3H), 0.35-0.25(m,1H).

Example 173 (S)-2-Cyclopropyl-2-((1-(2-methoxyquinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 173

173 was prepared following the procedure of Example 164. LCMS (ESI): _RT (min) = 2.47, [M+H] ⁺ = 445, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.70 (s, 1H), 8.37 (s, 1H), 8.17-8.14 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.7 Hz, 1H), 7.36 (s, 1H), 6.98 (s, 1H), 6.42 (s, 1H), 6.28 (s, 1H), 5.52 (d, J = 7.2 Hz, 1H), 4.45-4.25 (m, 4H), 4.09 (s, 3H), 3.19-3.14 (m, 1H), 2.29-2.28(m,2H),1.15-1.09(m,1H),0.52-0.44(m,3H),0.38-0.25(m,1H).

Example 174 (S)-2-[1-(3-cyanopiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino]-2-cyclopropylacetamide 174

Step 1: 1-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidine-3-carboxylic acid

A mixture of 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (0.20 g, 0.53 mmol), piperidine-3-carboxylic acid (88 mg, 0.68 mmol), cuprous iodide (20 mg, 0.11 mmol) and potassium phosphate (0.28 g, 1.32 mmol) in DMSO (2.0 mL) was heated at 100 ° C. for 16 h in a sealed vial. The reaction mixture was cooled and diluted with DCM (40 mL) and then purified via silica gel flash chromatography (solvent gradient: 5-35% (2N ammonia/methanol)/DCM) to give 0.17 g (86%) of the title compound as a cream-colored solid. LCMS (ESI): [M+H] ⁺ = 380/382.

Step 2: 1-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidine-3-carboxamide

To a mixture of 1-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)piperidine-3-carboxylic acid (77.5 mg, 0.204 mmol), ammonium chloride (21.8 mg, 0.407 mmol), and DIPEA (0.14 mL, 0.82 mmol) in DMF (0.7 mL) was added HATU (155 mg, 0.41 mmol) portionwise over 5 minutes, and the reaction mixture was stirred at room temperature for 10 minutes. The resulting mixture was diluted with DCM (20 mL) and purified via silica gel flash chromatography (solvent gradient: 2-10% (2N ammonia/methanol)/DCM) to give the title compound (quantitative) as a cream-colored solid. LCMS (ESI): [M+H] ⁺ = 379/381.

Step 3: 1-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidine-3-carbonitrile

Trifluoroacetic anhydride (34 μL, 0.246 mmol) was added to a mixture of 1-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidine-3-carboxamide (estimated to be 0.204 mmol) and pyridine (33 μL, 0.403 mmol) in THF (1.5 mL) over 3 minutes. The reaction mixture was stirred at room temperature for 30 min and then evaporated in vacuo. The residue was partitioned between DCM and a saturated aqueous potassium carbonate solution. The aqueous phase was extracted with DCM and the combined organic extracts were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 50-100% ethyl acetate/toluene) to give 44 mg (60% over 2 steps) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =361/363.

Step 4: Following the procedure of Example 126, 174 was prepared. LCMS (ESI): _RT (min) = 2.31, 2.33, [M+H] ⁺ = 395.2, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ) δ esp. 7.27 (br s, 1H), 6.91 (br s, 1H), 6.23 (d, J = 2.0 Hz, 1H), 6.06 (d, J = 2.0 Hz, 1H), 5.29 (d, J = 7.4 Hz, 1H), 4.27-4.24 (m, 2H), 4.01-3.87 (m, 2H), 3.10-3.01 (m, 2H), 2.23-2.18 (m, 2H), 1.90-1.66(m,4H),1.12-1.04(m,1H),0.50-0.42(m,3H),0.30-0.25(m,1H).

Example 175 (S)-2-Cyclopropyl-2-((1-(5-(methylsulfonyl)pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 175

175 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 2.75, [M+H] ⁺ = 442, method = B; ^1H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 2.0 Hz, 1H), 9.18 (d, J = 1.8 Hz, 1H), 8.67 (t, J = 2.1 Hz, 1H), 7.35 (br s, 1H), 6.96 (br s, 1H), 6.41 (d, J = 2.0 Hz, 1H), 6.32 (d, J = 1.9 Hz, 1H), 5.57 (d, J = 7.2 Hz, 1H), 4.39-4.30 (m, 4H), 3.43 (s, 3H), 3.16(t,J＝7.7Hz,1H),2.32-2.27(m,2H),1.15-1.07(m,1H),0.57-0.42(m,3H), 0.33-0.28(m,1H).

Example 176 (S)-2-((1-(3H-imidazo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 176

176 was prepared following the procedure of Example 125. LCMS (ESI): _RT (min) = 1.08, [M+H] ⁺ = 404, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 13.40 (s, 0.6H), 12.74 (s, 0.4H), 8.57-8.54 (m, 1H), 8.48-8.46 (m, 1H), 7.59-7.50 (m, 1H), 7.34 (s, 1H), 6.96 (s, 1H), 6.43 (d, J = 10.2 Hz, 1H), 6.34 (d, J = 11.4 Hz, 1H), 5.61-5.53 (m, 1H), 4.37-4.22 (m, 4H),3.19-3.14(m,1H),2.27-2.24(m,2H),1.13(m,1H),0.51(m,3H),0.32(m,1H).

Example 177 (S)-2-Cyclopropyl-2-((1-(thieno[2,3-b]pyridin-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 177

177 was prepared following the procedure of Example 158. LCMS (ESI): _RT (min) = 2.10, [M+H] ⁺ = 420, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.73 (d, J = 4.8 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.37 (s, 1H), 6.98 (s, 1H), 6.44 (d, J = 1.8 Hz, 1H), 6.35 (d, J = 1.8 Hz, 1H), 5.59 (d, J = 7.2 Hz, 1H), 4.36-4.33 (m, 2H), 4.18-4.14(m,2H),3.19-3.14(m,1H),2.27(m,2H),1.14-1.11(m,1H),0.52-0.48(m,3H),0.31(m,1H).

Example 178 (S)-2-((1-(Benzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 178

178 was prepared following the procedure of Example 158. LCMS (ESI): _RT (min) = 1.18, [M+H] ⁺ = 420, method = C; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 8.61 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.34 (s, 1H), 6.97 (s, 1H), 6.41 (d, J = 1.6 Hz, 1H), 6.28 (d, J = 1.6 Hz, 1H), 5.50 (d, J = 7.6 Hz, 1H), 4.36-4.34 (m, 2H), 4.32-4.28 (m, 2H),3.18-3.14(m,1H),2.28-2.27(m,2H),1.14-1.11(m,1H),0.52-0.46(m,3H), 0.33-0.31(m,1H).

Example 179 (S)-2-Cyclopropyl-2-((1-(7,8-dihydropyrido[3,4-b]pyrazin-6(5H)-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 179

179 was prepared following the procedure of Example 161. LCMS (ESI): _RT (min) = 1.18, [M+H] ⁺ = 420, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.49-8.46 (m, 2H), 7.27 (s, 1H), 6.90 (s, 1H), 6.23 (s, 1H), 6.07 (s, 1H), 5.29 (d, J = 7.5 Hz, 1H), 4.48 (s, 2H), 4.29-4.28 (m, 2H), 4.03-4.00 (m, 2H), 3.62-3.58 (m, 2H), 3.13-3.05 (m, 3H), 2.26-2.22 (m, 2H), 1.09-1.06(m,1H),0.48-0.43(m,3H),0.28-0.27(m,1H).

Example 180 (S)-2-((1-(1,4-oxazepan-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 180

180 was prepared following the procedure of Example 161. LCMS (ESI): _RT (min) = 1.71, [M+H] ⁺ = 386, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.26 (s, 1H), 6.90 (s, 1H), 6.17 (d, J = 2.0 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H), 5.22 (d, J = 7.4 Hz, 1H), 4.29-4.19 (m, 2H), 3.91-3.87 (m, 2H), 3.82-3.70 (m, 4H), 3.55-3.40 (m, 4H), 3.08-3.03 (m, 1H), 2.25-2.12(m,2H),1.98-1.90(m,2H),1.08-1.04(m,1H),0.53-0.37(m,3H), 0.30-0.20(m,1H).

Example 181 2-(4-{4-[((S)-carbamoylcyclopropylmethyl)amino]-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl}pyrazol-1-yl)isobutyramide formate 181

Step 1: tert-Butyl 4-(1-amino-3-bromo-7,8-dihydro-6H-5-oxa-9-azabenzocycloheptene-9-carbonyl)pyrazole-1-carboxylate and tert-butyl 4-(3-bromo-6,7,8,9-tetrahydro-5-oxa-9-azabenzocycloheptene-1-ylcarbamoyl)pyrazole-1-carboxylate

To a mixture of 1-tert-butyl pyrazole-1,4-dicarboxylate (865 mg, 4.07 mmol) and DIPEA (0.78 mL, 4.50 mmol) in DCM (10.0 mL) was added methanesulfonyl chloride (0.34 mL, 4.44 mmol) at 0 ° C under nitrogen, and the resulting mixture was stirred at 0 ° C for 15 min. Another portion of DIPEA (0.32 mL, 1.82 mmol) was added at 0 ° C, and the resulting mixture was then added to a solution of 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine (900 mg, 3.70 mmol) from Example 101 in DCM (10.0 mL) at 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C for 30 min, then warmed to room temperature and stirred at ambient temperature for 18 h. The resulting mixture was diluted with water. The organic extract was dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel (solvent gradient: 0-5% methanol/DCM) to give 1.06 g (67%, approximately 1:1 mixture of isomers) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =435/437.

Step 2: 4-Bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of tert-butyl 4-(1-amino-3-bromo-7,8-dihydro-6H-5-oxa-9-azabenzocycloheptene-9-carbonyl)pyrazole-1-carboxylate and tert-butyl 4-(3-bromo-6,7,8,9-tetrahydro-5-oxa-9-azabenzocycloheptene-1-ylcarbamoyl)pyrazole-1-carboxylate (1.08 g, 2.47 mmol) in acetic acid (20 mL) was heated at 90° C. for 2 h. The reaction mixture was evaporated in vacuo and the crude residue was purified via silica gel flash chromatography (solvent gradient: 0-8% methanol/DCM) to give 490 mg (63%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 319/321.

Step 3: Ethyl 2-[4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)pyrazol-1-yl]-2-methylpropanoate

To a suspension of 4-bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (253 mg, 0.79 mmol) and cesium carbonate (388 mg, 1.19 mmol) in DMF (8.0 mL) was added ethyl 2-bromo-2-methylpropanoate (240 mg, 1.19 mmol) and the reaction mixture was heated at 90 ° C for 3 h. The resulting mixture was concentrated in vacuo and then partitioned between ethyl acetate and water. The organic layer was then washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo to give 300 mg (87%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =433/435.

Step 4: 2-(4-{4-[((S)-carboxycyclopropylmethyl)amino]-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl}pyrazol-1-yl)-2-methylpropanoic acid

A mixture of ethyl 2-[4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)pyrazol-1-yl]-2-methylpropanoate (300 mg, 0.69 mmol), L-cyclopropylglycine (203 mg, 1.73 mmol), cuprous iodide (27 mg, 0.138 mmol) and potassium phosphate (591 mg, 2.76 mmol) in DMSO (3.0 mL) was degassed with argon under ultrasonic conditions. The reaction mixture was heated at 100 ° C for 18 h and then cooled to room temperature. DCM (60 mL) was added and the resulting gray solid was dried under vacuum to give (> 100%, estimated to be 0.69 mmol) of the crude title compound, which was used in the next step without further purification. LCMS (ESI): [M+H] ⁺ =440.

Step 5: 2-(4-{4-[((S)-carbamoylcyclopropylmethyl)amino]-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl}pyrazol-1-yl)isobutyramide formate

To a mixture of crude 2-(4-{4-[((S)-carboxycyclopropylmethyl)amino]-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl}pyrazol-1-yl)-2-methylpropanoic acid (estimated 0.69 mmol), ammonium chloride (230 mg, 4.10 mmol), and triethylamine (1.0 mL, 6.84 mmol) in DMF (5.0 mL) was added HATU (1.60 g, 4.10 mmol) portionwise and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was evaporated in vacuo and the crude residue was purified by silica gel flash chromatography [solvent gradient: 0-20% methanol (2N ammonia)/DCM] followed by further purification by reverse phase HPLC to afford 17 mg (6%) of the formate salt of 181 as an off-white solid. LCMS (ESI): R _T (min) = 2.34, [M+H] ⁺ = 438.2, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.34 (d, J = 0.6Hz, 1H), 8.21 (s, 0.6H), 8.02 (d, J＝0.6Hz,1H),7.33(d,J＝2.2Hz,1H),7.23(br s,1H),6.94(s,2H),6.32(d,J＝1.9Hz,1H),6.16(d,J＝2.1Hz,1H),5.41(br s,1H),4.37-4.28(m,4H),3.10(d,J＝7.8Hz, 1H),2.34-2.26(m,2H),1.77(s,6H),1.15-1.05(m,1H),0.54-0.44(m,3H), 0.32-0.26(m,1H).

Example 182 (S)-2-Cyclopropyl-2-[1-(3-hydroxypiperidin-1-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ylamino]acetamide 182

Step 1: 1-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)piperidin-3-ol

A mixture of 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (50 mg, 0.132 mmol), 3-hydroxypiperidine (20.1 mg, 0.20 mmol), 3,4,7,8-tetramethyl-1,10-phenanthroline (6.2 mg, 0.026 mmol), Cu(OTf).PhMe (6.9 mg, 0.013 mmol), potassium phosphate (56 mg, 0.26 mmol) and 2-methylbutan-2-ol (0.75 ml) was heated in a sealed vial at 100° C. for 16 h. The cooled reaction mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-100% methyl acetate/ethyl acetate) to give 14.3 mg (31%) of the title compound. LCMS (ESI): [M+H] ⁺ =352/354.

Step 2: 182 was prepared following the procedure of Example 126. LCMS (ESI): _RT (min) = 2.20, [M+H] ⁺ = 386.2, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ) δ esp 7.28 (br s, 1H), 6.91 (br s, 1H), 6.21 (d, J = 2.0 Hz, 1H), 6.02 (d, J = 2.0 Hz, 1H), 5.26 (d, J = 7.4 Hz, 1H), 4.95-4.93 (m, 1H), 4.26-4.23 (m, 2H), 3.90-3.87 (m, 2H), 3.73-3.65 (m, 1H), 3.07 (t, J＝7.7Hz,1H)2.85-2.79(m,1H),2.71-2.65(m,1H),2.20-2.15(m,2H), 1.91-1.85(m,1H),1.79-1.72(m,1H),1.62-1.52(m,1H),1.38-1.29(m,1H), 1.12-1.04(m,1H),0.50-0.42(m,3H),0.30-0.24(m,1H).

Example 183 (S)-2-Cyclopropyl-2-((1-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 183

183 was prepared following the procedure of Example 137. LCMS (ESI): _RT (min) = 3.10, [M+H] ⁺ = 386.2, method = B; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 7.24 (s, 1H), 6.84 (s, 1H), 6.44 (d, J = 2.0 Hz, 1H), 6.37 (d, J = 2.0 Hz, 1H), 5.50 (d, J = 7.3 Hz, 1H), 4.66-4.58 (m, 2H), 4.39-4.31 (m, 2H), 4.23 (s, 3H), 2.37-2.23 (m, 2H), 1.29-1.22(m,1H),1.18-1.06(m,1H),0.59-0.43(m,3H),0.36-0.24(m,1H).

Example 184 (S)-2-((1-(2-aminobenzo[d]thiazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 184

184 was prepared following the procedure of Example 158. LCMS (ESI): _RT (min) = 1.27, [M+H] ⁺ = 435, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.81 (d, J = 8.1 Hz, 1H), 7.71-7.61 (m, 3H), 7.41-7.31 (m, 2H), 6.96 (s, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.25 (d, J = 2.0 Hz, 1H), 5.46 (d, J = 7.3 Hz, 1H), 4.34-4.33 (m, 2H), 4.28-4.23 (m, 2H), 3.17-3.13 (m, 1H), 2.25-2.24(m,2H),1.14-1.07(m,1H),0.58-0.43(m,3H),0.37-0.26(m,1H).

Example 185 (S)-2-((1-(2-(methylamino)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)propanamide 185

185 was prepared following the procedure of Example 186. LCMS (ESI): _RT (min) = 1.18, [M+H] ⁺ = 407, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.97-7.96 (m, 1H), 7.56 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.28 (s, 1H), 6.93 (s, 1H), 6.37 (d, J = 2.0 Hz, 1H), 6.20 (d, J = 2.0 Hz, 1H), 5.42 (d, J = 7.3 Hz, 1H), 4.34-4.31 (m, 2H), 4.20-4.18 (m, 2H), 3.73-3.71 (m, 1H), 2.93 (d, J = 4.7Hz, 3H), 2.27-2.24 (m, 2H), 1.32-1.29 (d, J = 6.9Hz, 3H).

Example 187 (S)-2-((1-(2-aminoquinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 187

187 was prepared following the procedure of Example 158. LCMS (ESI): _RT (min) = 1.75, [M+H] ⁺ = 430, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.36 (s, 1H), 8.11 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 2H), 6.96 (s, 1H), 6.39 (d, J = 1.8 Hz, 1H), 6.25 (d, J = 1.8 Hz, 1H), 5.47 (d, J = 7.5 Hz, 1H), 4.35-4.29 (m, 4H), 3.18-3.13(m,1H),2.32-2.21(m,2H),1.17-1.05(m,1H),0.53-0.47(m,3H), 0.33-0.32(m,1H).

Example 188 (S)-4-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-2-fluorobenzamide 188

188 was prepared following the procedure of Example 150. LCMS (ESI): _RT (min) = 1.14, [M+H] ⁺ = 424, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.82-7.65 (m, 5H), 7.33 (s, 1H), 6.96 (s, 1H), 6.38 (s, 1H), 6.28 (s, 1H), 5.52 (d, J = 7.2 Hz, 1H), 4.34-4.32 (m, 2H), 4.28-4.17 (m, 2H), 3.17-3.12 (m, 1H), 2.27-2.26 (m, 2H), 1.14-1.08 (m, 1H), 0.53-0.46 (m, 3H), 0.35-2.22 (m, 1H).

Example 189 (S)-2-Cyclopropyl-2-((1-(3-hydroxyquinolin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 189

189 was prepared following the procedure of Example 158. LCMS (ESI): _RT (min) = 0.83, [M+H] ⁺ = 430, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 10.48 (br s, 1H), 8.66 (d, J = 2.8 Hz, 1H), 8.24 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H), 7.37 (s, 1H), 6.99 (s, 1H), 6.42 (d, J = 2.0 Hz, 1H), 6.29 (d, J = 2.0 Hz, 1H), 5.53 (d, J＝7.3Hz,1H),4.42-4.26(m,4H),3.20-3.08(m,1H),2.35-2.24(m,2H), 1.15-1.02(m,1H),0.60-0.43(m,3H),0.35-0.25(m,1H).

Example 190 (S)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 190

190 was prepared following the procedure of Example 158. LCMS (ESI): _RT (min) = 1.15, [M+H] ⁺ = 430, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 14.65 (s, 0.2H) 14.23 (s, 0.8H), 8.69 (s, 1H), 8.19-8.17 (m, 2H), 7.89-7.87 (m, 2H), 7.36 (s, 1H), 6.98 (s, 1H), 6.39 (s, 1H), 6.30 (s, 1H), 5.65 (br s, 1H), 4.49-4.18 (m, 4H), 3.18-3.08 (m, 1H), 2.33-2.18 (m, 2H),1.21-1.06(m,1H),0.52-0.48(m,3H),0.32-0.30(m,1H).

Example 191 (S)-5-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)pyridine-2-carboxamide 191

191 was prepared following the procedure of Example 150. LCMS (ESI): _RT (min) = 1.08, [M+H] ⁺ = 407, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 8.39-8.36 (d, J = 8.1 Hz, 1H), 8.23 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 6.97 (s, 1H), 6.40 (d, J = 1.5 Hz, 1H), 6.31 (d, J = 2.1 Hz, 1H), 5.56 (d, J = 7.5 Hz, 1H), 4.36-4.30 (m, 4H), 3.17-3.12(m,1H),2.35-2.20(m,2H),1.14-1.08(m,1H),0.51-0.4(m,3H), 0.34-0.29(m,1H).

Example 192 1-(2-aminobenzo[d]oxazol-5-yl)-N-(3,3-difluorocyclobutyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-amine 192

A mixture of 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine (Example 101, 200 mg, 0.519 mmol), 3,3-difluorocyclobutane hydrochloride (157 mg, 1.09 mmol), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (45.0 mg, 0.106 mmol), tris(dibenzylideneacetone)dipalladium(0) (93.0 mg, 0.117 mmol) and lithium bis(trimethylsilyl)amide (1 M solution in THF, 2.00 mL, 2.00 mmol) in THF (10.0 mL) was degassed with nitrogen. The reaction mixture was heated at 100° C. under microwave irradiation for 2 h. The reaction mixture was diluted with methanol and then filtered. The filtrate was evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to afford 17.5 mg (8%) of 192 as a light yellow solid. LCMS (ESI): R _T (min) = 2.58, [M+H] ⁺ = 412, method = C; ¹ HNMR (300MHz, DMSO-d ₆ ) δ7.56-7.46 (m, 4H), 7.35-7.32 (m, 1H), 6.35(d,J＝1.8Hz,1H),6.14(d,J＝1.8Hz,1H),5.81(d,J＝6.6Hz,1H),4.35-4.32(m, 2H), 4.23-4.20(m,2H), 3.81-3.74(m,1H), 3.14-2.93(m,2H), 2.49-2.30(m,2H), 2.27-2.20(m,2H).

Example 193 5-(4-Bromo-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine 193

Step 1: 1-Bromo-5-(3,3-diethoxypropoxy)-2-fluoro-4-nitrobenzene

To a solution of 1-bromo-2,5-difluoro-4-nitrobenzene (6.1 g, 25.6 mmol) and 3,3-diethoxy-1-propanol (3.8 g, 25.6 mmol) in DMF (30 mL) was added portionwise sodium hydride (60% in mineral oil, 1.14 g, 28.1 mmol) over 10 min. The reaction mixture was stirred at 0 ° C for 30 min, then warmed to room temperature and stirred for an additional 30 min. The mixture was partitioned between ethyl acetate and 1N hydrochloric acid, and the phases were separated. The aqueous layer was extracted with ethyl acetate, the organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel flash chromatography (solvent gradient: 5-20% ethyl acetate/cyclohexane) to give 7.71 g (82%) of the title compound as a yellow oil. LCMS (ESI): [M+Na] ⁺ = 388/390.

Step 2: 3-Bromo-5-(3,3-diethoxypropoxy)-2-fluoro-6-nitroaniline

To a solution of 1-bromo-5-(3,3-diethoxypropoxy)-2-fluoro-4-nitrobenzene (3.50 g, 9.56 mmol) and 1,1,1-trimethylhydrazine iodide (2.12 g, 10.5 mmol) in DMSO (35 mL) was added potassium tert-butoxide (2.57 g, 22.9 mmol) at 10 ° C. The mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was adjusted to approximately pH 3 with 1N hydrochloric acid (about 20 mL) and then extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated. The process was repeated and two batches were combined, and the residue was then purified via silica gel flash chromatography (solvent gradient: 2-15% ethyl acetate/toluene) to give 3.24 g (45%) of the title compound as a yellow solid. LCMS (ESI): [M+Na] ⁺ =403/405.

Step 3: 4-Bromo-6-(3,3-diethoxypropoxy)-3-fluorobenzene-1,2-diamine

To a suspension of 3-bromo-5-(3,3-diethoxypropoxy)-2-fluoro-6-nitroaniline (3.73 g, 9.77 mmol) in methanol (30 mL) was added a solution of ammonium chloride (4.72 g, 87.9 mmol) in water (20 mL), followed by the addition of iron powder (3.29 g, 58.6 mmol). The mixture was stirred at 90 ° C for 30 min. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water, then filtered through a celite pad. The filtrate was collected and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 10-60% ethyl acetate/toluene) to give 3.32 g (97%) of the title compound as a light brown oil. ¹ H NMR (400MHz, CDCl ₃ )δ6.50(d,J＝5.4Hz,1H),4.74(t,J＝6.3Hz,1H),4.03(t,J＝6.3Hz,2H),3.72- 3.64(m,2H),3.58-3.42(m,6H),2.10(q,J＝6.3Hz,2H),1.22(t,J＝6.9Hz,6H).

Step 4: 8-Bromo-7-fluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine

To a solution of 4-bromo-6-(3,3-diethoxypropoxy)-3-fluorobenzene-1,2-diamine (3.32 g, 9.43 mmol) in DCM (33 mL) was added TFA (33 mL) and triethylsilane (7.4 mL, 47 mmol) dropwise at 0 ° C over 5 min. The reaction mixture was stirred at 0 ° C for 10 min, then warmed to room temperature and stirred for an additional 10 min. The solvent was removed by azeotropic distillation with toluene. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was further extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 5-30% ethyl acetate/toluene) to give 2.31 g (94%) of the title compound and a 1:1 mixture of 5-bromo-6-fluorochroman-7,8-diamine as a light brown oil. LCMS(ESI): [M+H] ⁺ =261/263.

Step 5: 4-Bromo-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of 8-bromo-7-fluoro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine and 5-bromo-6-fluorochroman-7,8-diamine (2.31 g, 8.86 mmol) and p-toluenesulfonic acid (150 mg, 0.87 mmol) in trimethyl orthoformate (30 mL) was stirred at 105° C. for 16 h. The solvent was removed azeotropically with toluene. The residue was purified by silica gel flash chromatography (solvent gradient: 2-10% (2N ammonia/methanol)/DCM) to give 1.14 g (47%) of the title compound as a cream-colored solid. LCMS (ESI): [M+H] ⁺ = 271/273.

Step 6: 4-Bromo-3-fluoro-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

To a solution of diisopropylamine (0.58 mL, 4.10 mmol) in THF (20 mL) was added n-butyllithium (2.5 N in hexane, 1.5 mL, 3.75 mmol) dropwise at -40 °C under nitrogen. The mixture was allowed to warm to -20 °C over 10 min and then cooled to -78 °C. A solution of 4-bromo-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (926 mg, 3.42 mmol) in THF (8.0 mL) was added dropwise over 5 min. The mixture was stirred for an additional 15 min, and then a solution of iodine (1.13 g, 4.45 mmol) in THF (5.0 mL) was added dropwise over 5 min. The mixture was stirred for an additional 1 h and then quenched with saturated aqueous ammonium chloride. The mixture was partitioned between ethyl acetate and saturated aqueous sodium thiosulfate, and the phases were separated. The aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, then dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (solvent gradient: 1-3% methanol/DCM) to give 1.04 g (77%) of the title compound as a cream-colored solid. LCMS (ESI): [M+H] ⁺ = 397/399.

Step 7: To a suspension of 4-bromo-3-fluoro-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (103 mg, 0.26 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoxazol-2-ylamine (74 mg, 0.28 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (21 mg, 0.026 mmol) in 1,2-dimethoxyethane (2.0 mL) was added 2N aqueous sodium carbonate solution (0.52 mL, 1.04 mmol). The reaction mixture was stirred at 100 ° C. under nitrogen in a sealed vial for 5 h. The resulting mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated.The crude residue was purified by silica gel flash chromatography (solvent gradient: 2-10% methanol/DCM) to afford 78 mg (75%) of 193 as a beige solid. LCMS (ESI): _RT (min) = 4.02, [M+H] ⁺ = 403/405, method = A; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.63 (s, 2H), 7.60 (d, J = 1.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 8.1, 1.3 Hz, 1H), 6.95 (d, J = 5.2 Hz, 1H), 4.44-4.39 (m, 2H), 4.33 (t, J = 5.2 Hz, 2H), 2.36-2.29 (m, 2H).

Example 194 (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 194

Step 1: (1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-L-proline

5-(4-Bromo-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine (86 mg, 0.21 mmol), L-proline (99 mg, 0.84 mmol), copper(I) iodide (41 mg, 0.21 mmol), and potassium phosphate (274 mg, 1.26 mmol) were suspended in DMSO (3.0 mL) and heated at 120° C. under microwave irradiation for 3.5 h. The crude reaction mixture was diluted with DCM (60 mL) and purified via silica gel flash chromatography (solvent gradient: 5-60% (2N ammonia/methanol)/DCM) to afford 50 mg (53%) of the title compound as a gray solid. LCMS (ESI): [M+H] ⁺ = 438.

Step 2: To a solution of (1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-L-proline (107 mg, 0.24 mmol) in DMF (1.2 mL) was added ammonium chloride (26 mg, 0.49 mmol) and DIPEA (169 μL, 0.98 mmol), followed by portionwise addition of HATU (185 mg, 0.49 mmol) over 5 min, and the reaction mixture was stirred at room temperature for 10 min. The resulting mixture was directly purified via silica gel flash chromatography (solvent gradient: 2-14% (2N ammonia/methanol)/DCM). The resulting residue was triturated with methanol to afford 53 mg (50%) of 194 as an off-white solid. LCMS (ESI): R _T (min) = 2.57, [M+H] ⁺ = 437, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.58 (s, 2H),7.56(d,J＝1.3Hz,1H),7.49(d,J＝8.1Hz,1H),7.37(dd,J＝8.1,1.3Hz,1H),7 .23(d,J＝1.8Hz,1H),6.93(d,J＝1.8Hz,1H),6.22(d,J＝6.7Hz,1H),4.35-4.31(m, 2H),4.27-4.21(m,2H),4.10-4.04(m,1H),3.76-3.69(m,1H),3.31-3.24(m,1H), 2.30-2.15(m,3H),1.96-1.84(m,3H).

Example 195: (S)-2-((1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide

Step 1: Ethyl [1,3]dioxolo[4,5-b]pyridine-7-carboxylate

To a microwave vial was added 7-bromo-[1,3]dioxolo[4,5-b]pyridine (200 mg, 0.99 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (73 mg, 0.099 mmol), potassium carbonate (205 mg, 1.49 mmol), ethanol (3 mL), and DMF (7.5 mL). The flask was purged of air and backfilled with carbon monoxide three times. The reaction was then heated to 70°C and stirred under a balloon containing carbon monoxide gas. After 16 h, the reaction was cooled to room temperature and filtered through celite. The filtrate was diluted with water and extracted with isopropyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by silica gel flash chromatography (solvent gradient: 0-80% ethyl acetate/heptane) to yield 111 mg (58%) of the title compound. LCMS (ESI): [M+H] ⁺ =195.1; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.64 (d, J = 5.7Hz, 1H), 7.14 (d, J = 6.0Hz, 1H), 6.25 (s, 2H), 4.33 (q, J = 7.1Hz, 2H), 1.31 (t, J=7.1Hz,3H).

Step 2: [1,3]dioxolo[4,5-b]pyridine-7-carboxylic acid

The title compound (143 mg, 88%) was prepared from ethyl [1,3]dioxolo[4,5-b]pyridine-7-carboxylate following a procedure similar to that described in Step 2 of Example 116. LCMS (ESI): [M+H] ⁺ = 168; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.43 (d, J = 5.3 Hz, 1H), 7.00 (d, J = 5.4 Hz, 1H), 6.02 (s, 2H).

Step 3: 1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (0.238 g, 51%) was prepared from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene and [1,3]dioxolo[4,5-b]pyridine-7-carboxylic acid following procedures similar to those described in Steps 1-2 of Example 125. LCMS (ESI): [M+H] ⁺ =374.

Step 4: (S)-2-((1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid

The title compound (0.153 g, 99% yield) was prepared from 1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene and (S)-2-amino-2-cyclopropylacetic acid following a procedure similar to that described in Example 125, Step 3. LCMS (ESI): [M+H] ⁺ = 409.

Step 5: 195 (18.5 mg, 12%) was prepared from (S)-2-((1-([1,3]dioxolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid following a procedure similar to that of Example 125, step 4. LCMS (ESI): R _T (min) = 2.69, [M+H] ⁺ = 409.1, method = B; ¹ HNMR (400MHz, DMSO-d ₆ ) δ7.71 (d, J = 5.6Hz, 1H), 7.34(d,J＝2.7Hz,1H),7.12(d,J＝5.5Hz,1H),6.95(d,J＝2.6Hz,1H),6.38(d, J＝1.9Hz,1H),6.30(d,J＝1.9Hz,1H),6.25(d,J＝2.8Hz,2H),5.56(d,J＝7.3Hz,1H), 4.36-4.29(m,2H),4.23-4.09(m,2H),3.14(t,J=7.8Hz,1H),2.30-2.20(m,2H), 1.18-1.04(m,1H),0.57-0.41(m,3H),0.35-0.25(m,1H).

Example 196 (S)-2-Cyclopropyl-2-((1-(2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 196

Step 1: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2(3H)-one

To a solution of 2-amino-4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)phenol (Example 101, Step 8) (1.00 g, 2.77 mmol) in DCM (10 mL) was added 1,1'-carbonyldiimidazole (500 mg, 3.08 mmol). The reaction mixture was stirred at room temperature for 3 h and then evaporated in vacuo. The resulting residue was washed with ethyl acetate to give 700 mg (crude) of the title compound as a brown solid. The solid was used in the next step without further purification. LCMS (ESI): [M+H] ⁺ =386/388.

Step 2: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one

To a solution of 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2(3H)-one (600 mg, 1.55 mmol) in DMF (10 mL) was added sodium hydride (72.0 mg, 3.08 mmol) at 0 ° C. The reaction mixture was stirred for 30 min, and then (2-(chloromethoxy)ethyl)trimethylsilane (312 mg, 1.87 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h and then quenched with water. The solid was collected by filtration and dried in vacuo to give 680 mg (85%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =516/518.

Step 3: (S)-2-Cyclopropyl-2-((1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid

The title compound (100 mg, 16% yield) was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (600 mg, 1.16 mmol) and (S)-2-amino-2-cyclopropylacetic acid (700 mg, 6.00 mmol) following a procedure analogous to that described in Step 1 of Example 104. LCMS (ESI): [M+H] ⁺ = 551.

Step 4: (S)-2-Cyclopropyl-2-((1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (45 mg, 45% yield) was prepared from (S)-2-cyclopropyl-2-((1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetic acid (100 mg, 1.18 mmol) and ammonium chloride (193 mg, 3.61 mmol). LCMS (ESI): [M+H] ⁺ = 550.

Step 5: A solution of (S)-2-cyclopropyl-2-((1-(2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide (45 mg, 0.082 mmol) in TFA (2.0 mL) was stirred at room temperature for 1 h. The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (solvent gradient: 10% methanol in dichloromethane) followed by chiral SFC and lyophilization to afford 6.20 mg (18%) of 196 as a white solid. LCMS (ESI): R _T (min) = 2.11, [M+H] ⁺ = 420, method = D; ¹ HNMR (300MHz, DMSO-d ₆ ) δ 11.86 (s, 1H), 7.50-7.29 (m, 4H), 6.96 (s, 1H), 6.36 (d, J = 2.0Hz, 1H), 6.24(d,J＝2.0Hz,1H),5.47(d,J＝7.4Hz,1H),4.37-4.27(m,2H),4.21-4.19(m,2 H),3.14-3.11(m,1H),2.26-2.23(m,2H),1.17-1.03(m,1H),0.53-0.48(m,3H), 0.50-0.47 (m, 1H).

Example 197 (S)-2-((1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 197

Step 1: 6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

A mixture of 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (2 g, 9.39 mmol), bis(pinacolato)diboron (2.82 g, 11.1 mmol), potassium acetate (2.77 g, 28.2 mmol) and 1,1'-bis(diphenylphosphino)ferrocenedichloridepalladium(II) (768 mg, 1.05 mmol) in 1,4-dioxane (50 mL) was stirred at 120 ° C under a nitrogen atmosphere for 16 h. The resulting mixture was cooled to room temperature and the solvent was evaporated in vacuo. The residue was washed with water and then with methanol to give 1.2 g (49%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ =261.

Step 2: 6-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine

The title compound (660 mg, 72% yield) was prepared from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (Example 150, Step 2) (900 mg, 2.38 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (750 mg, 2.88 mmol) following a procedure similar to that of Example 150, Step 3. LCMS (ESI): [M+H] ⁺ = 385/387.

Step 3: 4-Bromo-1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

Under a nitrogen atmosphere, 6-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-amine (130 mg, 0.337 mmol), copper(II) chloride (90.0 mg, 0.669 mmol) and tert-butyl nitrite (70.0 mg, 0.679 mmol) were suspended in acetonitrile (5.0 mL) and the reaction mixture was stirred at 70 ° C for 3 h. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 60 mg (44%) of the title compound as a brown solid. LCMS(ESI):[M+H] ⁺ =404/406.

Step 4: (S)-2-((1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid

The title compound (30 mg, 46% yield) was prepared from 4-bromo-1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (60.0 mg, 0.148 mmol) and (S)-2-amino-2-cyclopropylacetic acid (86.0 mg, 0.747 mmol) following a procedure similar to that described in Example 104, Step 1. LCMS (ESI): [M+H] ⁺ = 439.

Step 5: 197 (10.3 mg, 17% yield) was prepared from (S)-2-((1-(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid (60 mg, 0.137 mmol) and ammonium chloride (145 mg, 2.71 mmol) following a procedure similar to that of Example 104, step 2. LCMS (ESI): R _T (min) = 2.12, [M+H] ⁺ = 438, method = D; ¹ H NMR (400MHz, DMSO-d ₆ ) 9.38 (d, J = 0.6Hz, 1H), 8.15-8.11 (m, 1H), 7.98-7.95 (m, 1H),7.36(s,1H),6.98(s,1H),6.39(d,J＝1.8Hz,1H),6.30(d,J＝2.1Hz,1H),5.57(d, J＝7.5Hz,1H),4.34-4.32(m,4H),3.17-3.12(m,1H),2.28-2.27(m,2H), 1.14-1.08(m,1H),0.53-0.44(m,3H),0.35-0.28(m,1H).

Example 198 (6-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)quinoxalin-2-yl)methanol 198

Step 1: 6-Bromo-2-vinylquinoxaline

A mixture of 6-bromo-2-chloroquinoxaline (5.00 g, 20.5 mmol), potassium trimethyl(vinyl)borate (2.50 g, 18.7 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.60 g, 2.19 mmol) and triethylamine (7.50 mL, 54.0 mmol) in 1,4-dioxane (100 mL) was degassed with nitrogen. The reaction mixture was stirred at 80 ° C for 4 h and then filtered. The filtrate was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% ethyl acetate/petroleum ether) to give 2.00 g (41%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 235/237.

Step 2: 6-Bromoquinoxaline-2-carboxylic acid

To a solution of 6-bromo-2-vinylquinoxaline (2.00 g, 8.51 mmol) in THF (60 mL) and water (20 mL) was added potassium osmate (1.60 g, 4.34 mmol) and sodium periodate (4.75 g, 22.2 mmol). The resulting mixture was stirred at room temperature for 16 h and then diluted with water. The resulting mixture was extracted with DCM and the organic phase was discarded. The aqueous layer was adjusted to approximately pH 5 with acetic acid and the resulting solid was collected by filtration to give 3 g of the crude title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ = 253/255. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.96 (s, 1H), 9.43 (s, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.22-8.04 (m, 2H).

Step 3: Methyl 6-bromoquinoxaline-2-carboxylate

To a solution of 6-bromoquinoxaline-2-carboxylic acid (3.00 g, 11.8 mmol) in methanol (60.0 mL) was added (diazomethyl)trimethylsilane (40.0 mL, 2 mol/L in hexane) dropwise with stirring at room temperature. The reaction mixture was stirred at room temperature for 4 h and then evaporated in vacuo. The resulting residue was purified by silica gel flash chromatography (solvent gradient: 0-20% ethyl acetate/petroleum ether) to give 1.6 g (53%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 267/269. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 8.47 (d, J = 2.1 Hz, 1H), 8.25-8.08 (m, 2H), 4.00 (s, 3H).

Step 4: (6-Bromoquinoxalin-2-yl)methanol

To a solution of methyl 6-bromoquinoxaline-2-carboxylate (1.60 g, 5.99 mmol) in DCM (10.0 mL) and methanol (20.0 mL) was added _NaBH4 (737 mg, 19.5 mmol) portionwise at 10 ° C. The reaction mixture was stirred at 10 ° C for 1 h and then quenched with water. The resulting mixture was extracted with DCM, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 600 mg (42%) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ = 239/241. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.07 (s, 1H), 8.34 (d, J = 1.3 Hz, 1H), 8.05-7.93 (m, 2H), 5.81-5.77 (m, 1H), 4.80 (d, J = 5.9 Hz, 2H).

Step 5: (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)methanol

A mixture of (6-bromoquinoxaline-2-yl)methanol (207 mg, 0.864 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (483 mg, 1.90 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (85.5 mg, 0.117 mmol) and potassium acetate (315 mg, 3.21 mmol) in 1,4-dioxane (12 mL) was degassed with nitrogen. The reaction mixture was heated at 90 ° C for 4 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-60% ethyl acetate/petroleum ether) to give 88 mg (36%) of the title compound as a brown oil. LCMS (ESI): [M+H] ⁺ = 287.

Step 6: 198 (50 mg, 21% yield) was prepared following a procedure similar to that of Example 150, Step 3, from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (Example 150, Step 2) (220 mg, 0.580 mmol) and (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-yl)methanol (160 mg, 0.559 mmol). LCMS (ESI): R _T (min) = 2.510, [M+H] ⁺ = 411, method = C; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.16 (s, 1H), 8.54 (d, J＝1.6Hz,1H),8.29-8.27(m,1H),8.22(d,J＝8.4Hz,1H),7.55(d,J＝1.6Hz,1H), 6.98(d,J＝1.6Hz,1H),5.88-5.85(m,1H),4.88(d,J＝5.6Hz,2H),4.53-4.45(m,4H), 2.43-2.33(m,2H).

Example 199 (S)-1-(1-(1H-benzo[d]imidazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 199

199 was prepared following a procedure similar to Example 150. LCMS (ESI): R _T (min) = 1.75, [M+H] ⁺ = 403, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 12.68 (s, 1H), 8.34 (s, 1H),8.02(d,J＝9.3Hz,1H),7.75-7.69(m,2H),7.28(s,1H),7.01(s,1H),6.36(s, 1H),6.07(s,1H),4.39-4.27(m,4H),3.90-3.85(m,1H),3.69-3.59(m,1H), 3.25-3.16(m,1H),2.27-2.26(m,3H),1.96(br s,3H).

Example 200 (S)-1-(1-(1H-benzo[d][1,2,3]triazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 200

200 was prepared following a procedure similar to Example 125. LCMS (ESI): R _T (min) = 1.19, [M+H] ⁺ = 404, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.31 (s, 1H), 8.03 (d, J＝8.7Hz,1H),7.85(d,J＝8.4Hz,1H),7.30(s,1H),7.02(s,1H),6.38(d,J＝2.1Hz, 1H),6.10(d,J＝2.1Hz,1H),4.39-4.27(m,4H),3.85(d,J＝7.5Hz,1H),3.70-3.30(m, 1H),3.21-3.18(m,1H),2.40-2.15(m,3H),2.10-1.85(m,3H).

Example 201 (S)-2-((1-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 201

201 was prepared following a procedure similar to Example 197. LCMS (ESI): _RT (min) = 1.06, [M+H] ⁺ = 419, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.93 (d, J = 0.6 Hz, 1H), 7.81-7.78 (m, 1H), 7.49-7.46 (m, 1H), 7.35 (d, J = 2.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 6.27 (d, J = 2.0 Hz, 1H), 6.20 (s, 1H), 5.52 (d, J = 7.6 Hz, 1H), 4.35-4.28(m,4H),3.17-3.12(m,1H),2.28-2.27(m,2H),1.14-1.08(m,1H), 0.52-0.48(m,3H),0.35-0.26(m,1H).

Examples 202 and 203 1-(2-aminobenzo[d]oxazol-5-yl)-N-((1r,3r)-3-fluorocyclobutyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-amine 202 and 1-(2-aminobenzo[d]oxazol-5-yl)-N-((1s,3s)-3-fluorocyclobutyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-amine 203

The title compound was prepared as a single unknown stereoisomer following a procedure analogous to Example 192 and followed by chiral HPLC separation.

202 (7.5mg): LCMS: _RT (min) = 3.5min, [M+H] ⁺ = 394, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.56-7.51 (m, 3H), 7.48-7.34 (m, 1H), 7.34-7.31 (m, 1H),6.26(d,J＝1.8Hz,1H),6.11(d,J＝1.8Hz,1H),5.65(d,J＝5.7Hz,1H), 5.35-5.18(m,1H),4.34-4.31(m,2H),4.22-4.18(m,2H),3.98-3.95(m,1H), 2.50-2.49(m,2H),2.30-2.23(m,4H).

203 (22mg): LCMS: _RT (min) = 3.5min, [M+H] ⁺ = 394, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.56-7.51 (m, 2H), 7.48-7.45 (m, 2H), 7.34-7.31 (m, 1H),6.34(d,J＝1.8Hz,1H),6.13(d,J＝1.8Hz,1H),5.62(d,J＝7.5Hz,1H), 4.99-4.80(m,1H),4.33-4.31(m,2H),4.22-4.18(m,2H),3.39(d,J＝6.9Hz,1H), 2.89-2.83(m,2H),2.24(s,2H),2.09-1.98(m,2H).

Example 204 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 204

Step 1: 2-Amino-5-bromo-3-nitrophenol hydrobromide

To a suspension of 2-amino-3-nitrophenol (192 g, 1.25 mol) in dioxane (4 L) was added bromine (239 g, 1.50 mol) dropwise at 10 ° C. The reaction mixture was stirred at 10 ° C for 15 min and then at 25 ° C for 3 h. The mixture was filtered and the filter cake was washed with dioxane to give 408.4 g (crude) of the title compound as a yellow solid. The material was used without further purification. LCMS (ESI): [M+H] ⁺ = 233/235.

Step 2: 2-(3-(1,3-dioxolan-2-yl)propoxy)-4-bromo-6-nitroaniline

A mixture of 2-amino-5-bromo-3-nitrophenol hydrobromide (300g, 0.955mol), 2-(3-chloropropyl)-1,3-dioxolane (143g, 0.955mol), potassium carbonate (396g, 2.87mol) and sodium iodide (43.0g, 0.287mol) in DMF (3.5L) was stirred at 80 ° C for 16h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 288g (crude) of the title compound as a brown solid. The substance was used without further purification. LCMC (ESI): [M+H] ⁺ =347/349.

Step 3: 9-Bromo-7-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazaoctene

To a solution of 2-(3-(1,3-dioxolane-2-yl)propoxy)-4-bromo-6-nitroaniline (390g, 1.12mol) in DCM (2L) was added TFA (1L, 13.5mol) dropwise at 0°C. The reaction mixture was stirred at 0°C for 15min, then triethylsilane (372g, 3.20mol) was added dropwise and the reaction mixture was stirred at 0°C for 15min, then at 25°C for 16h. The reaction mixture was diluted with water and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution and extracted with DCM. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 433g (crude) of the title compound as a red solid. The substance was used without further purification. LCMS (ESI): [M+H] ⁺ =287/289.

Step 4: 9-Bromo-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazaocten-7-amine

To a suspension of 9-bromo-7-nitro-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazacyclooctene (433g, 1.51mol) and ammonium chloride (410g, 7.67mol) in methanol (2.5L) and water (2.5L) was added iron powder (280g, 5.01mol) portionwise at 55°C and the reaction mixture was stirred at 70°C in a sealed container for 2h. The resulting mixture was filtered and the solid was thoroughly washed with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 242g (crude) of the title compound as a brown oil. The substance was used without further purification. LCMS(ESI): [M+H] ⁺ =257/259.

Step 5: 4-Bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

9-Bromo-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazaocten-7-amine (180 g, 700 mmol) and 4-methylbenzenesulfonic acid (18 g, 105 mmol) were dissolved in trimethyl orthoformate (2 L), and the reaction mixture was stirred at 100°C for 16 h. The resulting mixture was evaporated in vacuo and the product was purified via silica gel flash chromatography (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 126 g (67%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ = 267/269.

Step 6: 4-Bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

To a solution of 4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]indene (12 g, 44.9 mmol) in THF (1.5 L) was added LDA (2N solution in THF, 45 mL, 90.0 mmol) dropwise at -78 ° C and the reaction mixture was stirred at -78 ° C for 1 h. A solution of 1-iodopyrrolidine-2,5-dione (20.2 g, 89.8 mmol) in THF (200 mL) was added dropwise at -78 ° C and the reaction mixture was stirred at -78 ° C for 2 h. The resulting mixture was quenched with water and extracted with DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 8.8 g (50%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =393/395; ¹ H NMR (300MHz, DMSO-d ₆ ): δ7.59 (d, J = 1.8Hz, 1H), 7.05 (d, J = 1.5Hz, 1H), 4.45-4.41 (m, 2H), 4.27-4.23 (m, 2H), 1.99-1.92(m,2H),1.54-1.48(m,2H).

Step 7: 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine

A mixture of 5-bromobenzo[d]oxazol-2-amine (20.0 g, 93.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (28.6 g, 113 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (6.87 g, 9.39 mmol) and potassium acetate (27.6 g, 282 mmol) in DMF (200 mL) was stirred at 80 ° C under nitrogen for 6 h. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 10.5 g (43%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ = 261.

Step 8: 5-(4-Bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-1-yl)benzo[d]oxazol-2-amine

A mixture of 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]indene (1.20 g, 3.05 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (790 mg, 3.04 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (220 mg, 0.301 mmol) and sodium carbonate (2M aqueous solution, 3 mL, 6 mmol) in DMF (15 mL) was heated at 80 ° C for 45 min under microwave irradiation. The resulting solution was diluted with water and extracted with DCM. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 660 mg (54%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =399/401.

Step 9: 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaoctino[cd]inden-1-yl)benzo[d]oxazol-2-amine

The title compound (400 mg, 41% yield) was prepared from 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]oxazol-2-amine (700 mg, 1.75 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (891 mg, 3.51 mmol) following a procedure analogous to that described in Step 1 of Example 162. LCMS (ESI): [M+H] ⁺ = 447.

Step 10: 1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol

The title compound (281 mg, 98% yield) was prepared from 5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaoctino[cd]inden-1-yl)benzo[d]oxazol-2-amine (380 mg, 0.851 mmol) following a procedure analogous to that described in Step 2 of Example 162. LCMS (ESI): [M+H] ⁺ = 337.

Step 11: (S)-methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate

The title compound (700 mg, 56% yield) was prepared from 1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol (1.00 g, 2.97 mmol) and (R)-methyl 2-(tosyloxy)propanoate (1.15 g, 4.45 mmol) following a procedure similar to that described in Step 3 of Example 162. LCMS (ESI): [M+H] ⁺ = 423.

Step 12: The reaction vessel was charged with (S)-methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate (600 mg, 1.42 mmol) and 7N ammonia/methanol (6 mL). The reaction mixture was stirred at room temperature for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified via silica gel flash chromatography (solvent gradient: 5-10% methanol/DCM) followed by purification by chiral SFC and lyophilization to afford 309 mg (55%) of 204 as a light yellow solid. LCMS (ESI): _RT (min) = 1.47, [M+H] ⁺ = 408, method = D; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.61-7.44 (m, 5H), 7.29-7.26 (m, 2H), 6.92 (d, J = 2.1 Hz, 1H), 6.59 (d, J = 2.1 Hz, 1H), 4.66-4.59 (m, 1H), 4.39-4.35 (m, 2H), 4.26-4.23 (m, 2H), 2.11 (app s, 2H), 1.69 (app s, 2H), 1.45 (d, J = 8.8 Hz, 3H).

Example 205 (S)-2-((1-(2-amino-7-methylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 205

Step 1: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-methylbenzo[d]oxazol-2-amine

A reaction vessel was charged with 5-bromo-7-methylbenzo[d]oxazol-2-amine (200 mg, 0.88 mmol), bis(pinacolato)diboron (268 mg, 1.06 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloridopalladium dichloromethane complex (71.9 mg, 0.09 mmol), and potassium acetate (259 mg, 2.64 mmol) dissolved in 1,4-dioxane (2.6 mL). The reaction mixture was degassed under argon and then stirred at 110°C for 2 h. The resulting mixture was cooled to room temperature, and then 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (334 mg, 0.88 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride dichloromethane complex (71.9 mg, 0.088 mmol) and 2N aqueous sodium carbonate solution (1.75 mL, 3.52 mmol) were added. The reaction mixture was degassed under argon and stirred at 100 ° C for 24 h. The resulting mixture was cooled to room temperature and distributed between DCM and distilled water. The organic layer was separated, dried over magnesium sulfate and evaporated in vacuo. The residue was purified via silica gel flash chromatography (solvent gradient: 0-5% methanol/ethyl acetate) to give 128 mg (36%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =399/401.

Step 2: (S)-2-((1-(2-amino-7-methylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid

The title compound (148 mg, 58% yield) was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-methylbenzo[d]oxazol-2-amine (235 mg, 0.59 mmol) and (S)-2-amino-2-cyclopropylacetic acid (135 mg, 1.17 mmol) following a procedure similar to that described in Step 3 of Example 125. LCMS (ESI): [M+H] ⁺ = 434.

Step 3: 205 (24.3 mg, 16% yield) was prepared from (S)-2-((1-(2-amino-7-methylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid (148 mg, 0.34 mmol) following a procedure similar to that of Example 125, step 4. LCMS (ESI): R _T (min) = 2.52, [M+H] ⁺ = 433, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.51 (br s, 2H),7.33-7.32(m,2H),7.18-7.17(m,1H),6.96-6.95(m,1H),6.36(d,J＝2.0Hz, 1H),6.22(d,J＝2.0Hz,1H),5.44(d,J＝7.4Hz,1H),4.32-4.14(m,4H),3.14(t, J＝7.4Hz,1H),2.42(s,3H),2.26-2.20(m,2H),1.15-1.06(m,1H),0.54-0.44(m,3H),0.34-0.28(m,1H).

Example 206 (S)-1-(1-(3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 206

Step 1: 7-Chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridine

A mixture of 7-chloro-3H-[1,2,3]triazolo[4,5-b]pyridine (1.00 g, 6.47 mmol), cesium carbonate (4.22 g, 12.9 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.22 g, 7.79 mmol) in DMF (15 mL) was stirred at 25 ° C for 3 h. The resulting mixture was diluted with water and extracted with DCM. The organic extract was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 900 mg (51%) of the title compound as a white solid. LCMS: [M+H] ⁺ =275.

Step 2: 3-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine

A mixture of 7-chloro-3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridine (1.50 g, 5.46 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (400 mg, 0.547 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.66 g, 6.54 mmol) and potassium acetate (1.07 g, 10.9 mmol) in 1,4-dioxane (20 mL) was stirred at 100 ° C for 16 h. The resulting mixture was cooled to room temperature. The solid was filtered off and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 1.00 g (50%) of the title compound as a yellow solid. LCMS (53): [M+H] ⁺ =367.

Step 3: 4-Bromo-1-(3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (300 mg, 22% yield) was prepared from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (Example 150, Step 2) (1.03 g, 2.72 mmol) and 3-(4-methoxybenzyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-[1,2,3]triazolo[4,5-b]pyridine (1.00 g, 2.73 mmol) following a procedure similar to that of Example 150, Step 3. LCMS (ESI): [M+H] ⁺ = 491/493.

Step 4: (S)-1-(1-(3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide

The title compound (150 mg, 40% yield over two steps) was prepared from 4-bromo-1-(3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (350 mg, 3.04 mmol) following a procedure similar to that described in Steps 1-2 of Example 104. LCMS (ESI): [M+H] ⁺ = 525.

Step 5: A mixture of (S)-1-(1-(3-(4-methoxybenzyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide in TFA was stirred at 80 °C for 4 h. The resulting mixture was diluted with water and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 13.1 mg (11%) of 206 as a yellow solid. LCMS: R _T (min) = 4.5, [M+H] ⁺ = 405, method = D; ¹ HNMR (300MHz, DMSO-d ₆ ) δ 16.44 (s, 1H), 8.84 (d, J = 4.8Hz, 1H), 7.85 (d, J = 4.5Hz, 1H), 7.36 (s, 1H),7.05(s,1H),6.47(d,J＝2.1Hz,1H),6.22(d,J＝2.1Hz,1H),4.42(d,J＝3.9Hz, 4H),3.90-3.87(m,1H),3.64-3.59(m,1H),3.26-3.21(m,1H),2.33-2.28(m,3H), 2.27-2.21(m,3H).

Example 207 (S)-2-((1-(2-aminobenzo[d]oxazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 207

Step 1: 6-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine

The title compound (720 mg, 32% yield) was prepared from 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (1.50 g, 5.77 mmol) and 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (Example 150, Step 2) (2.70 g, 7.12 mmol) following a procedure similar to that of Example 204, Step 8. LCMS (ESI): [M+H] ⁺ = 385/387.

Step 2: 207 (40.3 mg, 11.2% yield over two steps) was prepared from 6-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine (220 mg, 0.571 mmol) and (2S)-2-amino-2-cyclopropylacetic acid (330 mg, 2.87 mmol) following a procedure similar to that of Example 104, steps 1-2. LCMS (ESI): R _T (min) = 1.16, [M+H] ⁺ = 419, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.71-7.76 (m, 3H), 7.51-7.48 (m, 1H), 7.35-7.29 (m, 2H),6.98(s,1H),6.36(d,J＝2.1Hz,1H),6.28(d,J＝2.1Hz,1H),5.46(d,J＝7.2Hz, 1H),4.34-4.23(m,4H),3.16-3.11(m,1H),2.24(d,J＝3.9Hz,2H),1.14-1.08(m, 1H),0.51-0.47(m,3H),0.31-0.29(m,1H).

Example 208 (S)-2-((2-(2-aminobenzo[d]oxazol-5-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)amino)-2-cyclopropylacetamide 208

Step 1: 7-Bromo-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 2-amino-5-bromo-3-nitrophenol (7.5g, 32.2mmol) and 1,2-dibromoethane (16.6mL, 193mmol) in DMF (40mL) was added potassium hydroxide (3.61g, 64.4mmol) and the reaction mixture was stirred at 140 ° C for 10h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic portion was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with methanol to obtain the first batch of product, which was a red solid. The mother liquor was purified via silica gel flash chromatography (solvent gradient: 0-70% ethyl acetate/cyclohexane). The resulting product was combined with the first batch to obtain 4.24g (51%) of the title compound as a red solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.48 (br s, 1H), 7.75 (d, J=2.3Hz, 1H), 7.19 (dd, J=2.3, 0.8Hz, 1H), 4.21 (t, J=9.2Hz, 2H), 3.57-3.51 (m, 2H).

Step 2: 7-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine

To a suspension of 7-bromo-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.24 g, 16.4 mmol) and ammonium chloride (7.88 g, 147 mmol) in methanol (75 mL) and water (75 mL) was added iron powder (5.48 g, 98.2 mmol) and the reaction mixture was heated at 55 ° C for 2 h. The reaction mixture was filtered through celite and concentrated in vacuo to remove methanol. The aqueous residue was extracted with ethyl acetate. The combined organic portions were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 3.69 g (75%) of the crude title compound as a brown oil. ¹ H NMR (400MHz, CDCl ₃ ) δ 6.52 (d, J = 2.3 Hz, 1H), 6.46 (d, J = 2.3 Hz, 1H), 4.17-4.14 (m, 2H), 3.41-3.36 (m, 2H).

Step 3: 7-Bromo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene

A solution of 7-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (3.20 g, 13.9 mmol) and p-toluenesulfonic acid (0.04 g, 0.2 mmol) in trimethyl orthoformate (10 mL, 91.4 mmol) was heated at reflux for 1 h. The reaction mixture was dry-loaded onto celite and purified via silica gel flash chromatography (solvent gradient: 0-5% methanol/DCM) to give 2.70 g (81%) of the title compound as a beige solid. LCMS (ESI): [M+H] ⁺ = 239/241.

Step 4: 7-Bromo-2-iodo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene

To a solution of diisopropylamine (2.5 mL, 18.1 mmol) in THF (30 mL) was added n-butyl lithium (6.32 mL, 2.5 N in hexane, 15.8 mmol) dropwise at -40 ° C and the reaction mixture was allowed to warm to -20 ° C. The reaction mixture was cooled to -78 ° C and a solution of 7-bromo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (2.70 g, 11.3 mmol) in THF (20 mL) was added. The reaction mixture was stirred at -78 ° C for 2 h. A solution of iodine (4.01 g, 15.8 mmol) in THF (12 mL) was added dropwise and the reaction mixture was stirred at -78 ° C for 2 h. The resulting mixture was diluted with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-100% ethyl acetate/cyclohexane) to give 2.55 g (62%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ =365/367.

Step 5: 5-(7-Bromo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-2-yl)benzo[d]oxazol-2-amine

A mixture of 7-bromo-2-iodo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (200 mg, 0.55 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoxazol-2-ylamine (214 mg, 0.83 mmol), cesium carbonate (303 mg, 0.93 mmol) and tetrakis(triphenylphosphine)palladium(0) (63 mg, 0.05 mmol) in 1,4-dioxane (5.0 mL) and water (0.5 mL) was degassed with argon. The reaction mixture was heated at 100° C. for 16 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-100% ethyl acetate/cyclohexane) to afford 80 mg (40%) of the title compound as a beige solid. LCMS (ESI): [M+H] ⁺ =371/373.

Step 6: (S)-2-((2-(2-aminobenzo[d]oxazol-5-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)amino)-2-cyclopropylacetic acid

A mixture of 5-(7-bromo-3,4-dihydro-5-oxa-1,2a-diazaacenaphthen-2-yl)benzo[d]oxazol-2-amine (80 mg, 0.22 mmol), (S)-aminocyclopropylacetic acid (50 mg, 0.43 mmol), copper(I) iodide (8 mg, 0.04 mmol) and potassium phosphate (91 mg, 0.43 mmol) was dissolved in DMSO (1.2 mL) and the mixture was degassed with argon. The reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was purified via silica gel flash chromatography (solvent gradient: 0-50% (2N ammonia/methanol)/DCM) to give 63 mg (72%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ =406.

Step 7: To a solution of (S)-2-((2-(2-aminobenzo[d]oxazol-5-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)amino)-2-cyclopropylacetic acid (63 mg, 0.16 mmol), ammonium chloride (17 mg, 0.31 mmol), and triethylamine (65 μL, 0.47 mmol) in DMF (2.0 mL) was added HATU (89 mg, 0.23 mmol) and the reaction was stirred at room temperature for 1.5 h. The reaction mixture was purified on silica gel (solvent gradient: 0-15% ammonia methanol/DCM) and then purified via reverse phase HPLC to afford 16 mg (25%) of 208 as a white solid. LCMS (ESI): R _T (min) = 2.28, [M+H] ⁺ = 405, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.68 (d, J = 1.6 Hz, 1H), 7.56 (br, s, 2H), 7.53 (dd, J＝8.4,1.6Hz,1H),7.46(d,J＝8.4Hz,1H),7.35(d,J＝2.1Hz,1H),6.97(d,J＝2.1Hz, 1H),6.28(d,J＝1.6Hz,1H),6.23(d,J＝1.6Hz,1H),5.49(d,J＝7.3Hz,1H), 4.59-4.49(m,2H),4.44-4.36(m,2H),3.13(t,J＝7.8Hz,1H),1.17-1.05(m,1H), 0.56-0.44(m,3H),0.36-0.27(m,1H).

Example 209 (S)-2-((1-(2-amino-7-chlorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 209

Step 1: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-chlorobenzo[d]oxazol-2-amine

The title compound (180 mg, 28% yield) was prepared from 5-bromo-7-chlorobenzo[d]oxazol-2-amine (370 mg, 1.50 mmol) following a procedure similar to that described in Example 205, Step 1. LCMS (ESI): [M+H] ⁺ =418/420.

Step 2: (S)-2-((1-(2-amino-7-chlorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid

The title compound (72.9 mg, 37% yield) was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-chlorobenzo[d]oxazol-2-amine (180 mg, 0.428 mmol) and (S)-2-amino-2-cyclopropylacetic acid (98.6 mg, 0.856 mmol) following a procedure similar to that described in Step 3 of Example 125. LCMS (ESI): [M+H] ⁺ = 454.

Step 3: 209 (4.1 mg, 6% yield) was prepared from (S)-2-((1-(2-amino-7-chlorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid (72.9 mg, 0.161 mmol) following a procedure similar to that of Example 125, step 4. LCMS (ESI): R _T (min) = 2.62, [M+H] ⁺ = 453, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.88 (br s, 2H),7.45(d,J＝1.4Hz,1H),7.40(d,J＝1.4Hz,1H),7.33(d,J＝2.0Hz,1H),6.96(d, J＝2.0Hz,1H),6.36(d,J＝2.0Hz,1H),6.25(d,J＝2.0Hz,1H),5.47(d,J＝6.0Hz,1H), 4.32-4.17(m,4H),3.14(t,J＝6.0Hz,1H),2.27-2.22(m,2H),1.15-1.06(m,1H), 0.54-0.43(m,3H),0.33-0.27(m,1H).

Example 210 (S)-2-Cyclopropyl-2-((1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 210

Step 1: 4-Bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (490 mg, 42% yield) was prepared from 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-amine (900 mg, 3.70 mmol) and 1-tert-butyl pyrazole-1,4-dicarboxylate (865 mg, 4.07 mmol) following procedures similar to those in Steps 1 and 2 of Example 160. LCMS (ESI): [M+H] ⁺ = 319/321.

Step 2: 4-Bromo-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

To a solution of 4-bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (270 mg, 0.85 mmol) in DMF (11 mL) was added cesium carbonate (414 mg, 1.27 mmol) followed by 3-bromooxetane (105 μL, 1.27 mmol), and the reaction mixture was stirred at 90° C. for 3 h. The resulting mixture was cooled to room temperature and filtered. The solid was collected, washed with water, and dried to give 190 mg (60%) of the title compound. LCMS (ESI): [M+H] ⁺ = 375/377.

Step 3: 4-Bromo-1-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (190 mg, 0.51 mmol), (S)-aminocyclopropylacetic acid (152 mg, 1.28 mmol), copper(I) iodide (21 mg, 0.10 mmol), and potassium phosphate (435 mg, 2.04 mmol) were suspended in DMSO (2.0 mL) and degassed with nitrogen. The reaction mixture was heated at 100° C. for 16 h and then cooled to room temperature. To this mixture were added ammonium chloride (172 mg, 3.06 mmol), triethylamine (0.761 mL, 5.1 mmol), and HATU (1.2 g, 3.06 mmol) portionwise. The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was purified via silica gel flash chromatography (solvent gradient: 0-30% (2N ammonia/methanol)/DCM) and further purified on HPLC (solvent gradient: 10-40% acetonitrile/water (containing 0.1% formic acid)) to afford 70 mg (34%) of 210. LCMS (ESI): R _T (min) = 2.26, [M+H] ⁺ = 409, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.48 (s, 1H), 8.12 (s, 1H), 7.32 (br s, 1H), 6.95 (br s, 1H),6.32(d,J＝1.9Hz,1H),6.17(d,J＝1.9Hz,1H),5.67(quint,J＝6.4Hz,1H), 5.42(br s,1H),4.96(d,J＝7.0Hz,4H),4.34-4.28(m,4H),3.13-3.08(m,1H), 2.33-2.27(m,2H),1.15-1.05(m,1H),0.53-0.45(m,3H),0.32-0.26(m,1H).

Example 211 (S)-2-cyclopropyl-2-((1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 211

Step 1: 4-Bromo-1-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (350 mg, 100%) was prepared from 4-bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (250 mg, 0.78 mmol) and 2-(2-bromo-ethoxy)-tetrahydropyran (177 μL, 1.17 mmol) following a procedure similar to that described in Example 210, Step 2. LCMS (ESI): [M+H] ⁺ = 447/449.

Step 2: (2S)-2-Cyclopropyl-2-((1-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (380 mg, 100%) was prepared from 4-bromo-1-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (350 mg, 0.78 mmol) following a procedure similar to that described in Step 3 of Example 210. LCMS (ESI): [M+H] ⁺ = 482.

Step 3: (S)-2-Cyclopropyl-2-((1-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

To a solution of (2S)-2-cyclopropyl-2-((1-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide (376 mg, 0.78 mmol) in DCM (8.0 mL) was added trifluoroacetic acid (2 mL) dropwise and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was poured onto a 10 g SCX-2 column. The column was washed with acetonitrile and methanol, then eluted with 2N ammonia in methanol. The eluent was collected and the solvent was evaporated. The residue was purified via reverse phase HPLC to afford 34 mg (11%) of 211. LCMS (ESI): R _T (min) = 2.14, [M+H] ⁺ = 397, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 7.97 (s, 1H), 7.32 (br s, 1H), 6.94 (br s,1H),6.31(d,J＝1.9Hz,1H),6.16(d,J＝1.9Hz,1H),5.42(br s,1H),4.95(t,J＝5.0Hz,1H),4.34-4.27(m,4H),4.23(t,J＝5.3Hz,2H), 3.79(q,J＝5.3Hz,2H),3.11(d,J＝7.6Hz,1H),2.33-2.27(m,2H),1.15-1.05(m,1H), 0.54-0.43(m,3H),0.32-0.26(m,1H).

Example 212 (S)-2-((1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)-2-cyclopropylacetamide 212

Step 1: 4-Bromo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

To a suspension of 4-bromo-1-(1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (250 mg, 0.78 mmol) in toluene (5.0 mL) was added trifluoroacetic acid (10 μL), followed by dihydropyran (107 μL, 1.18 mmol), and the mixture was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated to give 310 mg (98%) of the title compound. LCMS (ESI): [M+H] ⁺ = 403/405.

Step 2: (2S)-2-Cyclopropyl-2-((1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide

The title compound (320 mg, 100% yield) was prepared from 4-bromo-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (300 mg, 0.74 mmol) following a procedure similar to that described in Step 3 of Example 210. LCMS (ESI): [M+H] ⁺ = 438.

Step 3: 212 (70 mg, 27% yield) was prepared from (2S)-2-cyclopropyl-2-((1-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide (320 mg, 0.74 mmol) following a procedure similar to that of Step 3 of Example 211. LCMS (ESI): R _T (min) = 2.16, [M+H] ⁺ = 353, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.3 (br s, 1H), 8.27 (br s,1H),8.07(brs,1H),7.32(s,1H),6.95(s,1H),6.32(d,J＝1.9Hz, 1H),6.17(d,J＝1.9Hz,1H),5.45(brs,1H),4.35-4.27(m,4H),3.11(d,J＝7.6Hz, 1H),2.34-2.25(m,2H),1.15-1.05(m,1H),0.54-0.43(m,3H),0.32-0.26(m,1H).

Example 213 (S)-2-cyclopropyl-2-((1-(6-methoxypyridin-3-yl)-1,7,8,9-tetrahydrooxa[4,3,2-cd]indazol-4-yl)amino)acetamide 213

Step 1: Methyl 4-(3-bromo-5-fluorophenoxy)butyrate

To a solution of 3-bromo-5-fluoro-phenol (5.24mmol, 1.0g) in acetone (20mL) was added potassium iodide (0.26mmol, 43mg), potassium carbonate (5.76mmol, 800mg) and methyl 4-bromobutyrate (5.76mmol, 0.73mL). The reactants were heated at reflux overnight. The mixture was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate, the organic extracts were combined, washed with brine, dried over sodium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography (solvent gradient: 0-30% ethyl acetate/heptane) to give 1370mg (90%) of the title compound.

Step 2: 4-(3-bromo-5-fluorophenoxy)butyric acid

To a solution of methyl 4-(3-bromo-5-fluorophenoxy)butanoate (4.71mmol, 1370mg) in methanol (10mL) and water (1mL) was added lithium hydroxide (9.41mmol, 225mg) and the reaction mixture was heated at 60°C overnight. After overnight, methanol was removed in vacuo. The mixture was partitioned between DCM and water and the phases were separated. The aqueous layer was extracted with DCM, the organic extracts were combined, washed with brine, dried over sodium sulfate and the solvent was evaporated to give the title compound (1300mg, 99% yield), which was used directly in the next step.

Step 3: 8-Bromo-6-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one and 6-Bromo-8-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one

To a solution of 4-(3-bromo-5-fluorophenoxy)butanoic acid (1.80mmol, 500mg) in DCM (10mL) was added thionyl chloride (3.61mmol, 0.263mL) dropwise. The reactant was stirred at 50°C for 4 hours. After 4 hours, the solvent was removed. DCM (10mL) and aluminum chloride (2.71mmol, 361mg) were added to the resulting residue at 0°C. The reaction mixture was stirred at room temperature overnight and then carefully quenched with water. The mixture was distributed between DCM and water and the phases were separated. The aqueous layer was extracted with DCM, the organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (solvent gradient: 0-30% ethyl acetate/heptane) to give the title compound (220mg, 47% combined yield), which is a 1:1 mixture of two regioisomers. LCMS (ESI): [M+H] ⁺ =259/261.

Step 4: 4-Bromo-1-(6-methoxypyridin-3-yl)-1,7,8,9-tetrahydrooxa[4,3,2-cd]indazole

To a solution of a mixture of 8-bromo-6-fluoro-3,4-dihydro-2H-1-benzoxan-5-one (0.386 mmol, 100 mg) and 6-bromo-8-fluoro-3,4-dihydro-2H-1-benzoxan-5-one (100 mg) in pyridine (5 mL) was added (6-methoxy-3-pyridyl)hydrazine dihydrochloride (0.772 mmol, 164 mg). The reaction mixture was heated at 60 ° C. The mixture was partitioned between DCM and water and the phases were separated. The aqueous layer was extracted with DCM, the organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (solvent gradient: 0-80% (isopropyl acetate / methanol (3: 1)) / heptane) to give 8-bromo-6-[2-(6-methoxy-3-pyridyl) hydrazine] -3,4-dihydro-2H-1-benzoxan-5-one (100 mg). Methanol (1 mL) was added to the residue, followed by zinc (0.529 mmol, 35 mg) and ammonium chloride (0.793 mmol, 42 mg). The reaction mixture was stirred at room temperature for 20 min. The resulting slurry was diluted with water and filtered. The filtrate was then extracted with DCM and dried over magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel chromatography (solvent gradient: 0-40% (isopropyl acetate / methanol (3: 1)) / heptane) to give the desired product (60 mg). LCMS (ESI): [M+H] ⁺ = 360.

Step 5: (S)-2-Cyclopropyl-2-((1-(6-methoxypyridin-3-yl)-1,7,8,9-tetrahydrooxa[4,3,2-cd]indazol-4-yl)amino)acetic acid was prepared from 4-bromo-1-(6-methoxypyridin-3-yl)-1,7,8,9-tetrahydrooxa[4,3,2-cd]indazole (45 mg, 0.125 mmol) and (S)-2-amino-2-cyclopropylacetic acid following a procedure analogous to that of Example 125, Step 3. LCMS (ESI): [M+H] = 395. The crude product was used directly in the next step and 213 (5.9 mg) was prepared following a procedure analogous to that of Example 125, Step 4. LCMS (ESI): R _T (min) = 4.17, [M+H] ⁺ = 394.1, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.40 (dd, J＝2.8,0.7Hz,1H),7.92(dd,J＝8.9,2.8Hz,1H),7.36(d,J＝2.3Hz,1H),6.99(d, J＝0.6Hz,1H),6.97(d,J＝0.6Hz,1H),6.20(d,J＝1.6Hz,1H),6.16(d,J＝7.0Hz,1H), 6.09(d,J＝1.6Hz,1H),4.31-4.33(m,2H),3.92(s,3H),3.21-3.12(m,1H),3.00(t, J＝6.2Hz,2H),2.17-2.11(m,2H),1.16-1.03(m,1H),0.57-0.41(m,3H),0.33-0.23(m,1H).

Example 214 (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)amino)-2-cyclopropylacetamide 214

Step 1: tert-Butyl 6-bromobenzo[d]thiazol-2-ylcarbamate

A mixture of 6-bromobenzo[d]thiazol-2-amine (14.7 g, 64.2 mmol), di-tert-butyl dicarbonate (14.0 g, 64.1 mmol) and N,N-dimethylpyridin-4-amine (40.0 mg, 0.327 mmol) in DCM (200 mL) was stirred at room temperature for 24 h and then filtered. The filtrate was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% ethyl acetate/petroleum ether) to give 7.26 g (34%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =329/331.

Step 2: tert-Butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-ylcarbamate

A mixture of tert-butyl 6-bromobenzo[d]thiazol-2-ylcarbamate (2.00 g, 6.07 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2.32 g, 9.12 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (444 mg, 0.607 mmol) and potassium acetate (1.78 g, 18.2 mmol) in 1,4-dioxane (60.0 mL) was degassed with argon. The reaction mixture was heated at 100 ° C for 16 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% ethyl acetate/petroleum ether) to give 1.17 g (51%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =377.

Step 3: Tert-butyl (6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound (768 mg, 48% yield) was prepared from tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-ylcarbamate (1.17 g, 3.12 mmol) and 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaoctano[cd]indene (Example 204, Step 6) (1.47 g, 3.75 mmol) following a procedure similar to that of Example 204, Step 8. LCMS (ESI): [M+H] ⁺ = 515/517.

Step 4: (S)-tert-Butyl(6-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound (380 mg, crude) was prepared from tert-butyl (6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (380 mg, 0.737 mmol) and (S)-2-amino-2-cyclopropylacetic acid (420 mg, 3.64 mmol) following a procedure similar to that described in Steps 1-2 of Example 104. LCMS (ESI): [M+H] ⁺ = 549.

Step 5: To a solution of tert-butyl (S)-(6-(4-((2-amino-1-cyclopropyl-2-oxoethyl)amino)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (380 mg crude) in DCM (5 mL) was added TFA (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min. The pH value of the reaction mixture was adjusted to 7 with sodium bicarbonate (1 mol/L aqueous solution) and then extracted with DCM. The organic portion was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-50% methanol/DCM) and then purified via reverse phase HPLC and lyophilized to afford 42.5 mg (14%) of 214 as a white solid. LCMS (ESI): _RT (min) = 1.22, [M+H] ⁺ = 449, method = E; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.96 (d, J = 1.2 Hz, 1H), 7.70 (s, 2H), 7.60-7.45 (m, 3H), 7.00 (s, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.37 (d, J = 1.8 Hz, 1H), 5.58 (d, J = 7.2 Hz, 1H), 4.38-4.28 (m, 2H), 4.23-4.15 (m, 2H), 3.17-3.07(m,1H),2.14-2.08(m,2H),1.71-1.65(m,2H),1.17-1.05(m,1H), 0.55-0.42(m,3H),0.37-0.27(m,1H).

Example 215 (S)-2-Cyclopropyl-2-((1-(8-fluoroquinoxalin-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)acetamide 215

215 was prepared following the procedure of Example 158. LCMS: _RT (min) = 4.50, [M+H] ⁺ = 433, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 9.10 (m, 2H), 8.33 (m, 1H), 8.14 (m, 1H), 7.37 (d, J = 2.7 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.41 (d, J = 1.9 Hz, 1H), 6.32 (d, J = 2.0 Hz, 1H), 5.59 (d, J = 7.3 Hz, 1H), 4.48-4.32 (m, 4H), 3.20-3.05 (m, 1H), 2.40-2.15(m,2H),1.20-1.00(m,1H),0.60-0.40(m,3H),0.35-0.20(m,1H).

Examples 216 and 217 (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)butanamide 216 and (S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)butanamide 217

Following procedures analogous to Examples 230 and 231, 216 and 217 were prepared as single unknown isomers.

216 (31.0mg): LCMS (ESI): R _T (min) = 2.53, [M+H] ⁺ = 458, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.24 (s, 1H), 7.91 (s, 1H), 7.58 (br s, 3H), 7.53 (br s, 1H),7.51(d,J＝1.5Hz,1H),7.50(d,J＝8.1Hz,1H),7.40(dd,J＝8.1,1,5Hz,1H), 7.27(br s,1H),7.04(d,J＝1.5Hz,1H),4.75(t,J＝7.8Hz,1H),4.44-4.40(m,2H), 4.30 (t, J = 5.2 Hz, 2H), 2.35-2.29 (m, 2H), 2.08 (apparent quintet, J = 7.3 Hz, 2H), 0.85 (t, J = 7.8 Hz, 3H).

217 (34.6mg): LCMS (ESI): R _T (min) = 2.53, [M+H] ⁺ = 458, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 7.91 (s, 1H), 7.58 (br s, 3H), 7.53 (br s, 1H),7.51(d,J＝1.5Hz,1H),7.50(d,J＝8.1Hz,1H),7.40(dd,J＝8.1,1,5Hz,1H), 7.27(br s,1H),7.04(d,J＝1.5Hz,1H),4.75(t,J＝7.8Hz,1H),4.44-4.40(m,2H), 4.30 (t, J = 5.2 Hz, 2H), 2.35-2.29 (m, 2H), 2.08 (apparent quintet, J = 7.3 Hz, 2H), 0.85 (t, J = 7.8 Hz, 3H).

Examples 218 and 219 (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)propanamide 218 and (S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)propanamide 219

The title compounds were prepared following procedures analogous to Examples 230 and 231, each as a single unknown isomer.

218 (45.2mg): LCMS (ESI): R _T (min) = 2.35, [M+H] ⁺ = 444, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 7.91 (s, 1H), 7.58 (br s, 3H), 7.52 (d, J＝1.5Hz,1H),7.50(d,J＝8.1Hz,1H),7.46(br s,1H),7.39(dd,J＝8.1,1.5Hz,1H), 7.24(br s,1H),7.05(d,J＝1.5Hz,1H),4.96(q,J＝7.4Hz,1H),4.44-4.40(m,2H), 4.30(t,J＝5.2Hz,2H),2.35-2.29(m,2H),1.65(d,J＝7.4Hz,3H).

219 (42.5mg): LCMS (ESI): R _T (min) = 2.35, [M+H] ⁺ = 444, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.24 (s, 1H), 7.91 (s, 1H), 7.58 (br s, 3H), 7.52 (d, J＝1.5Hz,1H),7.50(d,J＝8.1Hz,1H),7.46(br s,1H),7.39(dd,J＝8.1,1.5Hz,1H), 7.24(br s,1H),7.05(d,J＝1.5Hz,1H),4.96(q,J＝7.4Hz,1H),4.44-4.40(m,2H), 4.30(t,J＝5.2Hz,2H),2.35-2.29(m,2H),1.65(d,J＝7.4Hz,3H).

Example 220 (S)-1-(1-(2-oxo-3,4-dihydro-2H-benzo[4,5]oxazolo[3,2-a]pyrimidin-7-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 220

A mixture of (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide (150 mg, 0.358 mmol) from Example 104, 3-bromopropionic acid (83.4 mg, 0.545 mmol), HATU (307 mg, 0.808 mmol) and DIPEA (0.400 mL) in DMF (12.0 mL) was heated at 60 ° C for 6 h. The reaction was repeated additionally on the same scale. The two reaction mixtures were combined, diluted with water, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-13% methanol/DCM) to give the crude product. The crude product was triturated with DMF and DMSO. The solid was collected to give 58.9 mg (35%) of 220 as an off-white solid. LCMS (ESI): _RT (min) = 2.34 min, [M+H] ⁺ = 473, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ): δ 7.86 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.03 (s, 1H), 6.35 (d, J = 1.5 Hz, 1H), 6.10 (d, J = 1.2 Hz, 1H), 4.37-4.23 (m, 6H), 3.86-3.83 (m, 1H), 3.60-3.58 (m, 1H),3.20-3.10(m,1H),2.76-2.70(m,2H),2.28-2.19(m,3H),2.08-1.97(m,3H).

Example 221 (S)-1-(1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 221

221 was prepared using commercially available 3-(4-bromophenyl)-1H-1,2,4-triazole and following a procedure similar to Example 158. LCMS: R _T (min) = 3.00, [M+H] ⁺ = 430, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 14.22 (s, 1H), 8.68 (s, 1H), 8.17 (d, J = 8.1Hz, 2H), 7.90 (d, J = 7.8Hz, 2H),7.31(d,J＝2.3Hz,1H),7.03(s,1H),6.37(d,J＝2.1Hz,1H),6.09(d,J＝2.1Hz, 1H),4.37-4.29(m,4H),3.90-3.80(m,1H),3.70-3.60(m,1H),3.30-3.08(m,1H), 2.35-2.15(m,3H),2.09-1.87(m,3H).

Example 222 (S)-1-(1-(3-chloro-4-(1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 222

Step 1: 4-Bromo-2-chlorobenzamide

To a solution of 4-bromo-2-chlorobenzoic acid (10.0 g, 42.5 mmol) in DCM (100 mL) was added oxalyl chloride (21.5 g, 0.169 mol) portionwise at 0 ° C over 10 min, followed by the addition of DMF (1 mL). The reaction mixture was stirred at room temperature for 60 min, and then the solvent was removed in vacuo. The residue was dissolved in THF (400 mL), and then ammonium hydroxide (312 mL 25-28% aqueous solution) was added dropwise at 0 ° C. The reaction mixture was allowed to warm to room temperature and stirred for another 60 min. THF was removed in vacuo and the residue was filtered. The solid was collected, washed with water and dried to give 8.66 g (87%) of the title compound. LCMS (ESI): [M+H] ⁺ = 234/236.

Step 2: 3-(4-bromo-2-chlorophenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole

4-Bromo-2-chlorobenzamide (8.00 g, 34.1 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (50 mL). The resulting mixture was stirred at 130 ° C for 120 min, and then the solvent was removed in vacuo. The residue was dissolved in acetic acid (100 mL), and then (4-methoxybenzyl) hydrazine (7.10 g, 0.046 mol) was added. The reaction mixture was stirred at 100 ° C for 60 min. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 50% ethyl acetate/petroleum ether) to give 3.5 g (27%) of the title compound as a yellow oil. LCMS (ESI): [M+H] ⁺ = 378/380.

Step 3: 3-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole

The title compound (2.2 g, 98% yield) was prepared from 3-(4-bromo-2-chlorophenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (2.00 g, 5.28 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.6 g, 6.30 mmol) following a procedure similar to that of Example 158, Step 2. LCMS (ESI): [M+H] ⁺ = 426.

Step 4: 4-Bromo-1-(3-chloro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (700 mg, 24% yield) was prepared from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (2.00 g, 5.28 mmol) and 3-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (2.69 g, 6.32 mmol) following a procedure analogous to that described in Step 3 of Example 150. LCMS (ESI): [M+H] ⁺ = 550/552.

Step 5: (S)-1-(1-(3-chloro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide

The title compound (200 mg, 36% yield) was prepared from 4-bromo-1-(3-chloro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (600 mg, 1.09 mmol) following a procedure similar to that described in Steps 1-2 of Example 104. LCMS (ESI): [M+H] ⁺ = 584.

Step 6: A mixture of (S)-1-(1-(3-chloro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide (200 mg, 0.341 mmol) in TFA (5.00 mL) was stirred at 80 ° C for 2 h. The solvent was removed in vacuo. The residue was purified by silica gel flash chromatography (solvent gradient: 10% methanol/dichloromethane) and then purified by chiral SFC and lyophilized to afford 47.6 mg (30% yield) of 222 as a yellow solid. LCMS: R _T (min) = 0.92, [M+H] ⁺ = 464, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ): δ 14.47-14.37(m,1H),8.75(s,1H),8.18-7.87(m,3H),7.35(s,1H),7.05(s,1H), 6.39(d,J＝2.1Hz,1H),6.13(d,J＝2.2Hz,1H),4.40-4.35(m,4H),3.88-3.85(m,1H), 3.61-3.58(m,1H),3.23-3.17(m,1H),2.36-2.16(m,3H),2.11-1.90(m,3H).

Example 223 (S)-1-(1-(6-(1H-pyrazol-4-yl)pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 223

Step 1: Methyl 6-(1H-pyrazol-4-yl)pyridine-3-carboxylate

A mixture of methyl 6-bromopyridine-3-carboxylate (4.80 g, 22.2 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (7.20 g, 24.4 mmol), potassium carbonate (10 mL, 2N aqueous solution) and 1,1'-bis(diphenylphosphino)ferrocenedichloride palladium(II) (1.63 g, 2.23 mmol) in 1.4-dioxane was stirred at 100 ° C for 16 h under a nitrogen atmosphere. The resulting mixture was cooled to room temperature and diluted with water. The resulting solid was collected by filtration and dried in vacuo to give 3.1 g (crude) of the title compound as a brown solid. The solid was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ =204.

Step 2: Methyl 6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridine-3-carboxylate

To a solution of methyl 6-(1H-pyrazol-4-yl)pyridine-3-carboxylate (3.00 g, 14.8 mmol) and cesium carbonate (10.5 g, 32.2 mmol) in DMF (35 mL) was added 1-(chloromethyl)-4-methoxybenzene (2.50 g, 15.9 mmol). The reaction mixture was stirred at 25 ° C for 2 h and then diluted with water. The resulting solid was collected by filtration and dried in vacuo to give 4.05 g (crude) of the title compound as a brown solid. The solid was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ = 324.

Step 3: 6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridine-3-carboxylic acid

A mixture of methyl 6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridine-3-carboxylate (4.00 g, 12.4 mmol) and potassium hydroxide (2.40 g, 42.8 mmol) in THF (35 mL) and water (35 mL) was stirred at 25 ° C for 12 h. The THF was removed in vacuo and the mixture was adjusted to pH 6 with 1N aqueous hydrogen chloride solution. The resulting solid was collected by filtration and dried in vacuo to give 3.5 g (91%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 309.

Step 4: (S)-1-(1-(6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide

The title compound (550 mg, 40% yield over four steps) was prepared from 6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridine-3-carboxylic acid (770 mg, 2.49 mmol) following a procedure similar to Example 125. LCMS (ESI): [M+H] ⁺ =550.

Step 5: A solution of (S)-1-(1-(6-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyridin-3-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide (500 mg, 0.910 mmol) in TFA (4 mL) was stirred at 80° C. for 4 h. The solvent was evaporated in vacuo and the crude product was purified by preparative HPLC and then lyophilized to afford 32.8 mg (8%) of 223 as a yellow solid. LCMS (ESI): R _T (min) = 1.18, [M+H] ⁺ = 430, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 13.18 (m, 1H), 8.92-8.91 (m, 1H), 8.45-8.39 (m, 1H), 8.19-8.16 (m, 2H),7.87-7.84(m,1H),7.32(s,1H),7.03(s,1H),6.38(m,1H),6.10-6.09(m,1 H),4.38-4.31(m,4H),3.87-3.84(m,1H),3.61-3.56(m,1H),3.23-3.15(m,1H), 2.30-2.20(m,3H),2.08-2.01(m,3H).

Example 224 (S)-1-(1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 224

Step 1: (1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-L-proline

The title compound (116 mg, 39% yield) was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-ethylbenzoxazol-2-ylamine (275 mg, 0.666 mmol) and (S)-pyrrolidine-2-carboxylic acid (153 mg, 1.33 mmol) following a procedure similar to that described in Step 1 of Example 104. LCMS (ESI): [M+H] ⁺ = 448.

Step 2: (S)-1-(1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide

224 (10.0 mg, 9% yield) was prepared from (1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-L-proline (116.5 mg, 0.260 mmol) following a procedure analogous to Example 104, Step 2. LCMS (ESI): R _T (min) = 2.76, [M+H] ⁺ = 447, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.52 (br s, 2H), 7.38 (d, J＝1.6Hz,1H),7.29(d,J＝2.1Hz,1H),7.23(d,J＝1.6Hz,1H),7.01(d,J＝2.1Hz,1H), 6.35(d,J＝2.0Hz,1H),6.06(d,J＝2.0Hz,1H),4.35(t,J＝4.6Hz,2H),4.24(t, J＝5.2Hz,2H),3.84-3.82(m,1H),3.60-3.56(m,1H),3.21-3.15(m,1H),2.81(q, J＝7.7Hz,2H),2.30-2.17(m,3H),2.05-1.91(m,3H),1.29(t,J＝7.7Hz,3H).

Example 225 (S)-2-((1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 225

Step 1: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-ethylbenzo[d]oxazol-2-amine

The title compound (139 mg, 35% yield) was prepared from 5-bromo-7-ethylbenzo[d]oxazol-2-amine (232 mg, 0.962 mmol) following a procedure similar to that described in Example 205, Step 1. LCMS (ESI): [M+H] ⁺ =413/415.

Step 2: (S)-2-((1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid

The title compound (148 mg, 58% yield) was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-ethylbenzo[d]oxazol-2-amine (139 mg, 0.336 mmol) and (S)-2-amino-2-cyclopropylacetic acid (77.3 mg, 0.67 mmol) following a procedure similar to that described in Step 3 of Example 125. LCMS (ESI): [M+H] ⁺ = 448.

Step 3: (S)-2-((1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide

225 (26.6 mg, 27% yield) was prepared from (S)-2-((1-(2-amino-7-ethylbenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid (97.5 mg, 0.218 mmol) following a procedure similar to that of Example 125, step 4. LCMS (ESI):

R _T (min) = 2.71, [M+H] ⁺ = 447, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.51 (br s,2H),7.35(d,J＝1.5Hz,1H),7.33(d,J＝2.1Hz,1H),7.19(d,J＝1.5Hz,1H),6.96(d, J＝2.1Hz,1H),6.36(d,J＝2.0Hz,1H),6.22(d,J＝2.0Hz,1H),5.44(d,J＝7.2Hz,1H), 4.33-4.15(m,4H),3.14(t,J＝7.2Hz,1H),2.81(q,J＝7.5Hz,2H),2.26-2.21(m,2H), 1.29(t,J＝7.5Hz,3H),1.15-1.06(m,1H),0.54-0.44(m,3H),0.34-0.28(m,1H).

Example 227 (S)-1-(1-(5-(1H-1,2,4-triazol-3-yl)pyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 227

Step 1: 3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole

A mixture of 3-bromo-1H-1,2,4-triazole (10.0 g, 67.6 mmol), 1-(chloromethyl)-4-methoxybenzene (10.6 g, 67.6 mmol), DIPEA (17.5 g, 135 mmol), and potassium iodide (5.61 g, 33.8 mmol) in acetonitrile (300 mL) was stirred at 65° C. for 120 min. The solvent was evaporated in vacuo, and the residue was purified by silica gel flash chromatography (solvent gradient: 0-30% ethyl acetate/petroleum ether) to give 12.9 g (71%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 268/270.

Step 2: 5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridine-2-carboxylic acid

A mixture of 3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole (500 mg, 1.86 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylic acid methyl ester (520 mg, 1.98 mmol), tetrakis(triphenylphosphine)palladium (220 mg, 0.190 mmol) and sodium carbonate (590 mg, 5.57 mmol) in water (1 mL) and dioxane (9 mL) was heated at 140 ° C for 30 min under microwave irradiation. This operation was repeated ten times. Ten batches of reaction mixtures were combined, diluted with water (100 mL) and extracted with ethyl acetate. The pH of the aqueous layer was adjusted to pH 6 with 0.5N aqueous hydrogen chloride solution and the resulting solid was collected by filtration and dried in vacuo to give 636 mg (11%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =311.

Step 3: (S)-1-(1-(5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide

The title compound (287 mg, 27% yield over 4 steps) was prepared from 5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridine-2-carboxylic acid (600 mg, 1.94 mmol) following a procedure similar to Example 125. LCMS (ESI): [M+H] ⁺ =551.

Step 4: A solution of (S)-1-(1-(5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide (140 mg, 0.254 mmol) in TFA (6 mL) was stirred at 80° C. for 6 h. The solvent was evaporated in vacuo and the crude product was purified by preparative reverse phase HPLC and then lyophilized to afford 2.4 mg (2%) of 226 as a white solid. LCMS (ESI): R _T (min) = 1.21, [M+H] ⁺ = 431, method = E; ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.29 (s, 1H), 8.65 (s, 1H), 8.51-8.48 (m, 1H), 8.37-8.34 (m, 1H), 7.35 (s, 1H),7.03(s,1H),6.39(s,1H),6.14(s,1H),4.85-4.81(m,2H),4.40-4.30(m,2H), 3.87-3.84(m,1H),3.61-3.58(m,1H),3.24-3.16(m,1H),2.26-2.19(m,3H), 2.03-1.97 (m, 3H).

Example 227 (S)-1-(1-(4-(1,2,4-thiadiazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 227

Step 1: 5-(4-bromophenyl)-1,3,4-oxathiazol-2-one

To a solution of 4-bromobenzamide (11.0 g, 55.0 mmol) in toluene (150 mL) was added carbonochloridic hypochlorous thioanhydride (14.3 g, 110 mmol). The reaction mixture was stirred at 100° C. for 180 min, and the solvent was evaporated in vacuo to afford 12.8 g (90%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ = 258/260.

Step 2: Ethyl 3-(4-bromophenyl)-1,2,4-thiadiazole-5-carboxylate

To a solution of 5-(4-bromophenyl)-1,3,4-oxathiazol-2-one (9.00 g, 34.9 mmol) in dodecane (100 mL) was added ethyl cyanoformate (13.8 g, 140 mmol). The reaction mixture was stirred at 160° C. for 180 min, and the solvent was evaporated in vacuo to afford 8.1 g (74%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ = 313/315.

Step 3: 3-(4-bromophenyl)-1,2,4-thiadiazole

To a solution of ethyl 3-(4-bromophenyl)-1,2,4-thiadiazole-5-carboxylate (8.00 g, 25.5 mmol) in ethanol (100 mL) and water (60 mL) was added sodium hydroxide (1.13 g, 28.2 mmol). The reaction mixture was stirred at 100 ° C for 120 min, then cooled to room temperature and concentrated aqueous hydrogen chloride solution (7 mL) was added. The reaction mixture was stirred at 100 ° C for 180 min. The reaction mixture was adjusted to about pH 3 with 2N sodium bicarbonate and then extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate and the solvent was removed in vacuo to give 6.1 g (99%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =241/243.

Step 4: 227 (41.3 mg, 9.5% yield) was prepared from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (Example 150 Step 2) (400 mg, 0.971 mmol) following procedures similar to Example 158 Steps 2-5. LCMS: R _T (min) = 2.15, [M+H] ⁺ = 447, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 8.40 (d, J = 8.4, 2H), 7.98 (d, J = 8.4, 2H), 7.32(s,1H),7.03(s,1H),6.38(d,J＝2.1Hz,1H),6.10(d,J＝2.1Hz,1H), 4.38-4.31(m,4H),3.90-3.80(m,1H),3.59(d,J＝7.8Hz,1H),3.19(d,J＝8.2Hz,1H), 2.33-2.25(m,3H),2.10-1.87(m,3H).

Example 228 (S)-2-Cyclopropyl-2-((1-(pyrazolo[1,5-a]pyrimidin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)amino)acetamide 228

228 was prepared following a procedure similar to Example 125. LCMS (ESI): _RT (min) = 1.05, [M+H] ⁺ = 404, Method = D;. ¹ H NMR (300MHz, DMSO-d ₆ ) δ9.17(d,J＝7.2Hz,1H), 8.29(s,1H),7.82(d,J＝7.2Hz,1H),7.38(s,1H),6.99(s,1H),6.84(s,1H), 6.40-6.37(m,2H),5.68(d,J＝7.2Hz,1H),4.91-4.88(m,2H),4.37-4.35(m,2H), 3.17-3.12(m,1H),2.40-2.20(m,2H),1.13-1.11(m,1H),0.54-0.48(m,3H), 0.32-0.30(m,1H).

Example 229 (S)-1-(1-(4-(1H-pyrazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 229

Step 1: 4-Bromo-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

A mixture of 4-bromo-1-(4-iodophenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (Example 235, Step 1) (1.00 g, 2.20 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (610 mg, 2.19 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (160 mg, 0.219 mmol) and sodium carbonate (2M aqueous solution, 10 mL) in DMF (20 mL) was stirred at 60° C. for 3 h. The reaction mixture was quenched with water, extracted with DCM, the organic layers combined, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (solvent gradient: 10% ethyl acetate/hexane) to give 737 mg (70%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =479/481.

Step 2: (2S)-1-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide

The title compound (320 mg, 44% yield) was prepared from 4-bromo-1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (680 mg, 1.42 mmol) following a procedure similar to that of Example 104. LCMS (ESI): [M+H] ⁺ = 513.

Step 3: (S)-1-(1-(4-(1H-pyrazol-3-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide

A solution of (2S)-1-(1-(4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxamide (270 mg, 0.527 mmol) in TFA (3 mL) and DCM (6 mL) was stirred at 20° C. for 30 min. The solvent was evaporated in vacuo and the crude product was purified by preparative reverse phase HPLC and lyophilized to afford 18.5 mg (8%) of 229 as a white solid. LCMS (ESI): R _T (min) = 0.97, [M+H] ⁺ = 429, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 13.02 (br, 1H), 7.98-7.95 (m, 2H), 7.84-7.77 (m, 3H), 7.30 (s, 1H), 7.02(s,1H),6.82(d,J＝2.4Hz,1H),6.36(s,1H),6.08(s,1H),4.37-4.28(m,4H), 3.85-3.82(m,1H),3.75-3.45(m,1H),3.20-3.17(m,1H),2.40-2.10(m,3H),2.05-1.85(m,3H).

Examples 230 and 231 (S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-cyclopropylacetamide 230 and (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-cyclopropylacetamide 231

Step 1: Ethyl 2-cyclopropyl-2-(1H-pyrazol-1-yl)acetate

A mixture of pyrazole (110 mg, 1.61 mmol), ethyl 2-bromo-2-cyclopropylacetate (0.33 g, 1.61 mmol) and cesium carbonate (576 mg, 1.77 mmol) in DMF (3.0 mL) was stirred at 60 ° C for 16 h. The reaction mixture was partitioned between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 10-50% ethyl acetate/cyclohexane) to give 186 mg (60%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ =195.

Step 2: Ethyl 2-(4-bromo-1H-pyrazol-1-yl)-2-cyclopropylacetate

To a solution of ethyl 2-cyclopropyl-2-(1H-pyrazol-1-yl)acetate (186 mg, 0.96 mmol) in THF (3.0 mL) was added N-bromosuccinimide (188 mg, 1.06 mmol) and the reaction mixture was stirred at room temperature for 2.5 h. The solvent was evaporated by azeotropic evaporation with toluene and the residue was purified by silica gel flash chromatography (solvent gradient: 5-20% ethyl acetate/cyclohexane) to give 253 mg (97%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ = 273/275.

Step 3: Ethyl 2-cyclopropyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate

Under a nitrogen atmosphere, ethyl 2-(4-bromo-1H-pyrazol-1-yl)-2-cyclopropylacetate (253 mg, 0.93 mmol), bis(pinacolato)diboron (283 mg, 1.11 mmol), potassium acetate (270 mg, 2.8 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (75 mg, 0.093 mmol) were suspended in 1,4-dioxane (2.0 mL) and the reaction mixture was stirred at 110 ° C for 6.5 h. The resulting mixture was allowed to warm to room temperature and the solvent was evaporated azeotropically with toluene. The crude residue was purified via silica gel flash chromatography (solvent gradient: 2-25% ethyl acetate/toluene) to give 169 mg (57%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ =321.

Step 4: 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-cyclopropylacetic acid

[0266] 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine from Example 101 (84 mg, 0.218 mmol), ethyl 2-cyclopropyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetate (168 mg, 0.436 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (18 mg, 0.022 mmol), 2N aqueous sodium carbonate solution (0.4 mL, 0.80 mmol) and 1,2-dimethoxyethane (1.5 mL) were heated in a sealed vial under nitrogen at 100 °C for 16 h. The reaction mixture was cooled to 45 ° C and a solution of methanol (1.0 mL) and lithium hydroxide (37 mg, 0.872 mmol) in water (1.0 mL) was added to the resulting mixture and stirred for another 1.5 h. The reaction mixture was allowed to warm to room temperature and 1N HCl (5 mL) was added and the mixture was poured onto 10 g SCX-2 posts. The post was washed with methanol and then eluted with 2N ammonia/methanol. The eluent was collected and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 5-50% (2N ammonia/methanol)/DCM) to give 97 mg (95%) of the title compound as a gray solid. LCMS (ESI): [M+H] ⁺ =471.

Step 5: To a mixture of 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-2-cyclopropylacetic acid (97 mg, 0.21 mmol), ammonium chloride (22 mg, 0.42 mmol), and DIPEA (143 μl, 0.84 mmol) in DMF (1.0 mL) was added HATU (157 mg, 0.42 mmol) portionwise over 5 min and stirred for an additional 10 min. The mixture was purified via silica gel flash chromatography (solvent gradient: 2-14% (2N ammonia in methanol) in DCM) and the resulting residue was dissolved in methanol and loaded onto a 2 g SCX-2 column. The column was washed with methanol and then eluted with 2N ammonia in methanol. The eluate was collected and the solvent removed to give a racemic mixture 74 mg (76%) of the title compound as an off-white solid. The two stereoisomers were separated by chiral SFC to give 230 and 231 as off-white solids, each as a single unknown stereoisomer.

Example 230 (30 mg, 31% yield): LCMS (ESI): _RT (min) = 2.54 min, [M+H] ⁺ = 470, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ): δ 8.35 (s, 1H), 7.90 (s, 1H), 7.58 (br s, 3H), 7.53 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.1, 1.3 Hz, 1H), 7.28 (br s, 1H), 7.06 (d, J = 1.3 Hz, 1H), 4.46-4.40 (m, 2H), 4.20 (t, J = 5.1 Hz, 2H), 4.11(d,J=10.2Hz,1H),2.36-2.29(m,2H),1.68-1.58(m,1H),0.75-0.62(m,3H), 0.37-0.29(m,1H).

Example 231 (31 mg, 32% yield): LCMS (ESI): _RT (min) = 2.54 min, [M+H] ⁺ = 470, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ): δ 8.35 (s, 1H), 7.90 (s, 1H), 7.58 (br s, 3H), 7.53 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.1, 1.3 Hz, 1H), 7.28 (br s, 1H), 7.06 (d, J = 1.3 Hz, 1H), 4.46-4.40 (m, 2H), 4.20 (t, J = 5.1 Hz, 2H), 4.11(d,J=10.2Hz,1H),2.36-2.29(m,2H),1.68-1.58(m,1H),0.75-0.62(m,3H), 0.37-0.29(m,1H).

Examples 232 and 233 (R)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanamide 232 and (S)-2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanamide 233

Step 1: Diethyl 2-methyl-2-(1H-pyrazol-1-yl)malonate

A mixture of pyrazole (1.34 g, 19.75 mmol), diethyl 2-bromo-2-methylmalonate (5.0 g, 19.75 mmol) and cesium carbonate (7.08 g, 21.73 mmol) in DMF (35 mL) was stirred at 60 ° C for 2 h. The reaction mixture was distributed between ethyl acetate and water and the phases were separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 5-25% ethyl acetate/cyclohexane) to give 4.06 g (86%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ = 241.

Step 2: Ethyl 3-hydroxy-2-methyl-2-(1H-pyrazol-1-yl)propanoate

To a solution of diethyl 2-methyl-2-(1H-pyrazol-1-yl)malonate (480 mg, 2.0 mmol) in THF (5.0 mL) was added tri-tert-butoxy lithium aluminum hydride (1 N in THF, 4.5 mL, 4.5 mmol) dropwise over 2 min. The reaction mixture was then refluxed for 30 min. The resulting mixture was cooled to 0 ° C and quenched with 10% aqueous sodium bisulfate solution (30 mL), then extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 30-60% ethyl acetate/cyclohexane) to give 235 mg (59%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ = 199.

Step 3: Ethyl 3-methoxy-2-methyl-2-(1H-pyrazol-1-yl)propanoate

To a solution of ethyl 3-hydroxy-2-methyl-2-(1H-pyrazol-1-yl)propanoate (235 mg, 1.19 mmol) in THF (5.0 mL) was added iodomethane (148 μL, 2.37 mmol), and then sodium hydride (60% in mineral oil, 57 mg, 1.42 mmol) was added portionwise over 3 min. The reaction mixture was stirred at room temperature for 45 min. The resulting mixture was quenched with saturated aqueous ammonium chloride solution and then extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 10-40% ethyl acetate/cyclohexane) to give 168 mg (67%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ = 213.

Step 4: Ethyl 2-(4-bromo-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanoate

To a solution of ethyl 3-methoxy-2-methyl-2-(1H-pyrazol-1-yl)propanoate (168 mg, 0.79 mmol) in THF (3.0 mL) was added N-bromosuccinimide (155 mg, 0.87 mmol) and the reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated by azeotropic evaporation with toluene and the residue was purified by silica gel flash chromatography (solvent gradient: 5-20% ethyl acetate/cyclohexane) to give 219 mg (95%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ = 291/293.

Step 5: Ethyl 3-methoxy-2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate

Under a nitrogen atmosphere, ethyl 2-(4-bromo-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanoate (219 mg, 0.75 mmol), bis(pinacolato)diboron (230 mg, 0.90 mmol), potassium acetate (219 mg, 2.25 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (75 mg, 0.075 mmol) were suspended in 1,4-dioxane (1.75 mL) and stirred at 110°C for 5 h before warming to room temperature. The solvent was removed under reduced pressure by azeotropic distillation with toluene, and the residue was purified by silica gel flash chromatography (solvent gradient: 5-30% ethyl acetate/toluene) to give 125 mg (49%) of the title compound as a colorless oil. LCMS (ESI): [M+H] ⁺ = 339.

Step 6: 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanoic acid

[0265] 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine from Example 101 (99 mg, 0.257 mmol), ethyl 3-methoxy-2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (124 mg, 0.257 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride (21 mg, 0.026 mmol), 2N aqueous sodium carbonate solution (0.5 mL, 1.0 mmol) and 1,2-dimethoxyethane (1.8 mL) were heated in a sealed vial under nitrogen at 100 °C for 3 h. The reaction mixture was cooled to 45 ° C and a solution of methanol (3 mL) and lithium hydroxide (42 mg, 1.0 mmol) in water (2 mL) was added to the resulting mixture, which was stirred for another 1.5 h. The resulting mixture was allowed to warm to room temperature and 1N HCl (5 mL) was added and the mixture was poured onto 10 g SCX-2 columns. The column was washed with methanol and then eluted with 2N ammonia/methanol. The eluent was collected and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 10-60% (2N ammonia/methanol)/DCM) to give 84 mg (67%) of the title compound as a gray solid. LCMS (ESI): [M+H] ⁺ =489.

Step 7: To a mixture of racemic 2-(4-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)-1H-pyrazol-1-yl)-3-methoxy-2-methylpropanoic acid (84 mg, 0.17 mmol), ammonium chloride (18 mg, 0.35 mmol), and DIPEA (120 μL, 0.69 mmol) in DMF (1.0 mL) was added HATU (132 mg, 0.35 mmol) portionwise over 5 min and stirred for an additional 10 min. The reaction mixture was directly purified via silica gel flash chromatography (solvent gradient: 2-14% (2N ammonia in methanol) in DCM) and the resulting residue was dissolved in methanol and loaded onto a 2 g SCX-2 column. The column was washed with methanol and then eluted with 2N ammonia in methanol. The eluate was collected and the solvent was evaporated to give a racemic mixture 73 mg (86%) of the title compound as an off-white solid. The two stereoisomers were separated by chiral SFC to give 232 and 233 as off-white solids, each as a single unknown stereoisomer.

Example 232 (20 mg, 24% yield): LCMS (ESI): _RT (min) = 2.63 min, [M+H] ⁺ = 470, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ): δ 8.25 (s, 1H), 7.97 (s, 1H), 7.58 (br s, 3H), 7.55 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.1, 1.3 Hz, 1H), 7.29 (br s, 1H), 7.08 (d, J = 1.5 Hz, 1H), 6.86 (br s, 1H), 4.44-4.40 (m, 2H), 4.30 (t, J＝5.3Hz,2H),4.00(d,J＝10.0Hz,1H),3.86(d,J＝10.0Hz,1H),3.25(s,3H), 2.36-2.28(m,2H),1.77(s,3H).

Example 233 (23 mg, 27% yield): LCMS (ESI): _RT (min) = 2.63 min, [M+H] ⁺ = 470, method = A; ^1H NMR (400 MHz, DMSO-d ₆ ): δ 8.25 (s, 1H), 7.97 (s, 1H), 7.58 (br s, 3H), 7.55 (d, J = 1.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.39 (dd, J = 8.1, 1.3 Hz, 1H), 7.29 (br s, 1H), 7.08 (d, J = 1.5 Hz, 1H), 6.86 (br s, 1H), 4.44-4.40 (m, 2H), 4.30 (t, J＝5.3Hz,2H),4.00(d,J＝10.0Hz,1H),3.86(d,J＝10.0Hz,1H),3.25(s,3H), 2.36-2.28(m,2H),1.77(s,3H).

Example 234 (S)-1-(1-(4-(2-oxoimidazolidin-1-yl)phenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 234

Step 1: 4-Bromo-1-(4-iodophenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene

The title compound (5.8 g, 31% yield over two steps) was prepared from 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-amine (9.8 g, 40.3 mmol) following procedures similar to those in Steps 1-2 of Example 125. LCMS (ESI): [M+H] ⁺ =455/457.

Step 2: 1-(4-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)phenyl)imidazolidin-2-one

A mixture of 4-bromo-1-(4-iodophenyl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (500 mg, 1.10 mmol), imidazolidin-2-one (760 mg, 8.83 mmol), copper (I) iodide (40 mg, 0.210 mmol), N ¹ ,N ² -dimethylethane-1,2-diamine (60 mg, 0.681 mmol) and potassium phosphate (700 mg, 3.30 mmol) in DMF (11 mL) was heated at 130 ° C for 1 h under microwave irradiation. The crude reaction mixture was diluted with water and extracted with DCM. The organic layers were combined and dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 10% methanol/DCM) to give 330 mg (73%) of the title compound as a yellow solid. LCMS(ESI): [M+H] ⁺ =413/415.

Step 3: 234 (33.4 mg, 6.1% yield over two steps) was prepared from 1-(4-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)phenyl)imidazolidin-2-one (500 mg, 1.21 mmol) following a procedure similar to that of Example 104, steps 1-2. LCMS (ESI): _RT (min) = 1.24, [M+H] ⁺ = 447, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.72 (s, 4H), 7.30 (s, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 6.34 (d, J = 1.8 Hz, 1H), 6.05 (d, J = 1.8 Hz, 1H), 4.35-4.27 (m, 2H), 4.25-4.23 (m, 2H), 3.94-3.81 (m, 3H), 3.65-3.50 (m, 1H), 3.47-3.41(m,2H),3.25-3.05(m,1H),2.35-2.10(m,3H),2.08-1.85(m,3H).

Example 235 (S)-2-((1-(2-amino-7-(trifluoromethyl)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetamide 235

Step 1: 5-Bromo-7-(trifluoromethyl)benzo[d]oxazol-2-amine

The reaction vessel was charged with 2-amino-4-bromo-6-(trifluoromethyl)phenol (0.37 g, 1.44 mmol), cyanogen bromide (184 mg, 1.74 mmol) and methanol (10 mL) and the reaction mixture was stirred at 35 ° C for 16 h. The resulting mixture was cooled to room temperature and cyanogen bromide (62 mg, 0.59 mmol) was added. The reaction mixture was stirred at 35 ° C for 2 h. The resulting mixture was quenched with saturated aqueous sodium carbonate (10 mL) and the solvent was concentrated in vacuo. The mixture was partitioned between ethyl acetate and water and the phases were separated. The aqueous phase was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 350 mg (86%) of the title compound. The residue was used without further purification. LCMS (ESI): [M+H] ⁺ 282.

Step 2: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-(trifluoromethyl)benzo[d]oxazol-2-amine

The title compound (105 mg, 19% yield) was obtained from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene (472 mg, 1.25 mmol) and 5-bromo-7-(trifluoromethyl)benzo[d]oxazol-2-amine (350 mg, 1.25 mmol) following a procedure similar to Example 205. LCMS (ESI): [M+H] ⁺ =453.

Step 3: (S)-2-((1-(2-amino-7-(trifluoromethyl)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid

The title compound was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-(trifluoromethyl)benzo[d]oxazol-2-amine (105 mg, 0.23 mmol) and (S)-2-amino-2-cyclopropylacetic acid (66.7 mg, 0.58 mmol) following a procedure analogous to that of Example 125, Step 3. LCMS (ESI): [M+H] ⁺ = 488.

Step 4: 235 (3.0 mg, 2.3% yield) was prepared from (S)-2-((1-(2-amino-7-(trifluoromethyl)benzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)amino)-2-cyclopropylacetic acid (129 mg, 0.265 mmol) following a procedure similar to that of Example 125, step 4.

LCMS (ESI): _RT (min) = 2.89 min, [M+H] ⁺ = 487, method = A; ¹ H NMR (400 MHz,

MeOD-d ₄ ): δ7.75(s,1H),7.61(s,1H),6.50(d,J＝2.0Hz,1H),6.34(d,J＝2.0Hz,1H),4 .42-4.36(m,2H),4.26(t,J＝2.0Hz,2H),3.14(d,J＝8.6Hz,1H),2.37-2.30(m, 2H),1.23-1.13(m,1H),0.69-0.57(m,3H),0.45-0.37(m,1H).

Example 236 (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)-N-(4-methoxybenzyl)pyrrolidine-2-carboxamide

236 was prepared from (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)pyrrolidine-2-carboxylic acid using 4-methoxybenzylamine following a procedure analogous to Example 104, Step 2. LCMS (ESI): _RT (min) = 3.539, [M+H] ⁺ = 539.3, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (t, J = 6.2 Hz, 1H), 7.60-7.51 (m, 3H), 7.48 (d, J = 8.2 Hz, 1H), 7.36 (dd, J = 8.2, 1.7 Hz, 1H), 7.17-7.09 (m, 2H), 6.85-6.76 (m, 2H), 6.40 (d, J = 2.1 Hz, 1H), 6.09 (d, J = 2.1 Hz, 1H), 4.41-4.32 (m, 2H), 4.29-4.23 (m, 2H), 4.20(d,J＝6.2Hz,2H),3.97(dd,J＝9.3,2.3Hz,1H),3.69(s,3H),3.66-3.58(m,1H), 3.25-3.15(m,1H),2.34-2.18(m,3H),2.06-1.88(m,3H).

Example 237 (S)-1-(1-(3-oxo-2,3-dihydrobenzo[d]isoxazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)pyrrolidine-2-carboxamide 237

237 was prepared following a procedure similar to Example 158. LCMS (ESI): _RT (min) = 1.22, [M+H] ⁺ = 420, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 11.89-11.80 (m, 1H), 7.70-7.69 (m, 1H), 7.58-7.55 (m, 1H), 7.30 (s, 1H), 7.24-7.21 (m, 1H), 7.03 (s, 1H), 6.35-6.34 (m, 1H), 6.07 (d, J = 2.1 Hz, 1H), 4.46-4.34 (m, 2H), 4.26-4.18 (m, 2H), 3.84-3.82(m,1H),3.68-3.57(m,1H),3.19-3.16(m,1H),2.26-2.15(m,3H), 2.08-1.96(m,3H).

Example 238 (S)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)amino)-2-cyclopropylacetamide 238

Step 1: 2,5-Dibromo-3-nitrophenol

To a suspension of 2-amino-5-bromo-3-nitrophenol (10.0 g, 42.9 mmol) in 48% aqueous hydrobromic acid solution (20 mL) was added dropwise a solution of sodium nitrite (3.15 g, 45.1 mmol) in water (20 mL) at 0 ° C. The reaction mixture was stirred at 0 ° C for 15 min. Copper (II) bromide (4.79 g, 21.5 mmol) in 48% aqueous hydrobromic acid solution (20 mL) was then added dropwise and the reaction mixture was stirred at 0 ° C for 15 min, then stirred at 100 ° C for 2 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The product was purified via silica gel flash chromatography (solvent gradient: 0-100% ethyl acetate/cyclohexane) to give 6.28 g (49%) of the title compound as an orange solid. ¹ H NMR (400MHz, CDCl ₃ ) δ 7.62 (d, J = 2.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 6.17 (brs, 1H).

Step 2: (R)-tert-Butyl (2-(2,5-dibromo-3-nitrophenoxy)propyl)carbamate

To a solution of 2,5-dibromo-3-nitrophenol (1.0 g, 3.40 mmol), N-Boc-(S)-1-amino-2-propanol (708 mg, 4.0 mmol) and triphenylphosphine (1.24 g, 4.70 mmol) in THF (6.0 mL) was added diisopropyl azodicarboxylate (0.86 mL, 4.4 mmol) dropwise at room temperature and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography (solvent gradient: 0-50% ethyl acetate/cyclohexane) to give 1.61 g (>100%) of the title compound as a yellow oil. LCMS (ESI): [M+H-100] ⁺ = 353/355/357.

Step 3: (R)-7-Bromo-2-methyl-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

Tert-butyl (R)-(2-(2,5-dibromo-3-nitrophenoxy)propyl)carbamate (1.61 g, 3.60 mmol) was dissolved in hydrochloric acid (4N in 1,4-dioxane, 12 mL, 48 mmol) and the reaction mixture was stirred at 50 ° C for 1 h. The resulting mixture was concentrated in vacuo and the residue was dissolved in DMF (7.0 mL). Potassium carbonate (1.23 g, 8.9 mmol) was added and the reaction mixture was stirred at 90 ° C for 2 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 1.19 g (>100%) of the title product as a bright red solid. This material was used without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ7.90 (d, J = 2.0Hz, 1H), 7.88 (br s,1H),7.09(dd,J＝2.3,0.6Hz,1H),4.23-4.14(m,1H),3.60(ddd,J＝12.5,4.4,2.7Hz,1H),3.29(ddd, J＝12.6,8.3,1.3Hz,1H),1.42(d,J＝6.1Hz,3H).

Step 4: (R)-7-Bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine

To a suspension of (R)-7-bromo-2-methyl-5-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (968 mg, 3.50 mmol) in methanol (10 mL) and water (10 mL) was added iron powder (1.12 g, 21.3 mmol) and ammonium chloride (1.7 g, 31.9 mmol) and the reaction mixture was stirred at 80 ° C for 30 min. The resulting mixture was filtered and the solid was washed thoroughly with ethyl acetate. The filtrate was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 860 mg (99%) of the title compound as a brown oil. The material was used without purification. ¹ H NMR (400MHz, CDCl ₃ ) δ6.52 (d, J＝2.1Hz, 1H), 6.45 (d, J＝2.1Hz, 1H), 4.13-4.05 (m, 1H), 3.37 (dd, J＝12.4, 2.2Hz, 1H), 2.99 (dd, J=12.4, 8.1Hz, 1H), 1.34 (d, J=6.2Hz, 3H).

Step 5: (R)-7-Bromo-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene

(R)-7-Bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-amine (861 mg, 3.54 mmol) was dissolved in trimethyl orthoformate (5.0 mL, 45.7 mmol) and the reaction mixture was heated at 100° C. for 30 min. The resulting mixture was directly loaded onto celite and the product was purified via silica gel flash chromatography (solvent gradient: 0-5% methanol/DCM) to give 735 mg (82%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ = 253/255.

Step 6: (R)-7-Bromo-2-iodo-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene

To a solution of diisopropylamine (0.65 mL, 4.65 mmol) in THF (3.0 mL) was added n-butyl lithium (0.58 mL, 2.5 N in hexane, 1.46 mmol) dropwise at -40 ° C. The reaction mixture was warmed to -20 ° C and then cooled to -78 ° C. A solution of (R)-7-bromo-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (735 mg, 2.9 mmol) in THF (6.0 mL) was added dropwise and the reaction mixture was stirred at -78 ° C for 2 h. A solution of iodine (1.03 g, 4.1 mmol) in THF (6.0 mL) was added and the reaction mixture was stirred at -78 ° C for 3 h. The resulting mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-100% ethyl acetate/cyclohexane) to give 378 mg (34%) of the title compound as a beige solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46 (d, J=1.2 Hz, 1H), 6.87 (d, J=1.2 Hz, 1H), 4.51-4.41 (m, 1H), 4.19 (dd, J=12.7, 2.9 Hz, 1H), 3.83 (dd, J=12.7, 9.2 Hz, 1H), 1.61 (d, J=6.4 Hz, 3H).

Step 7: (R)-5-(7-bromo-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-2-yl)benzo[d]oxazol-2-amine

A mixture of tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.03 mmol), cesium carbonate (180 mg, 0.55 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazol-2-amine (154 mg, 0.60 mmol) and (R)-7-bromo-2-iodo-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene (150 mg, 0.40 mmol) in 1,4-dioxane (2.5 mL) and water (0.5 mL) was sealed in a vial and degassed with argon, and the reaction mixture was heated at 100 ° C for 16 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-7% methanol/DCM) to afford 50 mg (30%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =385/387.

Step 8: (S)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)amino)-2-cyclopropylacetic acid

A mixture of (R)-5-(7-bromo-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthen-2-yl)benzo[d]oxazol-2-amine (145 mg, 0.38 mmol), (2S)-2-amino-2-cyclopropylacetic acid (87 mg, 0.75 mmol), copper(I) iodide (14 mg, 0.08 mmol) and potassium phosphate (160 mg, 0.75 mmol) in DMSO (2.0 mL) was degassed with argon and the reaction mixture was heated at 110 ° C. for 16 h. The resulting mixture was diluted with DCM (40 mL) and directly purified via silica gel flash chromatography (solvent gradient: 0-50% (2N ammonia/methanol)/DCM) to give 168 mg (106%) of the title compound as a yellow oil. LCMS (ESI): [M+H] ⁺ =420.

Step 9: To a mixture of (S)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)amino)-2-cyclopropylacetic acid (164 mg, 0.39 mmol), ammonium chloride (42 mg, 0.78 mmol) and triethylamine (0.16 mL, 1.17 mmol) in DMF (3.0 mL) was added HATU (223 mg, 0.59 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified via reverse phase HPLC to afford 9 mg (6%) of 238 as a white solid. LCMS (ESI): R _T (min) = 2.50 min, [M+H] ⁺ = 419, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.17 (s, 1H), 7.68 (d, J = 1.2Hz, 1H), 7.56 (br s, 2H), 7.53(dd,J＝8.1,1.8Hz,1H),7.46(d,J＝8.1Hz,1H),7.36(d,J＝1.8Hz,1H),6.97(d, J＝1.7Hz,1H),6.27(d,J＝1.4Hz,1H),6.21(d,J＝1.4Hz,1H),4.64(dd,J＝12.6, 2.8Hz, 1H), 4.42-4.33 (m, 1H), 4.19 (dd, J = 12.7, 9.2Hz, 1H), 3.13 (d, J = 8.3Hz, 1H), 1.47 (d, J = 6.2Hz, 3H).

Example 239 (S)-1-(1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)pyrrolidine-2-carboxamide 239

239 was prepared following a procedure similar to Example 214. LCMS (ESI): _RT (min) = 4.5, [M+H] ⁺ = 449, method = D; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.00 (d, J = 1.6 Hz, 1H), 7.74 (s, 2H), 7.62-7.43 (m, 2H), 7.43-7.32 (m, 1H), 7.21-7.01 (m, 1H), 6.46 (d, J = 1.9 Hz, 1H), 6.23 (d, J = 2.0 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 4.23-4.20 (m, 2H), 4.00-3.76(m,1H),3.69-3.52(m,1H),3.19(d,J＝9.0Hz,1H),2.25-2.11(m,3H), 2.03-1.88(m,3H),1.70(s,2H).

Example 240 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanamide 240

Step 1: 5-(3-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine

Under a nitrogen atmosphere, 5-(4-bromo-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine (530 mg, 1.30 mmol), bis(pinacolato)diboron (495 mg, 1.95 mmol), potassium acetate (382 mg, 3.90 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (106 mg, 0.13 mmol) were suspended in 1,4-dioxane (10 mL) and stirred at 110°C for 6 h. The resulting mixture was allowed to warm to room temperature, the solvent was evaporated, and the residue was partitioned between ethyl acetate and water and filtered through celite. The organic phase was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was used in the next step without further purification. LCMS(ESI): [M+H] ⁺ =450/451/452.

Step 2: 1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol

To a solution of 5-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-1-yl)benzo[d]oxazol-2-amine (crude, estimated to be 1.30 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (271 mg, 3.90 mmol) and sodium hydroxide (208 mg, 5.20 mmol) and the reaction mixture was stirred at room temperature for 18 h. The resulting mixture was diluted with methanol, acidified with 1N hydrochloric acid, and then loaded onto a 10 g SCX-2 column. The column was washed thoroughly with methanol and then eluted with 2N ammonia/methanol. The eluent was collected and the solvent evaporated. The residue was purified by silica gel flash chromatography (solvent gradient: 5-10% (2N ammonia/methanol)/DCM) to give 152 mg (34% over 2 steps) of the title compound as a light brown solid. LCMS (ESI): [M+H] ⁺ =341.

Step 3: To a solution of 1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol (159 mg, 0.47 mmol) in DMF (5.0 mL) were added potassium carbonate (105 mg, 0.75 mmol) and (R)-1-carbamoylethyl toluene-4-sulfonate (135 mg, 0.55 mmol) and the reaction mixture was stirred at 80 ° C for 6 h. Potassium carbonate (42 mg, 0.3 mmol) and (R)-1-carbamoylethyl toluene-4-sulfonate (34 mg, 0.14 mmol) were added and the reaction was stirred at 80 ° C for another 18 h. The resulting mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The aqueous layer was further extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. The residue was purified via reverse phase HPLC followed by chiral SFC and lyophilized to afford 38 mg (25% yield) of 240 as a white solid. LCMS (ESI): R _T (min) = 2.56, [M+H] ⁺ = 412, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.60 (s, 2H), 7.57 (d, J = 1.3Hz, 1H), 7.50 (d, J = 8.1Hz, 1H), 7.49 (s, 1H), 7.38(dd,J＝8.1,1.3Hz,1H),7.27(s,1H),6.57(d,J＝6.3Hz,1H),4.57(q,J＝6.8Hz, 1H), 4.39-4.34 (m, 2H), 4.28 (t, J = 5.5Hz, 2H), 2.32-2.25 (m, 2H), 1.44 (d, J = 6.8Hz, 3H).

Example 241 (S)-2-((1-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 241

241 was prepared following a procedure analogous to Example 249. LCMS (ESI): _RT (min) = 1.17, [M+H] ⁺ = 426, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.81 (s, 2H), 7.54 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.25 (s, 1H), 7.17-7.12 (m, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.63 (d, J = 2.1 Hz, 1H), 4.66-4.60 (m, 1H), 4.22-4.21 (m, 4H), 2.05-1.85 (m, 2H), 1.70-1.55 (m, 2H), 1.45 (d, J = 6.6 Hz, 3H).

Example 242 (S)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 242

Step 1: 6-Bromo-4-fluorobenzo[d]thiazol-2-amine

A mixture of 4-bromo-2-fluoroaniline (144g, 758mmol), acetic acid (1000mL) and potassium thiocyanate (243g, 2.50mol) was stirred at room temperature for 15min. A solution of bromine (243g, 1.52mol) in acetic acid (200mL) was then added dropwise to the mixture. The reaction mixture was stirred at room temperature for 16h and then diluted with water. The mixture was adjusted to approximately pH 7 with aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-20% ethyl acetate/petroleum ether) to give 46.7g (25%) of the title compound as a pale white solid. LCMS (ESI): [M+H] ⁺ = 247/249. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.87 (s, 2H), 7.78 (d, J = 2.0Hz, 1H), 7.38-7.34 (m, 1H).

Step 2: 6-Bromo-4-fluoro-N,N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine

A mixture of 6-bromo-4-fluorobenzo[d]thiazol-2-amine (16.2 g, 65.5 mmol), potassium carbonate (33.8 g, 244 mmol) and 1-(chloromethyl)-4-methoxybenzene (33.0 g, 210 mmol) in DMF (350 mL) was heated at 60 ° C for 16 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% ethyl acetate/petroleum ether) to give 20.2 g (51%) of the title compound as a light yellow solid.

LCMS(ESI): [M+H] ⁺ =487/489. ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.87-7.84 (m, 1H), 7.46-7.41 (m, 1H), 7.26-7.22 (m, 4H), 6.94-6.84 (m, 4H), 4.69 (s, 4H), 3.73 (s, 6H).

Step 3: 4-Fluoro-N,N-di(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

The title compound (14.2 g, 64% yield) was prepared from 6-bromo-4-fluoro-N,N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine (20.2 g, 41.4 mmol) following a procedure analogous to that described in Step 7 of Example 204. LCMS (ESI): [M+H] ⁺ = 535. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.86 (s, 1H), 7.33-7.20 (m, 5H), 6.91 (d, J=8.5 Hz, 4H), 4.70 (s, 4H), 3.73 (s, 6H), 1.29 (s, 12H).

Step 4: 6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-1-yl)-4-fluoro-N,N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine

A mixture of 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (Example 204, Step 6) (320 mg, 0.814 mmol), 4-fluoro-N,N-di(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine (430 mg, 0.805 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (116 mg, 0.159 mmol), and cesium carbonate (767 mg, 2.35 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was degassed with nitrogen. The reaction mixture was heated at 100° C. for 1 h under microwave irradiation. This procedure was repeated 29 additional times. The reaction mixtures were combined, diluted with water, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-30% ethyl acetate/petroleum ether) to afford 11.5 g (69.9%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 673/675.

Step 5: (S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaocta[cd]inden-4-yl)oxy)propanamide

The title compound (1.3 g, 43.3% yield over four steps) was prepared from 6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-4-fluoro-N,N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine (3 g, 4.45 mmol) following procedures similar to those described in Steps 9-12 of Example 204. LCMS (ESI): [M+H] ⁺ = 682.

Step 6: A solution of (S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide (1.30 g, 1.91 mmol) in TFA (20 mL) was heated at 90 °C for 2 h. The reaction mixture was evaporated in vacuo. The resulting residue was purified by silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) followed by chiral HPLC to afford 177.8 mg (21% yield) of 242 as a white solid. LCMS (ESI): R _T (min) = 1.26, [M+H] ⁺ = 442, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.94 (s, 2H),7.84(s,1H),7.50(s,1H),7.39(d,J＝11.4Hz,1H),7.22(s,1H),6.92(d, J＝1.2Hz,1H),6.59(d,J＝1.2Hz,1H),4.66-4.59(m,1H),4.47-4.36(m,2H), 4.29-4.20(m,2H),2.19-2.06(m,2H),1.75-1.60(m,2H),1.45(d,J＝6.6Hz,3H).

Example 243 (S)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 243

243 was prepared using commercially available 3-(4-bromophenyl)-1H-1,2,4-triazole and following a procedure similar to Example 242. LCMS (ESI): R _T (min) = 1.02, [M+H] ⁺ = 419, method = F; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 12.28 (br, 1H), 8.53 (s, 1H), 8.20 (d, J = 8.4Hz, 2H), 7.82 (d, J = 8.4Hz, 2H),7.55(s,1H),7.25(s,1H),6.94(d,J＝2.1Hz,1H),6.62(d,J＝2.1Hz,1H), 4.67-4.60(m,1H),4.44-4.40(m,2H),4.27-4.24(m,2H),2.20-2.00(m,2H), 1.80-1.55(m,2H),1.45(d,J＝6.6Hz,3H).

Example 244 (S)-2-((1-(2-aminoquinoxalin-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 244

244 was prepared following a procedure similar to Example 204. LCMS (ESI): _RT (min) = 1.79, [M+H] ⁺ = 419, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (s, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.89-7.86 (m, 1H), 7.65-7.62 (m, 1H), 7.54 (s, 1H), 7.25 (s, 3H), 6.95-6.94 (m, 1H), 6.61-6.60 (m, 1H), 4.66-4.60 (m, 1H), 4.47-4.43 (m, 2H), 4.42-4.27(m,2H),2.17(s,2H),1.72-1.71(m,2H),1.45(d,J＝6.6Hz,3H).

Example 245 (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 245

245 was separated by chiral SFC into the minor epimer of Example 204. LCMS (ESI): _RT (min) = 1.47, [M+H] ⁺ = 408, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.61-7.44 (m, 5H), 7.29-7.26 (m, 2H), 6.92 (d, J = 2.1 Hz, 1H), 6.59 (d, J = 2.1 Hz, 1H), 4.66-4.59 (m, 1H), 4.39-4.35 (m, 2H), 4.26-4.23 (m, 2H), 2.11 (app s, 2H), 1.69 (app s, 2H), 1.45 (d, J = 8.8 Hz, 3H).

Example 246 (S)-2-((1-(2-aminobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)amino)-2-cyclopropylacetamide 246

246 was prepared following a procedure similar to Example 214. LCMS (ESI): _RT (min) = 1.24, [M+H] ⁺ = 449, method = E; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.81 (d, J = 8.1 Hz, 1H), 7.66 (s, 2H), 7.54 (d, J = 1.2 Hz, 1H), 7.41 (d, J = 1.8 Hz, 1H), 7.29-7.25 (m, 1H), 7.01 (s, 1H), 6.46-6.39 (m, 2H), 5.59 (d, J = 7.2 Hz, 1H), 4.37-4.27 (m, 2H), 4.23-4.14(m,2H),3.15-3.09(m,1H),2.15-2.05(m,2H),1.75-1.63(m,2H), 1.15-1.08(m,1H),0.58-0.42(m,3H),0.40-0.28(m,1H).

Example 247 (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-3-fluoro-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)pyrrolidine-2-carboxamide 247

Step 1: 3-Bromo-2-fluoro-5-methoxy-6-nitroaniline

A solution of 1-bromo-2-fluoro-5-methoxy-4-nitrobenzene (10.0 g, 40 mmol) and 1,1,1-trimethylhydrazine iodide (8.89 g, 44 mmol) in DMSO (50 mL) was added dropwise over 15 min to a solution of potassium tert-butoxide (10.77 g, 96.0 mmol) in DMSO (150 mL) cooled in an ice-water bath. After the addition was complete, the water bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured onto a mixture of 1N hydrochloric acid (200 mL) and 30 g of ice and then extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-20% ethyl acetate/cyclohexane) to give 1.73 g (16%) of the title compound as a bright yellow solid. ¹ H NMR (400MHz, CDCl ₃ ) δ6.43 (d, J=5.4Hz, 1H), 5.31 (br s, 2H), 3.87 (s, 3H).

Step 2: 4-Bromo-3-fluoro-6-methoxybenzene-1,2-diamine

To a suspension of 3-bromo-2-fluoro-5-methoxy-6-nitroaniline (1.73 g, 6.53 mmol) in ethanol (21 mL) and THF (7.0 mL) was added a solution of ammonium chloride (3.14 g, 58.8 mmol) in water (14 mL) and iron powder (2.19 g, 39.2 mmol). The reactants were stirred at 100 ° C for 1 h and then warmed to room temperature. The reaction mixture was diluted with ethyl acetate and water, then filtered through a celite pad and eluted with ethyl acetate. The filtrate was collected, the phases were separated, and the organic extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 30% ethyl acetate/cyclohexane) to give 1.34 g (88%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ = 235/237.

Step 3: 5-Bromo-4-fluoro-7-methoxy-1H-benzo[d]imidazole

To a solution of 4-bromo-3-fluoro-6-methoxybenzene-1,2-diamine (1.34 g, 5.70 mmol) in trimethyl orthoformate (40 mL) was added p-toluenesulfonic acid (49 mg, 0.29 mmol). The reaction mixture was stirred at 100 ° C for 1 h and cooled to room temperature. The solvent was evaporated and the residue was triturated with DCM/methanol, filtered and dried to give 1.18 g (84%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 245/247.

Step 4: 5-Bromo-4-fluoro-1H-benzo[d]imidazol-7-ol

To a solution of 5-bromo-4-fluoro-7-methoxy-1H-benzo[d]imidazole (2.00 g, 8.16 mmol) in DCM (75 mL) was added boron tribromide (1 N in DCM) (32.6 mL, 32.6 mmol) at 20 ° C and the reaction mixture was stirred at 40 ° C. After 16 h, boron tribromide (8.20 mmol) was added and after 40 h, boron tribromide (8.20 mmol) was added. After 64 h, the mixture was cooled in an ice bath and then carefully quenched with methanol. The resulting mixture was washed twice with brine. The combined aqueous extracts were treated with 1N sodium hydroxide (50 ml) to reach about pH 5 and then treated with saturated sodium bicarbonate aqueous solution. A precipitate was formed and the mixture was filtered and the solid was collected. The aqueous layer was extracted twice with DCM and the organic extracts were combined and the solvent was removed. The residue from the extraction was combined with the filtered precipitate and dried to give 1.22 g (65%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ = 231/233.

Step 5: 4-Bromo-3-fluoro-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

To a solution of 5-bromo-4-fluoro-1H-benzo[d]imidazol-7-ol (1.22 g, 5.28 mmol) in DMF (50 mL) was added potassium carbonate (1.85 g, 13.2 mmol) and 1,4-dibromobutane (0.69 mL, 5.81 mmol) under nitrogen, and the mixture was stirred at 100 ° C for 16 h. The resulting mixture was cooled to room temperature, the solvent was evaporated, and the residue was distributed between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 60-70% ethyl acetate/cyclohexane) to give 728 mg (48%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 285/287.

Step 6: 4-Bromo-3-fluoro-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

To a solution of diisopropylethylamine (0.56 mL, 4.03 mmol) in THF (4.0 mL) at -20°C under nitrogen was added n-butyllithium (1.6 N in hexanes, 2.52 mL, 4.03 mmol) and the reaction mixture was stirred at -20°C for 30 min and then cooled to -50°C. To this solution was added dropwise a solution of 4-bromo-3-fluoro-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (718 mg, 2.52 mmol) in THF (16 mL). The mixture was stirred at -50°C for 1 h and allowed to warm to -25°C, then aged at -25°C for 3 h. The reaction mixture was cooled to -50 ° C and a solution of iodine (1.11 g, 4.41 mmol) in THF (8.0 mL) was added dropwise and the reaction mixture was stirred at -50 ° C for 30 min, then warmed to room temperature and stirred for 1 h. The resulting mixture was quenched with an aqueous sodium thiosulfate solution and diluted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated. The residue was purified via flash chromatography on silica gel (solvent gradient: 20-50% ethyl acetate/cyclohexane). The residue was triturated with cyclohexane to give 378 mg (37%) of the title compound as a beige solid. LCMS (ESI): [M+H] ⁺ =411/413.

Step 7: 5-(4-bromo-3-fluoro-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]oxazol-2-amine

4-Bromo-3-fluoro-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]indene (324 mg, 0.79 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (246 mg, 0.95 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (96.8 mg, 0.12 mmol) were dissolved in DMF (5.0 mL). The flask was evacuated and flushed with nitrogen, then 2N aqueous sodium carbonate solution (1.18 mL, 2.36 mmol) was added and the reaction mixture was stirred at 70°C for 4 h. 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (96.8 mg, 0.12 mmol) was then added and the reaction mixture was stirred at 70 ° C for another 1.5 h and then cooled to room temperature. The resulting mixture was distributed between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 4% methanol/DCM) to give 159 mg (43%) of the title compound as a light brown solid. LCMS (ESI): [M+H] ⁺ =417/419.

Step 8: 5-(4-bromo-3-fluoro-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]inden-1-yl)benzo[d]oxazol-2-amine (155 mg, 0.37 mmol), (2S)-pyrrolidine-2-carboxylic acid (171 mg, 1.49 mmol), copper(I) iodide (71 mg, 0.37 mmol) and potassium phosphate (473 mg, 2.23 mmol) were suspended in DMSO (4.0 mL) in a microwave vial. The vial was sealed, evacuated and flushed with nitrogen twice. The reaction mixture was heated at 120 ° C in a microwave reactor for 2 h. The crude reaction mixture was cooled to ambient temperature and diluted with DMSO (2.0 mL). Triethylamine (0.52 mL, 3.71 mmol), ammonium chloride (79 mg, 1.48 mmol) and HATU (846 mg, 2.23 mmol) were added and the reaction mixture was stirred at 20 ° C for 3 h. The resulting mixture was partitioned between ethyl acetate and water. A precipitate was formed, so the mixture was filtered and the solid was collected. The filtrate was also collected and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate and the solvent was evaporated. The resulting residue and the above precipitate were combined and purified via silica gel flash chromatography (solvent gradient: 6-8% (2N ammonia / methanol) / DCM), then purified again via silica gel flash chromatography (solvent: 7% (2N ammonia / methanol) / DCM) to obtain 36 mg (22%) of 247 as a beige solid. LCMS (ESI): R _T (min) = 2.58, [M+H] ⁺ = 451, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.60 (s, 2H),7.50(d,J＝8.1Hz,1H),7.44(d,J＝1.3Hz,1H),7.29(dd,J＝8.1,1.3Hz,1H), 7.26(br s,1H),6.96(br s,1H),6.44(d,J＝6.5Hz,1H),4.35(t,J＝5.5Hz,2H),4.20(t,J＝5.5Hz,2H),4.13-4.08(m,1H),3.75-3.68(m,1H),3.31-3.24(m,1H), 2.25-2.16(m,1H),2.13-2.06(m,2H),1.95-1.86(m,3H),1.72-1.65(m,2H).

Example 248 (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 248

Step 1: (S)-tert-Butyl(6-(4-((1-amino-1-oxopropan-2-yl)oxy)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound (42 mg, 5% yield over four steps) was prepared from tert-butyl (6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (Example 214, Step 3) (826 mg, 1.60 mmol) following procedures similar to those in Example 204, Steps 9-12. LCMS (ESI): [M+H] ⁺ = 524.

Step 2: (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaoctin[cd]inden-4-yl)oxy)propanamide

A mixture of (S)-tert-butyl(6-(4-((1-amino-1-oxopropan-2-yl)oxy)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (45.0 mg, 0.086 mmol) and TFA (0.3 mL) in DCM was stirred at room temperature for 30 min. The resulting mixture was evaporated in vacuo. The crude product was purified by chiral HPLC to give 11.5 mg (32%) of the title compound as a white solid. LCMS (ESI): R _T (min) = 3.50, [M+H] ⁺ = 424, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.02 (d, J = 1.6Hz, 1H), 7.76 (s, 2H), 7.63-7.39 (m, 3H), 7.28(s,1H),6.92(d,J＝2.2Hz,1H),6.60(d,J＝2.1Hz,1H),4.63(d,J＝6.7Hz,1H), 4.41 (m, 2H), 4.33-4.17 (m, 2H), 2.15 (d, J = 7.2Hz, 2H), 1.68 (d, J = 9.4Hz, 2H), 1.46 (d, J = 6.6Hz, 3H).

Example 249 (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 249

Step 1: 5-Bromo-7-fluorobenzo[d]oxazol-2-amine

To a solution of 2-amino-4-bromo-6-fluorophenol (18.0 g, 87.4 mmol) in methanol (180 mL) was added cyanogen bromide (18.4 g, 174 mmol). The reaction mixture was heated at 35 ° C for 16 h and then cooled to room temperature. The resulting mixture was quenched with aqueous sodium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 20-70% ethyl acetate/petroleum ether) to give 18 g (89%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ = 231/233.

Step 2: 7-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine

Under a nitrogen atmosphere, 5-bromo-7-fluorobenzo[d]oxazol-2-amine (5.85 g, 25.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (7.84 g, 30.9 mmol), potassium acetate (7.80 g, 79.5 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.92 g, 2.62 mmol) were suspended in DMF (100 mL) and the reaction mixture was stirred at 100 ° C for 3 h. The resulting mixture was partitioned between ethyl acetate and distilled water. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 30-70% ethyl acetate/petroleum ether) to give 3.5 g (50%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =279.

Step 3: 5-(4-Bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-7-fluorobenzo[d]oxazol-2-amine

To a solution of 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]indene (Example 204, Step 6) (320 mg, 0.814 mmol), 7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (279 mg, 1.00 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (124 mg, 0.169 mmol) in tetrahydrofuran (9.00 mL) was added 2N aqueous sodium carbonate solution (1.60 mL, 3.20 mmol). The reaction mixture was stirred at 80°C for 5 h. The resulting mixture was partitioned between DCM and water and the aqueous layer was extracted with DCM. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude residue was purified by flash chromatography on silica gel (solvent gradient: 2-10% methanol/DCM) to give 150 mg (44.3% yield) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ =417/419.

Step 4: 7-Fluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaoctin[cd]inden-1-yl)benzo[d]oxazol-2-amine

Under nitrogen atmosphere, 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-1-yl)-7-fluorobenzo[d]oxazol-2-amine (300 mg, 0.719 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (389 mg, 1.53 mmol), potassium acetate (253 mg, 2.58 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (107 mg, 0.146 mmol) were suspended in 1,4-dioxane (12 mL) and the reaction mixture was stirred at 100 ° C for 16 h. The resulting mixture was cooled to room temperature and partitioned between DCM and distilled water. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by flash chromatography on silica gel (solvent gradient: 2-10% methanol/DCM) to give 490 mg (73.5% yield) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =465.

Step 5: 1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol

The reaction vessel was charged with 7-fluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-1-yl)benzo[d]oxazol-2-amine, acetic acid (4.00 mL) and water (4.00 mL). Hydrogen peroxide (30%, 2 mL) was added and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was quenched with aqueous sodium bisulfite and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on reverse phase silica gel (solvent gradient: 0-100% methanol/water) to give 345 mg (63.0%) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ = 355.

Step 6: (S)-methyl 2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate

The title compound (900 mg, 72.0% yield) was prepared from 1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol (1.00 g, 2.82 mmol) and (R)-methyl 2-(tosyloxy)propanoate (1.09 g, 4.22 mmol) following a procedure similar to that described in Step 11 of Example 204. LCMS (ESI): [M+H] ⁺ = 441.

Step 7: 249 (322 mg, 37.0% yield) was prepared from (S)-methyl 2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate following a procedure similar to that of Example 204, step 12. LCMS (ESI): _RT (min) = 1.03, [M+H] ⁺ = 426, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.89 (s, 2H), 7.55 (s, 1H), 7.29-7.19 (m, 3H), 6.93 (d, J = 2.1 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 4.68-4.55 (s, 1H), 4.40-4.36 (m, 2H), 4.26-4.23 (m, 2H), 2.10 (s, 2H), 1.68 (s, 2H), 1.45 (d, J = 6.6 Hz, 3H).

Example 250 (S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)pyrrolidine-2-carboxamide 250

250 was prepared following a procedure analogous to Examples 104 and 204. LCMS (ESI): _RT (min) = 1.23, [M+H] ⁺ = 433, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.60 (s, 2H), 7.49 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.38 (s, 1H), 7.28-7.26 (m, 1H), 7.07 (s, 1H), 6.45 (d, J = 2.0 Hz, 1H), 6.23 (d, J = 1.6 Hz, 1H), 4.36-4.33 (m, 2H), 4.24-4.21 (m, 2H), 3.87-3.84(m,1H),3.62-3.58(m,1H),3.31-3.19(m,1H),2.24-2.20(m,1H), 2.14-2.06(m,2H),2.03-1.95(m,3H),1.71-1.69(m,2H).

Examples 251 and 252 (R)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)oxy)propanamide 251 and (S)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)oxy)propanamide 252

Step 1: (R)-5-(4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-2-yl)benzo[d]oxazol-2-amine

The title compound (282 mg, 100% yield) was prepared from (R)-5-(7-bromo-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-2-yl)benzo[d]oxazol-2-amine (251 mg, 0.65 mmol) following a procedure similar to that described in Step 1 of Example 162. LCMS (ESI): [M+H] ⁺ = 433.

Step 2: (R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylene-7-ol

The reaction vessel was charged with (R)-5-(4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-2-yl)benzo[d]oxazol-2-amine (282 mg, 0.65 mmol) and THF (5.0 mL). Hydrogen peroxide (30%, 222 μL) was added and the reaction mixture was stirred at room temperature for 6.5 h. The mixture was loaded directly onto an SCX-2 column, washed with methanol, and eluted with 2N ammonia in methanol. Fractions containing the title compound were evaporated in vacuo. The residue was further purified via flash chromatography (solvent gradient: 0-5% methanol in ethyl acetate) to give 96 mg (46%) of the title compound. LCMS (ESI): [M+H] ⁺ = 323.

Step 3: (S)-methyl 2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)oxy)propanoate

A reaction vessel was charged with (R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthen-7-ol (96 mg, 0.30 mmol), methyl (R)-2-methanesulfonyloxypropionate (65.1 mg, 1.20 mmol), potassium carbonate (53.5 mg, 0.39 mmol), and DMSO (2.0 mL). The reaction mixture was heated at 35°C for 24 h. The resulting mixture was then cooled to room temperature and additional methyl (R)-2-methanesulfonyloxypropionate (65.1 mg, 1.20 mmol) and potassium carbonate (53.5 mg, 0.39 mmol) were added. The reaction mixture was heated at 35°C for an additional 24 h. The resulting mixture was allowed to cool to room temperature and partitioned between ethyl acetate and distilled water. The organic layer was dried over magnesium sulfate and concentrated in vacuo to yield 122 mg of the title compound (ee undetermined). LCMS (ESI): [M+H] ⁺ =409.

Step 4: (R)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)oxy)propanamide and (S)-2-(((R)-2-(2-aminobenzo[d]oxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)oxy)propanamide

A reaction vessel was charged with methyl (S)-2-[(R)-2-(2-aminobenzoxazol-5-yl)-4-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthen-7-yloxy]propanoate (122 mg, 0.3 mmol) and 7N ammonia/methanol (10 mL). The reaction mixture was stirred at room temperature for 24 h. The resulting mixture was concentrated in vacuo and triturated with DCM. The solids were filtered to afford 40 mg (34%, 31% deuterated) of the title compound. The filtrate was concentrated in vacuo and the residue was purified via flash chromatography (solvent gradient: 0-10% methanol/ethyl acetate) to afford 30 mg (26%, 88% deuterated) of the title compound. The filtered solid and the material recovered from flash chromatography were combined and resolved by chiral SFC to afford the title compound.

251 (minor stereoisomer): LCMS (ESI): _RT (min) = 2.37, [M+H] ⁺ = 394, method = A; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (d, J = 1.5 Hz, 1H), 7.59 (br s, 2H), 7.56 (dd, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 7.48 (br s, 1H), 7.22 (br s, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 4.69 (dd, J = 12.7, 2.6 Hz, 1H), 4.61 (q, J＝6.5Hz, 1H), 4.48-4.39 (m, 1H), 4.28 (dd, J＝12.7, 9.2Hz, 1H), 1.50 (d, J＝6.3Hz, 3H), 1.44 (d, J＝6.5Hz, 3H).

252 (major stereoisomer). LCMS (ESI): _RT (min) = 2.32, [M+H] ⁺ = 394, method = A; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.71 (d, J = 1.5 Hz, 1H), 7.59 (br s, 2H), 7.56 (dd, J = 8.1, 1.5 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 6.75 (d, J = 1.7 Hz, 1H), 6.42 (d, J = 1.7 Hz, 1H), 4.70 (dd, J = 12.5, 3.0 Hz, 1H), 4.60 (q, J＝6.0Hz, 1H), 4.49-4.40 (m, 1H), 4.27 (dd, J＝12.5, 9.0Hz, 1H), 1.50 (d, J＝6.0Hz, 3H), 1.44 (d, J＝6.0Hz, 3H).

Example 253 5-(4-Bromo-8,9-dihydrooxa[4,3,2-cd]indazol-1(7H)-yl)benzo[d]oxazol-2-amine 253

Step 1: 5-Bromo-N,N-di(4-methoxybenzyl)benzo[d]oxazol-2-amine

The title compound (3.07 g, 47% yield) was prepared from 5-bromobenzo[d]oxazol-2-amine (3.10 g, 14.5 mmol) following a procedure similar to that described in Example 242, Step 2. LCMS (ESI): [M+H] ⁺ =453/455.

Step 2: N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine

The title compound (1.06 g, 94% yield) was prepared from 5-bromo-N,N-di(4-methoxybenzyl)benzo[d]oxazol-2-amine (1.02 g, 2.25 mmol) following a procedure similar to that described in Step 7 of Example 204. LCMS (ESI): [M+H] ⁺ =501.

Step 3: 4-Bromo-2,7,8,9-tetrahydrooxa[4,3,2-cd]indazole

A mixture of 8-bromo-6-fluoro-3,4-dihydrobenzo[b]oxa-5(2H)-one and 6-bromo-8-fluoro-3,4-dihydrobenzo[b]oxa-5(2H)-one (Example 213, Step 3) (500 mg, 1.93 mmol) and hydrazine (8 mL, 80%) in ethylene glycol dimethyl ether (7.00 mL, 72.3 mmol) was heated at 120 ° C. for 90 min under microwave irradiation. The reaction was repeated five times. The five batches of reaction mixture were combined, diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 1.40 g (55%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =253/255.

Step 4: 5-(4-Bromo-8,9-dihydrooxa[4,3,2-cd]indazol-1(7H)-yl)-N,N-di(4-methoxybenzyl)benzo[d]oxazol-2-amine and 5-(4-Bromo-8,9-dihydrooxa[4,3,2-cd]indazol-2(7H)-yl)-N,N-di(4-methoxybenzyl)benzo[d]oxazol-2-amine

A mixture of 4-bromo-2,7,8,9-tetrahydrooxa[4,3,2-cd]indazole (312 mg, 1.23 mmol), N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (720 mg, 1.43 mmol), copper(II) acetate (152 mg, 0.840 mmol) and molecular sieves (100 mg) in pyridine (15.0 mL) was degassed with oxygen. The reaction mixture was heated at 90 ° C for 16 h. The mixture was cooled to room temperature and then filtered. The filtrate was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give a mixture of the two title compounds (620 mg) as a yellow solid that was used without further purification. LCMS(ESI): [M+H] ⁺ =625/627.

Step 8: A mixture of 5-(4-bromo-8,9-dihydrooxa[4,3,2-cd]indazol-1(7H)-yl)-N,N-bis(4-methoxybenzyl)benzo[d]oxazol-2-amine and 5-(4-bromo-8,9-dihydrooxa[4,3,2-cd]indazol-2(7H)-yl)-N,N-bis(4-methoxybenzyl)benzo[d]oxazol-2-amine (620 mg, 0.990 mmol) in TFA (20 mL) was heated at 80 ° C for 24 h. The reaction mixture was diluted with water. The aqueous layer was adjusted to approximately pH 8 with aqueous sodium bicarbonate solution. The mixture was extracted with DCM, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to afford 253 as the minor regioisomer (2.5 mg, 1% yield). LCMS (ESI): _RT (min) = 1.83, [M+H] ⁺ = 385/387, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.69 (s, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.39 (d, J = 1.2 Hz, 1H), 7.25-7.21 (m, 1H), 6.51 (d, J = 1.5 Hz, 1H), 4.44-4.41 (m, 2H), 3.14-3.09 (m, 2H), 2.30-2.10 (m, 2H).

Example 254 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide 254

254 was prepared following a procedure similar to Example 104. LCMS (ESI): R _T (min) = 1.21, [M+H] ⁺ = 421, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.59 (s, 2H), 7.49 (d, J＝8.4Hz,1H),7.43(d,J＝1.5Hz,1H),7.36(s,1H),7.28-7.25(m,1H),7.08(s,1H), 6.78(d,J＝1.8Hz,1H),6.57(d,J＝2.1Hz,1H),4.37-4.21(m,5H),2.80(s,3H)2.18-2.02(m,2H),1.76-1.64(m,2H),1.22(d,J＝6.9Hz,3H).

Example 255 (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide 255

255 was prepared following a procedure analogous to Example 214. LCMS (ESI): _RT (min) = 3.50, [M+H] ⁺ = 437, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.00 (s, 1H), 7.74 (s, 2H), 7.52-7.44 (m, 2H), 7.38 (s, 1H), 7.09 (s, 1H), 6.76 (s, 1H), 6.56 (s, 1H), 4.37-4.23 (m, 5H), 2.79 (s, 3H), 2.23-2.15 (m, 2H), 1.80-1.60 (m, 2H), 1.22 (d, J = 6.7 Hz, 3H).

Examples 256 and 257: (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)butanamide 256 and (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)butanamide 257.

To a suspension of 1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ol (Example 162, Step 2) (178 mg, 0.552 mmol) and potassium carbonate (305 mg, 2.21 mmol) in acetone (2.7 mL) was added 2-bromobutanamide (145 mg, 0.828 mmol). The reaction was sealed in a vial under nitrogen and heated to 60°C. After stirring for 1 h, the temperature was increased to 70°C and the reaction was stirred overnight. After 18 h, the reaction was diluted with methanol and filtered. The filtrate was evaporated in vacuo and the crude product was purified via silica gel flash chromatography (solvent gradient: 0-20% methanol/DCM) followed by chiral SFC separation to provide the two title compounds as a single, unknown stereoisomer.

256 (8.5 mg): LCMS (ESI): _RT (min) = 2.82, [M+H] ⁺ = 408.1, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.59-7.52 (m, 3H), 7.53-7.42 (m, 2H), 7.36 (dd, J = 8.2, 1.7 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.44 (d, J = 2.2 Hz, 1H), 4.45-4.35 (m, 3H), 4.26 (t, J = 5.5 Hz, 2H), 2.33-2.26 (m, 2H), 1.88-1.76 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H).

257 (7.2mg): LCMS (ESI): R _T (min) = 2.83, [M+H] ⁺ = 408.1, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.59-7.52 (m, 3H), 7.52-7.42 (m, 2H), 7.36 (dd, J = 8.2, 1.7Hz,1H),7.22(d,J＝2.1Hz,1H),6.79(d,J＝2.3Hz,1H),6.44(d,J＝2.1Hz,1H), 4.45-4.35(m,3H),4.26(t,J＝5.6Hz,2H),2.33-2.24(m,2H),1.88-1.76(m,2H), 0.98 (t, J = 7.4 Hz, 3H).

Example 258 (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanamide 258

Step 1: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-fluorobenzo[d]oxazol-2-amine

The title compound (456 mg, 19% yield) was prepared from 5-bromo-7-fluorobenzoxazol-2-ylamine (1.38 g, 5.97 mmol) following a procedure similar to that described in Example 205, Step 1. LCMS (ESI): [M+H] ⁺ =404/406.

Step 2: 7-Fluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine

The title compound (509 mg, quantitative yield) was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)-7-fluorobenzo[d]oxazol-2-amine (456 mg, 1.13 mmol) following a procedure similar to that described in Step 1 of Example 162. LCMS (ESI): [M+H] ⁺ =451.

Step 3: 1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol

The title compound (161 mg, 41% yield) was prepared from 7-fluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]oxazol-2-amine (509 mg, 1.13 mmol) following a procedure similar to that described in Step 2 of Examples 251 and 252. LCMS (ESI): [M+H] ⁺ = 451.

Step 4: (S)-methyl 2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoate

The title compound (202 mg, 100% yield) was prepared from 1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol (161 mg, 0.47 mmol) following a procedure similar to that described in Step 3 of Examples 251 and 252. LCMS (ESI): [M+H] ⁺ = 427.

Step 5: 258 (31.8 mg, 27% yield) was prepared from (S)-methyl 2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoate (202 mg, 0.47 mmol) following a procedure similar to that of Step 4 of Examples 251 and 252. LCMS (ESI): R _T (min) = 2.45, [M+H] ⁺ = 412, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.86 (br s, 2H),7.47(s,1H),7.43(d,J＝1.4,1H),7.32(dd,J＝10.7,1.4Hz,1H),7.21(s,1H), 6.78(d,J＝2.1Hz,1H),6.44(d,J＝2.1Hz,1H),4.60(q,J＝6.5Hz,1H),4.42-4.36(m, 2H), 4.32-4.26 (m, 2H), 2.34-2.25 (m, 2H), 1.44 (d, J = 6.5Hz, 3H).

Examples 259 and 260 (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)-2-cyclopropylacetamide 259 and (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)-2-cyclopropylacetamide 260

Step 1: Methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)-2-cyclopropylacetate

To a suspension of 1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ol (0.5895 mmol, 190 mg) and potassium carbonate (3.537 mmol, 488.9 mg) in acetone (3 mL) was added ethyl 2-bromo-2-cyclopropylacetate (0.728 mmol, 157 mg). The reaction was sealed in a vial under nitrogen and heated to 70°C. After 2 h, an additional 3 equivalents of potassium carbonate and 0.5 equivalents of ethyl 2-bromo-2-cyclopropylacetate were added, and the reaction mixture was heated at 40°C overnight. 3.0 mL of DMF and 70 mg of ethyl 2-bromo-2-cyclopropylacetate were then added to the reaction mixture, and the reaction mixture was heated at 35°C for 3 days. The reaction mixture was evaporated onto celite and the crude product was purified via silica gel flash chromatography (12 g silica gel, solvent gradient: 0-5% methanol in DCM) to give 42.4 mg (17%) of the title compound. LCMS(ESI): [M+H] ⁺ =435; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.56 (s, 1H), 7.54 (d, J = 1.7Hz, 1H), 7.48(d,J＝8.2Hz,1H),7.35(dd,J＝8.2,1.7Hz,1H),6.67(d,J＝2.3Hz,1H),6.38(d, J＝2.3Hz,1H),4.45-4.35(m,2H),4.31-4.22(m,3H),3.67(s,3H),2.28(t,J＝6.0Hz,2H),1.35-1.26(m,1H),0.68-0.50(m,4H).

Step 2: (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)-2-cyclopropylacetamide and (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)-2-cyclopropylacetamide

A mixture of methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)-2-cyclopropylacetate (42 mg, 0.10 mmol) and ammonia (7 M solution in methanol, 3.0 mL, 21 mmol) was heated in a sealed tube at 50 ° C. for 48 h. The reaction mixture was then evaporated in vacuo and purified by reverse phase HPLC and resolved by chiral SFC to give the title compounds as a single unknown stereoisomer.

259 (9.7mg): LCMS (ESI): R _T (min) = 2.839, [M+H] ⁺ = 420.1, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.56 (s, 2H), 7.54 (d, J = 1.7Hz, 1H), 7.50-7.44 (m, 2H), 7.35(dd,J＝8.2,1.7Hz,1H),7.17(s,1H),6.73(d,J＝2.3Hz,1H),6.41(d,J＝2.3Hz, 1H),4.44-4.34(m,2H),4.31-4.21(m,2H),3.93(d,J＝8.0Hz,1H),2.36-2.19(m, 2H),1.33-1.20(m,1H),0.62-0.52(m,3H),0.48-0.38(m,1H).

260 (9.5mg): LCMS (ESI): R _T (min) = 2.849, [M+H] ⁺ = 420.1, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.56 (s, 2H), 7.54 (d, J = 1.7, 1H), 7.50-7.45 (m, 2H), 7.35(dd,J＝8.2,1.7Hz,1H),7.17(d,J＝2.0Hz,1H),6.73(d,J＝2.3Hz,1H),6.41(d, J＝2.3Hz,1H),4.44-4.34(m,2H),4.30-4.19(m,2H),3.93(d,J＝8.0Hz,1H), 2.33-2.22(m,2H),1.32-1.20(m,1H),0.63-0.52(m,3H),0.49-0.39(m,1H).

Example 261 (S)-2-((1-(2-amino-4,7-difluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 261

Step 1: 4-Bromo-3,6-difluoro-2-nitrophenol

A solution of 4-bromo-2,5-difluoro-phenol (21.09 g, 100.9 mmol) in acetic acid (50.0 mL, 872 mmol) was cooled in an ice bath. Nitric acid (6.00 mL, 120 mmol) was added and the reaction mixture was stirred at room temperature. After 3 h, the reaction mixture was transferred to a separatory funnel with 500 mL of EtOAc and 250 mL of water. The organic phase was separated, washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (330 g silica gel, solvent gradient: 0-100% ethyl acetate/heptane) to give 11.43 g (44%) of the title compound. LCMS (ESI): [MH] ⁻ = 252; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.03 (dd, J = 10.4, 6.6 Hz, 1H).

Step 2: 2-Amino-4-bromo-3,6-difluorophenol

A mixture of 4-bromo-3,6-difluoro-2-nitrophenol (11.43 g, 45.00 mmol), iron powder (325 mesh) (13.03 g, 226.3 mmol), ammonium chloride (9.68 g, 181 mmol), ethanol (25 mL) and water (25 mL) was heated at 60 ° C for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (300 mL) and water (200 mL) and filtered through celite. Brine (100 mL) was added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (125 g silica gel, solvent gradient: 0-40% ethyl acetate/heptane) to give 5.92 g (59%) of the title compound as a peach-colored solid. LCMS (ESI): [M+H] ⁺ =224; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 6.72 (dd, J = 9.9, 6.2Hz, 1H), 5.12 (s, 2H).

Step 3: 5-Bromo-4,7-difluorobenzo[d]oxazol-2-amine

A mixture of 2-amino-4-bromo-3,6-difluorophenol (5.92 g, 26.4 mmol), methanol (30.0 mL), and cyanogen bromide (8.40 g, 79.3 mmol) was heated at 35°C for 15 h. The reaction mixture was evaporated under reduced pressure to remove most of the solvent, then partitioned between 200 mL of DCM and 150 mL of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with 3 x 150 mL of DCM. The combined organic layers were dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (80 g of silica gel, solvent gradient: 0-20% ethyl acetate/DCM) to yield 4.43 g (67%) of the title compound as a peach-colored solid. LCMS (ESI): [M+H] ⁺ = 249; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 2H), 7.34 (dd, J = 9.3, 4.9 Hz, 1H).

Step 4: 4,7-Difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine

A 200 mL flask was charged with 5-bromo-4,7-difluorobenzo[d]oxazol-2-amine (4.43 g, 17.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (163 mg, 0.178 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (342 mg, 0.703 mmol), bis(pinacolato)diboron (9.30 g, 36.6 mmol), and potassium acetate (5.48 g, 55.8 mmol). The flask was evacuated and backfilled with nitrogen twice. 1,4-Dioxane (75 mL) was then added via syringe. The mixture was heated at 100° C. under a nitrogen atmosphere for 2 h. The reaction mixture was evaporated onto celite. The crude product was purified via silica gel flash chromatography (80 g silica gel, solvent gradient: 20-60% ethyl acetate/heptane) to yield 4.31 g (82%) of the title compound. LCMS (ESI): [M+H] ⁺ =297.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.89 (s, 2H), 6.99 (dd, J = 9.8, 3.3Hz, 1H), 1.17 (s, 12H).

Step 5: 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-4,7-difluorobenzo[d]oxazol-2-amine

A 100 mL flask containing 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (1.046 g, 2.66 mmol), 4,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (887 mg, 3.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (1:1) (444 mg, 0.54 mmol) and sodium carbonate (592 mg, 5.53 mmol) was evacuated and backfilled with nitrogen. DMF (10 mL) and water (1 mL) were added, and the flask was heated at 90° C. under a nitrogen balloon for 7 h. To the reaction was added 4,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (309 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (1:1) (201 mg, 1.04 mmol) and 2M aqueous sodium carbonate solution (1.5 mL, 3.0 mmol) and the reaction mixture was heated at 80°C overnight. The reaction mixture was diluted with ethyl acetate, filtered through celite, washed with water and brine, and evaporated in vacuo. The crude product was purified via silica gel flash chromatography (40 g silica gel, solvent gradient: 0-100% ethyl acetate/DCM) to give 0.44 g (38%) of the title compound. LCMS (ESI): [M+H] ⁺ =434.9; ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.10 (s, 2H), 7.70 (d, J＝1.7Hz, 1H), 7.19 (dd, J＝9.8, 4.7Hz, 1H), 7.14 (d, J＝1.7Hz, 1H), 4.28 (t, J＝5.5Hz, 4H), 2.03-1.94 (m, 2H), 1.69-1.58 (m, 2H).

Step 6: 4,7-Difluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaoctino[cd]inden-1-yl)benzo[d]oxazol-2-amine

The title compound (256 mg, 52% yield) was prepared from 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-4,7-difluorobenzo[d]oxazol-2-amine following a procedure similar to that described in Step 1 of Example 162. LCMS (ESI): [M+H] ⁺ = 483.1.

Step 7: 1-(2-amino-4,7-difluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol

The title compound (47.9 mg, 58% yield) was prepared from 4,7-difluoro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaocta[cd]inden-1-yl)benzo[d]oxazol-2-amine following a similar procedure as in step 2 of Example 162. LCMS(ESI): [M+H] ⁺ =372.95; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9.17 (s, 1H), 8.06 (s, 2H), 7.13(dd,J＝9.8,4.7Hz,1H),6.77(d,J＝2.1Hz,1H),6.44(d,J＝2.1Hz,1H),4.20(t,J＝5.6Hz,4H),2.00-1.90(m,2H),1.67-1.57(m,2H).

Step 8: (S)-methyl 2-((1-(2-amino-4,7-difluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate

The title compound (36.1 mg, 22%) was prepared from 1-(2-amino-4,7-difluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol following a procedure similar to that in step 3 of Example 162. LCMS (ESI): [M+H] ⁺ =459.0; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.08 (s, 2H), 7.15 (dd, J = 9.8, 4.6Hz, 1H), 6.90 (d, J = 2.2Hz, 1H), 6.61 (d, J = 2.2Hz, 1H), 5.00 (q, J = 6.7Hz, 1H), 4.28-4.20 (m, 4H), 3.70 (s, 3H), 2.01-1.94 (m, 2H), 1.68-1.61 (m, 2H), 1.53 (d, J = 6.7Hz, 3H).

Step 9: A mixture of (S)-methyl 2-((1-(2-amino-4,7-difluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate (36 mg, 0.07853 mmol) and ammonia (7 M in methanol) (3.0 mL, 21 mmol) was stirred in a sealed tube at room temperature for 21 h. The reaction mixture was evaporated in vacuo and the crude product was purified via reverse phase HPLC followed by chiral SFC to remove the minor epimer to afford 20.7 mg (58%) of 261. LCMS (ESI): R _T (min) = 3.22, [M+H] ⁺ = 444.1, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.08 (s, 2H),7.53(s,1H),7.23(s,1H),7.15(dd,J＝9.8,4.7Hz,1H),6.94(d,J＝2.2Hz,1H), 6.64(d,J＝2.1Hz,1H),4.63(q,J＝6.6Hz,1H),4.30-4.15(m,4H),2.03-1.90(m,2H), 1.71-1.59(m,2H),1.45(d,J＝6.6Hz,3H).

Example 262 (S)-4-(1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)morpholine-3-carboxamide 262

Step 1: tert-Butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate

A 100 mL flask containing 2-amino-6-bromobenzothiazole (2.52 g, 10.77 mmol), bis(pinacolato)diboron (5.45 g, 21.24 mmol), potassium acetate (3.28 g, 33.09 mmol), 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (212.2 mg, 0.436 mmol), and tris(dibenzylideneacetone)dipalladium (chloroform complex) (117.9 mg, 0.110 mmol) was evacuated and backfilled with nitrogen. 1,4-Dioxane (20.0 mL, 233 mmol) was added, and the reaction mixture was stirred at 100° C. under a nitrogen balloon for 1 h. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (1:1) (285.9 mg, 0.350 mmol) was then added to the reaction. After another 17 hours, the reaction mixture was cooled to room temperature, filtered through celite, rinsed with ethyl acetate, and then evaporated to dryness on celite. The crude product was purified via silica gel flash chromatography (80 g silica gel, solvent gradient: 0-100% isopropyl acetate/heptane) to yield 2.85 g. 2.64 g of this substance was combined with di-tert-butyl dicarbonate (2.58 g, 11.45 mmol), 4-dimethylaminopyridine (79.9 mg, 0.654 mmol), and DCM (20.0 mL, 312 mmol) and stirred at room temperature for 2 hours. The mixture was evaporated in vacuo and the crude product was purified via silica gel flash chromatography (40 g silica gel, solvent gradient: 0-50% ethyl acetate/heptane) to yield 2.24 g of the title compound. LCMS (ESI): [M+H] ⁺ = 377.

Step 2: tert-Butyl (6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate

A mixture of 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (1.0323 g, 2.6266 mmol), tert-butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate (2.031 g, 3.239 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (1:1) (324.8 mg, 0.3977 mmol), sodium carbonate (847.5 mg, 7.92 mmol), water (3.0 mL, 170 mmol) and THF (9.0 mL, 110 mmol) was heated in a sealed vessel under nitrogen at 80° C. for 20 h. The reaction mixture was degassed by bubbling nitrogen for 10 minutes, and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride DCM complex (1:1) (523 mg) was added and the mixture was heated at 80°C for 6 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, filtered, washed with water and brine, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (40 g silica gel, solvent gradient: 0-100% ethyl acetate/dichloromethane) to give 0.4242 g (31%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =514.95; ¹ H NMR (400MHz, DMSO-d ₆ ) δ11.94 (s, 1H), 8.32 (d, J = 1.2Hz, 1H), 7.84 (d, J = 8.4Hz, 1H), 7.72 (dd, J = 8.3, 1.7Hz, 1H), 7.69-7.64(m,1H),7.12-7.06(m,1H),4.52-4.41(m,2H),4.36-4.26(m,2H), 2.24-2.11(m,2H),1.78-1.63(m,2H),1.53(s,9H).

Step 3: (S)-tert-Butyl(6-(4-(3-carbamoylmorpholino)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound was prepared from tert-butyl (6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate following procedures similar to those described in Steps 1-2 of Example 104. LCMS (ESI): [M+H] ⁺ =565.1.

Step 4: To a solution of tert-butyl (S)-(6-(4-(3-carbamoylmorpholino)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (0.2072 mmol, 0.2072 mmol) in DCM (3.0 mL, 47 mmol) was added hydrogen chloride (4.0 mol/L in dioxane, 0.50 mL, 2.0 mmol) and methanol (0.5 mL). The reaction mixture was stirred at room temperature for 3 h, then heated at 35 °C overnight, followed by heating at 50 °C for another 4 h. The reaction mixture was evaporated in vacuo and the crude product was purified by reverse phase HPLC and achiral SFC to afford 6.3 mg (6%) of 262. LCMS (ESI): R _T (min) = 2.74, [M+H] ⁺ = 465.1, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.98 (d, J＝1.7Hz,1H),7.70(s,2H),7.51(dd,J＝8.3,1.8Hz,1H),7.45(d,J＝8.3Hz,1H), 7.19(d,J＝1.9Hz,1H),7.02(s,1H),6.84(d,J＝2.1Hz,1H),6.60(d,J＝2.1Hz,1H), 4.37(t,J＝6.1Hz,2H),4.22(t,J＝5.4Hz,2H),4.11-3.98(m,2H),3.92-3.79(m,2H), 3.70-3.53(m,2H),3.21-3.15(m,1H),2.19-2.08(m,2H),1.75-1.65(m,2H).

Example 263 (R)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanamide 263

263 was separated into the minor epimer generated during the preparation of Example 258 via chiral SFC. LCMS (ESI): R _T (min) = 2.44, [M+H] ⁺ = 412, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.86 (br s, 2H), 7.47 (s, 1H), 7.43 (d, J = 1.4, 1H), 7.32 (dd, J = 10.7, 1.4Hz,1H),7.21(s,1H),6.78(d,J＝2.1Hz,1H),6.44(d,J＝2.1Hz,1H),4.60(q, J＝6.5Hz,1H),4.42-4.36(m,2H),4.32-4.26(m,2H),2.34-2.25(m,2H),1.44(d, J＝6.5Hz,3H).

Example 264 (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide 264

264 (99.5 mg, 9.4% yield) was prepared from 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-7-fluorobenzo[d]oxazol-2-amine (Example 249 Step 3) (1.00 g, 2.40 mmol) following a procedure similar to Example 104. LCMS (ESI): R _T (min) = 3.50, [M+H] ⁺ = 439, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.86 (s, 2H), 7.36 (s, 1H), 7.29(s,1H),7.19(d,J＝10.8Hz,1H),7.06(s,1H),6.83(s,1H),6.59(s,1H), 4.36-4.23(m,5H),2.79(s,3H),2.20-2.02(m,2H),1.80-1.55(m,2H),1.22(d, J＝6.9Hz,3H).

Example 265 (S)-2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 265

Step 1: 5-Bromothiazolo[5,4-b]pyridin-2-amine

To a suspension of 6-bromopyridin-3-amine (20.0 g, 115 mmol) and potassium thiocyanate (56.0 g, 576 mmol) in acetic acid (250 mL) was added dropwise a solution of bromine (23.88 g, 149 mmol) in acetic acid (100 mL) at room temperature. The reaction mixture was stirred at room temperature for 15 h. The solid was filtered out, and the resulting solution was extracted with ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated in vacuo. The crude product was purified via silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) to give 18 g (68%) of the title compound. LCMS (ESI): [M+H] ⁺ = 230/232.

Step 2: tert-Butyl 5-bromothiazolo[5,4-b]pyridin-2-ylcarbamate

To a suspension of 5-bromothiazolo[5,4-b]pyridin-2-amine (15.0 g, 65.1 mmol) in DCM (300 mL) was added di-tert-butyl dicarbonate (21.0 g, 96.2 mmol) and 4-dimethylaminopyridine (8 g, 65.5 mmol). The reaction mixture was stirred at room temperature for 2 h and evaporated in vacuo. The residue was purified by silica gel flash chromatography (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 13 g (60%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 330/332.

Step 3: Methyl 2-(tert-Butoxycarbonylamino)thiazolo[5,4-b]pyridine-5-carboxylate

A mixture of tert-butyl 5-bromothiazolo[5,4-b]pyridin-2-ylcarbamate (14.0g, 42.4mmol), potassium carbonate (17g, 123mmol), palladium (II) acetate (2.80g, 12.5mmol) and [3-(diphenylphosphino)propyl]diphenylphosphine (4.2g, 10.1mmol) in methanol (300mL) and DMF (150mL) was saturated with carbon monoxide gas and stirred at 60 ° C for 6h. The resulting mixture was cooled to room temperature and evaporated in vacuo. The residue was distributed between ethyl acetate and water and then filtered through diatomaceous earth. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (solvent gradient: 0-5% methanol/DCM) to give 8g (61%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =310.

Step 4: 2-(tert-Butoxycarbonylamino)thiazolo[5,4-b]pyridine-5-carboxylic acid

To a suspension of methyl 2-(tert-butoxycarbonylamino)thiazolo[5,4-b]pyridine-5-carboxylate (8.00 g, 25.8 mmol) in THF (100 mL) was added lithium hydroxide (1N aqueous solution, 140 mL, 133 mmol), and the mixture was stirred at room temperature for 4 h. The pH of the solution was adjusted to 6 with hydrogen chloride. The solvent was evaporated, and the crude product was used in the next step without further purification. LCMS (ESI): [M+H] ⁺ = 296.

Step 5: Tert-butyl (5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate

The title compound (3.1 g, 67.4% yield over two steps) was prepared from 9-bromo-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazaocten-7-amine (Example 204, Step 4) (2.3 g, 8.94 mmol) and 2-(tert-butoxycarbonylamino)thiazolo[5,4-b]pyridine-5-carboxylic acid (3.40 g, 11.5 mmol) following procedures similar to those in Steps 1-2 of Example 125. LCMS (ESI): [M+H] ⁺ = 516/518.

Step 6: tert-Butyl (5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate

Under nitrogen atmosphere, tert-butyl (5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate (3.00 g, 5.81 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.80 g, 7.09 mmol), potassium acetate (1.80 g, 18.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (700 mg, 0.957 mmol) were suspended in DMF (100 mL) and heated at 90° C. for 16 h. The resulting mixture was cooled to room temperature and diluted with water. The mixture was extracted with DCM, dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to afford 1.3 g (40%) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ =564.

Step 7: tert-Butyl (5-(4-hydroxy-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate

To a solution of tert-butyl (5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaocino[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate (1.30 g, 2.31 mmol) in acetic acid (10 mL) and water (10 mL) was added hydrogen peroxide (5 mL, 30% aqueous solution) and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was quenched by the addition of sodium bisulfite. The solid was collected by filtration and dried under vacuum to give the crude product, which was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ = 454.

Step 8: 1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol

Tert-butyl (5-(4-hydroxy-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate (900 mg, 1.99 mmol) was dissolved in hydrochloric acid (20 mL, 4 M solution in dioxane) and stirred at room temperature for 2 h. The solvent was then evaporated in vacuo. The solid was collected and used in the next step without further purification. LCMS (ESI): [M+H] ⁺ = 354.

Step 9: (S)-methyl 2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate

The reaction vessel was charged with 1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]inden-4-ol (900 mg, 2.55 mmol), (S)-methyl 2-(tosyloxy)propanoate (1.00 g, 3.88 mmol l), potassium carbonate (1.20 g, 8.68 mmol) and DMSO (15 mL). The reaction mixture was heated at 40 ° C for 20 h. The resulting mixture was cooled to room temperature and partitioned between DCM and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) to give 150 mg (13%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =440.

Step 10: The reaction vessel was charged with (S)-methyl 2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate (180 mg, 0.410 mmol) and 7N ammonia/methanol (10 mL). The reaction mixture was stirred at room temperature for 6 h. The resulting mixture was concentrated in vacuo. The crude product was purified via chiral SFC to afford 34.2 mg (20%) of 265 as a light yellow solid. LCMS (ESI): _RT (min) = 1.20, [M+H] ⁺ = 425, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.11-8.06 (m, 3H), 7.76-7.73 (m, 1H), 7.54 (s, 1H), 7.25 (s, 1H), 6.92-6.91 (m, 1H), 6.59-6.58 (m, 1H), 4.95-4.91 (m, 2H), 4.65-4.58 (m, 1H), 4.26-4.22 (m, 2H), 2.14-2.12 (m, 2H), 1.59 (s, 2H), 1.45-1.43 (m, 3H).

Example 266 (S)-2-((1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanamide 266

Step 1: 5-bromooxazolo[4,5-b]pyridin-2-amine

The title compound (1.45 g, 64% yield) was prepared from 2-amino-6-bromopyridin-3-ol (2.0 g, 10.6 mmol) following a procedure similar to that described in Example 235, Step 1. LCMS (ESI): [M+H] ⁺ =214/216.

Step 2: tert-Butyl (5-bromooxazolo[4,5-b]pyridin-2-yl)carbamate

To a suspension of 5-bromooxazolo[4,5-b]pyridin-2-amine (1.10 g, 5.12 mmol) in DCM (20 mL) was added triethylamine (2.14 mL, 15.4 mmol) and di-tert-butyl dicarbonate (2.46 g, 11.3 mmol), followed by addition of catalytic 4-dimethylaminopyridine and stirring the reaction mixture at room temperature for 16 h. The resulting mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo to give 2.24 g (66%) of the title compound as a yellow solid. The crude residue was used without further purification. LCMS (ESI): [M+Na] ⁺ = 336/338.

Step 3: Methyl 2-((tert-Butoxycarbonyl)amino)oxazolo[4,5-b]pyridine-5-carboxylate

A mixture of tert-butyl (5-bromooxazolo[4,5-b]pyridin-2-yl)carbamate (2.00g, 6.37mmol), triethylamine (30mL, 23.4mmol), palladium (II) acetate (71.4mg, 0.32mmol) and Xantphos (195mg, 0.34mmol) in methanol (10mL) was fully degassed with argon. The resulting mixture was saturated with carbon monoxide gas for 10min under stirring and the reaction mixture was heated at 65 ° C for 24h. The resulting mixture was cooled to room temperature and evaporated in vacuo. The residue was distributed between ethyl acetate and water and then filtered through diatomaceous earth. The water layer was washed with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (solvent gradient: 0-5% methanol/DCM) to give 650mg (35%) of the title compound as a light red solid. LCMS (ESI): [M+H] ⁺ =294.

Step 4: 2-((tert-Butoxycarbonyl)amino)oxazolo[4,5-b]pyridine-5-carboxylic acid

To a suspension of methyl 2-((tert-butoxycarbonyl)amino)oxazolo[4,5-b]pyridine-5-carboxylate (650 mg, 2.22 mmol) in THF (10 mL) was added lithium hydroxide (1N aqueous solution, 2.5 mL, 2.50 mmol), and the mixture was stirred at room temperature for 16 h. Additional lithium hydroxide (1N aqueous solution, 1.7 mL, 1.70 mmol) was added, and the reaction mixture was stirred for an additional 30 min. The solvent was evaporated, and the crude product was used in the next step without further purification. LCMS (ESI): [M+Na] ⁺ = 302.

Step 5: tert-Butyl (5-((8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-6-yl)carbamoyl)oxazolo[4,5-b]pyridin-2-yl)carbamate

To a solution of 2-((tert-butoxycarbonyl)amino)oxazolo[4,5-b]pyridine-5-carboxylic acid (614 mg, 2.22 mmol) in DMF (10 mL) was added DIPEA (0.77 mL, 4.40 mmol) followed by HATU (1.25 g, 3.30 mmol). The resulting mixture was stirred at room temperature for 5 min, then 8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-amine (534 mg, 2.20 mmol) was added and the reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was partitioned between ethyl acetate and water, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated. The crude residue was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ =504/506.

Step 6: 5-(4-Bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)oxazolo[4,5-b]pyridin-2-amine

Tert-butyl (5-((8-bromo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-6-yl)carbamoyl)oxazolo[4,5-b]pyridin-2-yl)carbamate (crude, estimated to be 2.22 mmol) was dissolved in acetic acid (10 mL) and stirred at 90 ° C for 2 h, then cooled to room temperature. The solvent was removed under reduced pressure, and the residue was suspended in DCM and then washed with saturated aqueous sodium bicarbonate solution. The precipitate was filtered and the solid was collected. The organic phase of the filtrate was washed with brine and the solvent was removed in vacuo. The residue was combined with the filtered solid and triturated with DCM, filtered and the solid was dried in vacuo to give 622 mg (73% over 3 steps) of the title compound as a beige solid. LCMS (ESI): [M+H] ⁺ =386/388.

Step 7: 1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-ol

The title compound (128 mg, 54% yield over 2 steps) was prepared from 5-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)oxazolo[4,5-b]pyridin-2-amine (282 mg, 0.73 mmol) following procedures similar to those in Steps 1-2 of Example 240. LCMS (ESI): [M+H] ⁺ = 324.

Step 8: 266 (16 mg, 10% yield over 2 steps) was prepared from 1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol (125 mg, 0.39 mmol) following procedures similar to those of Examples 251 and 252, steps 3-4. LCMS (ESI): R _T (min) = 2.24, [M+H] ⁺ = 395, method = A; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.09 (s, 2H), 7.83 (d, J＝8.1Hz,1H),7.80(d,J＝8.1Hz,1H),7.49(s,1H),7.21(s,1H),6.79(d,J＝2.2Hz, 1H), 6.45 (d, J = 2.2Hz, 1H), 4.75 (t, J = 5.5Hz, 2H), 4.61 (q, J = 6.5Hz, 1H), 4.42-4.37 (m, 2H), 2.37-2.30 (m, 2H), 1.44 (d, J = 6.5Hz, 3H).

Examples 267 and 268 (R)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide 267 and (S)-2-((1-(4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide 268

Step 1: 3-(4-bromophenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole

A mixture of 3-(4-bromophenyl)-1H-1,2,4-triazole (5 g, 22.3 mmol), 1-(chloromethyl)-4-methoxybenzene (4.19 g, 26.8 mmol) and cesium carbonate (14.6 g, 44.9 mmol) in DMF (100 mL) was stirred at room temperature for 16 h. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (solvent gradient: 0-5% ethyl acetate/petroleum ether) to give 6 g (78%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =344/346.

Step 2: 4-Bromo-1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

The title compound (2.2 g, 47% yield over two steps) was prepared from 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (Example 204, Step 6) (3.46 g, 8.80 mmol) and 3-(4-bromophenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (3.64 g, 9.30 mmol) following procedures similar to those in Steps 2-3 of Example 158. LCMS (ESI): [M+H] ⁺ = 530/532.

Step 3: 1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol

Under a nitrogen atmosphere, 4-bromo-1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (1.3 g, 3.31 mmol), 2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (150 mg, 0.353 mmol), tris(dibenzylideneacetone)dipalladium(0) (170 mg, 0.186 mmol), and potassium hydroxide (270 mg, 4.81 mmol) were suspended in 1,4-dioxane (15 mL) and water (1.5 mL), and the mixture was heated at 100° C. for 7 h. The reaction system was diluted with water and extracted with DCM. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to afford 760 mg (67%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =468.

Step 4: Methyl 2-((1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanoate

The reaction vessel was charged with 1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctadecano[cd]inden-4-ol (700 mg, 1.50 mmol), methyl 2-bromobutyrate (400 mg, 2.21 mmol), potassium carbonate (1.20 g, 8.68 mmol) and DMSO (15.0 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was partitioned between DCM and water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 620 mg (73%) of the title compound as a gray solid. LCMS(ESI): [M+H] ⁺ =568.

Step 5: 2-((1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaocta[cd]inden-4-yl)oxy)butanamide

A mixture of methyl 2-((1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanoate (650 mg, 1.15 mmol) and ammonia (20 mL, 7 M solution in methanol) was stirred at room temperature for 48 h. The resulting mixture was evaporated in vacuo to give 600 mg (crude) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 553.

Step 6: A solution of 2-((1-(4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide (600 mg, 1.08 mmol) in TFA (20 mL) was heated at 90 °C for 4 h. The reaction mixture was evaporated in vacuo. The resulting residue was purified by silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) to give 350 mg of a racemic mixture of 267 and 268 as a yellow solid. The two stereoisomers were separated by chiral SFC to give the title compound as a single unknown stereoisomer.

267 (102.4 mg, 21% yield): LCMS (ESI): _RT (min) = 1.99, [M+H] ⁺ = 433, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 14.23 (s, 1H), 8.69 (s, 1H), 8.22-8.11 (m, 2H), 7.91-7.80 (m, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.64 (d, J = 2.8 Hz, 1H), 4.47-4.41 (m, 3H), 4.28-4.25 (m, 2H), 2.17 (s, 2H), 1.89-1.79 (m, 2H),1.71(s,2H),1.07-0.98(m,3H).

268 (90.2 mg, 19% yield): LCMS (ESI): _RT (min) = 1.99, [M+H] ⁺ = 433, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 14.23 (s, 1H), 8.69 (s, 1H), 8.22-8.11 (m, 2H), 7.91-7.80 (m, 1H), 7.53 (s, 1H), 7.27 (s, 1H), 6.96 (d, J = 1.8 Hz, 1H), 6.64 (d, J = 2.8 Hz, 1H), 4.47-4.41 (m, 3H), 4.28-4.25 (m, 2H), 2.17 (s, 2H), 1.89-1.79 (m, 2H),1.71(s,2H),1.07-0.98(m,3H).

Example 269 (S)-2-((1-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 269

Step 1: (S)-methyl 2-((1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate

The title compound (1.00 g, 85% yield) was prepared from 1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol (Example 305, Step 7) (1.00 g, 2.06 mmol) following a procedure similar to that of Example 162, Step 3. LCMS: [M+H] ⁺ = 572.

Step 2: (S)-2-((1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide

The title compound (0.5 g, 64% yield) was prepared from (S)-methyl 2-((1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate (800 mg, 1.40 mmol) following a procedure similar to that described in Step 5 of Example 267. LCMS: [M+H] ⁺ = 557.

Step 4: 269 (165 mg, 23% yield) was prepared from (S)-2-((1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide (900 mg, 1.61 mmol) following a procedure similar to that of Example 267, Step 6. LCMS: R _T (min) = 3.50, [M+H] ⁺ = 437, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 14.38(s,1H),8.67-8.43(m,1H),8.31-8.19(m,1H),7.69-7.64(m,3H),7.32-7.26(s, 1H),6.96-6.91(m,1H),6.64-6.63(m,1H),4.67-4.61(m,1H),4.45(d,J＝6.3Hz, 2H),4.27-4.25(m,2H),2.15-2.14(m,2H),1.69-1.65(m,2H),1.47-1.23(m,3H).

Example 270 (S)-2-((1-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide 270

Step 1: 1-Bromo-2-fluoro-4-methoxy-3-nitrobenzene

To a solution of 1-fluoro-3-methoxy-2-nitrobenzene (45.0 g, 0.263 mol) in acetic acid (300 mL) was added bromine (54.0 g, 0.338 mol) dropwise with stirring. The reaction mixture was stirred at 55 ° C for 17 h. The resulting mixture was evaporated in vacuo to give 63.8 g (97%) of the title compound as a yellow solid.

Step 2: 3-Bromo-2-fluoro-6-methoxyaniline

To a solution of 1-bromo-2-fluoro-4-methoxy-3-nitrobenzene (65.5 g, 0.262 mol) and ammonium chloride (56.7 g, 1.06 mol) in methanol (720 mL) and water (720 mL) was added iron powder (44.1 g, 0.790 mol) at room temperature. The mixture was stirred at 60 ° C for 2 h and then filtered. The solvent was evaporated in vacuo to give 54.1 g (94%) of the title compound as an orange solid. LCMS (ESI): [M+H] ⁺ = 220/222.

Step 3: 2-Amino-4-bromo-3-fluorophenol

To a suspension of 3-bromo-2-fluoro-6-methoxyaniline (30.0 g, 0.136 mmol) in DCM (950 mL) was added boron tribromide (330 mL, 1 M solution in DCM) dropwise with stirring at 0 ° C. The resulting solution was stirred at room temperature for 16 h and then quenched by adding aqueous sodium bicarbonate. The aqueous layer was extracted with DCM and the organic portion was dried over sodium sulfate and evaporated in vacuo to give 27.5 g (98%) of the title compound as an orange solid. LCMS (ESI): [M+H] ⁺ = 206/208.

Step 4: 5-Bromo-4-fluorobenzo[d]oxazol-2-amine

To a solution of 2-amino-4-bromo-3-fluorophenol (22.0 g, 0.107 mol) in methanol (120 mL) was added cyanogen bromide (22.0 g, 208 mol). The reaction mixture was stirred at 35 ° C for 16 h. The reactant was then quenched by adding a saturated aqueous sodium bicarbonate solution. Methanol was removed under reduced pressure. The residue was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 5-33% ethyl acetate/petroleum ether) to give 22.3 g (90%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 231/233.

Step 5: 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-4-fluorobenzo[d]oxazol-2-amine

The title compound (870 mg, 29% yield over two steps) was prepared from 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (Example 204, Step 6) (2.80 g, 7.12 mmol) following procedures similar to those in Steps 7-8 of Example 204. LCMS (ESI): [M+H] ⁺ = 206/208.

Step 6: (S)-2-((1-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)(methyl)amino)propanamide

270 (75.9 mg, 14.4% yield over two steps) was prepared from 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-4-fluorobenzo[d]oxazol-2-amine (500 mg, 1.20 mmol) following a procedure similar to Example 264. LCMS (ESI): R _T (min) = 1.18, [M+H] ⁺ = 439, method = D; ¹ H NMR (400MHz, DMSO-d ₆ ): δ7.81 (s, 2H), 7.40-7.35 (m, 2H), 7.16-7.07(m,2H),6.79(d,J＝2.0Hz,1H),6.20(d,J＝2.0Hz,1H),4.33-4.27(m,1H), 4.23-4.17(m,4H),2.81(s,3H),2.00-1.94(m,2H),1.68-1.63(m,2H),1.23(d, J＝6.8Hz,3H).

Example 271: (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide 271

Step 1: (S)-methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanoate

The title compound (27 mg, 35%) was prepared from 1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol and methyl (2R)-2-(p-toluenesulfonyloxy)butanoate following a procedure similar to that of Example 204. LCMS (ESI) [M+H] ⁺ = 437.

Step 2: 271 (12.9 mg, 12% yield) was prepared from (S)-methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanoate following a procedure similar to that of Example 261, Step 9. LCMS (ESI): _RT (min) = 3.03, [M+H] ⁺ = 422.2, method = B; ^1H NMR (400 MHz, DMSO-d ₆ ) δ 7.58 (s, 2H), 7.54-7.47 (m, 2H), 7.44 (d, J = 1.7 Hz, 1H), 7.31-7.22 (m, 2H), 6.93 (d, J = 2.2 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H), 4.43 (t, J = 6.1 Hz, 1H), 4.37 (t, J = 6.2 Hz, 2H), 4.24 (t, J = 5.3 Hz, 2H), 2.16-2.05 (m, 2H),1.90-1.77(m,2H),1.75-1.65(m,2H),0.99(t,J＝7.4Hz,3H).

Example 272 (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide 272

272 was prepared following a procedure analogous to Example 249. LCMS (ESI): _RT (min) = 1.12, [M+H] ⁺ = 440, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.88 (s, 2H), 7.53 (s, 1H), 7.29-7.19 (m, 3H), 6.93 (d, J = 1.8 Hz, 1H), 6.61 (d, J = 2.1 Hz, 1H), 4.46-4.38 (m, 3H), 4.26-4.23 (m, 2H), 2.10 (s, 2H), 1.88-1.79 (m, 2H), 1.68 (s, 2H), 1.02-0.97 (m, 3H).

Example 273 (S)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide 273

273 was prepared following a procedure similar to Example 242. LCMS (ESI): _RT (min) = 1.11, [M+H] ⁺ = 456, method = D; ^1H NMR (300 MHz, DMSO- _d6 ): δ 7.97 (s, 2H), 7.84 (d, J = 1.5 Hz, 1H), 7.53 (s, 1H), 7.41-7.36 (m, 1H), 7.27 (s, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 4.45-4.39 (m, 3H), 4.26-4.23 (m, 2H), 2.20-2.09 (m, 2H), 1.88-1.79 (m, 2H), 1.74-1.61 (m, 2H), 1.01-0.96 (m, 3H).

Example 274 (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanamide 274

Step 1: tert-Butyl (6-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound (883.9 mg, 44% yield) was prepared from 4-bromo-1-iodo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene following a procedure analogous to that described in Step 5 of Example 261. LCMS (ESI): [M+H] ⁺ = 500.9; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.94 (s, 1H), 8.40 (s, 1H), 7.85-7.80 (m, 2H), 7.46 (d, J=1.8 Hz, 1H), 6.92 (d, J=1.8 Hz, 1H), 4.53-4.42 (m, 2H), 4.42-4.33 (m, 2H), 2.39-2.27 (m, 2H), 1.53 (s, 9H).

Step 2: tert-Butyl (6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound (491.9 mg, 51% yield) was prepared from tert-butyl (6-(4-bromo-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]thiazol-2-yl)carbamate following a procedure similar to that of Example 162, step 1. LCMS (ESI): [M+H] ⁺ =549; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 11.93 (s, 1H), 8.40 (s, 1H), 7.82 (s, 2H), 7.58 (d, J = 0.9Hz, 1H), 7.03 (d, J＝0.9Hz,1H),4.46-4.33(m,4H),2.39-2.29(m,2H),1.31(s,9H),1.07(s,12H).

Step 3: Tert-butyl (6-(4-hydroxy-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound (205.5 mg, 47% yield) was prepared from tert-butyl (6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]thiazol-2-yl)carbamate following a procedure similar to that described in Step 2 of Example 162. LCMS (ESI): [M+H] ⁺ = 439.

Step 4: 1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol

To a suspension of tert-butyl (6-(4-hydroxy-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-1-yl)benzo[d]thiazol-2-yl)carbamate (205.5 mg, 0.42 mmol) in DCM (4.0 mL, 62 mmol) was added methanol (1.0 mL, 20 mmol) and hydrogen chloride (4.0 mol/L in dioxane, 2.0 mL, 8.0 mmol). The resulting mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure, and the resulting residue was suspended in DCM (4.0 mL) containing hydrogen chloride (4.0 mol/L in dioxane, 4.0 mL, 16.0 mmol). The reaction mixture was stirred at room temperature for 2 h, then evaporated in vacuo and used without purification as the HCl salt. LCMS (ESI): [M+H] ⁺ = 338.95.

Step 5: (S)-methyl 2-((1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoate

The title compound (37.7 mg, 26%) was prepared from 1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-ol following a procedure similar to that in Step 3 of Example 162. LCMS (ESI): [M+H] ⁺ =425.0.

Step 6: 274 (9.8 mg, 27.5%) was prepared from (S)-methyl 2-((1-(2-aminobenzo[d]thiazol-6-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulen-4-yl)oxy)propanoate following a procedure similar to that of Example 261, Step 9. LCMS (ESI): R _T (min) = 2.77, [M+H] ⁺ = 410.1, method = B; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.09 (d, J = 1.7Hz, 1H), 7.71 (s, 2H), 7.62 (dd, J＝8.4,1.8Hz,1H),7.50-7.42(m,2H),7.20(s,1H),6.77(d,J＝2.2Hz,1H),6.42(d, J＝2.2Hz,1H),4.60(q,J＝6.7Hz,1H),4.43-4.35(m,2H),4.30(t,J＝5.3Hz,2H), 2.35-2.25(m,2H),1.44(d,J＝6.6Hz,3H).

Examples 275 and 276 (R)-2-((1-(2-aminobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 275 and (S)-2-((1-(2-aminobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 276

Step 1: tert-Butyl 5-bromobenzo[d]thiazol-2-ylcarbamate

The title compound (25.1 g, 94% yield) was prepared from 5-bromobenzo[d]thiazol-2-amine (18.4 g, 80.3 mmol) following a procedure similar to that described in Step 1 of Example 214. LCMS (ESI): [M+H] ⁺ =329/331.

Step 2: tert-Butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-ylcarbamate

The title compound (7.1 g, 56% yield) was prepared from tert-butyl 5-bromobenzo[d]thiazol-2-ylcarbamate (11 g, 33.4 mmol) following a procedure similar to that described in Example 214, Step 2. LCMS (ESI): [M+H] ⁺ =377.

Step 3: Tert-butyl (5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate

A mixture of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-ylcarbamate (6.00 g, 15.9 mmol), 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (6.00 g, 15.2 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (360 mg, 0.492 mmol), potassium acetate (2M aqueous solution, 35 mL, 70.0 mmol), and sodium carbonate (2M aqueous solution, 35 mL, 70.0 mmol) in acetonitrile (140 mL) was stirred at 90° C. under a nitrogen atmosphere for 3 h. The resulting mixture was diluted with water and extracted with DCM. The organic phase was dried over magnesium sulfate and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to afford 6 g (73%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =515/517.

Step 4: Following a procedure analogous to Example 265 steps 6-10 and followed by chiral HPLC separation, 275 and 276 were prepared from tert-butyl (5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (3 g, 5.83 mmol) as each a single unknown stereoisomer.

275 (13.0 mg, 5.3% yield, over five steps): LCMS (ESI): _RT (min) = 1.95 min, [M+H] ⁺ = 424, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.85-7.83 (m, 1H), 7.68 (s, 2H), 7.58-7.54 (m, 2H), 7.31-7.25 (m, 2H), 6.93 (d, J = 1.5 Hz, 1H), 6.59 (d, J = 1.2 Hz, 1H), 4.65-4.60 (m, 1H), 4.41-4.36 (m, 2H), 4.26-4.23 (m, 2H), 2.12-2.11(m,2H),1.69(s,2H),1.46-1.44(m,3H).

276 (16.2 mg, 6.5% yield, over five steps): LCMS (ESI): _RT (min) = 1.95 min, [M+H] ⁺ = 424, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.85-7.83 (m, 1H), 7.68 (s, 2H), 7.58-7.54 (m, 2H), 7.31-7.25 (m, 2H), 6.93 (d, J = 1.5 Hz, 1H), 6.59 (d, J = 1.2 Hz, 1H), 4.65-4.60 (m, 1H), 4.41-4.36 (m, 2H), 4.26-4.23 (m, 2H), 2.12-2.11(m,2H),1.69(s,2H),1.46-1.44(m,3H).

Examples 277 and 278 (S)-2-((1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)propanamide 277 and (R)-2-((1-(2-amino-5-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)propanamide 278

The title compounds were prepared as single unknown stereoisomers following a procedure analogous to Example 265 and followed by chiral SFC separation.

277 (45.3 mg): LCMS (ESI): _RT (min) = 1.14, [M+H] ⁺ = 442, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.91-7.87 (m, 3H), 7.54 (s, 1H), 7.34-7.30 (d, J = 12 Hz, 1H), 7.25 (s, 1H), 6.93-6.92 (m, 1H), 6.62-6.61 (m, 1H), 4.66-4.64 (m, 1H), 4.22 (br s, 4H), 1.98 (s, 2H), 1.63 (s, 2H), 1.46-1.44 (m, 3H).

278 (21.7mg): LCMS (ESI): R _T (min) = 1.14, [M+H] ⁺ = 442, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.91-7.87 (m, 3H), 7.54 (s, 1H), 7.32 (d, J = 12Hz, 1H), 7.25(s,1H),6.93-6.92(m,1H),6.62-6.61(m,1H),4.66-4.64(m,1H),4.22(br s,4H),1.98(s,2H),1.63(s,2H),1.46-1.44(m,3H).

Examples 279 and 280 (R)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 279 and (S)-2-((1-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 280

Step 1: Ethyl 2-((1-(2-(bis(4-methoxybenzyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetate

A mixture of 1-(2-(bis(4-methoxybenzyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol (Example 242, Step 4) (800 mg, 1.31 mmol), ethyl 2-bromo-2-cyclopropylacetate (410 mg, 1.98 mmol) and potassium carbonate (730 mg, 5.28 mmol) in DMSO (15 mL) was stirred at 35 °C for 16 h. The reaction mixture was diluted with water and extracted with DCM. The organic portion was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The resulting mixture was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 600 mg (62%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 737.

Step 2: 2-((1-(2-(bis(4-methoxybenzyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetamide

A mixture of ethyl 2-((1-(2-(bis(4-methoxybenzyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetate (520 mg, 0.706 mmol) and ammonia (7 M in methanol, 20 mL) was stirred in a sealed tube at 55 °C for 48 h. The reaction mixture was evaporated in vacuo to afford 480 mg (96%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 708.

Step 3: A racemic mixture of 2-((1-(2-(bis(4-methoxybenzyl)amino)-4-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide (420 mg, 0.593 mmol) was stirred in TFA (10 mL) at 80 ° C for 2.5 h. The reaction mixture was diluted with water and treated with saturated aqueous sodium bicarbonate solution to reach pH 8, then extracted with DCM. The organic portion was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The resulting mixture was purified via silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) and the two stereoisomers were separated by chiral SFC to afford 279 and 280 as off-white solids, each of which was a single unknown stereoisomer.

279 (62 mg, 22% yield): LCMS (ESI): _RT (min) = 1.11, [M+H] ⁺ = 468, method = D; ^1H NMR (300 MHz, DMSO- _d6 ): δ 7.97 (s, 2H), 7.84 (d, J = 1.5 Hz, 1H), 7.54 (s, 1H), 7.40-7.36 (m, 1H), 7.23 (s, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 4.42-4.35 (m, 2H), 4.26-4.22 (m, 2H), 3.93 (d, J = 8.1 Hz, 1H), 2.22-2.05 (m, 2H), 1.73-1.62(m,2H),1.33-1.28(m,1H),0.59-0.57(m,3H),0.48-0.39(m,1H).

280 (20.7 mg, 7% yield) LCMS (ESI): _RT (min) = 2.07, [M+H] ⁺ = 468, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ): δ 7.97 (s, 2H), 7.84 (d, J = 1.5 Hz, 1H), 7.54 (s, 1H), 7.40-7.36 (m, 1H), 7.23 (s, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.57 (d, J = 2.1 Hz, 1H), 4.50 (br, 2H), 4.24 (br, 2H), 3.95 (d, J = 7.8 Hz, 1H), 2.14 (br, 2H), 1.67 (br, 2H), 1.35(br,1H),0.59-0.57(m,3H),0.45-0.44(m,1H).

Examples 281 and 282: (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 281 and (R)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 282

Step 1: 1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol

The title compound was prepared from tert-butyl (6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (Example 214, Step 3) following procedures similar to those in Example 265, Steps 6-8. LCMS (ESI): [M+H] ⁺ = 353.

Step 2: Ethyl 2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetate

The title compound (117, 43% yield) was prepared from 1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol and ethyl 2-bromo-2-cyclopropylacetate following a procedure analogous to that described in Step 1 of Example 279. LCMS (ESI): [M+H] ⁺ =479.

Step 3: (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide and (R)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide

The title compounds were prepared as a single unknown stereoisomer from ethyl 2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaocta[cd]inden-4-yl)oxy)-2-cyclopropylacetate following a procedure analogous to Example 261, Step 9, and followed by chiral SFC separation.

281 (28.3 mg, 25% yield): LCMS (ESI): _RT (min) = 3.20, [M+H] ⁺ = 450, method = B; ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.34 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.74-7.67 (m, 1H), 7.49-7.31 (m, 4H), 6.94 (d, J = 2.5 Hz, 1H), 6.66 (d, J = 5.0 Hz, 1H), 6.03 (d, J = 5.1 Hz, 1H), 3.10 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 16.6 Hz, 1H), 2.49-2.44 (m, 4H), 1.56(t,J=6.1Hz,4H), 1.38(d,J=6.5Hz,2H).

282 (28.3 mg, 25% yield): LCMS (ESI): _RT (min) = 3.19, [M+H] ^{+ =} 450, method = B; ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.33 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.74-7.67 (m, 1H), 7.49-7.31 (m, 4H), 6.94 (d, J = 2.5 Hz, 1H), 6.66 (d, J = 5.1 Hz, 1H), 6.03 (d, J = 5.0 Hz, 1H), 3.10 (d, J = 16.4 Hz, 1H), 2.99 (d, J = 16.5 Hz, 1H), 2.49-2.44 (m, 4H), 1.56(t,J=6.1Hz,4H), 1.38(d,J=6.2Hz,2H).

Examples 283 and 284: (R)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 283 and (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 284

Step 1: Methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)-2-cyclopropylacetate

To a suspension of 1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol (Example 204, Step 10) (250 mg) in DMSO (1.5 mL) was added potassium carbonate (321 mg, 2.3 mmol) followed by methyl 2-bromo-2-cyclopropylacetate (201 mg, 0.93 mmol). The vial was purged with nitrogen, sealed, and stirred at room temperature for 16 h. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated in vacuo. The crude product was purified by flash chromatography on silica gel (solvent gradient: 0-15% methanol/DCM) to afford 0.243 g (70%) of the title compound. LCMS (ESI): [M+H] ⁺ = 449.

Step 2: Following a procedure analogous to Example 261, Step 9, and followed by chiral SFC separation, 283 and 284 were prepared from methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaoctin[cd]inden-4-yl)oxy)-2-cyclopropylacetate as a single unknown stereoisomer.

283 (67.2 mg, 28% yield): LCMS (ESI): _RT (min) = 3.10, [M+H] ⁺ = 434.2, method = B; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.61-7.46 (m, 4H), 7.43 (d, J = 1.7 Hz, 1H), 7.26 (dd, J = 8.1, 1.7 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 6.56 (d, J = 2.1 Hz, 1H), 4.36 (t, J = 6.2 Hz, 2H), 4.24 (t, J = 5.2 Hz, 2H), 3.95 (d, J = 8.0 Hz, 1H), 2.16-2.05(m,2H),1.76-1.59(m,2H),1.34-1.21(m,1H),0.65-0.51(m,3H), 0.50-0.40(m,1H).

284 (67.6 mg, 28% yield): LCMS (ESI): _RT (min) = 3.09, [M+H] ⁺ = 434.2, method = B; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.61-7.46 (m, 4H), 7.43 (d, J = 1.8 Hz, 1H), 7.26 (dd, J = 8.1, 1.7 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 6.56 (d, J = 2.1 Hz, 1H), 4.36 (t, J = 6.1 Hz, 2H), 4.24 (t, J = 5.4 Hz, 2H), 3.95 (d, J = 8.0 Hz, 1H), 2.16-2.04(m,2H),1.74-1.63(m,2H),1.34-1.21(m,1H),0.65-0.51(m,3H), 0.50-0.40(m,1H).

Example 285 (S)-2-((1-(2-amino-7-fluorobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 285

Step 1: 4-Bromo-2-fluoro-6-nitroaniline

A mixture of 5-bromo-1,2-difluoro-3-nitrobenzene (20.0 g, 84.0 mmol), ammonium carbonate (8.40 g, 87.4 mmol) and triethylamine (25.6 g, 0.252 mol) in DMF (200 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with water. The solid was collected by filtration, washed with water and dried in vacuo to give 16.7 g (85%) of the title compound as a yellow solid. LCMS (ESI): [M+1] ⁺ = 235/237.

Step 2: 5-Bromo-1-fluoro-3-nitro-2-thiocyanatobenzene

4-Bromo-2-fluoro-6-nitroaniline (10.0 g, 42.0 mmol) was suspended in sulfuric acid (100 mL) and water (100 mL). The reaction mixture was stirred at 60 ° C for 1 h, then cooled to -5 ° C, and then a solution of sodium nitrite (3.2 g, 46.0 mmol) in water (10 mL) was added dropwise. The reaction system was stirred at -5 ° C for 1 h, and the solution was then added to a mixture of copper thiocyanate (12.7 g, 104 mmol) and potassium thiocyanate (1.00 g, 10.0 mmol) in water (50 mL). The reaction mixture was stirred at room temperature for 0.5 h and then extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 10.1 g of the title compound, which was a brown solid and was used directly in the next step without purification.

Step 3: 5-Bromo-7-fluorobenzo[d]thiazol-2-amine

A mixture of 5-bromo-1-fluoro-3-nitro-2-thiocyanatobenzene (10.0 g, 36.0 mmol), ammonium chloride (9.60 g, 179 mmol) and iron powder (16.1 g, 0.310 mol) in ethanol (50.0 mL) and water (50.0 mL) was stirred at 90 ° C for 1 h. The reaction mixture was filtered and the filter cake was washed with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 5.5 g (62%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ = 247/249.

Step 4: 5-Bromo-7-fluoro-N,N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine

To a solution of 5-bromo-7-fluorobenzo[d]thiazole-2-amine (5.50 g, 22.2 mmol) and potassium carbonate (9.10 g, 66.0 mmol) in DMF (100 mL) was added 1-(chloromethyl)-4-methoxybenzene (10.3 g, 66.0 mmol). The reaction mixture was stirred at 60 ° C for 6 h, diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 20% ethyl acetate/petroleum ether) to give 5.00 g (46%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =487/489.

Step 5: 7-Fluoro-N,N-di(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-amine

A mixture of 5-bromo-7-fluoro-N, N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine (5.0 g, 10.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.730 g, 20.0 mmol), potassium acetate (2.94 g, 30.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (730 mg, 1 mmol) in DMF (100 mL) was stirred at 90 ° C under a nitrogen atmosphere for 2 h. The resulting mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent: 20% ethyl acetate/petroleum ether) to give 2.84 g (52%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =535.

Step 6: 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-1-yl)-7-fluoro-N,N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine

The title compound (2.0 g, 58% yield) was obtained from 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (Example 204, Step 6) (2.0 g, 5.10 mmol) following a procedure similar to that of Example 242, Step 4. LCMS (ESI): [M+H] ⁺ = 673/675.

Step 7: (S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-7-fluorobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaocta[cd]inden-4-yl)oxy)propanamide

The title compound (1.1 g, 57% yield) was obtained from 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)-7-fluoro-N,N-di(4-methoxybenzyl)benzo[d]thiazol-2-amine (1.9 g, 2.8 mmol) following a procedure similar to that described in Step 5 of Example 242. LCMS (ESI): [M+H] ⁺ = 682.

Step 8: A solution of (S)-2-((1-(2-(bis(4-methoxybenzyl)amino)-7-fluorobenzo[d]thiazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide (1.1 g, 1.61 mmol) in TFA (10.0 mL) was stirred at 90 ° C for 4 h. The solvent was removed in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 10% methanol/dichloromethane) and then by chiral SFC to give 191.7 mg (26.9% yield) of 285 as an off-white solid. LCMS: R _T (min) = 1.33, [M+H] ⁺ = 442, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 7.96 (s, 2H), 7.54 (d, J＝2.2Hz,1H),7.45(d,J＝1.3Hz,1H),7.29-7.15(m,2H),6.95(d,J＝2.1Hz,1H), 6.62(d,J＝2.1Hz,1H),4.66-4.60(m,1H),4.48-4.41(m,2H),4.25-4.23(m,2H), 2.15-2.05(m,2H),1.72-1.62(m,2H),1.46(d,J＝6.5Hz,3H).

Examples 286 and 287 (S)-2-((1-(2-amino-7-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)propanamide 286 and (R)-2-((1-(2-amino-7-fluorobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)propanamide 287

The title compounds were prepared following a procedure analogous to Example 285 as a single unknown stereoisomer.

286 (96.6mg): LCMS: R _T (min) = 1.28, [M+H] ⁺ = 442, method = C; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.01 (s, 2H), 7.54 (d, J = 1.9Hz, 1H), 7.44-7.40 (m, 1H), 7.35-7.33(m,1H),7.25(d,J＝2.0Hz,1H),6.94(d,J＝2.2Hz,1H),6.63(d,J＝2.2Hz, 1H),4.66-4.61(m,1H),4.28-4.18(m,4H),2.01-1.97(m,2H),1.68-1.62(m,2H), 1.46 (d, J = 6.6 Hz, 3H).

287 (49.9mg): LCMS: R _T (min) = 1.28, [M+H] ⁺ = 442, method = C; ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.01 (s, 2H), 7.54 (d, J = 1.9Hz, 1H), 7.44-7.40 (m, 1H), 7.35-7.33(m,1H),7.25(d,J＝2.0Hz,1H),6.94(d,J＝2.2Hz,1H),6.63(d,J＝2.2Hz, 1H),4.66-4.61(m,1H),4.28-4.18(m,4H),2.01-1.97(m,2H),1.68-1.62(m,2H), 1.46 (d, J = 6.6 Hz, 3H).

Examples 288 and 289 (R)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 288 and (S)-2-((1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-2-cyclopropylacetamide 289

The title compounds, each as a single unknown stereoisomer, were prepared from 1-(2-amino-7-fluorobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol (Example 249 Step 5) (900 mg, 2.54 mmol) and following procedures analogous to Examples 279 and 280 Steps 1-2.

288 (246 mg, 21% yield): LCMS (ESI): _RT (min) = 2.12, [M+H] ⁺ = 452, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.87 (s, 2H), 7.53 (s, 1H), 7.28-7.15 (m, 3H), 6.87 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 4.44-4.34 (m, 2H), 4.30-4.18 (s, 2H), 3.95 (d, J = 8.1 Hz, 1H), 2.09 (s, 2H), 1.68 (s, 2H), 1.31-1.24 (m, 1H), 0.59-0.57 (m, 3H), 0.53-0.44 (m, 1H).

289 (231 mg, 20% yield): LCMS (ESI): _RT (min) = 2.12, [M+H] ⁺ = 452, method = C; ^1H NMR (300 MHz, DMSO- _d6 ) δ 7.87 (s, 2H), 7.53 (s, 1H), 7.28-7.15 (m, 3H), 6.87 (d, J = 1.8 Hz, 1H), 6.58 (d, J = 2.1 Hz, 1H), 4.44-4.34 (m, 2H), 4.30-4.18 (s, 2H), 3.95 (d, J = 8.1 Hz, 1H), 2.09 (s, 2H), 1.68 (s, 2H), 1.31-1.24 (m, 1H), 0.59-0.57 (m, 3H), 0.53-0.44 (m, 1H).

Examples 290 and 291 (S)-2-((2-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)oxy)-2-cyclopropylacetamide 290 and (R)-2-((2-(2-amino-4-fluorobenzo[d]thiazol-6-yl)-3,4-dihydro-5-oxa-1,2a-diazaacenaphthyl-7-yl)oxy)-2-cyclopropylacetamide 291

The title compounds were prepared following procedures analogous to Examples 208, 279, and 280 as a single unknown stereoisomer.

290: LCMS: R _T (min) = 4.5, [M+H] ⁺ = 440, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.12 (s, 1H), 7.97 (s, 2H), 7.68-7.64 (m, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 6.69(s,1H),6.42(s,1H),4.64-4.60(m,2H),4.49-4.48(m,2H),3.92(d,J＝8.1Hz, 1H),1.29-1.23(m,1H),0.58-0.52(m,3H),0.45-0.42(m,1H).

291: LCMS: R _T (min) = 4.5, [M+H] ⁺ = 440, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ8.12 (s, 1H), 7.97 (s, 2H), 7.68-7.64 (m, 1H), 7.49 (s, 1H), 7.20 (s, 1H), 6.69(s,1H),6.42(s,1H),4.64-4.60(m,2H),4.49-4.48(m,2H),3.92(d,J＝8.1Hz, 1H),1.29-1.23(m,1H),0.58-0.52(m,3H),0.45-0.42(m,1H).

Example 292 (S)-2-((1-(3-aminobenzo[e][1,2,4]triazin-7-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 292

292 was prepared following a procedure similar to Example 265. LCMS: R _T (min) = 1.91, [M+H] ⁺ = 420, method = C; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 8.41 (s, 1H), 8.14 (d, J = 9Hz, 1H), 7.91 (br s,2H),7.68(d,J＝8.7Hz,1H),7.55(s,1H),7.26(s,1H), 6.97(s,1H),6.64(s,2H),4.68-4.61(m,1H),4.52-4.48(m,2H),4.29-4.26(m,2H), 2.30-2.12(m,2H),1.80-1.65(m,2H),1.46(d,J＝6.6Hz,3H).

Example 293 (S)-2-((1-(2-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 293

293 was prepared following a procedure similar to Example 269. LCMS (ESI): _RT (min) = 0.63, [M+H] ⁺ = 437, method = F; ^1H NMR (400 MHz, DMSO-d ₆ ): δ 14.36 (s, 1H), 8.56 (s, 1H), 8.05-8.03 (m, 1H), 7.97-7.94 (m, 1H), 7.76-7.72 (m, 1H), 7.57-7.56 (m, 1H), 7.27-7.26 (m, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.66 (d, J = 2.0 Hz, 1H), 4.68-4.63 (m, 1H), 4.31-4.25(m,4H),2.04-1.98(m,2H),1.67-1.63(m,2H),1.46(d,J＝6.8Hz,3H).

Example 294 (2R,3S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-fluoropyrrolidine-2-carboxamide 294

Step 1: 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-1-yl)-N,N-di(4-methoxybenzyl)benzo[d]oxazol-2-amine

The title compound (3.5 g, 41% yield) was prepared from 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (Example 204, Step 6) (5.26 g, 13.4 mmol) and N,N-bis(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (Example 253, Step 2) (6.80 g, 13.6 mmol) following procedures similar to those in Steps 2-4 of Example 242. LCMS (ESI): [M+H] ⁺ = 639/641.

Step 2: Methyl (2S,3R)-1-(1-(2-(bis(4-methoxybenzyl)amino)benzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-hydroxypyrrolidine-2-carboxylate

A mixture of 5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]inden-1-yl)-N,N-di(4-methoxybenzyl)benzo[d]oxazol-2-amine (348 mg, 0.544 mmol), (2S,3R)-3-hydroxypyrrolidine-2-carboxylic acid (234 mg, 1.78 mmol), copper(I) iodide (101 mg, 0.534 mmol) and potassium phosphate (509 mg, 2.40 mmol) in DMSO (12.0 mL) was degassed with nitrogen. The reaction mixture was heated at 100 ° C for 2 h under microwave irradiation. The reaction mixture was filtered. The filtrate was diluted with ethyl acetate (15.0 mL) and treated dropwise with (diazomethyl)trimethylsilane (40.0 mL, 2 mol/L solution in hexane) at room temperature with stirring. The reaction mixture was stirred at room temperature for 6 h and diluted with water, extracted with ethyl acetate, washed with brine and evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-100% ethyl acetate/petroleum ether) to give 160 mg (52%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ =704.

Step 3: Methyl (2R,3S)-1-(1-(2-(bis(4-methoxybenzyl)amino)benzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-fluoropyrrolidine-2-carboxylate

To a solution of (2S,3R)-1-(1-(2-(bis(4-methoxybenzyl)amino)benzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-hydroxypyrrolidine-2-carboxylic acid methyl ester (405 mg, 0.575 mmol) in DCM (10.0 mL) was added diethylaminosulfur trifluoride (DAST) (1.00 mL) dropwise with stirring at -40 °C. The reaction mixture was allowed to warm to 15 °C and stirred for 8 h, then quenched with aqueous sodium bicarbonate, diluted with water, extracted with DCM, washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-30% ethyl acetate/petroleum ether) to give 230 mg (57%) of the title compound as a yellow solid. LCMS (ESI): [M+H]+=706.

Step 4: (2R,3S)-1-(1-(2-(bis(4-methoxybenzyl)amino)benzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-fluoropyrrolidine-2-carboxamide

A mixture of methyl (2R,3S)-1-(1-(2-(bis(4-methoxybenzyl)amino)benzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-fluoropyrrolidine-2-carboxylate (110 mg, 0.156 mmol) and ammonia (7 M in methanol, 20 mL) was stirred at 25 ° C. for 48 h. The reaction mixture was evaporated in vacuo. The resulting residue was purified by flash chromatography on silica gel (solvent gradient: 0-100% ethyl acetate/petroleum ether) to give 69 mg (64%) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ = 691.

Step 6: A solution of (2R, 3S)-1-(1-(2-(bis(4-methoxybenzyl)amino)benzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]inden-4-yl)-3-fluoropyrrolidine-2-carboxamide (40.0 mg, 0.058 mmol) in TFA (8.00 mL) was heated at 80 ° C for 24 h. The reaction mixture was diluted with water. The pH value of the mixture was adjusted to 7-8 with aqueous sodium bicarbonate solution and extracted with DCM. The organic portion was washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified via preparative HPLC and lyophilized to give 11.9 mg (46%) of 294 as an off-white solid. LCMS (ESI): R _T (min) = 2.36, [M+H] ⁺ = 451, method = C; ¹ H NMR (300MHz, DMSO-d ₆ )δ7.74(s,1H),7.58(s,2H),7.49(d,J＝8.1Hz,1H),7.43(d,J＝1.5Hz,1H),7.37(s,1H), 7.29-7.25(m,1H),6.50(d,J＝2.1Hz,1H),6.25(d,J＝1.8Hz,1H),5.35-5.17(m,1H), 4.37-4.30(m,2H),4.25-4.20(m,2H),4.09(d,J＝26.4Hz,1H),3.72-3.65(m,1H), 3.41-3.32(m,1H),2.30-2.07(m,4H),1.80-1.65(m,2H).

Example 295 (S)-2-((1-(2,5-difluoro-4-(1H-1,2,4-triazol-5-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanamide 295

295 was prepared following a procedure similar to Example 269. LCMS (ESI): _RT (min) = 1.19 min, [M+H] ⁺ = 469, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ): δ 14.14 (s, 1H), 8.78 (s, 1H), 8.21-7.97 (m, 1H), 7.82-7.64 (m, 1H), 7.54-7.53 (m, 1H), 7.27-7.26 (m, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.67 (d, J = 2.0 Hz, 1H), 4.48-4.45 (m, 1H), 4.30-4.23 (m, 4H), 2.04-1.99(m,2H),1.88-1.81(m,2H),1.68-1.63(m,2H),1.02-0.98(m,3H).

Example 296 (S)-2-((1-(5-(1H-1,2,4-triazol-5-yl)pyridin-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 296

Step 1: 6-Chloropyridine-3-carboxamide

To a solution of 6-bromopyridine-3-carboxylic acid (50 g, 247 mmol) in DCM (1 L) and DMF (3 mL) was added oxalyl chloride (80 mL) dropwise at room temperature. The mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure and ammonia (1 L, 25-28% aqueous solution) was added dropwise. The resulting mixture was stirred at room temperature for another 1 h. The solvent was evaporated in vacuo to give 43 g of crude product, which was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ =157/159.

Step 2: (Z)-6-Chloro-N-((dimethylamino)methylene)pyridine-3-carboxamide

6-Chloropyridine-3-carboxamide (43 g, 274 mmol) was dissolved in dimethoxy-N,N-dimethylmethanamine (1 L) and stirred at 100°C for 3 h. The solvent was evaporated in vacuo, and the residue was triturated with hexane and the solid collected by filtration. The crude product (40 g, 69% yield) was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ = 212.

Step 3: 2-Chloro-5-(2H-1,2,4-triazol-3-yl)pyridine

To a solution of (Z)-6-chloro-N-((dimethylamino)methylene)pyridine-3-carboxamide (40 g, 188 mmol) in acetic acid (1 L) was added hydrazine acetate (40 g, 434 mmol). The resulting mixture was stirred at 90 ° C for 3 h. The solvent was evaporated in vacuo. The pH value of the solution was adjusted to 8 with sodium bicarbonate. The solid was collected by filtration to give 38 g (69%) of crude product, which was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ =181.

Step 4: 2-Chloro-5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridine

To a solution of 2-chloro-5-(2H-1,2,4-triazol-3-yl)pyridine (20 g, 110 mmol) and cesium carbonate (72 g, 220 mmol) in DMF (1 L) was added 1-(chloromethyl)-4-methoxybenzene (20.3 g, 129 mmol). The reaction mixture was stirred at 25 ° C for 16 h and diluted with water. The solid was filtered and collected and dried to give 20 g (60%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 301.

Step 5: 5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridine-2-carboxylic acid

To a mixture of 2-chloro-5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridine (20 g, 67 mmol), sodium carbonate (22 g, 207 mmol) and bis(diphenylphosphino)ferrocenepalladium(II) chloride (7.3 g, 9.98 mmol) in methanol (300 mL) and water (18 mL) was charged with carbon monoxide and heated at 60 ° C for 18 h. The resulting mixture was cooled to room temperature and evaporated in vacuo. The residue was partitioned between DCM and water. The pH of the aqueous layer was adjusted to 6 with hydrogen chloride. The solvent was evaporated and the crude product 10 g (48%) was used directly in the next step without further purification. LCMS (ESI): [M+H] ⁺ =311.

Step 6: 4-Bromo-1-(5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

The title compound (8.5 g, 63% yield over two steps) was prepared from 9-bromo-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazaocten-7-amine (Example 204, Step 4) (6.5 g, 25.3 mmol) following procedures similar to those in Steps 1-2 of Example 125. LCMS (ESI): [M+H] ⁺ = 531/533.

Step 7: 296 (251 mg, 16% yield over five steps) was prepared from 4-bromo-1-(5-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-2-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (2 g, 3.77 mmol) following a procedure similar to that of Example 269. LCMS (ESI): R _T (min) = 1.07, [M+H] ⁺ = 420, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 14.38 (s, 1H),9.31-9.30(m,1H),8.75(s,1H),8.53-8.50(m,1H),8.37(d,J＝6Hz,1H), 7.59-7.52(m,1H),7.25(s,1H),6.96(d,J＝3Hz,1H),6.65(d,J＝3Hz,1H), 5.08-5.04(m,2H),4.68-4.61(m,1H),4.31-4.21(m,2H),2.16-2.14(m,2H), 1.60-1.58(m,2H),1.47-1.45(m,3H).

Example 297 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoic acid 297

To a solution of (S)-methyl 2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanoate (Example 204, Step 11) (521 mg, 1.23 mmol) in THF (10 mL) and water (5 mL) was added lithium hydroxide hydrate (148 mg, 3.53 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h and then evaporated in vacuo. The resulting residue was purified via reverse phase flash chromatography (solvent gradient: 0-60% methanol/water) followed by chiral SFC to afford 48.4 mg (10%) of 297 as a white solid. LCMS (ESI): _RT (min) = 1.27, [M+H] ⁺ = 409, method = C; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.11 (s, 1H), 7.59 (s, 2H), 7.50 (d, J = 8.4 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.28-7.25 (m, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.53(d,J＝2.1Hz,1H),4.78-4.73(m,1H),4.39-4.34(m,2H),4.25-4.22(m,2H),2.15-2.06(m,2H),1.75-1.65(m,2H),1.50(d,J＝6.9Hz,3H).

Examples 298 and 299 (S)-2-(4-(1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)-1H-pyrazol-1-yl)butanamide 298 and (R)-2-(4-(1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)-1H-pyrazol-1-yl)butanamide 299

Step 1: Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanoate

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (22 g, 113 mmol), methyl 2-bromobutyrate (24.5 g, 135 mmol) and cesium carbonate (55.3 g, 170 mmol) in acetonitrile (650 mL) was stirred at 60 ° C for 16 h. The resulting solution was diluted with DCM. The solid was filtered off. The filtrate was evaporated in vacuo and purified via silica gel flash chromatography (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 32.5 g (97%) of the title compound as a yellow oil. LCMS (ESI): [M+H] ⁺ = 295.

Step 2: Methyl 2-(4-(1-(2-((tert-Butoxycarbonyl)amino)thiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-1H-pyrazol-1-yl)butanoate

A mixture of tert-butyl (5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate (Example 265, Step 5) (1 g, 1.94 mmol), methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butanoate (860 mg, 2.92 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (280 mg, 0.383 mmol) and sodium carbonate (620 mg, 5.850 mmol) in dioxane (10 mL) and water (1 mL) was stirred at 80° C. for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The resulting mixture was purified by silica gel flash chromatography (solvent gradient: 0-10% methanol/DCM) to give 1.2 g (87%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 604.

Step 3: tert-Butyl (5-(4-(1-(1-amino-1-oxobutan-2-yl)-1H-pyrazol-4-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate

A mixture of methyl 2-(4-(1-(2-((tert-butoxycarbonyl)amino)thiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-1H-pyrazol-1-yl)butanoate (1.2 g, 1.69 mmol) and ammonia (7 M in methanol, 15 mL) was stirred at 25° C. for 20 h. The reaction mixture was evaporated in vacuo to afford 1 g (85%) of the title compound as a brown solid. LCMS (ESI): [M+H] ⁺ = 589.

Step 4: A mixture of tert-butyl (5-(4-(1-(1-amino-1-oxobutan-2-yl)-1H-pyrazol-4-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-1-yl)thiazolo[5,4-b]pyridin-2-yl)carbamate (1 g, 2.04 mmol) and TFA (10 mL) in DCM (30 mL) was stirred at 20 ° C for 3 h. The reaction mixture was diluted with water and treated with saturated aqueous sodium bicarbonate to reach pH 8, extracted with DCM and evaporated in vacuo. The resulting mixture was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) and the two stereoisomers were separated by chiral SFC to give 298 and 299 as a single unknown stereoisomer.

298 (143.2 mg, 14% yield): LCMS (ESI): _RT (min) = 1.23, [M+H] ⁺ = 489, method = D; ^1H NMR (300 MHz, DMSO- _d6 ): 8.26 (s, 1H), 8.15-8.08 (m, 3H), 7.94 (s, 1H), 7.79-7.76 (m, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 5.11-4.92 (m, 2H), 4.84-4.70 (m, 1H), 4.36-4.19 (m, 2H), 2.18-2.06 (m, 4H), 1.70-1.55 (m, 2H), 0.88-0.83(m,3H).

299 (68.6 mg, 7% yield): LCMS (ESI): _RT (min) = 1.23, [M+H] ⁺ = 489, method = D; ^1H NMR (300 MHz, DMSO- _d6 ): 8.26 (s, 1H), 8.15-8.08 (m, 3H), 7.94 (s, 1H), 7.79-7.76 (m, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 5.11-4.92 (m, 2H), 4.84-4.70 (m, 1H), 4.36-4.19 (m, 2H), 2.18-2.06 (m, 4H), 1.70-1.55 (m, 2H), 0.88-0.83(m,3H).

Example 300 (2S,3R)-1-(1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-methoxypyrrolidine-2-carboxamide 300

Step 1: 1-tert-Butyl 2-methyl (2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate

To a solution of (2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (5.00 g, 21.6 mmol) in methanol (50.0 mL) was added (diazomethyl)trimethylsilane (50.0 mL, 2 mol/L in hexane) dropwise at room temperature with stirring. The reaction mixture was stirred at room temperature for 1 h and then evaporated in vacuo to give 5.30 g of the crude title compound as a light yellow oil. LCMS (ESI): [M+H] ⁺ = 246. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.44 (d, J = 4.9 Hz, 1H), 4.48-4.42 (m, 1H), 4.20 (d, J = 7.0 Hz, 1H), 3.63 and 3.60 (rotamers, two apparent s, 3H total), 3.47-3.39 (m, 1H), 3.31-3.21 (m, 1H), 1.98-1.91 (m, 1H), 1.83-1.74 (m, 1H), 1.39 and 1.32 (rotamers, two apparent s, 9H total).

Step 2: 1-tert-Butyl 2-methyl (2S,3R)-3-methoxypyrrolidine-1,2-dicarboxylate

A mixture of 1-tert-butyl 2-methyl (2S, 3R)-3-hydroxypyrrolidine-1,2-dicarboxylate (5.30 g, 21.6 mmol), silver (I) oxide (17.0 g, 73.4 mmol) and iodomethane (11.0 mL, 176 mmol) in acetone (100 mL) was stirred at room temperature for 84 h. The mixture was filtered and evaporated in vacuo. The resulting residue was purified by silica gel flash chromatography (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 4.78 g (85%) of the title compound as a light yellow oil. LCMS (ESI): [M+H] ⁺ = 260. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 4.42-4.38 (m, 1H), 4.19-4.13 (m, 1H), 3.63 and 3.61 (rotamers, two apparent s, 3H total), 3.44-3.36 (m, 1H), 3.32-3.19 (m, 4H), 2.12-1.95 (m, 1H), 1.91-1.82 (m, 1H), 1.38 and 1.32 (rotamers, two apparent s, 9H total).

Step 3: (2S,3R)-1-(tert-Butoxycarbonyl)-3-methoxypyrrolidine-2-carboxylic acid

A mixture of 1-tert-butyl 2-methyl (2S, 3R)-3-methoxypyrrolidine-1,2-dicarboxylate (4.78 g, 18.4 mmol), lithium hydroxide hydrate (4.20 g, 100 mmol) in THF (40.0 mL) and water (20.0 mL) was heated at 50 ° C for 24 h. The solvent was evaporated in vacuo. The resulting residue was diluted with water. The pH value was adjusted to 3 with 1M aqueous hydrogen chloride solution. The mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 3.76 g (83%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ = 246. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.45 (s, 1H), 4.29-4.27 (m, 1H), 4.15-4.03 (m, 1H), 3.47-3.33 (m, 1H), 3.33-3.17 (m, 4H), 2.13-1.94 (m, 1H), 1.94-1.80 (m, 1H), 1.36 and 1.34 (rotamers, two apparent s, 9H).

Step 4: (2S,3R)-3-methoxypyrrolidine-2-carboxylic acid trifluoroacetate

A mixture of (2S,3R)-1-(tert-butoxycarbonyl)-3-methoxypyrrolidine-2-carboxylic acid (3.50 g, 14.3 mmol) and trifluoroacetic acid (5.00 mL) in DCM (20.0 mL) was stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo to give 3.30 g (crude) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ =146.

Step 5: Tert-butyl (6-(4-((2S,3R)-2-carbamoyl-3-methoxypyrrolidin-1-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate

The title compound (176 mg, 47% yield over two steps) was prepared from tert-butyl (6-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (Example 214, Step 3) (332 mg, 0.645 mmol) following procedures similar to those in Example 104, Steps 1-2. LCMS (ESI): [M+H] ⁺ = 579.

Step 6: A mixture of tert-butyl (6-(4-((2S,3R)-2-carbamoyl-3-methoxypyrrolidin-1-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctane[cd]inden-1-yl)benzo[d]thiazol-2-yl)carbamate (530 mg, 0.916 mmol), trifluoroacetic acid (3.00 mL) in DCM (10.0 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with water. The pH value of the mixture was adjusted to 8 with sodium bicarbonate solution and extracted with DCM, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The resulting residue was purified via flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) and then purified by chiral HPLC to give 123.4 mg (28%) of 300 as a light yellow solid. LCMS (ESI): _RT (min) = 1.83, [M+H] ⁺ = 479, method = C; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.99 (s, 1H), 7.72 (s, 2H), 7.53-7.43 (m, 3H), 7.05 (s, 1H), 6.47 (s, 1H), 6.24 (s, 1H), 4.37-4.30 (m, 2H), 4.26-4.09 (m, 4H), 3.60-3.56 (m, 1H), 3.39 (s, 3H), 3.24-3.17 (m, 1H), 2.33-2.08 (m, 4H), 1.75-1.65 (m, 2H).

Examples 301 and 302 (S)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)-1H-pyrazol-1-yl)butanamide 301 and (R)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)-1H-pyrazol-1-yl)butanamide 302

Step 1: 5-bromooxazolo[4,5-b]pyridin-2-amine

A mixture of 2-amino-6-bromopyridine-3-ol (20.0 g, 105 mmol) and cyanogen bromide (89.6 g, 846 mmol) in water (400 mL) was stirred at 100 ° C for 20 min. The resulting mixture was quenched with sodium carbonate. The pH value of the solution was adjusted to 9 and diluted with DCM. The organic extracts were combined, dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-5% methanol/DCM) to give 10 g (44%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 214/216.

Step 2: tert-Butyl 5-bromooxazolo[4,5-b]pyridin-2-ylcarbamate

A mixture of 5-bromooxazolo[4,5-b]pyridin-2-amine (10.0 g, 46.7 mmol), di-tert-butyl dicarbonate (22.4 g, 102 mmol), N,N-dimethylpyridin-4-amine (1.14 g, 9.33 mmol) and triethylamine (14.1 g, 140 mmol) in DCM (300 mL) was stirred at 25 ° C for 16 hours. The resulting mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-1% methanol/DCM) to give 7.80 g (53%) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ =314/316.

Step 3: Methyl 2-(tert-Butoxycarbonylamino)oxazolo[4,5-b]pyridine-5-carboxylate

A mixture of tert-butyl 5-bromooxazolo[4,5-b]pyridin-2-ylcarbamate (7.80 g, 24.8 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (2.73 g, 3.73 mmol), and sodium carbonate (7.90 g, 74.5 mmol) in methanol (260 mL) was stirred at 60 ° C for 16 h. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (solvent gradient: 0-60% ethyl acetate/petroleum ether) to give 7 g (96%) of the title compound as a light yellow solid. LCMS (ESI): [M+H] ⁺ = 294.

Step 4: 2-(tert-Butoxycarbonylamino)oxazolo[4,5-b]pyridine-5-carboxylic acid

A mixture of methyl 2-(tert-butoxycarbonylamino)oxazolo[4,5-b]pyridine-5-carboxylate (7.00 g, 23.8 mmol) and lithium hydroxide (2.00 g, 47.6 mmol) in THF (70.0 mL) and water (20 mL) was stirred at 25 ° C for 1 h. The reaction mixture was extracted with ethyl acetate. The pH value of the aqueous phase was adjusted to 3 with 1M aqueous hydrogen chloride solution. The solid was collected by filtration to give 5 g (75%) of the title compound as a yellow solid. LCMS (ESI): [M+H] ⁺ = 280.

Step 5: Tert-butyl (5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)oxazolo[4,5-b]pyridin-2-yl)carbamate

The title compound (2 g, 51% yield over 2 steps) was prepared from 9-bromo-3,4,5,6-tetrahydro-2H-benzo[b][1,4]oxazaocten-7-amine (2.00 g, 7.78 mmol) and 2-(tert-butoxycarbonylamino)oxazolo[4,5-b]pyridine-5-carboxylic acid (2.61 g, 9.34 mmol) following a procedure similar to that described in Steps 1-2 of Example 125. LCMS (ESI): [M+H] ⁺ = 500/502.

Step 6: Following a procedure analogous to Examples 298 and 299, 301 and 302 were prepared from tert-butyl (5-(4-bromo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-1-yl)oxazolo[4,5-b]pyridin-2-yl)carbamate (1.00 g, 1.99 mmol) as a single unknown stereoisomer.

301 (74.5 mg, 23% yield): LCMS (ESI): _RT (min) = 3.00, [M+H] ⁺ = 473, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.26 (s, 1H), 8.08 (s, 2H), 7.94 (s, 1H), 7.87-7.85 (m, 2H), 7.69-7.63 (m, 1H), 7.52 (s, 1H), 7.27-7.20 (m, 2H), 5.03-5.01 (m, 2H), 4.78-4.73 (m, 1H), 4.35-4.25 (m, 2H), 2.18-2.08 (m, 4H), 1.64-1.61 (m, 2H), 0.88-0.85(m,3H).

302 (128.9 mg, 39% yield): LCMS (ESI): _RT (min) = 3.00, [M+H] ⁺ = 473, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.26 (s, 1H), 8.07 (s, 2H), 7.93-7.82 (m, 3H), 7.68 (d, J = 1.4 Hz, 1H), 7.50 (s, 1H), 7.25-7.19 (m, 2H), 5.04-5.01 (m, 2H), 4.78-4.73 (m, 1H), 4.30-4.27 (m, 2H), 2.18-2.08 (m, 4H), 1.63-1.61 (m, 2H), 0.88-0.85 (m, 3H).

Examples 303 and 304 (S)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-3-methoxypropanamide 303 and (R)-2-((1-(2-aminobenzo[d]thiazol-6-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-3-methoxypropanamide 304

Following procedures analogous to Examples 275 and 276, 303 and 304 were prepared as single unknown stereoisomers.

303: LCMS (ESI): R _T (min) = 1.09, [M+H] ⁺ = 454, method = D; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.00 (d, J = 1.6Hz, 1H), 7.73 (s, 2H), 7.61-7.60 (m, 1H),7.54-7.51(m,1H),7.48-7.46(m,1H),7.40-7.39(m,1H),6.96(d,J＝2.4Hz, 1H),6.62(d,J＝2.0Hz,1H),4.72-4.70(m,1H),4.41-4.39(m,2H),4.27-4.24(m, 2H),3.77-3.67(m,2H),3.33(s,3H),2.18-2.12(m,2H),1.72-1.67(m,2H).

304: LCMS (ESI): R _T (min) = 1.09 min, [M + H] ⁺ = 454, method = D; ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.01 (d, J = 1.6Hz, 1H), 7.75 (s, 2H), 7.61-7.60 (m, 1H),7.54-7.52(m,1H),7.48-7.46(m,1H),7.40-7.39(m,1H),6.96(d,J＝2.0Hz, 1H),6.63(d,J＝2.4Hz,1H),4.73-4.70(m,1H),4.42-4.39(m,2H),4.27-4.25(m, 2H),3.77-3.68(m,2H),3.33(s,3H),2.18-2.12(m,2H),1.72-1.67(m,2H).

Examples 305 and 306 (S)-2-Cyclopropyl-2-((1-(3-fluoro-4-(1H-1,2,4-triazol-5-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)acetamide 305 and (R)-2-Cyclopropyl-2-((1-(3-fluoro-4-(1H-1,2,4-triazol-5-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)acetamide 306

Step 1: 4-Bromo-2-fluorobenzamide

A mixture of 4-bromo-2-fluorobenzonitrile (50.0 g, 249 mmol) and aluminum oxide (76.5 g, 750 mmol) in methanesulfonic acid (650 mL) was stirred at 120 ° C for 1 h. The resulting mixture was quenched with water and extracted with DCM. The organic extract was dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 40 g (73%) of the title compound as a gray solid. LCMS (ESI): [M+H] ⁺ = 218/220.

Step 2: (Z)-4-Bromo-N-((dimethylamino)methylene)-2-fluorobenzamide

A mixture of 4-bromo-2-fluorobenzamide (20.0 g, 91.7 mmol) in dimethoxy-N,N-dimethylmethanamine (150 mL) was stirred at 100 ° C for 3 h. The resulting mixture was cooled to room temperature and diluted with hexane. The solid was collected by filtration to give 23 g (92%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ = 273/275.

Step 3: 3-(4-Bromo-2-fluorophenyl)-1H-1,2,4-triazole

A mixture of (Z)-4-bromo-N-((dimethylamino)methylene)-2-fluorobenzamide (20.0 g, 73.2 mmol) and hydrazine hydrate (100 mL, 80% in water, 2.06 mol) in acetic acid (500 mL) was stirred at 20°C for 1 h. The residue was quenched with water, and the solid was collected by filtration to give 16.0 g (90%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ = 242/244.

Step 4: 3-(4-bromo-2-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole

The title compound (12.0 g, 47% yield) was prepared from 3-(4-bromo-2-fluorophenyl)-1H-1,2,4-triazole (17.0 g, 70.2 mmol) following a procedure similar to that described in Example 267, Step 1. LCMS (ESI): [M+H] ⁺ =362/364.

Step 5: 3-(2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole

A mixture of 3-(4-bromo-2-fluorophenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (11.0 g, 30.3 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloride (2.22 g, 3.03 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (9.25 g, 36.4 mmol) and potassium acetate (5.96 g, 60.7 mmol) in DMSO (300 mL) was stirred at 90 ° C for 2 h. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate/petroleum ether) to give 8.50 g (68%) of the title compound as a white solid. LCMS (ESI): [M+H] ⁺ =410.

Step 6: 4-Bromo-1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

A mixture of 4-bromo-1-iodo-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (Example 204, Step 6) (5.00 g, 12.7 mmol), 3-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(4-methoxybenzyl)-1H-1,2,4-triazole (6.25 g, 15.2 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (1.40 g, 1.91 mmol), and sodium carbonate (2M in water, 2 mL, 4.00 mmol) in DMF (100 mL) was stirred at 90°C for 2 h. The resulting mixture was quenched with water and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-70% ethyl acetate/petroleum ether) to give 3.10 g (44%) of the title compound as an off-white solid. LCMS (ESI): [M+H] ⁺ =548/550.

Step 7: 1-(3-Fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol

A mixture of 4-bromo-1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (3.00 g, 5.47 mmol), di-tert-butyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (1.16 g, 2.73 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.50 g, 2.73 mmol) and potassium hydroxide (770 mg, 13.7 mmol) in dioxane (90 mL) and water (18 mL) was stirred at 100° C. for 4 h. The resulting mixture was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent gradient: 0-10% methanol/DCM) to give 1.20 g (45%) of the title compound as a grey solid. LCMS: [M+H] ⁺ =486.

Step 8: Following procedures analogous to Example 279, Steps 1-3, 305 and 306 were prepared from 1-(3-fluoro-4-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)phenyl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-ol (3.00 g, 5.47 mmol) as a single unknown stereoisomer.

305 (124 mg, 4.3% yield, over 3 steps): LCMS (ESI): _RT (min) = 2.46, [M+H] ⁺ = 463, method = E; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 14.36 (s, 1H), 8.74 (s, 1H), 8.33-8.19 (m, 1H), 7.66-7.56 (m, 3H), 7.24 (s, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.22 (d, J = 1.8 Hz, 1H), 4.49-4.57 (m, 2H), 4.15-4.32 (m, 2H), 3.98-3.92 (m, 1H), 2.27-2.08(m,2H),1.69-1.58(m,2H),1.38-1.23(m,1H),0.60-0.54(m,3H), 0.48-0.43(m,1H).

306 (110 mg, 3.9% yield, over 3 steps): LCMS (ESI): _RT (min) = 2.45, [M+H] ⁺ = 463, method = E; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 14.36 (s, 1H), 8.74 (s, 1H), 8.33-8.19 (m, 1H), 7.66-7.56 (m, 3H), 7.24 (s, 1H), 6.91 (d, J = 2.1 Hz, 1H), 6.22 (d, J = 1.8 Hz, 1H), 4.57-4.49 (m, 2H), 4.32-4.15 (m, 2H), 3.98-3.92 (m, 1H), 2.27-2.08(m,2H),1.69-1.58(m,2H),1.38-1.23(m,1H),0.60-0.54(m,3H), 0.48-0.43(m,1H).

Example 307 (S)-2-((1-(5-fluoro-6-(1H-1,2,4-triazol-5-yl)pyridin-3-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide 307

Step 1: 4-Bromo-1-(5-fluoro-6-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene

The title compound (1.60 g, 9% yield over six steps) was prepared from 3-fluoro-2-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (6.26 g, 15.2 mmol) following procedures similar to those in Steps 1-6 of Example 305. LCMS (ESI): [M+H] ⁺ = 549/551.

Step 2: (S)-2-((1-(5-fluoro-6-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)propanamide

The title compound (0.80 g, 39.4% yield over four steps) was prepared from 4-bromo-1-(5-fluoro-6-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]indene (2.00 g, 3.64 mmol) following procedures similar to those described in Example 204, Steps 9-12. LCMS (ESI): [M+H] ⁺ = 558.

Step 3: 307 (181 mg, 29% yield) was prepared from (S)-2-((1-(5-fluoro-6-(1-(4-methoxybenzyl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazaocta[cd]inden-4-yl)oxy)propanamide (800 mg, 1.44 mmol) following a procedure similar to that of Example 267, Step 6. LCMS (ESI): R _T (min) = 5.00, [M+H] ⁺ = 438, method = D; ¹ H NMR (300MHz, DMSO-d ₆ ) δ 14.67 (s, 1H), 8.87 (s, 1H), 8.52 (s, 1H), 8.18 (d, J = 10.9Hz, 1H), 7.56 (s, 1H),7.26(s,1H),6.99(d,J＝2.1Hz,1H),6.66(d,J＝2.0Hz,1H),4.68-4.64(m,1H), 4.52-4.46(m,2H),4.28-4.25(m,2H),2.17-2.14(m,2H),1.79-1.61(m,2H), 1.47-1.45 (m, 3H).

Example 308 (2S,3S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)-3-methylpyrrolidine-2-carboxamide 308

308 was prepared following a procedure similar to Example 104. LCMS (ESI): _RT (min) = 3.60, [M+H] ⁺ = 433, method = E; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.57-7.53 (m, 3H), 7.47 (d, J = 8.2 Hz, 1H), 7.36-7.32 (m, 2H), 6.99 (d, J = 2.6 Hz, 1H), 6.32 (d, J = 2.1 Hz, 1H), 6.05 (d, J = 2.1 Hz, 1H), 4.37-4.32 (m, 2H), 4.26-4.18 (m, 2H), 3.58-3.55 (m, 1H), 3.44 (d, J = 4.1Hz, 1H), 2.37-2.12 (m, 5H), 1.59-1.52 (m, 1H), 1.09 (d, J = 6.8Hz, 3H).

Example 309 (2S,3S)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-methylpyrrolidine-2-carboxamide 309

309 was prepared following a procedure similar to Example 250. LCMS (ESI): _RT (min) = 0.83, [M+H] ⁺ = 447, method = C; ^1H NMR (300 MHz, DMSO-d ₆ ) δ 7.58 (s, 2H), 7.48 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 7.39 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 6.44 (s, 1H), 6.22 (s, 1H), 4.45-4.29 (m, 2H), 4.28-4.15 (m, 2H), 3.58 (s, 1H), 3.47 (s, 1H), 3.41-3.38(m,1H),2.33(s,1H),2.19-2.11(m,3H),1.70-1.59(m,3H),1.12-1.09(m,3H).

Example 310 (2S,3R)-1-(1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)-3-methoxypyrrolidine-2-carboxamide 310

310 was prepared following a procedure similar to Example 300. LCMS (ESI): _RT (min) = 1.24, [M+H] ⁺ = 463, method = C; ^1H NMR (300 MHz, DMSO- _d6 ): δ 7.57 (apparent s, 3H), 7.48 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.28-7.00 (m, 2H), 6.47-6.45 (m, 1H), 6.24-6.22 (m, 1H), 4.42-4.27 (m, 2H), 4.27-4.17 (m, 2H), 4.13-3.85 (m, 2H), 3.65-3.55 (m, 1H), 3.38 and 3.29 (rotamers, two apparent s, total 3H), 3.28-3.25 (m, 1H),2.17-2.03(m,4H),1.77-1.60(m,2H).

Examples 311 and 312 (S)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)-1H-pyrazol-1-yl)butanamide 311 and (R)-2-(4-(1-(2-aminooxazolo[4,5-b]pyridin-5-yl)-8,9-dihydro-7H-6-oxa-2,9a-diazabenzo[cd]azulene-4-yl)-1H-pyrazol-1-yl)butanamide 312

Following procedures analogous to Examples 301 and 302, 311 and 312 were prepared as single unknown stereoisomers.

311 (38.8 mg, 12% yield): LCMS (ESI): _RT (min) = 3.60, [M+H] ^{+ =} 459, method = E; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.24 (d, J = 2.1 Hz, 1H), 8.10 (s, 2H), 7.92 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 2.1 Hz, 2H), 7.55-7.41 (m, 2H), 7.27 (s, 1H), 7.08-7.05 (m, 1H), 4.78-4.72 (m, 3H), 4.45-4.41 (m, 2H), 2.37 (d, J = 7.5 Hz, 2H), 2.10-2.05 (m, 2H), 0.87-0.82 (m, 3H).

312 (108.8 mg, 33% yield): LCMS (ESI): _RT (min) = 3.00, [M+H] ⁺ = 459, method = D; ^1H NMR (300 MHz, DMSO- _d6 ) δ 8.26 (s, 1H), 8.11 (s, 2H), 7.93 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 1.8 Hz, 2H), 7.54 (d, J = 2.7 Hz, 2H), 7.28 (s, 1H), 7.08-7.06 (m, 1H), 4.78-4.72 (m, 3H), 4.45-4.41 (m, 2H), 2.37 (s, 2H), 2.11-2.03 (m, 2H), 0.87-0.83 (m, 3H).

Example 313 (S)-2-((1-(2-aminobenzo[d]oxazol-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacycloocta[cd]inden-4-yl)oxy)butanoic acid 313

313 was prepared following a procedure similar to Example 297. LCMS (ESI): _RT (min) = 0.90, [M+H] ⁺ = 423, method = D; ^1H NMR (400 MHz, DMSO-d ₆ ): δ 7.56 (s, 2H), 7.51-7.49 (m, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.28-7.26 (m, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H), 4.60-4.56 (m, 1H), 4.38-4.35 (m, 2H), 4.26-4.23 (m, 2H), 2.14-2.08(m,2H),1.92-1.82(m,2H),1.72-1.66(m,2H),1.03-1.00(m,3H).

Examples 314 and 315 (R)-2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-3-methoxypropanamide 314 and (S)-2-((1-(2-aminothiazolo[5,4-b]pyridin-5-yl)-7,8,9,10-tetrahydro-6-oxa-2,10a-diazacyclooctano[cd]inden-4-yl)oxy)-3-methoxypropanamide 315

Following procedures analogous to Examples 303 and 304, 314 and 315 were prepared as single unknown stereoisomers.

314: LCMS (ESI): _RT (min) = 1.13, [M+H] ⁺ = 455, method = D; ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.12-8.07 (m, 3H), 7.77-7.75 (m, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 6.97 (s, 1H), 6.63 (s, 1H), 5.11-4.88 (m, 2H), 4.74-4.66 (m, 1H), 4.35-4.18 (m, 2H), 3.81-3.63 (m, 2H), 3.32 (s, 3H), 2.21-2.05 (m, 2H), 1.71-1.56 (m, 2H).

315: LCMS (ESI): _RT (min) = 1.13, [M+H] ⁺ = 455, method = D; ^1H NMR (300 MHz, DMSO- _d6 ): δ 8.12-8.07 (m, 3H), 7.77-7.75 (m, 1H), 7.63 (s, 1H), 7.41 (s, 1H), 6.97 (s, 1H), 6.63 (s, 1H), 5.11-4.88 (m, 2H), 4.74-4.66 (m, 1H), 4.35-4.18 (m, 2H), 3.81-3.63 (m, 2H), 3.32 (s, 3H), 2.21-2.05 (m, 2H), 1.71-1.56 (m, 2H).

Example 901p110α PI3K binding assay

The PI3K binding assay is intended to determine the biochemical efficacy of small molecule PI3K inhibitors. The PI3K lipid kinase reaction is performed in the presence of PIP2:3PS lipid substrate (Promega #V1792) and ATP. After terminating the kinase reaction, the conversion of ATP to ADP via phosphorylation of the lipid substrate is detected using the Promega ADP-Glo ^™ (Promega #V1792) assay. The reaction is performed using the following conditions:

After 120 minutes of reaction, the kinase reaction is terminated. Any ATP remaining after the reaction is depleted, leaving only ADP. A kinase detection reagent is then added to convert ADP into ATP, which is used in the coupled luciferin/luciferase reaction. The luminescent output is measured and correlated with kinase activity.

All reactions were performed at room temperature. 3 μl of a 1:1 mixture of enzyme/lipid substrate solution was added to a 384-well white assay plate (Perkin Elmer #6007299) containing 50 nl of test compound or DMSO alone (used as an untreated control). The reaction was initiated by adding 2 μl of ATP/MgCl _2. The kinase reaction buffer contained 50 mM HEPES, 50 mM NaCl, 3 mM MgCl ₂ , 0.01% BSA, 1% DMSO, and the enzyme and substrate concentrations shown in the table above. The reaction was stopped by adding 10 μl of ADP-Glo reagent. The plates were read using the luminescence mode on a Perkin Elmer Envision system. A 10-point dose-response curve was plotted for each test compound. The Ki value for each compound was determined using the Morrison equation.

Binding assay: Initial polarization experiments were performed on an Analyst HT 96-384 (Molecular Devices Corp, Sunnyvale, CA). Samples for fluorescence polarization affinity measurements were prepared as follows: 1:3 serial dilutions of p110α PI3K (Upstate Cell Signaling Solutions, Charlottesville, VA) starting at a final concentration of 20 μg/mL in polarization buffer (10 mM Tris pH 7.5, 50 mM NaCl, 4 mM MgCl ₂ , 0.05% Chaps, and 1 mM DTT) were added to a final concentration of 10 mM PIP ₂ (Echelon-Inc., Salt Lake City, UT). After incubation at room temperature for 30 minutes, the reaction was stopped by adding GRP-1 and PIP3-TAMRA probes (Echelon-Inc., Salt Lake City, UT) at final concentrations of 100 nM and 5 nM, respectively. Rhodamine fluorophore readings were performed in a 384-well black low-volume (PerkinElmer, Wellesley, MA) using standard cutoff filters (λ _excitation = 530 nm; λ _emission = 590 nm). Fluorescence polarization values were plotted as a function of protein concentration. _EC50 values were obtained by fitting the data to a four-parameter equation using software (Synergy software, Reading, PA). This experiment also determined the protein concentration appropriate for subsequent inhibitor competition experiments.

Inhibitor _IC50 values were determined as follows: 0.04 mg/mL p110α PI3K (final concentration) was added to wells containing a 1: ₃ serial dilution of the antagonist in polarization buffer with a final concentration of 25 mM ATP (Cell Signaling Technology, Inc., Danvers, MA). After incubation at room temperature for 30 minutes, the reaction was stopped by adding GRP-1 and PIP3-TAMRA probes (Echelon-Inc., Salt Lake City, UT) at final concentrations of 100 nM and 5 nM, respectively. The rhodamine fluorophore was read using standard cutoff filters (λ _excitation = 530 nm; λ _emission = 590 nm) in a 384-well black low-volume (PerkinElmer, Wellesley, MA). Fluorescence polarization values were plotted as a function of antagonist concentration and _IC50 values were derived by fitting the data to a four-parameter equation in Assay Explorer software (MDL, San Ramon, CA.).

Alternatively, inhibition of PI3K is determined in a radioassay using purified recombinant enzyme and 1 μM (micromolar) ATP. Compounds are serially diluted in 100% DMSO. The kinase reaction mixture is incubated at room temperature for 1 hour and the reaction is terminated by adding PBS. _IC50 values are then determined using a sigmoidal dose-response curve fit (variable slope).

Although the above invention has been described in some detail by way of illustration and example for the purpose of clear understanding, said description and example should not be construed as limiting the scope of the invention. The entire disclosures of all patents and scientific literature cited in this application are expressly incorporated into this application by reference.

Claims (34)

1. Compounds selected from formulas Ig and Il, or their tautomers and pharmaceutical salts: in ^R1 is selected from Br, Cl, I, _C1 - _C20 heteroaryl, ^-NR3R4 , ^{and -OR5} , wherein the _C1 - _C20 heteroaryl is a monovalent aromatic group of a 5-membered ring containing one or more heteroatoms independently selected from nitrogen and optionally substituted with one or more groups independently selected from the following: _{C(CH3)2CONH2 , -CH2OH , -CH2CH2OH} , _-C( CH3) _2OH , -CH(OH)CH( _CH3 ) _{2 ,} -C( _CH3 ) _2CH2OH , _{-CH3 , -CH2CH3, -CH(CH3)2 , -C ( CH3} ) _{3 , and -CH2CH} ( _CH3 ) ₂ ; ^R2 is selected from H, F, and Cl; ^R3 is selected from H and _C1 - _C6 alkyl groups; ^R4 is selected from _C1 - _C6 alkyl groups, wherein the _C1 - _C6 alkyl groups are optionally substituted with one or more groups independently selected from _-CONH2 , cyclopropyl and cyclobutyl; ^R3 and ^R4 may form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is a saturated carbocyclic ring, wherein at least one ring atom in the saturated carbocyclic ring is a heteroatom selected from nitrogen and oxygen, and the remaining ring atoms are carbon, and wherein the 5- or 6-membered heterocyclic ring may optionally be substituted with one or more groups independently selected from the following: _-CONH2 , F, Cl, Br, I, _{-OCH3 , -OCH2CH3} , _-CH3 , _-CH2CH3 , _-CH ( _CH3 ) ₂ , C( _CH3 ) ₃ and -CH2CH( _{CH3 ) 2} ; ^R5 is selected from _C1 - _C6 alkyl groups, wherein the _C1 - _C6 alkyl groups are optionally substituted with one or more groups independently selected from the following: _-CONH2 , _-OCH3 , _-OCH2CH3 , _cyclopropyl and cyclobutyl; ^R6 is independently selected from H and _C1 - _C4 alkyl groups; p is 2, 3, or 4; and A is selected from _C6 aryl, -( _C6 aryl)-( _C1 - _C20 heteroaryl), -( _C6 aryl)-(C2- _C20 heterocyclic), -( _C1 -C20 heteroaryl)-( _C2 - _C20 heterocyclic), -( _C1 - _C20 heteroaryl)-( _C1 - _C20 heteroaryl), _C2 - _C20 heterocyclic, and _C1 - _C20 heteroaryl, wherein the _{C1 - C20} heteroaryl is a 5- or 6-membered ring monovalent aromatic group and comprises a fused ring system of 5-20 atoms, wherein at least one ring is aromatic, and the _C1 - _{C20 heteroaryl} contains one or more heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the _C2 -C... The ₂₀ heterocyclic group is saturated or partially unsaturated, and is a monocyclic ring with 3-7 ring members or a bicyclic ring with 7-10 ring members, wherein the 3-7 ring members consist of 2-6 carbon atoms and 1-4 heteroatoms selected from N and O, and the 7-10 ring members consist of 4-9 carbon atoms and 1-6 heteroatoms selected from N and O, and wherein the aryl, heterocyclic, and heteroaryl groups are optionally substituted with one or more groups independently selected from: _-NH₂ , _-CH₃ , _-CH₂CH₃ , _-CH ( _CH₃ ) _₂ , _-C ( _CH₃ ) _₃ , -CH₂CH( _CH₃ ) _₂ , -CN, _-OCH₃ , _-OCH₂CH₃ , F, Cl, Br, _I , =O, _{-CH₂OH , -CH₂CH₂OH} , -C( _CH₃ ) _₂ OH, -CH(OH)CH( _CH3 ) ₂ , -C( _CH3 ) _2CH2OH , -S(O) _2CH3 , _{-CONH2, -CO2CH3, -CO2C(CH3)3 , -C(CH3)2CONH2, -OH, -NHCH3, -N(CH3)2 , -CH2F , -CHF2 , -CF3 , -CH2CF3 and -CH2CHF2 ; provided that the compounds selected from formulas} Ig and Il are _not 2. The compound of claim 1 or its tautomer and pharmaceutical salt, wherein p is 2. 3. The compound of claim 1 or its tautomer and pharmaceutical salt, wherein p is 3. 4. The compound of claim 1 or its tautomer and pharmaceutical salt, wherein p is 4. 5. The compound of any one of claims 1-4 or its tautomer and pharmaceutical salt, wherein each R ⁶ is H. 6. The compound of claim 1 or its tautomer and pharmaceutical salt, wherein the compound is selected from formula Ih-j: 7. The compound of claim 6 or its tautomer and pharmaceutical salt, wherein the compound is selected from the formula In-p: Where Y is 0 or NR ³ ; and ^R7 is selected from H, cyclopropyl, cyclobutyl and _C1 - _C6 alkyl, optionally substituted with _-OCH3 ; or ^R3 and ^R7 form a 5- or 6-membered heterocyclic ring, wherein the 5- or 6-membered heterocyclic ring is a saturated carbocyclic ring, wherein at least one ring atom in the saturated carbocyclic ring is a heteroatom selected from nitrogen and oxygen, and the remaining ring atoms are carbon. 8. The compound of claim 7 or its tautomer and pharmaceutical salt, wherein Y is NH. 9. The compound of claim 7 or its tautomer and pharmaceutical salt, wherein Y is NR ³ and R ³ and R ⁷ form a pyrrolidinyl ring. 10. The compound of claim 7 or its tautomer and pharmaceutical salt, wherein Y is O. 11. The compound of any one of claims 1-4 and 6-10, or its tautomer and pharmaceutical salt, wherein ^R1 is Br or a substituted pyrazolyl group. 12. The compound of any one of claims 1-4 and 6-10, or its tautomer and pharmaceutical salt, wherein ^R1 is selected from: The wavy line indicates the connection point. 13. The compound of any one of claims 1-4 and 6-10, or its tautomer and pharmaceutical salt, wherein A is a substituted benzo[d]oxazolyl or a substituted benzothiazolyl. 14. The compound of any one of claims 1-4 and 6-10, or its tautomer and pharmaceutical salt, wherein A is selected from the following structures: The wavy line indicates the connection point. 15. A compound or its tautomer and a pharmaceutical salt, wherein the compound is selected from: 16. A compound or its tautomer and a pharmaceutical salt, said compound being selected from: 17. A pharmaceutical composition comprising a compound of any one of claims 1-16 or a pharmaceutical salt thereof and a pharmaceutical carrier, gliding agent, diluent or excipient. 18. The pharmaceutical composition of claim 17, wherein the pharmaceutical carrier, flow aid, diluent, or excipient is selected from silica, powdered cellulose, microcrystalline cellulose, metal stearate, sodium aluminosilicate, sodium benzoate, calcium carbonate, calcium silicate, magnesium carbonate, asbestos-free talc, Stearot C, starch, magnesium lauryl sulfate, magnesium oxide, and combinations thereof. 19. The pharmaceutical composition of claim 18, wherein the starch is selected from corn starch, starch 1500, and combinations thereof. 20. A method for preparing a pharmaceutical composition, comprising combining a compound of any one of claims 1-16 or a pharmaceutical salt thereof with a pharmaceutical carrier, a flow aid, a diluent or an excipient. 21. The pharmaceutical composition of claim 17, further comprising a therapeutic agent selected from: chemotherapeutic agents, anti-inflammatory agents, immunomodulators, neurotrophic factors, cardiovascular disease therapeutic agents, liver disease therapeutic agents, antiviral agents, hematologic disorders therapeutic agents, diabetes therapeutic agents, and immunodeficiency disorder therapeutic agents, wherein the chemotherapeutic agent is selected from alkylating agents, antimetabolites, spindle-toxic phytoalkaloids, cytotoxic/antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. 22. Use of any compound of claims 1-16 or a pharmaceutical salt thereof in the preparation of a medicament for treating cancer, wherein the cancer is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, and uterine cancer. 23. The use of claim 22, wherein the treatment further comprises administering to the patient a therapeutic agent selected from: 5-FU, docetaxel, eribulin, gemcitabine, cobimetinib, ipatasertib, paclitaxel, tamoxifen, fulvestrant, GDC-0810, dexamethasone, perpoxib, bevacizumab, pertuzumab, trastuzumab-mettansin conjugate, trastuzumab, and letrozole. 24. The use of claim 22, wherein the cancer is breast cancer. 25. The use of claim 24, wherein the breast cancer is estrogen receptor-positive (ER ⁺ ) breast cancer. 26. The use of claim 22, wherein the breast cancer subtype is basal or ductal. 27. The use of claim 22, wherein the cancer expression is selected from the following PIK3CA mutants: E542K, E545K, Q546R, H1047L and H1047R. 28. The use of claim 22, wherein the cancer expresses a PTEN mutant. 29. The use of claim 22, wherein the cancer is hormone receptor positive (HR ⁺ ). 30. The use of claim 22, wherein the patient is HER2-negative, ER (estrogen receptor)-negative, and PR (progesterone receptor)-negative. 31. A kit for the therapeutic treatment of breast cancer, comprising: a) the pharmaceutical composition of claim 17; and b) Instructions for use in the therapeutic treatment of breast cancer. 32. Use of any compound of claims 1-16 or a pharmaceutical salt thereof in the preparation of a medicament for treating cancer, wherein the cancer is selected from breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, gastric cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone cancer, adenoma, adenocarcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, and gallbladder cancer. Cancer of the genital tract, kidney, myeloid diseases, lymphoma, pilocarcinoma, oral cavity, nasopharyngeal carcinoma, lip, tongue, mouth, small intestine, colorectal cancer, large intestine, brain and central nervous system cancers, Hodgkin's cancer, leukemia, bronchial cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, glioma, endometrial cancer, renal pelvis cancer, multiple myeloma, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, chronic lymphocytic leukemia (CLL), myeloid leukemia, non-Hodgkin's lymphoma, and villonodular adenomas. 33. Use of the compound of any one of claims 1-16 or a pharmaceutical salt thereof in the preparation of a medicament for treating cancers selected from non-small cell lung cancer (NSCLC), colon cancer, rectal cancer and pharyngeal cancer. 34. Use of any compound of claims 1-16 or a pharmaceutical salt thereof in the preparation of a medicament for treating pancreatic cancer and thyroid cancer.