Heterocyclic compounds as ras inhibitors

Abstract

Disclosed herein are compounds, and salts thereof, which inhibit targeted Ras mutants, pharmaceutical formulations, and methods of treatment of NRAS-, KRAS, or HRAS-mediated diseases, such as certain cancers.

Description

Attorney Docket No. MDA0094-401-PC HETEROCYCLIC COMPOUNDS AS RAS INHIBITORS

[0001] This application claims the benefit of priority of United States provisional application no.63 / 682,997, filed August 14, 2024, the contents of which are incorporated by reference as if written herein in their entirety.

[0002] Ras proteins serve a critical role in cell proliferation as they regulate signal transduction received from extracellular stimuli to downstream pathways such as MAPK, PI3K-AKT and Ral-GDS. These pathways are involved in cellular events such as cell cycle, cell differentiation and cell survival. Dysregulation in Ras signaling is most often associated with activating mutations in the Ras protein typically found at codons 12,13 and 61. Such activating mutations break down the cycling between active (GTP-bound) and inactive (GDP-bound) Ras leading to cancer.

[0003] Approximately 20% of all human cancers present with mutations in Ras proteins. KRAS mutations are responsible for 75% of these cases and are predominantly found in PDAC, colorectal cancer and adenocarcinoma, followed by NRAS (17%) in hematopoietic cancers and malignant melanoma and HRAS (7%) in head and neck squamous cell carcinomas and bladder tumors. NRAS mutant-driven acute myeloid leukemia (AML) accounts for 11–30% of all AML patients.44% of occurring mutation in AML is observed at codon 12 (NRAS G12D represents 30%) followed by codon 13 and 61. In contrast, in melanoma, NRAS mutations are predominantly observed at codon 61 and to a lesser extent at codons 12 and 13.

[0004] Targeting Ras mutant cancers has been historically challenging. After the initial failed attempts to prevent KRAS attachment and activation in the membrane by using farnesyl transferase inhibitors, focus has shifted to upstream and downstream targets in the Ras signaling pathway. Inhibition of RTKs (receptor tyrosine kinases), SHP2 and SOS, all found upstream of Ras, has shown limited impact on Ras driven cancers, while regulation of downstream proteins such as MEK, RAF and PI3K are often plagued by toxicity issues. However, it has been discovered that directly targeting the mutant Ras proteins offers new possibilities for inhibiting the main oncogene. The direct targeting of KRAS G12C mutant tumors has been demonstrated in the clinic to be an effective mode of treatment of NSCLC (non-small cell lung cancer), resulting in the FDA approval of sotorasib. Others have shown that KRAS G12D mutant cancers can also be targeted with non-covalent inhibitors, with the non-conserved KRAS residue H95 theorized to play a significant role in binding selectivity. 1Attorney Docket No. MDA0094-401-PC

[0005] Despite the significant attention focused on targeting Ras mutants, there exists a need for compounds and methods for the treatment of Ras-mediated diseases, specifically NRAS-, KRAS-, and HRAS-mediated diseases. The present disclosure fulfills these and other needs, as evident in reference to the following disclosure.

[0006] Provided is a compound of Formula I (I) or a pharmaceutically a r thereof, wherein 1J is chosen from N and CH; X is chosen from CH2, O, S, and NR7; R1is chosen from aryl and heteroaryl, either of which may be optionally substituted with one or more R12; each R2is chosen from halo, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, cyano, -C(O)N(R8)2, alkylamino, dialkylamino, - C(O)OR8, -C(O)R8, and haloalkyl, wherein alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino, dialkylamino, and haloalkyl may be optionally substituted with one or more R15; R3is chosen from alkyl, cycloalkyl, alkynyl, halo, and cyano, wherein alkyl, cycloalkyl, and alkynyl may be optionally substituted with one or more R9; R4is chosen from hydrogen, alkyl, alkoxy, cyano and halo; R5is chosen from hydrogen, alkyl, alkoxy, and halo; R6is chosen from hydrogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, -C(O)OR10, -S(O)(NH)-alkyl, alkylthio, and halo, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, and alkylthio may be optionally substituted with one or more groups chosen from R11; R7is chosen from hydrogen and alkyl; 2Attorney Docket No. MDA0094-401-PC each R8is independently chosen from hydrogen, alkyl, heterocycloalkyl, heteroaryl, and cycloalkyl, any of which may be optionally substituted by one or more R13OR two R8may combine to form a heterocycloalkyl optionally substituted by one or more R16; each R9is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy; R10is independently chosen from hydrogen and alkyl; each R11is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, amidoalkyl, alkylcycloalkyl, halocycloalkyl, halocycloalkylalkyl, hydroxycycloalkylalkyl, alkylheterocycloalkyl, cyanoheterocycloalkyl, perdeuteroalkyl, cyano, halo, haloalkyl, oxo, amino, alkylamino, dialkylamino, and hydroxy; each R12is independently chosen from alkyl, amino, cyanocycloalkyloxy, cyano, haloalkyl, and haloalkoxy; each R13is independently chosen from hydroxy, halo, alkylamino, dialkylamino, -SO3H, heterocycloalkyl, heteroaryl, and cycloalkyl, wherein heterocycloalkyl, heteroaryl, and cycloalkyl may be substituted with one or more R17; each R15is independently chosen from halo, alkoxy, deuteroalkoxy, perdeuteroalkoxy, alkyl, aryl, cyano, heteroaryl, heterocycloalkyl, alkylamino, dialkylamino, hydroxy, oxo, and -SO3H; each R16and R17is independently chosen from alkyl, alkoxy, amino, cyano, halo, and hydroxy; and n is 1, 2, or 3.

[0007] Also provided is a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0008] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

[0009] Also provided is a method for treating a disease or condition that benefits from or is treatable by inhibition of NRAS G12D, comprising the administration of a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to a subject in need thereof. 3Attorney Docket No. MDA0094-401-PC

[0010] Also provided are methods of inhibiting at least one NRAS, KRAS, or HRAS function comprising the step of contacting NRAS, KRAS, or HRAS with a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof. The cell phenotype, cell proliferation, activity of NRAS, KRAS, or HRAS, change in biochemical output produced by active NRAS, KRAS, or HRAS, expression of NRAS, KRAS, or HRAS, or binding of NRAS, KRAS, or HRAS with a natural binding partner may be monitored. Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.

[0011] Also provided are methods of treatment of an NRAS-, KRAS-, or HRAS- mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof, to a patient in need thereof.

[0012] Also provided is a method of inhibition of NRAS, KRAS, or HRAS comprising contacting NRAS, KRAS, or HRAS with a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0013] Also provided is a method of modulation of an NRAS-, KRAS-, or HRAS - mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0014] These and other aspects of the invention will be apparent upon reference to the following detailed description. DETAILED DESCRIPTION

[0015] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0016] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as 4Attorney Docket No. MDA0094-401-PC “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0017] Reference throughout this specification to “one embodiment” or “an embodiment” or “some embodiments” or “a certain embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” or “in some embodiments” or “in a certain embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.

[0019] When ranges of values are disclosed, and the notation “from n1 … to n2” or “between n1 … and n2” is used, where n1 and n2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 µM (micromolar),” which is intended to include 1 µM, 3 µM, and everything in between to any number of significant figures (e.g., 1.255 µM, 2.1 µM, 2.9999 µM, etc.).

[0020] The term “alkenyl,” as used herein, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkenyl will comprise from 2 to 6 carbon atoms.

[0021] The term “alkoxy”, and, interchangeably, “(alkyl)oxy”, as used herein, refers to an alkyl radical attached to a molecule by oxygen.

[0022] The term “alkyl,” as used herein, refers to a straight-chain or branched-chain saturated, hydrocarbon radical containing from 1 to 20 carbon atoms. In some embodiments, alkyl will comprise from 1 to 10 carbon atoms. In some embodiments, alkyl will comprise from 1 to 8 carbon atoms. In some embodiments, alkyl will comprise from 1 to 3 carbon atoms.

[0023] The term “alkylamino,” as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. The term “dialkylamino,” as used herein, refers to an amino group that is attached to the parent moiety 5Attorney Docket No. MDA0094-401-PC and two alkyl groups. The alkyl groups in a dialkylamino group may be the same (i.e., dimethylamino) or different (i.e., ethyl(methyl)amino).

[0024] The term “alkylthio,” as used herein, refers to an alkyl thioether (R–S–) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized.

[0025] The term “alkynyl,” as used herein, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, said alkynyl comprises from 2 to 6 carbon atoms. In further embodiments, said alkynyl comprises from 2 to 4 carbon atoms.

[0026] The terms “amido” and “carbamoyl,” as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa.

[0027] The term “amino,” as used herein, refers to -NRR’, wherein R and R’are independently chosen from hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl. Additionally, R and R’ may combine to form heterocycloalkyl. In some embodiments, “amino” refers to -NH2.

[0028] The term "aryl," as used herein, means a carbocyclic aromatic system containing one, two or three rings wherein such polycyclic ring systems are fused together.

[0029] The term “cyano,” as used herein, refers to -CN.

[0030] The term “cycloalkoxy,” as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0031] The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein, refers to a saturated monocyclic, bicyclic, or tricyclic alkyl group wherein each cyclic moiety contains from 3 to 12 carbon atom ring members. In some embodiments, cycloalkyl will comprise from 5 to 7 carbon atoms. In some embodiments, cycloalkyl will comprise a spirocyclic ring system. “Bicyclic” and “tricyclic” as used herein are intended to include both fused ring systems, as well as the multicyclic (multicentered) saturated type.

[0032] As used herein, “is / are deuterium,” or “deuterated,” when used to describe a given position in a molecule or the symbol “D”, when used to represent a given position in a drawing of a molecular structure, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium. In one embodiment deuterium enrichment is no less than about 1%, in another no less than about 5%, in another no less than about 10%, in another no less than about 20%, in another no less than about 50%, in another 6Attorney Docket No. MDA0094-401-PC no less than about 70%, in another no less than about 80%, in another no less than about 90%, or in another no less than about 98% of deuterium at the specified position.

[0033] As used herein, the term “deuteroalkyl” refers to an alkyl group in which one or more of the positions that would have been occupied by hydrogen is deuterium (i.e., is enriched with deuterium above the naturally occurring distribution of deuterium, as defined above). A deuteroalkoxy group is a deuteroalkyl group attached to the parent molecular moiety through an oxygen atom. Similarly, a “perdeuteroalkyl” group is a deuteroalkyl group in which all of the positions that would have been occupied by hydrogen are deuterium (again, as defined above), and a perdeuteroalkoxy” group is a perdeuteroalkyl group attached to the parent molecular moiety through an oxygen atom.

[0034] The term “halo,” or “halogen,” as used herein, refers to fluorine, chlorine, bromine, or iodine.

[0035] The term "heteroaryl," as used herein, refers to a 3 to 15 membered unsaturated heteromonocyclic ring, or a fused monocyclic, bicyclic, or tricyclic ring system in which at least one of the fused rings is aromatic, which contains at least one atom chosen from N, O, and S. In some embodiments, heteroaryl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heteroaryl will comprise from 5 to 7 atoms. The term also embraces fused polycyclic groups wherein heterocyclic rings are fused with aryl rings wherein heteroaryl rings are fused with other heteroaryl rings wherein heteroaryl rings are fused with heterocycloalkyl rings, or wherein heteroaryl rings are fused with cycloalkyl rings.

[0036] The term “heterocycloalkoxy,” as used herein, refers to a heterocycloalkyl group attached to the parent molecular moiety through an oxygen atom.

[0037] The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” as used herein, refers to a saturated, partially unsaturated, or fully unsaturated (but nonaromatic) monocyclic; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bridged; saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) bicyclic; or saturated, partially unsaturated, or fully unsaturated (but not fully aromatic) tricyclic heterocyclic group containing at least one heteroatom as a ring member wherein each heteroatom may be independently chosen from nitrogen, oxygen, and sulfur.

[0038] In some embodiments, heterocycloalkyl will comprise a spirocyclic ring system. In some embodiments, heterocycloalkyl will comprise from 1 to 4 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 1 to 2 heteroatoms as ring members. In some embodiments, heterocycloalkyl will comprise from 3 to 8 ring 7Attorney Docket No. MDA0094-401-PC members in each ring. In some embodiments, heterocycloalkyl will comprise from 3 to 7 ring members in each ring. In some embodiments, heterocycloalkyl will comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl” and “heterocycle” are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl or heteroaryl group, as defined herein, or an additional heterocycle group.

[0039] The terms “hydroxy” and, interchangeably, “hydroxyl,” as used herein, refers to - OH.

[0040] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0041] Asymmetric centers exist in the compounds and pharmaceutically acceptable salts thereof, disclosed herein. These centers are designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, as well as d-isomers and 1-isomers, and mixtures thereof. Individual stereoisomers of compounds, and pharmaceutically acceptable salts thereof, can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds, and pharmaceutically acceptable salts thereof, of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds, and pharmaceutically acceptable salts thereof, disclosed herein may exist as geometric isomers. The present disclosure includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0042] Additionally, the compounds disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms. 8Attorney Docket No. MDA0094-401-PC

[0043] The term “activator,” as used herein, refers to a compound or salt that induces or accelerates a chemical reaction.

[0044] As used herein, "administering to a patient" refers to the process of introducing a composition or dosage form into the patient via an art-recognized means of introduction.

[0045] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder,” “syndrome,” and “condition” (as in medical condition), in that all reflect an abnormal condition of the human or animal body or of one of its parts that impairs normal functioning, is typically manifested by distinguishing signs and symptoms, and causes the human or animal to have a reduced duration or quality of life.

[0046] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0047] The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder or on the effecting of a clinical endpoint. The precise therapeutically effective amount for a subject may depend upon, e.g., the subject’s size and health, the nature and extent of the condition, the therapeutics or combination of therapeutics selected for administration, and other variables known to those of skill in the art. The effective amount for a given situation is determined by routine experimentation and is within the judgment of the clinician.

[0048] As used herein, the term “treat,” “treating”, or “treatment” means the administration of therapy to an individual who already manifests at least one symptom of a disease or condition or who has previously manifested at least one symptom of a disease or condition. For example, “treating” can include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. For example, the term “treating” in reference to a disorder means a reduction in severity of one or more symptoms 9Attorney Docket No. MDA0094-401-PC associated with that particular disorder. Therefore, treating a disorder does not necessarily mean a reduction in severity of all symptoms associated with a disorder and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a disorder.

[0049] The term “patient” is generally synonymous with the term “subject” and includes all mammals including humans. Examples of patients include humans, livestock such as cows, goats, sheep, pigs, and rabbits, and companion animals such as dogs, cats, rabbits, and horses. Preferably, the patient is a human.

[0050] Those skilled in the art will appreciate that the invention(s) described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention(s) includes all such variations and modifications. The invention(s) also includes all the steps, features, compositions, and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of steps or features unless specifically stated otherwise.

[0051] The present invention(s) is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention(s), as described herein.

[0052] It is appreciated that certain features of the invention(s), which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention(s), which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0053] In embodiment 1, provided is a compound of Formula I (I) or a pharmaceutically ar thereof, wherein J1is chosen from N and CH; X is chosen from CH2, O, S, and NR7; 10Attorney Docket No. MDA0094-401-PC R1is chosen from aryl and heteroaryl, either of which may be optionally substituted with one or more R12; each R2is chosen from halo, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, cyano, -C(O)N(R8)2, alkylamino, dialkylamino, - C(O)OR8, -C(O)R8, and haloalkyl, wherein alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino, dialkylamino, and haloalkyl may be optionally substituted with one or more R15; R3is chosen from alkyl, cycloalkyl, alkynyl, halo, and cyano, wherein alkyl, cycloalkyl, and alkynyl may be optionally substituted with one or more R9; R4is chosen from hydrogen, alkyl, alkoxy, cyano and halo; R5is chosen from hydrogen, alkyl, alkoxy, and halo; R6is chosen from hydrogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, -C(O)OR10, -S(O)(NH)-alkyl, alkylthio, and halo, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, and alkylthio may be optionally substituted with one or more groups chosen from R11; R7is chosen from hydrogen and alkyl; each R8is independently chosen from hydrogen, alkyl, heterocycloalkyl, heteroaryl, and cycloalkyl, any of which may be optionally substituted by one or more R13OR two R8may combine to form a heterocycloalkyl optionally substituted by one or more R16; each R9is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy; R10is independently chosen from hydrogen and alkyl; each R11is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, amidoalkyl, alkylcycloalkyl, halocycloalkyl, halocycloalkylalkyl, hydroxycycloalkylalkyl, alkylheterocycloalkyl, cyanoheterocycloalkyl, perdeuteroalkyl, cyano, halo, haloalkyl, oxo, amino, alkylamino, dialkylamino, and hydroxy; each R12is independently chosen from alkyl, amino, cyanocycloalkyloxy, cyano, haloalkyl, and haloalkoxy; each R13is independently chosen from hydroxy, halo, alkylamino, dialkylamino, -SO3H, heterocycloalkyl, heteroaryl, and cycloalkyl, wherein 11Attorney Docket No. MDA0094-401-PC heterocycloalkyl, heteroaryl, and cycloalkyl may be substituted with one or more R17; each R15is independently chosen from halo, alkoxy, deuteroalkoxy, perdeuteroalkoxy, alkyl, aryl, cyano, heteroaryl, heterocycloalkyl, alkylamino, dialkylamino, hydroxy, oxo, and -SO3H; each R16and R17is independently chosen from alkyl, alkoxy, amino, cyano, halo, and hydroxy; and n is 1, 2, or 3.

[0054] In embodiment 2, the compound has a structure of Formula IA A) or a pharmaceutically ac whereinJ2is chosen from CH and N; each R2is chosen from halo, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, cyano, -C(O)N(R8)2, alkylamino, dialkylamino, - C(O)OR8, -C(O)R8, and haloalkyl, wherein alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino, dialkylamino, and haloalkyl may be optionally substituted with one or more R15; R3is chosen from alkyl, cycloalkyl, alkynyl, halo, and cyano, wherein alkyl, cycloalkyl, and alkynyl may be optionally substituted with one or more R9; R4is chosen from hydrogen, alkyl, alkoxy, cyano and halo; R6is chosen from hydrogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, -C(O)OR10, -S(O)(NH)-alkyl, alkylthio, and halo, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, and alkylthio may be optionally substituted with one or more groups chosen from R11; each R8is independently chosen from hydrogen, alkyl, heterocycloalkyl, heteroaryl, and cycloalkyl, any of which may be optionally substituted by one or more 12Attorney Docket No. MDA0094-401-PC R13OR two R8may combine to form a heterocycloalkyl optionally substituted by one or more R16; each R9is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy; R10is independently chosen from hydrogen and alkyl; each R11is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, amidoalkyl, alkylcycloalkyl, halocycloalkyl, halocycloalkylalkyl, hydroxycycloalkylalkyl, alkylheterocycloalkyl, cyanoheterocycloalkyl, perdeuteroalkyl, cyano, halo, haloalkyl, oxo, amino, alkylamino, dialkylamino, and hydroxy; each R13is independently chosen from hydroxy, halo, alkylamino, dialkylamino, -SO3H, heterocycloalkyl, heteroaryl, and cycloalkyl, wherein heterocycloalkyl, heteroaryl, and cycloalkyl may be substituted with one or more R17; each R15is independently chosen from halo, alkoxy, deuteroalkoxy, perdeuteroalkoxy, alkyl, aryl, cyano, heteroaryl, heterocycloalkyl, alkylamino, dialkylamino, hydroxy, oxo, and -SO3H; each R16and R17is independently chosen from alkyl, alkoxy, amino, cyano, halo, and hydroxy; R18is chosen from haloalkyl and haloalkoxy; and R19is chosen from halo and alkyl.

[0055] In embodiment 3, disclosed herein is a compound of embodiment 1, or a pharmaceutically acceptable salt or tautomer thereof, wherein J1is N.

[0056] In embodiment 4, disclosed herein is a compound of embodiment 1, or a pharmaceutically acceptable salt or tautomer thereof, wherein X is O.

[0057] In embodiment 5, disclosed herein is a compound of embodiment 1-4, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is chosen from phenyl and pyridinyl, either of which may be optionally substituted with 1, 2, or 3 R12.

[0058] In embodiment 6, disclosed herein is a compound of embodiment 1-5, or a pharmaceutically acceptable salt or tautomer thereof, wherein each R12is independently chosen from fluoro, -NH2, methyl, trifluoromethyl, and trifluoromethoxy.

[0059] In embodiment 7, disclosed herein is a compound of embodiment 1-6, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is 13Attorney Docket No. MDA0094-401-PC , wherein J2is chosen from C 13R is chosen from haloalkyl and haloalkoxy; and R14is chosen from halo and alkyl.

[0060] In embodiment 8, disclosed herein is a compound of embodiment 1-7, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is CH.

[0061] In embodiment 9, disclosed herein is a compound of embodiment 1-8, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is N.

[0062] In embodiment 10, disclosed herein is a compound of embodiment 1-9, or a pharmaceutically acceptable salt or tautomer thereof, wherein R18is chosen from trifluoromethyl, -CH2CF3, and trifluoromethoxy.

[0063] In embodiment 11, disclosed herein is a compound of embodiment 1-10, or a pharmaceutically acceptable salt or tautomer thereof, wherein R19is chosen from fluoro and methyl.

[0064] In embodiment 12, disclosed herein is a compound of embodiment 1-11, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is chosen from methyl and cyclopropyl, either of which may be optionally substituted by one R9.

[0065] In embodiment 13, disclosed herein is a compound of embodiment 1-12, or a pharmaceutically acceptable salt or tautomer thereof, wherein R9is chosen from cyano and hydroxy.

[0066] In embodiment 14, disclosed herein is a compound of embodiment 1-12, or a pharmaceutically acceptable salt or tautomer thereof, wherein R5is fluoro.

[0067] In embodiment 15, disclosed herein is a compound of embodiment 1-13, or a pharmaceutically acceptable salt or tautomer thereof, wherein R6is chosen from amido and heterocycloalkyl, any of which may be optionally substituted by one R11.

[0068] In embodiment 16, disclosed herein is a compound of embodiment 1-14, or a pharmaceutically acceptable salt or tautomer thereof, wherein R11is chosen from alkyl and oxo.

[0069] In embodiment 17, disclosed herein is a compound of embodiment 1-15, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is methyl and R5is fluoro. 14Attorney Docket No. MDA0094-401-PC

[0070] In embodiment 18, disclosed herein is a compound of embodiment 1-16, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is chosen from hydrogen and alkyl.

[0071] In embodiment 19, disclosed herein is a compound of embodiment 1-17, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is alkyl.

[0072] In embodiment 20, disclosed herein is a compound of embodiment 1-18, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is methyl.

[0073] In embodiment 21, disclosed herein is a compound of embodiment 1-20, or a pharmaceutically acceptable salt or tautomer thereof, wherein n is 1.

[0074] In embodiment 22, disclosed herein is a compound of embodiment 1-21, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is chosen from ,

[0075] In embodiment 23, disclosed herein is a compound of embodiment 1-22, or a pharmaceutically acceptable salt or tautomer thereof, wherein R2 is chosen from methyl, ethyl, CH2F, CH2CN, CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH2OCD3, CH2OCHD2, - N ,15Attorney Docket No. MDA0094-401-PC O O N N ,

[0076] In embodiment 24, disclosed herein is a compound of embodiment 1-23, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3 is chosen from methyl, chloro, ;

[0077] 25, disclosed herein is a compound of embodiment 1-24, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4 is chosen from H and -CH3;

[0078] In embodiment 26, disclosed herein is a compound of embodiment 1-25, or a pharmaceutically acceptable salt or tautomer thereof, wherein R5 is fluoro;

[0079] In embodiment 27, disclosed herein is a compound of embodiment 1-26, or a pharmaceutically acceptable salt or tautomer thereof, wherein R6is chosen from -CN, methyl, ,16Attorney Docket No. MDA0094-401-PC O O O F N N N HOH, , ;

[0080] In embodiment 28, disclosed herein is a compound of embodiment 1-27, or a pharmaceutically acceptable salt or tautomer thereof, wherein n is 1.

[0081] In embodiment 29, disclosed herein is a compound of embodiment 1-28, or a pharmaceutically acceptable salt or tautomer thereof, wherein R2is alkyl.

[0082] In embodiment 30, disclosed herein is a compound of embodiment 1-29, or a pharmaceutically acceptable salt or tautomer thereof, wherein R2is methyl.

[0083] In embodiment 31, disclosed herein is a compound of embodiment 1-30, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is alkyl.

[0084] In embodiment 32, disclosed herein is a compound of embodiment 1-31, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is methyl.

[0085] In embodiment 33, disclosed herein is a compound of embodiment 1-32, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is alkyl.

[0086] In embodiment 34, disclosed herein is a compound of embodiment 1-33, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is methyl.

[0087] In embodiment 35, disclosed herein is a compound of embodiment 1-34, or a pharmaceutically acceptable salt or tautomer thereof, wherein each R6is chosen from amido and heterocycloalkyl, any of which may be optionally substituted by one R11. 17Attorney Docket No. MDA0094-401-PC

[0088] In embodiment 36, disclosed herein is a compound of embodiment 1-35, or a pharmaceutically acceptable salt or tautomer thereof, wherein each R11is chosen from alkyl and oxo.

[0089] In embodiment 37, disclosed herein is a compound of embodiment 1-36, or a pharmaceutically acceptable salt or tautomer thereof, wherein R11is methyl.

[0090] In embodiment 38, disclosed herein is a compound of embodiment 1-37, or a pharmaceutically acceptable salt or tautomer thereof, wherein both R6is chosen from OO. of embodiment 1-38, or apharmaceutically acceptable salt or tautomer thereof, wherein R18is trifluoromethyl, - CH2CF3, and trifluoromethoxy.

[0092] In embodiment 40, disclosed herein is a compound of embodiment 1-39, or a pharmaceutically acceptable salt or tautomer thereof, wherein R19is fluoro and methyl.

[0093] In embodiment 41, disclosed herein is a compound of embodiment 1-40, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is CH.

[0094] In embodiment 42, disclosed herein is a compound of embodiment 1-41, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is N.

[0095] In embodiment 43, disclosed herein is a compound of embodiment 1-41, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is CF.

[0096] In some embodiments, the compound has a structure chosen from Example 1-1 to 168-1, or a pharmaceutically acceptable salt or tautomer thereof: Ex. Ex.18Attorney Docket No. MDA0094-401-PC 3-1 H O 4-1 N O19Attorney Docket No. MDA0094-401-PC 11-1 12-1 H N F20Attorney Docket No. MDA0094-401-PC 19-1 20-121Attorney Docket No. MDA0094-401-PC 27-1 H O 28-1 H N N OH22Attorney Docket No. MDA0094-401-PC 35-1 H O 36-1 H O N N N N23Attorney Docket No. MDA0094-401-PC 43-1 H O 44-1 N N24Attorney Docket No. MDA0094-401-PC 51-1 H O 52-1 N N25Attorney Docket No. MDA0094-401-PC 59-1 60-126Attorney Docket No. MDA0094-401-PC 67-1 68-1 H O N OH27Attorney Docket No. MDA0094-401-PC 75-1 76-1 H N28Attorney Docket No. MDA0094-401-PC 85-1 86-129Attorney Docket No. MDA0094-401-PC 93-1 94-130Attorney Docket No. MDA0094-401-PC 101-1 103-131Attorney Docket No. MDA0094-401-PC 110-1 111-132Attorney Docket No. MDA0094-401-PC 118-1 119-133Attorney Docket No. MDA0094-401-PC 126-1 127-1 H N34Attorney Docket No. MDA0094-401-PC 134-1 H 135-1 N OH35Attorney Docket No. MDA0094-401-PC 142-1 143-1 H N O36Attorney Docket No. MDA0094-401-PC 150-1 151-137Attorney Docket No. MDA0094-401-PC 158-1 H N 159-138Attorney Docket No. MDA0094-401-PC 166-1 167-1

[0097] In some embodments, te compound as te structure cosen rom tat o Example 1-168, or a pharmaceutically acceptable salt or tautomer thereof.

[0098] In some embodiments, the compound has a structure chosen from H H N N ,39Attorney Docket No. MDA0094-401-PC H N r a

[0099] The compounds disclosed herein can exist as pharmaceutically acceptable salts. The present disclosure includes compounds listed herein in the form of salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non- pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

[0100] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form 40Attorney Docket No. MDA0094-401-PC pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present disclosure contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0101] Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

[0102] While it may be possible for the compounds, and pharmaceutically acceptable salts thereof, of the subject disclosure to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation.

[0103] Also provided is a pharmaceutical formulation comprising a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof, together with a pharmaceutically acceptable carrier. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association a compound, or pharmaceutically acceptable salts thereof, of the subject disclosure or a pharmaceutically acceptable salt or tautomer thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0104] Preferred unit dosage formulations are those containing an effective dose, or an appropriate fraction thereof, of the active ingredient.

[0105] Compounds, or pharmaceutically acceptable salts thereof, may be administered at a dose of from 0.1 to 500 mg / kg per day. The dose range for adult humans is generally from 41Attorney Docket No. MDA0094-401-PC 5 mg to 2 g / day. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

[0106] The compounds, or pharmaceutically acceptable salts thereof, can be administered in various modes. In some embodiments, the pharmaceutical formulation is formulated for oral administration.

[0107] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt or tautomer thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein, or pharmaceutically acceptable salt or tautomer thereof, is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein, or pharmaceutically acceptable salts thereof, may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein, or pharmaceutically acceptable salts thereof, with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit.

[0108] In any case, the multiple therapeutic agents (at least one of which is a compound disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

[0109] Also provided is a method for treating a disease or condition that benefits from or is treatable by inhibition of NRAS, KRAS, or HRAS, comprising the administration of a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt or tautomer thereof, to a subject in need thereof. 42Attorney Docket No. MDA0094-401-PC

[0110] Also provided are methods of inhibiting at least one NRAS, KRAS, or HRAS function comprising the step of contacting NRAS, KRAS, or HRAS with a compound as described herein, or a pharmaceutically acceptable salt or tautomer thereof. The cell phenotype, cell proliferation, activity of NRAS, KRAS, or HRAS, change in biochemical output produced by active NRAS, KRAS, or HRAS, expression of NRAS, KRAS, or HRAS, or binding of NRAS, KRAS, or HRAS with a natural binding partner may be monitored. Such methods may be modes of treatment of disease, biological assays, cellular assays, biochemical assays, or the like.

[0111] Also provided are methods of treatment of an NRAS-, KRAS-, or HRAS- mediated disease comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof, to a patient in need thereof.

[0112] Also provided is a method of inhibition of NRAS, KRAS, or HRAS comprising contacting NRAS, KRAS, or HRAS with a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0113] Also provided is a method of modulation of an NRAS-, KRAS-, or HRAS- mediated function in a subject comprising the administration of a therapeutically effective amount of a compound as disclosed herein, or a pharmaceutically acceptable salt or tautomer thereof.

[0114] In some embodiments, the NRAS, KRAS, or HRAS comprises an activating mutation.

[0115] In some embodiments, the activating mutation causes constitutive activation.

[0116] In some embodiments, the activating mutation is at amino acid or codon 12, 13 or 61.

[0117] In some embodiments, the activating mutation is at amino acid or codon 12.

[0118] In some embodiments, the activating mutation is chosen from G12D, G13D, G12V, and G12C.

[0119] In some embodiments, the activating mutation is G12D.

[0120] In some embodiments, the NRAS is NRAS G12D.

[0121] In some embodiments, the KRAS is KRAS G12D.

[0122] In some embodiments, the HRAS is HRAS G12D.

[0123] In some embodiments, the NRAS-, KRAS-, or HRAS-mediated disease is cancer.

[0124] In some embodiments, the cancer is chosen from a solid tumor and a hematologic malignancy. 43Attorney Docket No. MDA0094-401-PC

[0125] In some embodiments, the cancer is a solid tumor.

[0126] In some embodiments, the cancer is a hematologic malignancy.

[0127] In some embodiments, the hematologic malignancy is chosen from leukemia, lymphoma, and multiple myeloma.

[0128] Leukemias are cancers that typically originate in bone marrow and spread through the bloodstream. Leukemias include the lymphocytic (or "lymphoblastic") leukemias such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), as well as the myelogenous ("myeloid" or "nonlymphocytic") leukemias such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), as well as other less-common subtypes such as hairy cell leukemia (sometimes classified as a lymphoma), T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, and the like. These can also be characterized and divided as acute and chronic leukemias. Many leukemias are also sometimes classified or referred to as lymphomas (e.g., ALL, CLL, AML, CML) and vice versa. Myelodysplastic syndromes comprise a group of diseases affecting immature leukocytes and / or hematopoietic stem cells (HSCs); MDS may progress to AML.

[0129] Lymphomas are cancers that typically originate in lymph nodes or the spleen, and spread through the lymphatic system. Lymphomas can be classified various ways, often based on the underlying type of malignant cell, including Hodgkin’s lymphoma (often cancers of Reed-Sternberg cells, but also sometimes originating in B cells; all other lymphomas are non-Hodgkin’s lymphomas), non-Hodgkin’s lymphomas, B-cell lymphomas, T-cell lymphomas, mantle cell lymphomas, Burkitt’s lymphoma, follicular lymphoma, and others known in the art.

[0130] B-cell lymphomas include, but are not limited to, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL) , and others known in the art.

[0131] T-cell lymphomas include T-cell acute lymphoblastic leukemia / lymphoma (T- ALL), peripheral T-cell lymphoma (PTCL), T-cell chronic lymphocytic leukemia / lymphoma (T-CLL), Sezary syndrome, and others known in the art.

[0132] Leukemias include acute myeloid (or myelogenous) leukemia (AML), chronic myeloid (or myelogenous) leukemia (CML), acute lymphocytic (or lymphoblastic) leukemia (ALL), chronic lymphocytic leukemia (CLL) hairy cell leukemia (sometimes classified as a lymphoma), and others known in the art.

[0133] Plasma cell malignancies include lymphoplasmacytic lymphoma, plasmacytoma, and multiple myeloma. 44Attorney Docket No. MDA0094-401-PC

[0134] In some embodiments, the cancer is chosen from Melanoma, Malignant Solid Tumors, Colorectal Carcinoma, Non-Small Cell Lung Carcinoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Colorectal Adenocarcinoma, Multiple Myeloma, Non-Hodgkin Lymphoma, Pancreatic Carcinoma, Cutaneous Melanoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Acute Lymphoblastic Leukemia, Thyroid Gland Carcinoma, Glioma, Neurofibromatosis, Poorly Differentiated Thyroid Gland Carcinoma, Myelodysplastic Syndrome With Excess Blasts, Juvenile Myelomonocytic Leukemia, Histiocytic And Dendritic Cell Neoplasm, Head And Neck Squamous Cell Carcinoma, Small Cell Lung Carcinoma, Low Grade Glioma, Squamous Cell Lung Carcinoma, Breast Carcinoma, Chronic Myelomonocytic Leukemia, Thyroid Gland Undifferentiated (Anaplastic) Carcinoma, Embryonal Rhabdomyosarcoma, Thyroid Gland Follicular Carcinoma, T-Cell Acute Lymphoblastic Leukemia, Mucosal Melanoma, Low Grade Ovarian Serous Adenocarcinoma, Thyroid Gland Papillary Carcinoma, Refractory Anemia With Excess Blasts, Myeloid Neoplasm, Myelodysplastic / Myeloproliferative Neoplasm, Mucinous Carcinoma, Rectal Carcinoma, Colon Carcinoma, Malignant Peripheral Nerve Sheath Tumor, Cholangiocarcinoma, Endometrial Carcinoma, Mantle Cell Lymphoma, Secondary Myelodysplastic Syndrome, Therapy-Related Myelodysplastic Syndrome, Lymphoma, Neuronal And Mixed Neuronal- Glial Tumors, Ganglioglioma, Soft Tissue Sarcoma, Bladder Carcinoma, Esophageal Carcinoma, Sarcoma, Thymic Carcinoma, Lung Adenocarcinoma, Lung Carcinoma, Uveal Melanoma, Head And Neck Carcinoma, Diffuse Glioma, Squamous Cell Carcinoma, Chronic Myeloid Leukemia, Adenocarcinoma of the Gastroesophageal Junction, Glioblastoma, Neuroblastoma, Astrocytic Tumor, Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, Diffuse Large B-Cell Lymphoma, Anaplastic Astrocytoma, Gastric Adenocarcinoma, Gastric Carcinoma, Prostate Carcinoma, Renal Cell Carcinoma, B-Cell Acute Lymphoblastic Leukemia, Double-Hit Lymphoma, Dysembryoplastic Neuroepithelial Tumor, Gangliocytoma, Low-Grade Neuroepithelial Tumor, Peripheral T-Cell Lymphoma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Rhabdoid Tumor, and Schwannoma.

[0135] Further embodiments include the embodiments disclosed in the following Schemes, which are not to be construed as limiting in any way. SCHEMES Scheme I 45Attorney Docket No. MDA0094-401-PC ClOClOClO NOH Cl N NOH N H 03111 ormu a

[0136] According to Scheme I, compound 101 is treated with a chlorinating agent, such as a combination of oxalyl chloride and catalytic dimethylformamide, in a solvent such as dichloromethane, to give compound 102. Compound 102 is treated with hydroxylamine hrdrochloride and a base, such as sodium bicarbonate, in a solvent such as a combination of ethyl acetate and water, to give compound 103. Compound 103 is treated with a pivalic acid derivative, such as pivaloyl chloride, in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, to give compound 104. Compound 104 is reacted with compound 105 in the presence of a catalyst, such as [CpRhCl2]2, a base, such as cesium acetate, in a solvent, such as methanol, to give compound 106. To a solution of a strong non- 46Attorney Docket No. MDA0094-401-PC nucleophilic base, such as NaH, in a solvent, such as tetrahydrofuran, is added compound 107, followed by compound 106, to give compound 108. Compound 108 is reacted with an activator, such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), or 2-chloro-1-methylpyridinium iodide (CMPI), and a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or N,N-diisopropylethylamine (DIEA), in a solvent, such as dimethylformamide, to give compound 109. Compound 109 is reacted with compound 110 (R = hydrogen or alkyl, such as methyl, or two R groups in combination with the boron forms a heterocycloalkyl, such as pinacol borane), and a catalyst, such as cataCXium Pd G3, in the presence of a base, such as potassium phosphate, in a solvent, such as tetrahydrofuran, to give compound 111. Compound 111 is subjected to any set of deprotection conditions known in the art such as trifluoroacetic acid in a solvent such as dichloromethane, to give a compound of Formula I. Scheme IIas N-iodosuccinimide, in a solvent such as dimethyformamide, to give compound 113. Compound 113 is reacted with compound 114 or compound 115 (R = hydrogen or alkyl, such as methyl, or two R groups in combination with the boron forms a heterocycloalkyl, such as pinacol borane), and a metal catalyst, such as Pd(dppf)Cl2, in the presence of a base, such as potassium phosphate, in a solvent, such as dioxane, to give compound 116. Scheme III 47Attorney Docket No. MDA0094-401-PC

[0138] According to Scheme III, compound 117 is treated with an oxidizing agent, such as a combination of sodium chlorite, monosodium phosphate, and 2-methylbut-2-ene, in a solvent such as tert-butanol, to give compound 118. Compound 118 is treated with an acylating agent, such as pivaloyl chloride and a base, such as sodium bicarbonate, in a solvent such as dichloroethane, followed by treatment with hydrogen in the presence of an appropriate catalyst, such as palladium on carbon, in a solvent, such as methanol, to give compound 119. Compound 119 is treated with a triflating agent, such as triflic anhydride, and a base, such as diiosopropylethylamine, in a solvent, such as dichloromethane, to give compound 120. Compound 120 is reacted with compound 121 in the presence of a catalyst, such as Pd(dppf)Cl2, in the presence of a base, such as potassium carbonate, in a solvent, such as a mixture of dioxane and water, to give compound 122. Scheme IV48Attorney Docket No. MDA0094-401-PC

[0139] According to Scheme IV, compound 123 is treated with a stannylating agent, such as bis-tributyltin and a catalyst, such as a combination of lithium chloride, tricyclohexylphosphine, and Pd2(dba)3, in a solvent, such as dioxane, to give compound 124. Compound 124 is reacted with compound 125 (where Z is Br or SnBu3) in the presence of a catalyst, such as a combination of Pd(PPh3)4, cupric iodide, and lithium chloride, in a solvent, such as dioxane (where Z is Br), or a catalyst, such as a combination of Pd(PPh3)4, cupric iodide, and cesium fluoride, in a solvent, such as dimethylformamide (where Z is SnBu3) to give compound 126. Scheme V, , methylmagnesium bromide, in a solvent, such as tetrahydrofuran, to give compound 128. Compound 128 is treated with an oxidizing agent, such as Dess-Martin periodinane, in a solvent, such as dichloromethane, to give compound 129. Compound 129 is treated with an aldehyde or aldehyde equivalent, such as dimethylformamide-dimethylacetal, to give compound 130. Compound 130 is treated with hydrazine, in a solvent, such as ethanol, to give compound 131. Scheme VI 49Attorney Docket No. MDA0094-401-PC

[0140] According to Scheme VI, compound 132 is treated with toluenesulfonylmethyl isocyanide (TOSMIC reagent), and a base, such as potassium carbonate, in a solvent, such as methanol, to give compound 133. Scheme VII Boc Boc R104N R104N 2)n

[0141] According to Scheme VII, compound 134 is treated with an azide reagent, such as diphenyl phosphoryl azide, an appropriate base, such as 1,8-Diazabicyclo[5.4.0]undec-7-ene, in a solvent, such as tetrahydrofuran, to give compound 135. Compound 135 is treated with a reducing agent, such as triphenylphosphine, in a solvent, such as a mixture of tetrahydrofuran and water, to give compound 136. Compound 136 is reacted with compound 137 in the presence of an appropriate base, such as triethylamine, and a solvent, such as dichloromethane, to give compound 138. 50Attorney Docket No. MDA0094-401-PC Scheme VIII Boc Boc R104N R104N O XNR102 XN (R102)n202

[0142] 140 in thepresence of a catalyst, such as a combination of Pd2(dba)3and Xantphos, a base, such as cesium carbonate, in a solvent, such as toluene to give compound 141. Scheme XI

[0143] According to Scheme IX, compound 142 is treated with an azide reagent, such as diphenyl phosphoryl azide, an appropriate base, such as triethylamine, in a solvent, such as toluene, to give compound 143. Scheme X51Attorney Docket No. MDA0094-401-PC

[0144] According to Scheme X, compound 144 is reacted with a cyanide salt, such as zinc cyanide, in the presence of a catalyst, such as Pd(PPh3)4, in a solvent, such as dimethylformamide, to give compound 145. Scheme XI

[0145] According to Scheme XI, compound 118 is reacted with an activator, such as hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), and a base, such as N,N-diisopropylethylamine (DIEA), followed by compound 146, in a solvent, such as dimethylformamide, to give compound 147.

[0146] Additional methods of synthesizing compounds disclosed herein and intermediates useful in their synthesis can be found in WO 2024 / 243186 A2, which is incorporated by reference in its entirety.

[0147] The following intermediate compounds can be synthesized according to the procedures described below. Variants of these intermediates can be synthesized by using similar routes but selecting different starting materials of reagents as understood by those skilled in the art. INTERMEDIATE 1 6,8-dichloro-5-fluoro-, y H-2,7-naphthyridin-1-one Step 1 [(2,6-dichloro-5-fluoro-pyridine-3-carbonyl)amino] 2,2-dimethylpropanoate 52Attorney Docket No. MDA0094-401-PC xamic acid (96 g,426.66 mmol, 1 eq) and TEA (86.35 g, 853.32 mmol, 118.77 mL, 2 eq) in THF (1000 mL) was added 2, 2-dimethylpropanoyl chloride (46.30 g, 383.99 mmol, 47.25 mL, 0.9 eq) dropwise. The mixture was stirred at 25 °C for 1 hr. TLC (Petroleum ether : Ethyl acetate = 2:1) showed 2, 6-dichloro-5-fluoro-pyridine-3-carbohydroxamic acid was consumed and a main new spot. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (300-400 mesh silica gel, Petroleum ether / Ethyl acetate = 20 / 1, 4 / 1) to give 2,6-dichloro-5-fluoro-N-(pivaloyloxy)nicotinamide (82 g, 265.27 mmol, 62.17% yield) as white solid.1H NMR (400 MHz, CDCl3) δ = 10.10 (s, 1H), 7.91 (s, 1H), 1.33 (s, 9H). Step 2 6,8-dichloro-5-fluoro-3,4-dimethyl-2H-2,7-naphthyridin-1-one]2,2- dimethylpropanoate (3 g, 9.70 mmol, 1 eq) and cesium acetate (465.71 mg, 2.43 mmol, 0.25 eq) in MeOH (20 mL) was added but-2-yne (1.05 g, 19.41 mmol, 2 eq) and dichlororhodium;1, 2, 3, 4, 5-pentamethylcyclopentane (152.41 mg, 242.62 μmol, 0.025 eq) at 25 °C under N2. The mixture was stirred at 50 °C for 16 h under N2. TLC (Plate 1 Petroleum ether : Ethyl acetate = 2 : 1) showed the [ (2,6-dichloro-5-fluoro-pyridine-3- carbonyl) amino] 2,2-dimethylpropanoate was consumed completely and many news pots were formed. The mixture was filtered and washed with MeOH (5 mL x 2). Then the filtered cake was dried under vacuum to give 6,8-dichloro-5-fluoro-3, 4-dimethyl-2H-2,7- naphthyridin-1-one (19.4 g, 72.82 mmol, 83.37% yield, 98% purity) as white solid. MS (ES+) C10H7N2OCl2F requires: 260, found: 261 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 12.01 - 11.83 (m, 1H), 2.29 (s, 3H), 2.25 (d, J = 7.7 Hz, 3H). 53Attorney Docket No. MDA0094-401-PC INTERMEDIATE 2 6,8-dichloro-5-fluoro-3-(1-hyd -4-methyl-2H-2,7-naphthyridin-1-one Step 1 6,8-dichloro-5-fluoro-3-(1-hydroxy-1-methyl-ethyl)-4-methyl-2H-2,7-naphthyridin-1- one Cl O NNO OHamino] 2,2- dimethylpropanoate (11 g, 35.58 mmol, 1 eq) and 2-(1,1-dimethylbut-2- ynoxy)tetrahydropyran (9.73 g, 53.38 mmol, 1.5 eq) in MeOH (70 mL) were added dichlororhodium;1,2,3,4,5-pentamethylcyclopentane (558.82 mg, 889.62 μmol, 0.025 eq) and cesium;acetate (1.71 g, 8.90 mmol, 0.25 eq). The mixture was stirred at 60 °C for 32 h. LCMS showed the reaction was completed, several peaks were showed on LCMS and 21% of desired mass. The mixture was concentrated to remove methanol, diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 0-60% methanol / dichloromethane gradient @ 80 mL / min) to afford 6,8-dichloro-5-fluoro-3-(1-hydroxy-1-methyl-ethyl)-4-methyl-2H- 2,7-naphthyridin-1-one (3.1 g, 2.84 mmol, 7.99% yield, 28% purity) as a brown solid. MS (ES+) C12H11Cl2FN2O2 requires:304 and 306, found:305 and 307[M+H]+. INTERMEDIATE 3 54Attorney Docket No. MDA0094-401-PC F F O O 4-(difluoromethoxy)-2,3-difluoro ethyl-1,3,2-dioxaborolan-2-yl)anilineStep 1 6-bromo-2,3-difluoro-4-nitro-phenol OH OH HF BrFBr NO3, H2SO4henol (5 g, 23.92 mmol, 1 eq) in DCM (20mL) was added a mixture of HNO3 (4.02 g, 41.50 mmol, 2.87 mL, 65% purity, 1.73 eq) and H2SO4(18.40 g, 187.60 mmol, 10.00 mL, 7.84 eq) at -10 °C, the reaction was stirred at -10 °C for 3 h. LCMS showed the starting material was consumed completely and a peak (66%) with the desired mass. The mixture was poured into a mixture of saturated NH4Cl (10 mL) and water (10 mL). The organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with brine (10 mL × 2), dried over anhydrous Na2SO4,filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 7-10% ethyl acetate:commercial hexanes gradient @ 45 mL / min) to afford 6-bromo-2,3- difluoro-4-nitro-phenol (2.91 g, 11.46 mmol, 47.89% yield) as yellow solid. MS (ES+) C6H2BrF2NO3requires: 253 / 255, found: 252 / 254 [M-H]-.1H NMR (400 MHz, CDCl3) δ ppm 8.20 (dd, J = 2.3, 7.2 Hz, 1H), 6.72 (s, 1H). Step 2 1-bromo-2-(difluoromethoxy)-3,4-difluoro-5-nitro-benzene55Attorney Docket No. MDA0094-401-PC

[0152] To a solution of 6-bromo-2,3-difluoro-4-nitro-phenol (2.9 g, 11.42 mmol, 1 eq) in MeCN (50 mL) and H2O (50 mL) was added KOH (6.41 g, 114.18 mmol, 10 eq) followed by 1-[[bromo(difluoro)methyl]-ethoxy-phosphoryl]oxyethane (6.10 g, 22.84 mmol, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 3 hr. LCMS showed the starting material remained and one new peak formed. The mixture was concentrated under vacuum. The residue was poured into a mixture of saturated NH4Cl (30 mL) and water (80 mL). The organic phase was separated, the aqueous phase was extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with brine (80 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-2% Ethyl acetate / Commercial hexanes gradient @ 45 mL / min) to afford 1-bromo-2-(difluoromethoxy)-3,4-difluoro-5-nitro-benzene (1.01 g, 3.32 mmol, 29.10% yield) as yellow solid.1H NMR (400 MHz, CDCl3) δ ppm 8.23 (dd, J = 2.4, 7.1 Hz, 1H), 6.97 - 6.54 (m, 1H). Step 3 5-bromo-4-(difluoromethoxy)-2,3-difluoro-aniline,4-difluoro-5-nitro-benzene (1.01 g, 3.32 mmol, 1 eq) } in {MeOH (5 mL) } and {THF (5 mL) }. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst { 1%Platinum / C (1.00 eq) / C, WXSC1050, 2.5 g }. The H2back pressure regulator was adjusted to 1.0 Mpa, and the H2flow rate was {H2, 10 sccm }. The solution 1 was pumped by Pump 1 {S1, P1, 0.4 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 1 / 4(1 / 4")mm, 5.0 mL, 50.0 °C}. The reaction mixture was continuously collected from the reactor outlet into the container. LCMS showed the starting material was consumed completely and a peak (96%) with the desired mass. The fixed bed was washed by extra THF (30 mL). The mixture was concentrated under vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 7-12% Ethyl acetate / Commercial hexanes gradient @ 45 mL / min) to afford 5-bromo-4-(difluoromethoxy)-2,3-difluoro-aniline (865 mg, 3.16 mmol, 95.01% yield) as yellow oil. 56Attorney Docket No. MDA0094-401-PC MS (ES+) C7H4BrF4NO requires: 273, found: 272 [M-H]-.1H NMR (400 MHz, CDCl3) δ 6.79 (dd, J = 2.4, 8.3 Hz, 1H), 6.48 (t, J = 73.8 Hz, 1H), 3.90 (s, 2H). Step 4 4-(difluoromethoxy)-2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline luoro-aniline (695 mg, 2.54mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (1.61 g, 6.34 mmol, 2.5 eq) and KOAc (746.45 mg, 7.61 mmol, 3 eq) in dioxane (28 mL) was added Pd(dppf)Cl2(185.94 mg, 254.11 μmol, 0.1 eq), the mixture was stirred at 100 °C for 4 h under N2. LCMS showed the starting material was consumed completely and a peak (28%) with the desired mass. The mixture was cooled to 25 °C, filtered and washed with Ethyl acetate (10 mL), the filtrate was concentrated under vacuum. The mixture was concentrated under vacuum, and the residue was diluted with Ethyl acetate (20 mL) and concentrated under vacuum again. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 5-10% ethyl acetate / commercial hexanes gradient @ 45 mL / min) to afford 4-(difluoromethoxy)-2,3-difluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (320 mg, 996.65 μmol, 39.29% yield) as yellow solid. MS (ES+) C13H16BF4NO3 requires: 321, found: 322 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.05 – 6.68 (m, 2H), 5.58 (s, 2H), 1.27 (s, 12H). INTERMEDIATE 4 1-[4-amino-2-fluoro-6-, , , hyl-1,3,2-dioxaborolan-2- yl)phenoxy]cyclopropanecarbonitrile 57Attorney Docket No. MDA0094-401-PC Step 1 2-bromo-6-fluoro-4-nitro-phenol OH OH F Br2, AcOHF Br0-20 °C, 2 h NO2NO2

[0155] To a mixture of 2-fluoro-4-nitro-phenol (100 g, 636.54 mmol, 1 eq) in AcOH (560 mL) was added dropwise Br2 (111.90 g, 700.19 mmol, 36.07 mL, 1.1 eq) at 0 °C. The reaction was stirred at 20 °C for 2 h. LCMS showed the reaction was completed and a peak (88%) with desired mass. The mixture was poured into H2O (2000 mL) and stirred at 20 °C for 30 min. The suspension was filtered and the filter cake was dried to afford 2-bromo-6- fluoro-4-nitro-phenol (71 g, 270.77 mmol, 42.54% yield, 90% purity) as an off-white solid.1H NMR (400 MHz, CDCl3) δ = 8.30 (t, J = 1.9 Hz, 1H), 8.03 (dd, J = 2.5, 9.8 Hz, 1H), 6.29 (s, 1H). Step 2 methyl 4-bromo-2-(2-bromo-6-fluoro-4-nitro-phenoxy)butanoateg, 29.66 mmol, 1 eq) in DMF (70 mL) were added K2CO3 (8.20 g, 59.32 mmol, 2 eq) and methyl 2,4-dibromobutanoate (9.25 g, 35.59 mmol, 1.2 eq). The reaction was stirred at 60 °C for 3 h. TLC (petroleum ether:ethyl acetate=5:1) showed 2-bromo-6-fluoro-4-nitro-phenol was remained and two new spots with lower polarity. The mixture was diluted with H2O (200 mL) and extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-4% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford methyl 4-bromo-2-(2-bromo-6-fluoro-4-nitro-phenoxy)butanoate (8.5 g, 20.48 mmol, 69.05% yield) as yellow oil. 58Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, CDCl3)δ = 8.32 (dd, J = 1.8, 2.6 Hz, 1H), 7.98 (dd, J = 2.8, 11.9 Hz, 1H), 5.42 - 5.30 (m, 1H), 3.80 (s, 3H), 3.78 - 3.70 (m, 1H), 3.69 - 3.60 (m, 1H), 2.65 - 2.51 (m, 2H). Step 3 methyl 1-(2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarboxylate o-4-nitro-phenoxy)butanoate(4 g, 9.64 mmol, 1 eq) in THF (50 mL) was added t-BuOK (1 M in THF, 10.12 mL, 1.05 eq) at -40 °C under N2. The mixture was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate= 10:1) showed methyl 4-bromo-2-(2-bromo-6-fluoro-4-nitro-phenoxy)butanoate was consumed completely and a new spot with lower polarity. The mixture was adjusted pH to 6 with 1M HCl aqueous solution at 0 °C, diluted with H2O (100 mL) and extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-10% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford methyl 1-(2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarboxylate (2.25 g, 6.06 mmol, 62.89% yield, 90% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ = 8.29 (dd, J = 1.8, 2.6 Hz, 1H), 7.97 (dd, J = 2.6, 12.1 Hz, 1H), 3.79 (s, 3H), 1.68 - 1.62 (m, 2H), 1.49 - 1.42 (m, 2H). Step 4 1-(2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarboxylic acid59Attorney Docket No. MDA0094-401-PC

[0158] To a solution of methyl 1-(2-bromo-6-fluoro-4-nitro- phenoxy)cyclopropanecarboxylate (2.25 g, 6.73 mmol, 1 eq) in THF (45 mL) and H2O (22.5 mL) was added LiOH•H2O (1.41 g, 33.67 mmol, 5 eq). The mixture was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate=10:1) showed methyl 1-(2-bromo-6-fluoro-4-nitro- phenoxy)cyclopropanecarboxylate was consumed completely and a new spot with higher polarity. The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL). The aqueous layer was adjusted pH to 6 with 1M HCl aqueous solution and extracted with EtOAc (50 mL×2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford 1-(2-bromo-6- fluoro-4-nitro-phenoxy)cyclopropanecarboxylic acid (2.05 g, 5.76 mmol, 85.59% yield, 90% purity) as a white solid.1H NMR (400 MHz, CDCl3) δ = 8.28 (dd, J = 1.6, 2.6 Hz, 1H), 7.98 (dd, J = 2.8, 12.1 Hz, 1H), 1.76 - 1.70 (m, 2H), 1.58 - 1.51 (m, 2H). Step 5 1-(2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarboxamidephenoxy)cyclopropanecarboxylic acid (1.9 g, 5.94 mmol, 1 eq) in DMF (30 mL) were added DIEA (3.84 g, 29.68 mmol, 5.17 mL, 5 eq), NH4Cl (952.61 mg, 17.81 mmol, 3 eq) and HATU (3.39 g, 8.90 mmol, 1.5 eq). The reaction was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate=1:1) showed 1-(2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarboxylic acid was consumed completely and a new spot with lower polarity. The mixture was diluted with H2O (100 mL), then extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-50% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford 1-(2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarboxamide (1.5 g, 4.23 mmol, 71.27% yield, 90% purity) as a white solid. 60Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, CDCl3) δ = 8.30 (dd, J = 1.8, 2.6 Hz, 1H), 8.04 - 8.01 (m, 1H), 6.56 (s, 1H), 5.90 (s, 1H), 1.63 - 1.55 (m, 2H), 1.25 - 1.19 (m, 2H). Step 6 1-(2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarbonitrile itro-phenoxy)cyclopropanecarboxamide(1.5 g, 4.70 mmol, 1 eq) in dichloromethane (30 mL) were added pyridine (1.12 g, 14.10 mmol, 1.14 mL, 3 eq) and TFAA (1.97 g, 9.40 mmol, 1.31 mL, 2 eq) at 0 °C. The reaction was stirred at 20 °C for 16 h. TLC (petroleum ether:ethyl acetate=1:1) showed 1-(2-bromo-6- fluoro-4-nitro-phenoxy)cyclopropanecarboxamide was consumed completely and a new spot with lower polarity. The mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-20% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford 1- (2-bromo-6-fluoro-4-nitro-phenoxy)cyclopropanecarbonitrile (1.2 g, 3.59 mmol, 76.31% yield, 90% purity) as yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.38 - 8.25 (m, 1H), 8.08 (dd, J = 2.6, 10.6 Hz, 1H), 1.67 - 1.60 (m, 2H), 1.58 - 1.57 (m, 2H). Step 7 1-(4-amino-2-bromo-6-fluoro-phenoxy)cyclopropanecarbonitrileenoxy)cyclopropanecarbonitrile (1.2 g, 3.99 mmol, 1 eq)} in {THF (20 mL)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst {Pt / Al2O3 (2.5 g)}. The H2 back pressure regulator 61Attorney Docket No. MDA0094-401-PC was adjusted to 1 Mpa, and the H2flow rate was { 10.5 sccm }. The solution 1 was pumped by Pump 1 {S1, P1, 0.5 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 6.350(1 / 4")mm, 5.0 mL, 45.0°C}. The reaction mixture was continuously collected from the reactor outlet into the container after 1 h. LCMS showed the reaction was completed, several peaks and a peak (92%) with desired mass. The mixture was concentrated to afford a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-40% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford 1-(4-amino-2-bromo- 6-fluoro-phenoxy)cyclopropanecarbonitrile (0.76 g, 2.52 mmol, 63.30% yield, 90% purity) as yellow oil. MS (ES+) C10H8BrFN2O requires:270 and 272, found:271 and 273[M+H]+.1H NMR (400 MHz, CDCl3) δ = 6.64 (dd, J = 1.8, 2.5 Hz, 1H), 6.42 (dd, J = 2.7, 11.9 Hz, 1H), 3.99 - 3.57 (m, 2H), 1.64 - 1.58 (m, 2H), 1.40 - 1.33 (m, 2H). Step 8 1-[4-amino-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]cyclopropanecarbonitrile

[0162] To a solution of 1-(4-amino-2-bromo-6-fluoro-phenoxy)cyclopropanecarbonitrile (100 mg, 368.89 μmol, 1 eq), BPD (187.35 mg, 737.77 μmol, 2 eq) and KOAc (108.61 mg, 1.11 mmol, 3 eq) in dioxane (1.5 mL) was added Pd(dppf)Cl2 (13.50 mg, 18.44 μmol, 0.05 eq), the mixture was stirred at 100 °C for 16 h under N2. LCMS showed the reaction was completed, several peaks and a peak (52%) with desired mass. The mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-33% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford 1-[4-amino-2-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]cyclopropanecarbonitrile (74 mg, 148.86 μmol, 40.35% yield, 64% purity) as yellow oil. MS (ES+) C16H20BFN2O3requires:318, found:319[M+H]+. 62Attorney Docket No. MDA0094-401-PC INTERMEDIATE 5 3-fluoro-5-(4,4,5,5-tetramethyl-1 -2-yl)-4-(2,2,2-trifluoroethyl)anilineStep 1 1-bromo-2-(bromomethyl)-3-fluoro-5-nitro-benzene l-5-nitro-benzene (10 g, 42.73 mmol, 1eq) and AIBN (1.40 g, 8.55 mmol, 0.2 eq) in CCl4 (100 mL) was added NBS (11.41 g, 64.10 mmol, 1.5 eq) at 20 °C under N2. The mixture was stirred at 80 °C for 16 hr under N2. TLC (commercial hexanes:ethyl acetate=10:1) indicated part of 1-bromo-3-fluoro-2-methyl-5- nitro-benzene remained and one new main spot formed. The reaction mixture was quenched by water (100 mL) at 20 °C, and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue which was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent of 0-5% ethyl acetate:commercial hexanes gradient @ 100 mL / min) to afford 1-bromo-2-(bromomethyl)-3-fluoro-5-nitro-benzene (11.57 g, 36.97 mmol, 86.53% yield) as colorless oil and 1-bromo-3-fluoro-2-methyl-5-nitro- benzene (1.1 g, 4.70 mmol, 11.00% yield) as an white solid.1H NMR (400 MHz, CDCl3) δ = 8.31 (t, J = 1.8 Hz, 1H), 7.95 (dd, J = 2.1, 8.9 Hz, 1H), 4.64 (d, J = 2.0 Hz, 2H). Step 2 1-bromo-3-fluoro-5-nitro-2-(2,2,2-trifluoroethyl)benzene 63Attorney Docket No. MDA0094-401-PC oro-5-nitro-benzene (12.88 g,41.16 mmol, 1 eq) and Cu (7.85 g, 123.48 mmol, 875.76 μL, 3 eq) in NMP (120 mL) was added diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (29.63 g, 73.27 mmol, 1.78 eq) at 20 °C under N2. The mixture was stirred at 60 °C for 16 hrs under N2. TLC(Commercial hexanes:ethyl acetate= 10:1) indicated 1-bromo-2-(bromomethyl)-3- fluoro-5-nitro-benzene was consumed completely and new spots formed. The reaction mixture was quenched by water (100 mL) at 20 °C, and then extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (300 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue which was purified by flash silica gel chromatography (220 g SepaFlash® Silica Flash Column, eluent of 0-2% ethyl acetate:commercial hexanes gradient @ 100 mL / min) to afford desired product 1- bromo-3-fluoro-5-nitro-2-(2,2,2-trifluoroethyl)benzene (8.49 g, 28.11 mmol, 68.29% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.36 (t, J = 1.8 Hz, 1H), 7.98 (dd, J = 2.3, 8.8 Hz, 1H), 3.84 - 3.74 (m, 2H). Step 3 3-bromo-5-fluoro-4-(2,2,2-trifluoroethyl)aniline

[0165] Solution 1: 1-bromo-3-fluoro-5-nitro-2-(2,2,2-trifluoroethyl)benzene (8.49 g, 28.11 mmol, 1 eq) in MeOH (10 mL) and THF (80 mL). The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst {1%Pt / C, WXSC1050, 2.8 g}. The H2back pressure regulator was adjusted to 1.5 Mpa, and the H2flow rate was {H2, 10 sccm}. The solution 1 was pumped by Pump 1 {S1, P1, 0.4 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 6.350(1 / 4")mm, 5.0 mL, 55.0 °C}. The reaction mixture was 64Attorney Docket No. MDA0094-401-PC continuously collected from the reactor outlet into the container. LCMS showed 1-bromo-3- fluoro-5-nitro-2-(2,2,2-trifluoroethyl)benzene was consumed completely and desired mass was detected. The reaction mixture was filtered and concentrated in vacuum to afford a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 2-11% ethyl acetate:commercial hexanes gradient @ 30 mL / min) to afford desired product 3-bromo-5-fluoro-4-(2,2,2-trifluoroethyl)aniline (6.59 g, 24.22 mmol, 86.18% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ = 6.76 - 6.72 (m, 1H), 6.37 (dd, J = 2.4, 11.2 Hz, 1H), 3.92 (s, 2H), 3.58 - 3.50 (m, 2H). Step 4 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-4-ethyl-14-fluoro-17-formyl-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylateyl)aniline (6.29 g, 23.12 mmol, 1 eq) , BPD (8.81 g, 34.68 mmol, 1.5 eq) and KOAc (6.81 g, 69.37 mmol, 3 eq) in dioxane (70 mL) and H2O (14 mL) was added Pd(dppf)Cl2 (1.69 g, 2.31 mmol, 0.1 eq) at 20 °C under N2. The mixture was stirred at 90 °C for 2 hrs under N2. LCMS showed 3-bromo-5- fluoro-4-(2,2,2-trifluoroethyl)aniline was consumed completely and desired mass was detected. The organic phase was separated. The aqueous phase was extracted with EtOAc (14 mL x 3). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue which was diluted with the mixture solution(commercial hexanes:ethyl acetate= 10:1, 70 mL) and stirred for 0.15 hr at 20 °C. The mixture was filtered and washed with the mixture solution(commercial hexanes:ethyl acetate=10:1, 20 mL x 2), the combined organic phase was concentrated under reduced pressure to afford a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 2-20% Ethylacetate / Petroleum ether gradient @ 50 mL / min) to afford 3- fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(2,2,2-trifluoroethyl)aniline (6.1 g, 19.12 mmol, 82.68% yield) as yellow oil. 65Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, CDCl3) δ = 7.00 (d, J = 1.5 Hz, 1H), 6.55 (dd, J = 2.2, 11.5 Hz, 1H), 3.87 - 3.72 (m, 2H), 1.34 (s, 12H). INTERMEDIATE 6 3-methyl-5-(4,4,5,5-tetramethyl n-2-yl)-4-(trifluoromethoxy)anilineStep 1 1-bromo-2-[bromo(difluoro)methoxy]-3-methyl-5-nitro-benzenel (4 g, 17.24 mmol, 1 eq) in THF (40 mL) was added NaH (2.07 g, 51.72 mmol, 60% purity, 3 eq) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 hr. To the mixture was added dibromo(difluoro)methane (10.85 g, 51.72 mmol, 4.78 mL, 3 eq) at 0 °C, then the mixture was stirred at 25 °C for 12 hr under N2. TLC (Commercial hexanes: Ethyl acetate= 10: 1) indicated 2-bromo-6-methyl-4- nitro-phenol was consumed completely and one new spot formed. The mixture was quenched with NH4Cl (100 mL) at 0 °C, and extracted with Ethyl acetate (100 mL x 3). The combined organic phase was washed by brine (300 mL) and dried over Na2SO4, filtered and concentrated in vacuum to give a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 0-1% ethyl acetate:commercial hexanes gradient @ 100 mL / min) to afford 1-bromo-2- [bromo(difluoro)methoxy]-3-methyl-5-nitro-benzene (5.9 g, 16.35 mmol, 94.82% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J = 2.8 Hz, 1H), 8.35 (d, J = 2.6 Hz, 1H), 2.45 (s, 3H). Step 2 1-bromo-3-methyl-5-nitro-2-(trifluoromethoxy)benzene 66Attorney Docket No. MDA0094-401-PC hoxy]-3-methyl-5-nitro-benzene(5.9 g, 16.35 mmol, 1 eq) in DCE (30 mL) was added AgBF4 (3.82 g, 19.62 mmol, 1.2 eq) at 0 °C. The mixture was stirred at 60 °C for 16 hr. FNMR showed 1-bromo-2- [bromo(difluoro)methoxy]-3-fluoro-5-nitro-benzene was consumed completely. The mixture was filtered and the filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of commercial grade hexanes gradient with increasing concentrations of ethyl acetate @ 100 mL / min) to afford 1-bromo-3-methyl-5-nitro-2-(trifluoromethoxy)benzene (4.5 g, 15.00 mmol, 91.75% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 8.46 (d, J = 2.7 Hz, 1H), 8.35 (d, J = 2.7 Hz, 1H), 2.46 (s, 3H). Step 3 3-bromo-5-methyl-4-(trifluoromethoxy)anilineromethoxy)benzene (4.5 g, 15.00 mmol, 1 eq) } in {THF (45 mL) } and {MeOH (5 mL) }. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst {Pd / C (1% purity), WXSC1050, 2.7 g}. The H2 back pressure regulator was adjusted to 1 Mpa, and the H2 flow rate was {H2 (20 Psi), 10 sccm}. The solution 1 was pumped by Pump 1 {S1, P1, 0.4 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 6.350(1 / 4") mm, 5.0 mL, 50.0 °C}. The reaction mixture was continuously collected from the reactor outlet into the container. LCMS showed one main peak with desired mass. The mixture was concentrated to afford 3-bromo-5-methyl-4- (trifluoromethoxy)aniline (4 g, 13.03 mmol, 86.91% yield, 88% purity) as a yellow solid. MS (ES+) C8H7BrF3NO requires: 269, found: 270 [M+H]+. 67Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, DMSO-d6) δ = 6.71 (d, J = 2.6 Hz, 1H), 6.44 (d, J = 2.3 Hz, 1H), 6.06 - 4.74 (m, 2H), 2.17 (s, 3H). Step 4 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)aniline F3C F C O3O O (4 g, 14.81 mmol, 1eq), BPD (7.52 g, 29.62 mmol, 2 eq), KOAc (2.91 g, 29.62 mmol, 2 eq), Pd(dppf)Cl2(541.91 mg, 740.61 μmol, 0.05 eq) in dioxane (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hr under N2 atmosphere. LCMS showed 3- bromo-5-methyl-4-(trifluoromethoxy)aniline was consumed completely and one main peak with desired mass. The mixture was filtered and the filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 0-10% ethyl acetate:commercial hexanes gradient @ 100 mL / min) to afford 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)aniline (2.2 g, 6.52 mmol, 44.03% yield, 94% purity) as yellow oil. MS (ES+) C14H19BF3NO3requires: 317, found: 318 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 6.73 (d, J = 2.9 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 5.25 - 5.17 (m, 2H), 2.13 (s, 3H), 1.26 (s, 12H). INTERMEDIATE 7 4-tert-butoxy-3-fluoro-5-(4,4, , -1,3,2-dioxaborolan-2-yl)aniline Step 1 1-bromo-2-tert-butoxy-3-fluoro-5-nitro-benzene 68Attorney Docket No. MDA0094-401-PC o-benzene (2 g, 8.40 mmol, 1 eq) inTHF (20 mL) was added t-BuOK (1 M, 10.08 mL, 1.2 eq) at 0 °C, the mixture was stirred at 20 °C for 16 hours. TLC (commercial hexanes:ethyl acetate=20:1) showed 1-bromo-2,3- difluoro-5-nitro-benzene was consumed and new spot formed. To the mixture was added saturated NH4Cl (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic phase was washed with brine(50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (25 g SepaFlash® Silica Flash Column, eluent of 0-1% ethyl acetate:commercial hexanes gradient @ 80 mL / min) to afford 1-bromo-2-tert-butoxy-3-fluoro-5-nitro-benzene (2.4 g, 8.22 mmol, 97.77% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ = 8.30 (dd, J = 1.9, 2.5 Hz, 1H), 7.96 (dd, J = 2.8, 9.8 Hz, 1H), 1.51 (s, 9H). Step 2 3-bromo-4-tert-butoxy-5-fluoro-aniline O O Br5-nitro-benzene (2.4 g, 8.22 mmol, 1 eq) and NH4Cl (3.08 g, 57.51 mmol, 7 eq) in EtOH (30 mL) and H2O (6 mL) was added Fe (2.29 g, 41.08 mmol, 5 eq) at 75 °C, the mixture was stirred at 75 °C for 1.5 hours. TLC (commercial hexanes:ethyl acetate=20:1) showed 1-bromo-2-tert-butoxy-3-fluoro-5- nitro-benzene was consumed and new spot formed. The mixture was filtered and concentrated under reduced pressure to give a residue which was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (25 g SepaFlash® Silica Flash Column, eluent of 0-25% ethyl acetate:commercial hexanes 69Attorney Docket No. MDA0094-401-PC gradient @ 80 mL / min) to afford 3-bromo-4-tert-butoxy-5-fluoro-aniline (2 g, 7.63 mmol, 92.87% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ = 6.66 (dd, J = 1.8, 2.6 Hz, 1H), 6.37 (dd, J = 2.8, 11.8 Hz, 1H), 3.95 - 2.63 (m, 2H), 1.41 (d, J = 1.1 Hz, 9H). Step 3 4-tert-butoxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline O O O (0.5 g, 1.91 mmol, 1 eq)and BPD (968.79 mg, 3.82 mmol, 2 eq) in dioxane (5 mL) were added Pd(dppf)Cl2(139.58 mg, 190.75 μmol, 0.1 eq) and KOAc (468.03 mg, 4.77 mmol, 2.5 eq) under the protection of N2, the mixture was stirred at 100 °C for 16 hours. LCMS showed 3-bromo-4-tert-butoxy-5- fluoro-aniline was consumed and main peak with desired mass. To the mixture was added EtOAc (30 mL), filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (25 g SepaFlash® Silica Flash Column, eluent of 0-1% ethyl acetate:commercial hexanes gradient @ 80 mL / min) to afford 4-tert- butoxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.36 g, 1.16 mmol, 61.04% yield) as yellow oil. MS (ES+) C16H25BFNO3requires: 309, found: 310 [M+H]+. INTERMEDIATE 8 3-fluoro-4-isopropoxy-5-(4,4, , 1,3,2-dioxaborolan-2-yl)aniline Step 1 1-bromo-3-fluoro-2-isopropoxy-5-nitro-benzene 70Attorney Docket No. MDA0094-401-PC enol (2 g, 8.47 mmol, 1 eq) and 2-iodopropane (2.88 g, 16.95 mmol, 1.69 mL, 2 eq) in DMF (20 mL) was added K2CO3 (4.69 g, 33.90 mmol, 4 eq). The mixture was stirred at 60 °C for 16 h. TLC (petroleum ether:ethyl acetate=2:1) showed 2-bromo-6-fluoro-4-nitro-phenol was consumed completely and a new major spot with lower polarity. The mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-10% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford 1- bromo-3-fluoro-2-isopropoxy-5-nitro-benzene (2.5 g, 8.09 mmol, 95.48% yield, 90% purity) as red oil.1H NMR (400 MHz, CDCl3) δ = 8.31 - 8.26 (m, 1H), 7.97 (dd, J = 2.6, 10.8 Hz, 1H), 4.86 - 4.73 (m, 1H), 1.41 (d, J = 6.1 Hz, 6H). Step 2 3-bromo-5-fluoro-4-isopropoxy-aniline-nitro-benzene (2.5 g, 8.99 mmol, 1 eq)} in {THF (30 mL)}. The fixed bed (named FLR1, volume 5 mL) was completely packed with granular catalyst {Pt / C (1% purity), WXSC10502.5 g}. The H2 back pressure regulator was adjusted to 1 Mpa, and the H2flow rate was { 10 sccm }. The solution 1 was pumped by Pump 1 {S1, P1, 0.4 mL / min} to flow reactor 1 {FLR1, SS, Fixed bed, 6.350(1 / 4")mm, 5.0 mL, 50.0°C}. The reaction mixture was continuously collected from the reactor outlet into the container. LCMS showed the reaction was completed, several peaks and a peak (66%) with desired mass. The mixture was concentrated to afford a residue which was purified by 71Attorney Docket No. MDA0094-401-PC flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-20% ethyl acetate:petroleum ether gradient @ 80 mL / min) to afford 3-bromo-5-fluoro-4- isopropoxy-aniline (2 g, 7.90 mmol, 87.87% yield, 98% purity) as yellow oil. MS (ES+) C9H11BrFNO requires:247 and 249, found:248 and 250[M+H]+.1H NMR (400 MHz, CDCl3) δ = 6.65 (dd, J = 1.9, 2.5 Hz, 1H), 6.39 (dd, J = 2.8, 12.0 Hz, 1H), 4.40 - 4.28 (m, 1H), 3.90 - 3.30 (m, 2H), 1.33 (d, J = 6.1 Hz, 6H). Step 3 3-fluoro-4-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg, 2.02 mmol, 1eq) and BPD (1.02 g, 4.03 mmol, 2 eq) in dioxane (10 mL) were added KOAc (593.38 mg, 6.05 mmol, 3 eq) and Pd(dppf)Cl2 (73.73 mg, 100.77 μmol, 0.05 eq). The mixture was stirred at 100 °C for 16 h under N2. LCMS showed the reaction was completed, several peaks and a peak (40%) with desired mass. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic layers were washed with H2O (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-25% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford 3- fluoro-4-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (400 mg, 609.85 μmol, 30.26% yield, 45% purity) as yellow oil. MS (ES+) C15H23BFNO3requires:295, found:296[M+H]+. INTERMEDIATE 9 3-chloro-5-(4,4,5,5-tetramethyl-1, , -2-yl)-4-(2,2,2-trifluoroethyl)aniline Step 1 72Attorney Docket No. MDA0094-401-PC 1-bromo-3-chloro-2-methyl-5-nitro-benzene nzene (10 g, 58.28 mmol, 12.05 mL,1 eq) in n-heptane (40 mL) and H2SO4(40 mL) was added NBS (12.44 g, 69.89 mmol, 1.20 eq) in batches. The mixture was stirred at 50 °C for 16 h. TLC (commercial hexanes:ethyl acetate=10:1) showed starting material (Rf =0.4) was remained and the new spot (Rf =0.45). The mixture was dropwise added into ice water (300 mL) and extracted with ethyl acetate (100 * 3 mL). The combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase MPLC (0.1% FA condition) and lyophilized to afford 1-bromo-3-chloro-2- methyl-5-nitro-benzene (8 g, 28.43 mmol, 48.77% yield, 89% purity) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ = 8.39 (d, J = 2.3 Hz, 1H), 8.31 (d, J = 2.3 Hz, 1H), 2.56 (s, 3H). Step 2 1-bromo-2-(bromomethyl)-3-chloro-5-nitro-benzene5-nitro-benzene (7.5 g, 29.94 mmol, 1 eq) in CCl4(75 mL) was added NBS (7.99 g, 44.91 mmol, 1.5 eq) and AIBN (983.37 mg, 5.99 mmol, 0.2 eq). The mixture was stirred at 80 °C for 16 h. TLC (commercial hexanes:ethyl acetate=10:1) showed starting material (Rf=0.55) was remained and the new spot (Rf=0.50) was detected. The reaction mixture was quenched by addition water (100 mL) at 20 °C, and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, eluent of 0-5% ethyl acetate:commercial hexanes gradient @ 200 mL / min) to afford 1-bromo-2-(bromomethyl)-3-chloro-5-nitro-benzene (9 g, 22.41 mmol, 74.83% yield, 82% purity) as a colorless oil. 73Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, CDCl3) δ = 8.39 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 4.79 (s, 2H). Step 3 1-bromo-3-chloro-5-nitro-2-(2,2,2-trifluoroethyl)benzene F O Br zene (3 g, 9.11mmol, 1 eq) and diphenyl(trifluoromethyl)sulfonium;trifluoromethanesulfonate (6.56 g, 16.21 mmol, 1.78 eq) in NMP (30 mL) was added Cu (1.74 g, 27.32 mmol, 193.79 μL, 3 eq) under N2. The mixture was stirred at 60 °C for 12 h. TLC (commercial hexanes:ethyl acetate=10:1) showed starting material (Rf =0.6) was consumed and the new spot (Rf=0.55) was detected. The reaction mixture was diluted with H2O (100 mL) and filtered, filtrate was extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-5% ethyl acetate:commercial hexanes gradient @ 100 mL / min) to afford 1-bromo-3-chloro-5-nitro-2-(2,2,2-trifluoroethyl)benzene (1.8 g, crude) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.43 (d, J = 2.3 Hz, 1H), 8.30 (d, J = 2.4 Hz, 1H), 4.06 - 3.95 (m, 2H). Step 4 3-bromo-5-chloro-4-(2,2,2-trifluoroethyl)aniline-2-(2,2,2-trifluoroethyl)benzene (1.8 g, 5.65 mmol, 1 eq) and NH4Cl (3.02 g, 56.52 mmol, 10 eq) in EtOH (30 mL) and H2O (6 mL) was added Fe (3.16 g, 56.52 mmol, 10 eq) at 75 °C. The mixture was stirred at 75 °C for 1 h. TLC (commercial hexanes:ethyl acetate=10:1) showed starting material (Rf=0.65) was 74Attorney Docket No. MDA0094-401-PC consumed and the new spot (Rf=0.25) was detected. LCMS showed the starting material was consumed and a peak (47%) with desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-30% ethyl acetate:commercial hexanes gradient @ 100 mL / min) to afford 3-bromo-5-chloro-4-(2,2,2- trifluoroethyl)aniline (0.9 g, 1.84 mmol, 32.57% yield, 59% purity) as a yellow oil.1H NMR (400 MHz, CDCl3) δ = 6.87 (d, J = 1.7 Hz, 1H), 6.71 (d, J = 1.7 Hz, 1H), 3.75 (q, J = 10.1 Hz, 2H). MS (ES+) C8H6NClBrF3 requires: 287 / 289, found: 288 / 290 [M+H]+. Step 5 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(2,2,2-trifluoroethyl)aniline)aniline (0.1 g, 346.63 μmol, 1 eq) and BPD (132.03 mg, 519.95 μmol, 1.5 eq) in dioxane (1 mL) and H2O (0.2 mL) were added KOAc (102.06 mg, 1.04 mmol, 3 eq) and Pd(dppf)Cl2 (25.36 mg, 34.66 μmol, 0.1 eq) under N2. The mixture was stirred at 90 °C for 2 h. LCMS showed the starting material was consumed and a peak (51%) with desired mass. The reaction mixture was diluted with EtOAc (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-10% ethyl acetate:commercial hexanes gradient @ 100 mL / min) to afford 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(2,2,2- trifluoroethyl)aniline (80 mg, 174.04 μmol, 50.21% yield, 73% purity) as a colorless oil.1H NMR (400 MHz, CDCl3) δ = 7.07 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 2.6 Hz, 1H), 3.98 (q, J = 10.6 Hz, 2H), 1.34 (s, 12H). MS (ES+) C14H18NClBO2F3requires: 335, found: 336 [M+H]+. INTERMEDIATE 10 75Attorney Docket No. MDA0094-401-PC 2,3-difluoro-5-(4,4,5,5-tetramethy lan-2-yl)-4-(trifluoromethoxy)anilineStep 1 6-bromo-2,3-difluoro-4-nitro-phenol nol (25 g, 119.62 mmol, 1 eq) in DCM(100 mL) was added HNO3 (13.92 g, 143.55 mmol, 9.94 mL, 65% purity, 1.2 eq) at 0 °C, then the mixture was stirred at -10 °C for 1 h. TLC (petroleum ether:ethyl acetate = 5:1) indicated 6-bromo-2,3-difluoro-phenol was consumed completely and one new spot formed. The mixture was poured into ice-water (200 mL), then extracted with DCM (60 mL x 3), washed with brine (50 mL x 2), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (220 g SepaFlash® Silica Flash Column, eluent of 0-18% ethyl acetate:petroleum ether gradient @ 200 mL / min) to afford 6-bromo-2,3-difluoro-4-nitro- phenol (20 g, 78.74 mmol, 65.83% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.20 (dd, J = 2.3, 7.1 Hz, 1H), 6.90 - 6.54 (m, 1H). Step 2 1-bromo-2-[bromo(difluoro)methoxy]-3,4-difluoro-5-nitro-benzene

[0183] To a solution of 6-bromo-2,3-difluoro-4-nitro-phenol (20 g, 78.74 mmol, 1 eq) in THF (200 mL) was added NaH (9.45 g, 236.23 mmol, 60% purity, 3 eq) at 0 °C under N2, then the mixture was stirred at 0 °C for 0.5 h. To the mixture was added dibromo(difluoro)methane (49.57 g, 236.23 mmol, 21.84 mL, 3 eq) at 20 °C, then the mixture was stirred at 20 °C for 48 h. TLC (petroleum ether:ethyl acetate = 10:1) indicated 6-bromo- 76Attorney Docket No. MDA0094-401-PC 2,3-difluoro-4-nitro-phenol was consumed completely and one new spot formed. The mixture was cooled to 25 °C and poured into a mixture of saturated NH4Cl (300 mL) and water (300 mL) at 0 °C. The aqueous phase was extracted with ethyl acetate (200 mL x 2). The combined organic phase dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica Flash Column, eluent of 0-10% ethyl acetate:petroleum ether gradient @ 200 mL / min) to afford 1-bromo-2-[bromo(difluoro)methoxy]-3,4-difluoro-5-nitro-benzene (12 g, 31.34 mmol, 39.80% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 8.21 - 8.12 (m, 1H). Step 3 1-bromo-3,4-difluoro-5-nitro-2-(trifluoromethoxy)benzene)methoxy]-3,4-difluoro-5-nitro- benzene (11.17 g, 29.17 mmol, 1 eq) in DCE (120 mL) was added silver; tetrafluoroborate (17.04 g, 87.52 mmol, 3 eq) under N2, then the mixture was stirred at 60 °C for 24 h. HNMR showed 1-bromo-2-[bromo(difluoro)methoxy]-3,4-difluoro-5-nitro-benzene was consumed completely. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography(220 g SepaFlash® Silica Flash Column, eluent of 0-30% ethyl acetate:petroleum ether gradient @ 150 mL / min) to afford 1-bromo-3,4-difluoro-5-nitro-2-(trifluoromethoxy)benzene (5.5 g, 17.08 mmol, 58.55% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ = 8.25 (dd, J = 2.4, 7.0 Hz, 1H). Step 4 5-bromo-2,3-difluoro-4-(trifluoromethoxy)aniline, -nitro-2-(trifluoromethoxy) benzene, 1 eq, 0.3 g} in {THF, 100mL}. The fixed bed (named FLR1, volume 5 mL) was completely packed 77Attorney Docket No. MDA0094-401-PC with granular catalyst 1% Pt / C (WXC1050). The H2back pressure regulator was adjusted to 1 MPa, and the flow rate of H2was 30 mL / min. Then the solution S1 was pumped by Pump 1 {S1, P1, 0.3 mL / min} to fixed bed {FLR1, SS, Fixed bed,6.350(1 / 4’’) mm, 1 mL, 40 °C}. TLC (Petroleum ether : Ethyl acetate 10：1) indicated 1-bromo-3,4-difluoro-5-nitro-2- (trifluoromethoxy) benzene was consumed completely and one new spot formed. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 5-30% ethyl acetate:petroleum ether gradient @ 100 mL / min) to afford 5-bromo-2,3- difluoro-4-(trifluoromethoxy)aniline (3.5 g, 11.99 mmol, 77.19% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 6.80 (dd, J = 2.4, 8.3 Hz, 1H), 3.97 (s, 2H). Step 5 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)anilinexy)aniline (450 mg, 1.54 mmol, 1 eq) in ACN (10 mL) wad added BPD (782.68 mg, 3.08 mmol, 2 eq) KOAc (453.74 mg, 4.62 mmol, 3 eq) and Cy3P Pd G3 (100.20 mg, 154.11 μmol, 0.1 eq) at 20 °C under N2, then the mixture was stirred at 80 °C for 16 h. LCMS showed a peak (46%) with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 0-15% ethyl acetate:petroleum ether gradient @ 100 mL / min) to afford 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)aniline (240 mg, 707.83 μmol, 45.93% yield) as a yellow solid. MS (ES+) C13H15O3F5BN requires: 339, found: 340 [M+H]+. INTERMEDIATE 1178Attorney Docket No. MDA0094-401-PC 4-ethoxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline Step 1 1-bromo-2-ethoxy-3-fluoro-5-nitro-benzene ol (1 g, 4.24 mmol, 1 eq) in ACN(20 mL) were added iodoethane (1.32 g, 8.47 mmol, 677.83 μL, 2 eq) and K2CO3 (1.17 g, 8.47 mmol, 2 eq), then the mixture was stirred at 60 °C for 16 h. TLC (commercial hexanes:ethyl acetate = 3:1) indicated 2-bromo-6-fluoro-4-nitro-phenolwas consumed completely and one new spot formed. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-10% ethyl acetate:petroleum ether gradient @ 100 mL / min) to afford 1-bromo-2-ethoxy-3-fluoro-5- nitro-benzene (1 g, 3.79 mmol, 89.38% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ = 8.36 - 8.23 (m, 1H), 7.98 (dd, J = 2.7, 11.0 Hz, 1H), 4.47 - 4.31 (m, 2H), 1.48 (t, J = 7.0 Hz, 3H). Step 2 3-bromo-4-ethoxy-5-fluoro-aniline Britro-benzene (0.5 g, 1.89 mmol, 1 eq) in EtOH (10 mL) was added NH4Cl (1.52 g, 28.40 mmol, 15 eq) in H2O (4 mL) at 20 °C, to the mixture was added Fe (1.59 g, 28.40 mmol, 15 eq) at 80 °C, then the mixture was stirred at 80 °C for 1 h. LCMS showed a peak (94%) with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-15% ethyl acetate:petroleum ether gradient @ 100 mL / min) to afford 3-bromo-4-ethoxy-5- fluoro-aniline (440 mg, 1.88 mmol, 99.27% yield) as a yellow oil. 79Attorney Docket No. MDA0094-401-PC MS (ES+) C8H9OFBrN requires: 233, found: 234 [M+H]+. Step 3 4-ethoxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline 4 g, 1.88 mmol, 1 eq) indioxane (15 mL) were added BPD (954.72 mg, 3.76 mmol, 2 eq), KOAc (553.46 mg, 5.64 mmol, 3 eq) and Pd(dppf)Cl2(137.55 mg, 187.98 μmol, 0.1 eq) under N2, then the mixture was stirred at 100 °C for 16 h. LCMS showed a peak (37%) with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-15% ethyl acetate:petroleum ether gradient @ 100 mL / min) to afford 4- ethoxy-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (400 mg, 1.42 mmol, 75.69% yield) as a yellow oil. MS (ES+) C14H21O3FBN requires: 281, found: 282 [M+H]+. EXAMPLES

[0190] Examples of embodiments of the present disclosure are provided in the following examples. The following examples are presented only by way of illustration and to assist one of ordinary skill in using the disclosure. The examples are not intended in any way to otherwise limit the scope of the disclosure. Examples without procedures may be synthesized with procedures similar to the examples disclosed herein from the appropriate starting materials and / or intermediates. EXAMPLE 1 80Attorney Docket No. MDA0094-401-PC 4-((5aS,6S,9R)-1-fluoro-5, 6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridin-2-yl)-6-methyl-5- (trifluoromethyl)pyridin-2-amine Step 1 Tert-butyl (1S,2S,5R)-3-benzyl-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0191] To a solution of tert-butyl (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 1.50 mmol, 1 eq) in DCM (10 mL) was added imidazole (307.19 mg, 4.51 mmol, 3 eq) and TBSCl (272.03 mg, 1.80 mmol, 222.07 μL, 1.2 eq) at 20 °C. Then the mixture was stirred at 20 °C for 16 h. TLC (Plate 1 Dichloromethane : Methanol = 10:1) showed the tert-butyl (1S,2S,5R)-3-benzyl-2- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot was formed. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-9% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl (1S,2S,5R)-3- benzyl-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.28 mmol, 85.18% yield, 97% purity) as yellow solid. MS (ES+) C25H42N2O3Si requires: 446, found: 447 [M+H]+. Step 2 Tert-butyl (1R,4S,5S)-3-benzyl-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate 81Attorney Docket No. MDA0094-401-PC

[0192] To a solbutyl(dimethyl)silyl]oxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.32 mmol, 1 eq) and TMEDA (460.45 mg, 3.96 mmol, 597.99 μL, 3 eq) in THF (5 mL) was slowly added s-BuLi (1.3 M, 3.05 mL, 3 eq) at -40 °C under N2. Then the mixture was stirred at 0 °C for 0.5 h. Then the MeI (656.16 mg, 4.62 mmol, 287.79 μL, 3.5 eq) was added dropwise to the mixture at -78 °C under N2. Then the mixture was stirred at 0 °C for 1.5 h under N2. TLC (Plate 1 Petroleum ether : Ethyl acetate = 8:1) showed the tert-butyl (1S,2S,5R)-3-benzyl-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate was consumed completely and two new spots were formed. The mixture was quenched by sat. aq. Na2CO3 (4 mL), then the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-6% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4- [[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (480 mg, 948.08 μmol, 71.78% yield, 91% purity) as colorless oil. MS (ES+) C26H44N2O3Si requires: 460, found: 461 [M+H]+. Step 3 Tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0193] To a solution of tert-butyl (1R,4S,5S)-3-benzyl-4-[[tert- butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (480 mg, 1.04 mmol, 1 eq) in THF (5 mL) was added TBAF (1 M, 2.08 mL, 2 eq) at 25 °C. Then the mixture was stirred at 25 °C for 1 h. TLC (Plate 1 Petroleum ether : Ethyl acetate = 5:1) showed the tert-butyl (1R,4S,5S)-3-benzyl-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1- 82Attorney Docket No. MDA0094-401-PC methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot formed. The mixture was diluted with ethyl acetate (20 mL) and washed with sat. aq. NH4Cl (10 mL x 2), then the organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (346 mg, 968.70 μmol, 92.98% yield, 97% purity) as colorless oil. MS (ES+) C20H30N2O3 requires: 346, found: 347 [M+H]+. Step 4 tert-butyl (1R,4S,5S)-3-benzyl-4-formyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0194] To a so ut on o (COC )2(278.86 mg, 2.20 mmo , 192.32 μL, 2.2 eq) in DCM (10 mL) was added DMSO (195.07 mg, 2.50 mmol, 195.07 μL, 2.5 eq) in DCM (2 mL) at -78 °C under N2. Then the mixture was stirred at -78 °C for 20 min. Then tert-butyl (1R,4S,5S)-3- benzyl-4-(hydroxymethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (346 mg, 998.66 μmol, 1 eq) in DCM (2 mL) was added to the mixture at -78 °C under N2. Then the mixture was stirred at -78 °C for 40 min under N2. Then the TEA (808.43 mg, 7.99 mmol, 1.11 mL, 8 eq) was added to the mixture at -78 °C under N2. The resulting mixture was stirred at -78 °C for 0.5 h under N2. TLC (Plate 1 Petroleum ether : Ethyl acetate = 2:1) showed the tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot formed. The mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-9% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4-formyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (280 mg, 569.03 μmol, 56.98% yield, 70% purity) as colorless oil. MS (ES+) C20H28N2O3 requires: 344, found: 345 [M+H]+. 83Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, CDCl3) δ = 9.67 - 9.52 (m, 1H), 7.34-7.21 (m, 5H), 4.31 (d, J = 6.0 Hz, 1H), 3.75 (d, J = 13.5 Hz, 1H), 3.23 (d, J = 13.5 Hz, 1H), 3.12 (s, 1H), 2.45 (d, J = 11.0 Hz, 1H), 2.24 (d, J = 10.9 Hz, 1H), 1.99 - 1.60 (m, 4H), 1.43 (s, 9H), 1.41 - 1.38 (m, 3H). Step 5 Tert-butyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0195] To a soly , , y y methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 812.90 μmol, 1 eq) in THF (7.5 mL) was added MeMgBr (3 M, 1.63 mL, 6 eq) at -78 °C under N2. Then the mixture was stirred at -78 °C for 2 h under N2. LCMS showed the tert-butyl (1R,4S,5S)-3-benzyl-4-formyl-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and a peak (75%) with desired mass. The mixture was quenched by water (10mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 488.23 μmol, 60.06% yield, 88% purity) as colorless oil. MS (ES+) C21H32N2O3requires: 360, found: 361 [M+H]+. Step 6 Tert-butyl (1R,4S,5S)-4-(1-hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0196] To a suspension of Pd(OH)2 (0.2 g, 284.83 μmol, 20% purity) and Pd / C (0.2 g, 1.88 mmol, 10% purity) in MeOH (5 mL) was added tert-butyl (1R,4S,5S)-3-benzyl-4-(1- hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 554.80 μmol, 84Attorney Docket No. MDA0094-401-PC 1 eq) in MeOH (2 mL) at 25 °C under N2. Then the mixture was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(50psi) at 25°C for 16 hours. TLC (Plate 1 Petroleum ether : Ethyl acetate = 3:1) showed the tert-butyl (1R,4S,5S)-3- benzyl-4-(1-hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot formed. The mixture was filtered through celite, the filtrate was concentrated in vacuum to give tert-butyl (1R,4S,5S)-4-(1-hydroxyethyl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (127 mg, 469.73 μmol, 84.67% yield) as colorless oil. Step 7 Tert-butyl (1R,4S,5S)-4-[1-[(3-chloro-4-fluoro-5,6-dimethyl-8-oxo-7H-2,7-naphthyridin- 1-yl)oxy]ethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0197] Toa solution of NaH (65.76 mg, 1.64 mmol, 60% purity, 3.5 eq) in THF (5 mL) was added tert-butyl (1R,4S,5S)-4-(1-hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (127 mg, 469.73 μmol, 1 eq) in THF (1 mL) at 0 °C under N2. Then the mixture was stirred at 0 °C for 10 min. Then 6,8-dichloro-5-fluoro-3,4-dimethyl-2H-2,7- naphthyridin-1-one (122.64 mg, 469.73 μmol, 1 eq) was added to the mixture under N2 at 0 °C. The resulting mixture was stirred at 60 °C for 1 h under N2. LCMS showed the 6,8- dichloro-5-fluoro-3,4-dimethyl-2H-2,7-naphthyridin-1-one was consumed completely and a peak (85%) with desired mass. The mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford tert-butyl (1R,4S,5S)-4-[1-[(3-chloro- 4-fluoro-5,6-dimethyl-8-oxo-7H-2,7-naphthyridin-1-yl)oxy]ethyl]-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (211 mg, 362.33 μmol, 77.14% yield, 85% purity) as white solid. MS (ES+) C24H32ClFN4O4 requires: 494, found: 495 [M+H]+. Step 8 85Attorney Docket No. MDA0094-401-PC Tert-butyl (4R,7S,8S)-13-chloro-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene-20- carboxylate

[0198] y , , , methyl-8- oxo-7H-2,7-naphthyridin-1-yl)oxy]ethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (211 mg, 426.28 μmol, 1 eq) in DMF (5 mL) were added DIEA (165.28 mg, 1.28 mmol, 222.75 μL, 3 eq) and CMPI (217.81 mg, 852.55 μmol, 2 eq). Then the mixture was stirred at 70 °C for 16 h. LCMS showed a peak (79%) with desired mass. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL x 2), then the organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-13% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-chloro-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene-20- carboxylate (128 mg, 262.99 μmol, 61.70% yield, 98% purity) as colorless solid. MS (ES+) C24H30ClN4FO3requires: 476, found: 477 [M+H]+. Step 9 Tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro- 4,9,16,17-tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate 86Attorney Docket No. MDA0094-401-PC [01, , , , , ethyl- 10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16- pentaene-20-carboxylate (50 mg, 104.83 μmol, 1 eq), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (47.50 mg, 157.24 μmol, 1.5 eq) and K3PO4(3 M, 104.83 μL, 3 eq) in THF (1 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (7.63 mg, 10.48 μmol, 0.1 eq) at 25 °C under N2. Then the mixture was stirred at 60 °C for 16 h under N2. LCMS showed a peak (84%) with desired mass. The mixture was diluted with ethyl acetate (10 mL), and dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-33% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (48 mg, 74.73 μmol, 71.28% yield, 96% purity) as colorless solid. MS (ES+) C31H36N6F4O3 requires: 616, found: 617 [M+H]+. Step 10 4-[(4R,7S,8S)-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine87Attorney Docket No. MDA0094-401-PC

[0200] To a solution of tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)- 4-pyridyl]-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (48 mg, 77.84 μmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 25 °C. Then the mixture was stirred at 25 °C for 20 min. LCMS showed one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:15%-45% B over 10 min) and lyophilized to afford 4- [(4R,7S,8S)-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine (23.4 mg, 41.60 μmol, 53.44% yield, 100% purity, FA) as yellow solid. MS (ES+) C26H28F4N6O requires: 516, found: 517 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.54 - 8.44 (m, 1H), 6.51 - 6.18 (m, 1H), 5.08 (d, J = 14.1 Hz, 1H), 4.63-4.48 (m, 1H), 4.06 (d, J = 9.2 Hz, 1H), 3.97 (d, J = 6.4 Hz, 1H), 3.19 (d, J = 14.2 Hz, 1H), 2.89 - 2.73 (m, 1H), 2.63 - 2.47 (m, 9H), 2.12 - 1.91 (m, 2H), 1.78 - 1.65 (m, 1H), 1.59 - 1.46 (m, 6H). EXAMPLE 2 isopropyl (5aS,6S,9R)-2-(romethoxy)phenyl)-1-fluoro- 5,13,14-trimethyl-5a,6,7,8-tetrahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-9(10H)-carboxylate Step 1 tert-butyl (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate 88Attorney Docket No. MDA0094-401-PC

[0201] To a solu3,8- diazabicyclo[3.2.1]octane-8-carboxylate (6 g, 24.76 mmol, 1 eq) in MeCN (120 mL) was added BnBr (4.45 g, 26.00 mmol, 3.09 mL, 1.05 eq) and K2CO3(5.13 g, 37.14 mmol, 1.5 eq) at 20 °C, the mixture was stirred at 20 °C for 16 h. TLC (Dichloromethane : Methanol = 101) showed the tert-butyl (1S,2S,5R)-2- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate was consumed completely and one new spot was formed. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1S,2S,5R)-3-benzyl-2- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.1 g, 21.36 mmol, 86.25% yield) as yellow oil. MS (ES+) C19H28N2O3 requires: 332, found: 333 [M+H]+. Step 2 tert-butyl (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0202] To a solution of oxalyl dichloride (5.12 g, 40.37 mmol, 3.53 mL, 2.2 eq) in DCM (140 mL) was added DMSO (6.31 g, 80.74 mmol, 6.31 mL, 4.4 eq) at -70 °C under N2, then the mixture was stirred at -70 °C for 20 min, to the mixture was added tert-butyl (1S,2S,5R)- 3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.1 g, 18.35 mmol, 1 eq) in DCM (20 mL) at -70 °C under N2, The mixture was stirred at -70 °C for 40 min, to the mixture was added TEA (14.85 g, 146.80 mmol, 20.43 mL, 8 eq) and stirred at - 70 °C for 0.5 h. LCMS showed a peak (53%) with the desired mass. The mixture was poured into water (200 mL). The aqueous phase was extracted with DCM (100 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1S,2S,5R)-3- 89Attorney Docket No. MDA0094-401-PC benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 15.13 mmol, 82.47% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 9.61 (d, J = 2.6 Hz, 1H), 7.37 - 7.23 (m, 5H), 4.17 - 4.09 (m, 1H), 3.77 (d, J = 13.6 Hz, 1H), 3.32 (s, 2H), 3.27 (d, J = 13.6 Hz, 1H), 3.11 - 2.98 (m, 1H), 2.22 - 2.12(m,1H), 1.94 - 1.85 (m, 1H), 1.81 - 1.63 (m, 3H), 1.38 (s, 9H). Step 3 tert-butyl (1S,2S,5R)-3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0203] To a solutioy , , y yl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 15.13 mmol, 1 eq) in THF (50 mL) was added MeMgBr (3 M, 15.13 mL, 3 eq) slowly at -78 °C under N2. The mixture was stirred at -78 °C for 2 h under N2. TLC (Petroleum ether : Ethyl acetate = 2:1 ) and LCMS showed the tert- butyl (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely. The mixture was quenched by sat. aq. NH4Cl (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 2-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1S,2S,5R)-3-benzyl-2-(1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.7 g, 9.93 mmol, 65.63% yield, 93% purity) as colorless oil. MS (ES+) C20H30N2O3 requires: 346, found: 347 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.36 - 7.28 (m, 4H), 7.27 - 7.23 (m, 1H), 4.45 - 4.28 (m, 1H), 4.16 - 3.97 (m, 2H), 3.87 - 3.75 (m, 1H), 3.07 - 2.99 (m, 1H), 2.69 - 2.20 (m, 3H), 1.93 - 1.61 (m, 4H), 1.55 - 1.41 (m, 9H), 1.40 - 1.28 (m, 3H). Step 4 tert-butyl (1S,2S,5R)-3-benzyl-2-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate 90Attorney Docket No. MDA0094-401-PC

[0204] To a soyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3.7 g, 10.68 mmol, 1 eq) in DCM (37 mL) were added imidazole (2.18 g, 32.04 mmol, 3 eq) and TBSCl (2.41 g, 16.02 mmol, 1.97 mL, 1.5eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the tert-butyl (1S,2S,5R)- 3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate remained and then the mixture was stirred at 25°C for another 16 h. LCMS showed the tert-butyl (1S,2S,5R)-3- benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate remained and a peak (72%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 2-16% ethyl acetate / petroleum ether gradient @ 150 mL / min) to afford tert-butyl (1S,2S,5R)-3- benzyl-2-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 8.07 mmol, 75.61% yield, 93% purity) as colorless oil. MS (ES+) C26H44N2O3Si requires: 460, found: 461 [M+H]+. Step 5 O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-[1-[tert-butyl(dimethyl)silyl]oxyethyl]- 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate

[0205] To a solution of tert-butyl (1S,2S,5R)-3-benzyl-2-[1-[tert- butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 7.60 mmol, 1 eq) in THF (35 mL) were added TMEDA (2.65 g, 22.79 mmol, 3.44 mL, 3 eq) and s-BuLi (1.3 M, 17.53 mL, 3 eq) slowly at -40 °C under N2. The mixture was stirred at 0 °C for 0.5 h. The methyl carbonochloridate (2.52 g, 26.67 mmol, 2.06 mL, 3.51 eq) was added to the mixture at -78 °C under N2. The mixture was stirred at 0 °C for 1.5 h under N2. LCMS showed a peak (76%) with desired mass. The mixture was quenched by sat. aq. NH4Cl (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by 91Attorney Docket No. MDA0094-401-PC flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-3-6% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane- 1,8-dicarboxylate (3.2 g, 5.55 mmol, 73.08% yield, 90% purity) as colorless oil. MS (ES+) C28H46N2O5Si requires: 518, found: 519 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.37 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 4.53 - 4.37 (m, 1H), 4.33 - 4.17 (m, 2H), 3.69 (s, 3H), 3.07 (d, J = 13.6 Hz, 1H), 2.90 (d, J = 11.4 Hz, 1H), 2.57 - 2.29 (m, 2H), 2.23 - 2.05 (m, 3H), 2.03 - 1.93 (m, 1H), 1.45 (s, 9H), 1.27 (d, J = 7.0 Hz, 3H), 0.92 - 0.90 (m, 9H), 0.11 - 0.07 (m, 6H). Step 6 O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate

[0206] To a so ut on o O8-tert-buty O1-met y (1R,4S,5S)-3-benzy -4-[1-[tert- butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (0.5 g, 963.84 μmol, 1 eq) in THF (5 mL) was added TBAF (1 M, 1.93 mL, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed a peak (80%) with desired mass. The mixture was quenched by sat. aq. NH4Cl (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate (372 mg, 836.89 μmol, 86.83% yield, 91% purity) as colorless oil. MS (ES+) C22H32N2O5 requires: 404, found: 405 [M+H]+. Step 7 O8-tert-butyl O1-methyl (1R,4S,5S)-4-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane- 1,8-dicarboxylate 92Attorney Docket No. MDA0094-401-PC

[0207] H)2 (135 mg, 192.26 μmol, 20% purity) in EtOH (5 mL) was added O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (370 mg, 914.71 μmol, 1 eq) in EtOH (1 mL) at 25 °C under N2. Then the mixture was degassed under vacuum and purged with H2(50 Psi) several times. The mixture was stirred under H2 (50 psi) at 25 °C for 16 hours. TLC (Petroleum ether : Ethyl acetate = 1:1) showed the material was consumed completely. The mixture was filtered and the filtrate was concentrated in vacuum to afford O8-tert-butyl O1-methyl (1R,4S,5S)-4-(1-hydroxyethyl)- 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (243 mg, 772.96 μmol, 84.50% yield) as white solid.1H NMR (400 MHz, CDCl3) δ = 4.29 - 3.99 (m, 1H), 3.77 (s, 3H), 3.56 - 3.42 (m, 1H), 3.33 - 3.13 (m, 1H), 2.82 - 2.57 (m, 1H), 2.31-2.18 (m, 1H), 2.09 - 1.91 (m, 4H), 1.90 - 1.80 (m, 1H), 1.46 (s, 9H), 1.23 (d, J = 6.1 Hz, 3H). Step 8 O8-tert-butyl O1-methyl (1R,4S,5S)-4-[1-[(3-chloro-4-fluoro-8-hydroxy-5,6-dimethyl- 2,7-naphthyridin-1-yl)oxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate

[0208] To a solution of NaH (18.77 mg, 469.21 μmol, 60% purity, 3.5 eq) in THF (3 mL) was added O8-tert-butyl O1-methyl (1R,4S,5S)-4-(1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate (43 mg, 136.78 μmol, 1.02 eq) at 0 °C under the protection of N2. The mixture was stirred at 0 °C for 10 min under N2. The 6,8-dichloro-5- fluoro-3,4-dimethyl-2H-2,7-naphthyridin-1-one (35.00 mg, 134.06 μmol, 1 eq) was added to the mixture at 0° C under N2. The mixture was stirred at 25 °C for 0.5 h under N2. LCMS 93Attorney Docket No. MDA0094-401-PC showed a peak (39%) with desired mass. The mixture was quenched by sat. aq. NH4Cl (5 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford O8-tert-butyl O1-methyl (1R,4S,5S)-4-[1-[(3-chloro-4-fluoro-8-hydroxy-5,6-dimethyl-2,7-naphthyridin-1- yl)oxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (0.1 g, crude) as white solid. MS (ES+) C25H32ClN4FO6requires: 538, found: 539 [M+H]+. Step 9 O20-tert-butyl O4-methyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 4,20-dicarboxylate

[0209] To a solution of O8-tert-butyl O1-methyl (1R,4S,5S)-4-[1-[(3-chloro-4-fluoro-8- hydroxy-5,6-dimethyl-2,7-naphthyridin-1-yl)oxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-1,8- dicarboxylate (0.1 g, 185.53 μmol, 1 eq) in DMF (2 mL) were added DIEA (71.94 mg, 556.59 μmol, 96.95 μL, 3 eq) and CMPI (94.80 mg, 371.06 μmol, 2 eq). Then the mixture was stirred at 70 °C for 2 h. LCMS showed the starting material was consumed completely and a peak (26%) with desired mass. The mixture was diluted with ethyl acetate (10 mL) and washed with brine (10 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-9% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O20-tert-butyl O4-methyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 4,20-dicarboxylate (15 mg, 28.50 μmol, 15.36% yield, 99% purity) as yellow solid. MS (ES+) C25H30ClN4FO5 requires: 520, found: 521 [M+H]+. Step 10 94Attorney Docket No. MDA0094-401-PC (4R,7S,8S)-20-tert-butoxycarbonyl-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 4-carboxylic acid [0210, , ro- 9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4,20-dicarboxylate (0.4 g, 767.78 μmol, 1 eq) in THF (4 mL) and MeOH (4 mL) was added LiOH·H2O (96.65 mg, 2.30 mmol, 3 eq) in H2O (2 mL). The mixture was stirred at 50 °C for 16 h. LCMS showed the starting material remained and a peak (80%) with desired mass. The mixture was concentrated in vacuum and diluted with water (10 mL) the aqueous phase was washed with ethyl acetate (20 mL x 2). The aqueous phase was adjusted to pH = 5 by aq. HCl (1M) at 0 °C. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 3-66% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford (4R,7S,8S)-20-tert- butoxycarbonyl-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4-carboxylic acid (360 mg, 568.10 μmol, 73.99% yield, 80% purity) as yellow solid. MS (ES+) C24H28ClN4FO5 requires: 506, found: 507 [M+H]+. Step 11 O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 4,20-dicarboxylate 95Attorney Docket No. MDA0094-401-PC [021,16,17- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylic acid (50 mg, 98.63 μmol, 1 eq) and K2CO3(136.3 mg, 986.3 μmol, 10 eq) in DMF (2 mL) was added 2-iodopropane (100.60 mg, 591.77 μmol, 59.07 μL, 6 eq) at 20 °C. The mixture was stirred at 20 °C for 16 h. LCMS showed the starting material was consumed completely and a peak (26%) with desired mass. The mixture was filtered and diluted with ethyl acetate (5 mL) and washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-33% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate (45 mg, 69.67 μmol, 70.64% yield, 85% purity) as yellow solid. MS (ES+) C27H34ClN4FO5requires: 548, found: 549 [M+H]+. Step 12 O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate96Attorney Docket No. MDA0094-401-PC

[0212] To a s solution of O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-chloro-14-fluoro- 9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4,20-dicarboxylate (45 mg, 81.96 μmol, 1 eq), 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)aniline (39.47 mg, 122.94 μmol, 1.5 eq) and K3PO4 (1.5 M, 163.92 μL, 3 eq) in THF (1 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3) (5.97 mg, 8.20 μmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 16 h under N2. LCMS showed the material was consumed completely and a peak (58%) with desired mass. The mixture was added water (2 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-27% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate (46 mg, 49.40 μmol, 60.27% yield, 76% purity) as yellow solid. MS (ES+) C34H38N5F5O6 requires: 707, found: 708 [M+H]+. Step 13 isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro- 9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylate

[0213] To a solution of O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate (46 mg, 65.00 μmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 20 °C. The mixture was stirred at 20 °C for 10 min. LCMS showed the starting material was consumed completely and one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: 97Attorney Docket No. MDA0094-401-PC Phenomenex luna C18150*25mm*10um;mobile phase: [water(FA)-ACN];gradient:24%- 54% B over 10 min) and lyophilized to afford isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4-carboxylate (19.2 mg, 31.60 μmol, 48.62% yield, 100% purity) as white solid. MS (ES+) C29H30F5N5O4requires: 607, found: 608 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.68 - 6.53 (m, 2H), 5.45 (d, J = 13.1 Hz, 1H), 5.18 - 5.07 (m, 1H), 4.48 - 4.36 (m, 1H), 3.93 (d, J = 9.3 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.12 (d, J = 13.2 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.62 - 2.48 (m, 6H), 1.90 - 1.67 (m, 3H), 1.52 (d, J = 6.4 Hz, 3H), 1.34 (dd, J = 1.3, 6.2 Hz, 6H).

[0214] The following Examples were synthesized with procedures that were similar to the examples disclosed herein and can generally be made by methods disclosed herein from the appropriate starting materials. EXAMPLE 3 cyclopropyl (5aS,6S,9R)-2-oromethoxy)phenyl)-1-fluoro- 5,13,14-trimethyl-5a,6,7,8-tetrahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-9(10H)-carboxylate

[0215] MS (ES+) C29H28F5N5O4 requires: 605, found: 606 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.36 - 8.27 (m, 1H), 6.68 - 6.54 (m, 2H), 5.41 (d, J = 13.2 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.33 - 4.24 (m, 1H), 4.00 - 3.88 (m, 1H), 3.66 - 3.58 (m, 1H), 3.14 (d, J = 13.1 Hz, 1H), 2.88 - 2.77 (m, 1H), 2.65 - 2.49 (m, 6H), 1.91 - 1.71 (m, 3H), 1.52 (d, J = 6.4 Hz, 3H), 0.88 - 0.71 (m, 4H). EXAMPLE 4 98Attorney Docket No. MDA0094-401-PC methyl (5aS,6S,9R)-2-(6- ethyl)pyridin-4-yl)-1-fluoro-13,14-dimethyl-5a,6,7,8-tetrahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-9(10H)-carboxylate

[0216] MS (ES+) C26H26F4N6O3requires: 546, found: 547 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.44 - 6.26 (m, 1H), 4.63 - 4.40 (m, 3H), 4.03 - 3.93 (m, 1H), 3.89 (s, 3H), 3.86 - 3.77 (m, 1H), 3.53 - 3.44 (m, 1H), 2.62 - 2.50 (m, 10H), 2.41 - 2.32 (m, 1H), 2.15 - 1.98 (m, 2H). EXAMPLE 5 methyl (5aS,6S,9R)-2-(5-aoxy)phenyl)-1-fluoro-5,13,14- trimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxylate

[0217] MS (ES+) C27H26F5N5O4requires: 579, found: 580 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.68 - 6.56 (m, 2H), 5.50 (d, J = 14.1 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.11 - 4.01 (m, 2H), 3.94 (s, 3H), 3.41 (d, J = 14.1 Hz, 1H), 3.16 - 3.05 (m, 1H), 2.67 - 2.54 (m, 6H), 2.10 - 1.98 (m, 3H), 1.55 (d, J = 6.2 Hz, 3H). EXAMPLE 6 99Attorney Docket No. MDA0094-401-PC (5aS,6S,9R)-2-(6-amino-2- 0yridine-4-yl)-1-fluoro-13,14-dimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2’,1’:3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxamide Step 1 tert-butyl (4R,7S,8S)-4-carbamoyl-13-chloro-14-fluoro-16,17-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate

[0218] To a solution of (4R,7S,8S)-20-tert-butoxycarbonyl-13-chloro-14-fluoro-16,17- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylic acid (130 mg, 263.73 μmol, 1 eq), NH4Cl (56.43 mg, 1.05 mmol, 4 eq) and DIEA (340.85 mg, 2.64 mmol, 459.37 μL, 10 eq) in DMF (5 mL) was added HATU (200.56 mg, 527.46 μmol, 2 eq) at 25 °C. Then the mixture was stirred at 25 °C for 1 h. LCMS showed a main peak with desired mass. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 10-66% ethyl acetate / petroleum ether gradient @ 60 mL / min) to afford tert-butyl (4R,7S,8S)-4-carbamoyl-13- chloro-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (180 mg, crude) as white solid. 100Attorney Docket No. MDA0094-401-PC MS (ES+) C23H27ClN5FO4requires: 491, found: 492 [M+H]+. Step 2 tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-4-carbamoyl- 14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate [0] o a so ut on o tert- uty ( , , )- -car amoy - -c oro- - uoro- , 7- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (50 mg, 101.64 μmol, 1 eq) and 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (30.70 mg, 101.64 μmol, 1 eq) in THF (1 mL) were added K3PO4(1.5 M, 203.28 μL, 3 eq) and Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (7.40 mg, 10.16 μmol, 0.1 eq) under the protection of N2. Then the mixture was stirred at 60 °C for 16 h under N2. LCMS showed a peak (68%) with desired mass. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 4-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-4-carbamoyl-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (53 mg, 70.49 μmol, 69.35% yield, 84% purity) as yellow solid. MS (ES+) C30H33N7F4O4requires: 631, found: 632 [M+H]+. Step 3 101Attorney Docket No. MDA0094-401-PC (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-16,17- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxamide [022y , , y ethyl)- 4-pyridyl]-4-carbamoyl-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (53 mg, 83.91 μmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL, 48.13 eq) at 25 °C. Then the mixture was stirred at 25 °C for 10 min. LCMS showed a peak (86%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:8%-38% B over 10 min) and lyophilized to afford (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-16,17-dimethyl- 10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaene-4-carboxamide (11.2 mg, 17.35 μmol, 20.68% yield, 100% purity, TFA). MS (ES+) C25H25F4N7O2 requires: 531, found: 532 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.48 - 6.22 (m, 1H), 4.68 - 4.58 (m, 1H), 4.55 - 4.32 (m, 2H), 4.06 - 3.94 (m, 1H), 3.82 - 3.69 (m, 1H), 3.55 - 3.42 (m, 1H), 2.65 - 2.51 (m, 10H), 2.37 - 2.26 (m, 1H), 2.20 - 2.06 (m, 1H), 2.05 - 1.92 (m, 1H).

[0221] The following Examples were synthesized with procedures that were similar to the Examples disclosed herein and can generally be made by methods disclosed herein from the appropriate starting materials. EXAMPLE 7 102Attorney Docket No. MDA0094-401-PC (5aS,6S,9R)-2-(5-amino- phenyl)-1-fluoro-N,5,13,14-tetramethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxamide

[0222] MS (ES+) C27H27F5N6O3 requires: 578, found: 579 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.66 - 6.56 (m, 2H), 5.42 (d, J = 13.1 Hz, 1H), 4.49 - 4.38 (m, 1H), 3.88 (d, J = 8.9 Hz, 1H), 3.61 (d, J = 6.1 Hz, 1H), 3.08 (d, J = 12.9 Hz, 1H), 2.82 (s, 3H), 2.80 - 2.73 (m, 1H), 2.60 (s, 3H), 2.55 (d, J = 6.9 Hz, 3H), 1.93 - 1.70 (m, 3H), 1.50 (d, J = 6.4 Hz, 3H). EXAMPLE 8 (5aS,6S,9R)-2-(5-amino-3henyl)-1-fluoro-N,N,5,13,14- pentamethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxamide

[0223] MS (ES+) C28H29F5N6O3requires: 592, found: 593 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.66 - 6.55 (m, 2H), 5.53 (d, J = 13.8 Hz, 1H), 4.52 - 4.40 (m, 1H), 4.07 (d, J = 10.0 Hz, 1H), 3.61 - 3.52 (m, 4H), 3.20 - 3.08 (m, 2H), 3.03 (s, 3H), 2.59 - 2.51 (m, 6H), 2.01 - 1.74 (m, 3H), 1.56 (d, J = 6.3 Hz, 3H). 103Attorney Docket No. MDA0094-401-PC EXAMPLE 9 (5aS,6S,9R)-2-(6-amino-2- l)pyridin-4-yl)-1-fluoro-13,14-dimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carbonitrile Step 1 tert-butyl (4R,7S,8S)-13-chloro-4-cyano-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate

[0224] To a solution of tert-butyl (4R,7S,8S)-4-carbamoyl-13-chloro-14-fluoro-16,17- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (130 mg, 264.26 μmol, 1 eq) in DCM (3 mL) were added TEA (133.70 mg, 1.32 mmol, 183.91 μL, 5 eq) and TFAA (166.51 mg, 792.78 μmol, 110.20 μL, 3 eq) at 0 °C. Then the mixture was stirred at 20 °C for 1 h. LCMS showed a main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, eluent of 2-18% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-chloro-4-cyano-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (132 mg, 261.81 μmol, 99.07% yield, 94% purity) as yellow solid. MS (ES+) C23H25ClN5FO3requires: 473, found: 474 [M+H]+. Step 2 104Attorney Docket No. MDA0094-401-PC tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-4-cyano-14- fluoro-16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate [022y , , y , dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (65 mg, 137.15 μmol, 1 eq) and 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (62.15 mg, 205.73 μmol, 1.5 eq) in THF (1.2 mL) were added K3PO4(1.5 M, 274.30 μL, 3 eq) and Ad2nBuP Pd G3(cataCXium® A Pd G3) (9.99 mg, 13.72 μmol, 0.1 eq) under N2. Then the mixture was stirred at 60 °C for 16 h under N2. LCMS showed a peak (77%) with desired mass. The mixture was added water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-66% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-4-cyano- 14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (50 mg, 76.60 μmol, 55.85% yield, 94% purity) as yellow solid. MS (ES+) C30H31N7F4O3requires: 613, found: 614 [M+H]+. Step 3 (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-16,17- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carbonitrile 105Attorney Docket No. MDA0094-401-PC

[0226] , , romethyl)- 4-pyridyl]-4-cyano-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (45 mg, 73.34 μmol, 1 eq) in DCM (0.5 mL) was added HCl / dioxane (2 M, 1 mL) at 25 °C. Then the mixture was stirred at 25 °C for 20 min. LCMS showed the material remained and a peak (71%) with desired mass. The mixture was adjusted to pH = 7 by sat. aq. NaHCO3, extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)- ACN];gradient:28%-58% B over 10 min) and lyophilized to afford (4R,7S,8S)-13-[6-amino- 2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4-carbonitrile (7.5 mg, 14.61 μmol, 19.92% yield, 100% purity) as white solid. MS (ES+) C25H23N7F4O requires: 513, found: 514 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.40 - 6.26 (m, 1H), 4.52 - 4.28 (m, 3H), 3.83 - 3.69 (m, 1H), 3.58 (d, J = 6.1 Hz, 1H), 3.47 (d, J = 12.8 Hz, 1H), 2.64 - 2.49 (m, 9H), 2.46 - 2.22 (m, 2H), 2.17 - 2.06 (m, 1H), 2.03 - 1.89 (m, 1H). EXAMPLE 10106Attorney Docket No. MDA0094-401-PC 4-((5aS,6S,9R)-1-fluoro-9-(methoxymethyl)-13,14-dimethyl-5a,6,7,8,9,10-hexahydro-5H- 6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridin-2-yl)-6-methyl-5- (trifluoromethyl)pyridin-2-amine Step 1 tert-butyl (4R,7S,8S)-13-chloro-14-fluoro-4-(hydroxymethyl)-16,17-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate[ ] o a so u on o , , - - er - u oxycar ony - -c oro- - uoro- , - dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylic acid (330 mg, 669.47 μmol, 1 eq) in THF (6 mL) was added NMM (81.26 mg, 803.36 μmol, 88.32 μL, 1.2 eq) and isobutyl carbonochloridate (109.72 mg, 803.36 μmol, 105.10 μL, 1.2 eq) at -10 °C under N2. Then the mixture was stirred at -10 °C for 0.5 h under N2. Then the mixture was added dropwise into a solution of NaBH4(0.08 g, 2.11 mmol, 3.16 eq) in H2O (3 mL) at 0 °C under N2. The resulting mixture was stirred at 0 °C for another 0.5 h under N2. LCMS showed the material remained and a peak (47%) with desired mass. The mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with brine (10 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (25 g SepaFlash® Silica Flash Column, eluent of 0-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-chloro- 14-fluoro-4-(hydroxymethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (100 mg, 150.33 μmol, 22.46% yield, 72% purity) as white solid. MS (ES+) C23H28ClN4FO4 requires: 478, found: 479 [M+H]+. Step 2 107Attorney Docket No. MDA0094-401-PC tert-butyl (4R,7S,8S)-13-chloro-14-fluoro-4-(methoxymethyl)-16,17-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate

[0228] , , ymethyl)- 16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (20 mg, 41.76 μmol, 1 eq) in DCM (2 mL) was added trimethyloxonium tetrafluoroborate (6.49 mg, 43.85 μmol, 1.05 eq) at 25 °C under the protection of N2. Then the mixture was stirred at 25 °C for 1 h under N2. TLC (Plate 1 Petroleum ether : Ethyl acetate = 2:1) showed the material was consumed completely and one new spot was formed. The mixture was quenched by sat. aq. NaHCO3(5 mL) and extracted with ethyl acetate (3 mL x 2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 2:1)to afford tert-butyl (4R,7S,8S)-13-chloro-14-fluoro-4- (methoxymethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (20 mg, 35.70 μmol, 85.50% yield, 88% purity) as white solid. MS (ES+) C24H30ClN4FO4requires: 492, found: 493 [M+H]+. Step 3 tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-4- (methoxymethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate 108Attorney Docket No. MDA0094-401-PC, , 16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (20 mg, 40.57 μmol, 1 eq), 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (18.38 mg, 60.86 μmol, 1.5 eq) and K3PO4 (1.5 M, 81.14 μL, 3 eq) in THF (1 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3) (2.95 mg, 4.06 μmol, 0.1 eq) under N2. Then the mixture was stirred at 60 °C for 16 h under N2. LCMS showed a peak (51%) with desired mass. The mixture was added water (2 mL) and extracted with ethyl acetate (3 mL x 2). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-66% ethyl acetate / petroleum ether gradient @ 60 mL / min) to afford tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-4- (methoxymethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (40 mg, crude) as colorless oil. MS (ES+) C31H36N6F4O4 requires: 632, found: 633 [M+H]+. Step 4 4-[(4R,7S,8S)-14-fluoro-4-(methoxymethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine 109Attorney Docket No. MDA0094-401-PC Boc H N N O O [0, , hyl)- 4-pyridyl]-14-fluoro-4-(methoxymethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (25 mg, 39.52 μmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 25 °C. Then the mixture was stirred at 25 °C for 10 min. LCMS showed a peak (71%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:18%-38% B over 10 min) and lyophilized to afford 4- [(4R,7S,8S)-14-fluoro-4-(methoxymethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine (6.9 mg, 11.93 μmol, 30.18% yield, 100% purity, FA) as white solid. MS (ES+) C26H28F4N6O2 requires: 532, found: 533 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.56 - 8.46 (m, 1H), 6.46 - 6.26 (m, 1H), 4.65 - 4.46 (m, 2H), 4.21 - 4.01 (m, 1H), 3.97 - 3.75 (m, 2H), 3.72 - 3.57 (m, 2H), 3.50 - 3.40 (m, 4H), 2.72 - 2.40 (m, 10H), 2.12 - 1.94 (m, 2H), 1.86 - 1.72 (m, 1H).

[0231] The following Example was synthesized with procedures that were similar to the Examples disclosed herein and can generally be made by methods disclosed herein from the appropriate starting materials. EXAMPLE 11 110Attorney Docket No. MDA0094-401-PC ((5aS,6S,9R)-2-(6-amino pyridin-4-yl)-1-fluoro-13,14-dimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-9(10H)-yl)methanol

[0232] MS (ES+) C25H26F4N6O2 requires: 518, found: 519 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.56 - 8.41 (m, 1H), 6.23 (s, 1H), 4.68 - 4.48 (m, 2H), 4.20 - 4.01 (m, 2H), 3.93 - 3.75 (m, 3H), 3.57 - 3.46 (m, 1H), 2.74 - 2.48 (m, 10H), 2.17 - 1.98 (m, 2H), 1.93 - 1.80 (m, 1H). EXAMPLE 12 4-((5aS,6S,9R)-1-fluoro-9-(flyl-5a,6,7,8,9,10-hexahydro-5H- 6,9-epiminoazepino[2’,1’:3,4][1,4]oxazepino[5,6,7-ij][2,7]pyridine111dine-2-yl)-6- methyl-5-(trifluoromethyl)pyridine-2-amine Step 1 [(4R,7S,8S)-20-benzyl-13-chloro-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-4- yl]methanol 111Attorney Docket No. MDA0094-401-PC [- 16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (40 mg, 83.52 μmol, 1 eq) in DCM (0.3 mL) was added HCl / dioxane (2 M, 0.6 mL) at 25 °C. Then the mixture was stirred at 25°C for 10 min. LCMS showed the material was consumed completely and a peak (39% + 36%) with desired mass. The mixture was concentrated in vacuum. The residue was diluted with MeCN (2 mL), and the suspension was added K2CO3 (34.63 mg, 250.55 μmol, 3 eq) and BnBr (14.28 mg, 83.52 μmol, 9.92 μL, 1 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed a peak (41%) with desired mass. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 1： 1) to afford [(4R,7S,8S)-20-benzyl-13-chloro-14-fluoro-16,17-dimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaen-4-yl]methanol (23 mg, 49.05 μmol, 58.73% yield, 100% purity) as colorless solid. MS (ES+) C25H26ClN4FO2requires: 468, found: 469 [M+H]+. Step 2 (4R,7S,8S)-20-benzyl-13-chloro-14-fluoro-4-(fluoromethyl)-16,17-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene

[0234] To a solution of [(4R,7S,8S)-20-benzyl-13-chloro-14-fluoro-16,17-dimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaen-4-yl]methanol (23 mg, 49.05 μmol, 1 eq) in DCM (1 mL) was added DAST (23.72 mg, 147.14 μmol, 19.44 μL, 3 eq) at 0 °C. Then the mixture was stirred at 25 °C for 22 h. 112Attorney Docket No. MDA0094-401-PC LCMS showed the [(4R,7S,8S)-20-benzyl-13-chloro-14-fluoro-16,17-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-4- yl]methanol remained and a peak (25 %) with desired mass. The mixture was quenched by sat. aq. NaHCO3(5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 3:1) to afford (4R,7S,8S)-20- benzyl-13-chloro-14-fluoro-4-(fluoromethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene (8 mg, 16.31 μmol, 33.25% yield, 96% purity) as colorless solid. MS (ES+) C25H25ClN4F2O requires: 470, found: 471 [M+H]+. Step 3 4-[(4R,7S,8S)-20-benzyl-14-fluoro-4-(fluoromethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine

[0235] To a solution of (4R,7S,8S)-20-benzyl-13-chloro-14-fluoro-4-(fluoromethyl)- 16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene (8 mg, 16.99 μmol, 1 eq), 6-methyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (7.70 mg, 25.48 μmol, 1.5 eq) and K3PO4 (1.5 M, 33.97 μL, 3 eq) in THF (0.5 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3) (1.24 mg, 1.70 μmol, 0.1 eq) at 25 °C under N2. Then the mixture was stirred at 60 °C for 16 h under N2. LCMS showed the (4R,7S,8S)-20-benzyl-13-chloro-14-fluoro-4- (fluoromethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene was consumed completely and a peak (39 %) with desired mass. The mixture was diluted with ethyl acetate (10 mL) and dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC (Petroleum ether : Ethyl acetate = 1:1) to afford 4- 113Attorney Docket No. MDA0094-401-PC [(4R,7S,8S)-20-benzyl-14-fluoro-4-(fluoromethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine (10 mg, 15.89 μmol, 93.51% yield, 97% purity) as colorless oil. MS (ES+) C32H31N6F5O requires: 610, found: 611 [M+H]+. Step 4 4-[(4R,7S,8S)-14-fluoro-4-(fluoromethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine

[0236] o a suspens on o (O )2( 0 mg, . μmo , 0% purty) an C ( 0 mg, 9.40 μmol, 10% purity) in EtOH (3 mL) was added 4-[(4R,7S,8S)-20-benzyl-14-fluoro-4- (fluoromethyl)-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine (10 mg, 16.38 μmol, 1 eq) in EtOH (1 mL) at 25 °C under N2. Then the mixture was degassed under vacuum and purged with H2 (50 Psi) several times. The mixture was stirred under H2 (50 psi) at 25 °C for 16 hours. LCMS showed a peak (87 %) with desired mass. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:16%-46% B over 10 min) and lyophilized to afford 4-[(4R,7S,8S)-14-fluoro-4-(fluoromethyl)-16,17-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13- yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine (2.0 mg, 3.84 μmol, 23.46% yield, 100% purity) as white solid. MS (ES+) C25H25N6F5O requires: 520, found: 521 [M+H]+. 114Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, CD3OD) δ = 6.48 - 6.25 (m, 1H), 4.63 - 4.56 (m, 1H), 4.52 - 4.45 (m, 1H), 4.38 - 4.22 (m, 1H), 3.91 - 3.82 (m, 1H), 3.44 - 3.33 (m, 2H), 2.60 (s, 3H), 2.58 - 2.52 (m, 6H), 2.35 - 2.20 (m, 2H), 2.11-2.04 (m, 1H), 1.93 - 1.78 (m, 2H), 1.76 - 1.67 (m, 1H). EXAMPLE 13 4-[(4R,7S,8S)-14-fl hyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine Step 1 tert-butyl (1S,2S,5R)-3-benzyl-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate

[0237] To a solution of tert-butyR)-3-benzyl-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (0.5 g, 1.50 mmol, 1 eq) in DCM (10 mL) was added imidazole (307.19 mg, 4.51 mmol, 3 eq) and TBSCl (272.03 mg, 1.80 mmol, 222.07 μL, 1.2 eq) at 20 °C. Then the mixture was stirred at 20 °C for 16 h. TLC (Plate 1 Dichloromethane : Methanol = 10:1) showed the tert-butyl (1S,2S,5R)-3-benzyl-2- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot was formed. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-9% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give tert-butyl (1S,2S,5R)-3- benzyl-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.28 mmol, 85.18% yield, 97% purity) as yellow solid. MS (ES+) C25H42N2O3Si requires: 446, found: 447 [M+H]+. 115Attorney Docket No. MDA0094-401-PC Step 2 tert-butyl (1R,4S,5S)-3-benzyl-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate a solution of tert-butyl (1S,2S,5R)-3-benzyl-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (590 mg, 1.32 mmol, 1 eq) and TMEDA (460.45 mg, 3.96 mmol, 597.99 μL, 3 eq) in THF (5 mL) was slowly added s-BuLi (1.3 M, 3.05 mL, 3 eq) at -40 °C under N2. Then the mixture was stirred at 0 °C for 0.5 h. Then the MeI (656.16 mg, 4.62 mmol, 287.79 μL, 3.5 eq) was added dropwised to the mixture at -78 °C under N2. Then the mixture was stirred at 0 °C for 1.5 h under N2. TLC (Plate 1 Petroleum ether : Ethyl acetate = 8:1) showed the tert-butyl (1S,2S,5R)-3-benzyl-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate was consumed completely and two new spots were formed. The mixture was quenched by sat. aq. Na2CO3(4 mL), then the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-6% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4- [[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (480 mg, 948.08 μmol, 71.78% yield, 91% purity) as colorless oil. MS (ES+) C26H44N2O3Si requires: 460, found: 461 [M+H]+. Step 3 tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate, , benzyl-4-[[tert- butyl(dimethyl)silyl]oxymethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (480 mg, 1.04 mmol, 1 eq) in THF (5 mL) was added TBAF (1 M, 2.08 mL, 2 eq) at 25 °C. Then 116Attorney Docket No. MDA0094-401-PC the mixture was stirred at 25 °C for 1 h. TLC (Plate 1 Petroleum ether : Ethyl acetate = 5:1) showed the tert-butyl (1R,4S,5S)-3-benzyl-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot formed. The mixture was diluted with ethyl acetate (20 mL) and washed with sat. aq. NH4Cl（10 mL x 2, then the organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (346 mg, 968.70 μmol, 92.98% yield, 97% purity) as colorless oil. MS (ES+) C20H30N2O3requires: 346, found: 347 [M+H]+. Step 4 tert-butyl (1R,4S,5S)-3-benzyl-4-formyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate

[0240] To a solution of (COCl)2 (278.86 mg, 2.20 mmol, 192.32 μL, 2.2 eq) in DCM (10 mL) was added DMSO (195.07 mg, 2.50 mmol, 195.07 μL, 2.5 eq) in DCM (2 mL) at -78 °C under N2. Then the mixture was stirred at -78 °C for 20 min. Then tert-butyl (1R,4S,5S)-3- benzyl-4-(hydroxymethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (346 mg, 998.66 μmol, 1 eq) in DCM (2 mL) was added to the mixture at -78 °C under N2. Then the mixture was stirred at -78 °C for 40 min under N2. Then the TEA (808.43 mg, 7.99 mmol, 1.11 mL, 8 eq) was added to the mixture at -78 °C under N2. The resulting mixture was stirred at -78 °C for 0.5 h under N2. TLC (Plate 1 Petroleum ether : Ethyl acetate = 2:1) showed the tert-butyl (1R,4S,5S)-3-benzyl-4-(hydroxymethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot formed. The mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-9% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4-formyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (280 mg, 569.03 μmol, 56.98% yield, 70% purity) as colorless oil. 117Attorney Docket No. MDA0094-401-PC MS (ES+) C20H28N2O3requires: 344, found: 345 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 9.67 - 9.52 (m, 1H), 7.34-7.21 (m, 5H), 4.31 (d, J = 6.0 Hz, 1H), 3.75 (d, J = 13.5 Hz, 1H), 3.23 (d, J = 13.5 Hz, 1H), 3.12 (s, 1H), 2.45 (d, J = 11.0 Hz, 1H), 2.24 (d, J = 10.9 Hz, 1H), 1.99 - 1.60 (m, 4H), 1.43 (s, 9H), 1.41 - 1.38 (m, 3H). Step 5 tert-butyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate S)-3-benzyl-4-formyl-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (280 mg, 812.90 μmol, 1 eq) in THF (7.5 mL) was added MeMgBr (3 M, 1.63 mL, 6 eq) at -78 °C under N2. Then the mixture was stirred at -78 °C for 2 h under N2. LCMS showed the tert-butyl (1R,4S,5S)-3-benzyl-4-formyl-1-methyl- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and a peak (75%) with desired mass. The mixture was quenched by water (10mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 488.23 μmol, 60.06% yield, 88% purity) as colorless oil. MS (ES+) C21H32N2O3 requires: 360, found: 361 [M+H]+. Step 6 tert-butyl (1R,4S,5S)-4-(1-hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate. g, 284.83 μmol, 20% purity) and Pd / C (0.2 g, 1.88 mmol, 10% purity) in MeOH (5 mL) was added tert-butyl (1R,4S,5S)-3-benzyl-4-(1- hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 554.80 μmol, 118Attorney Docket No. MDA0094-401-PC 1 eq) in MeOH (2 mL) at 25 °C under N2. Then the mixture was degassed under vacuum and purged with H2for several times. The mixture was stirred under H2(50psi) at 25°C for 16 hours. TLC (Plate 1 Petroleum ether : Ethyl acetate = 3:1) showed the tert-butyl (1R,4S,5S)- 3-benzyl-4-(1-hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely and one new spot formed. The mixture was filtered through celite, the filtrate was concentrated in vacuum to give tert-butyl (1R,4S,5S)-4-(1-hydroxyethyl)-1- methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (127 mg, 469.73 μmol, 84.67% yield) as colorless oil. Step 7 tert-butyl (1R,4S,5S)-4-[1-[(3-chloro-4-fluoro-5,6-dimethyl-8-oxo-7H-2,7-naphthyridin- 1-yl)oxy]ethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate% purity, 3.5 eq) in THF (5 mL) was added tert-butyl (1R,4S,5S)-4-(1-hydroxyethyl)-1-methyl-3,8-diazabicyclo[3.2.1]octane- 8-carboxylate (127 mg, 469.73 μmol, 1 eq) in THF (1 mL) at 0 °C under N2. Then the mixture was stirred at 0 °C for 10 min. Then 6,8-dichloro-5-fluoro-3,4-dimethyl-2H-2,7- naphthyridin-1-one (122.64 mg, 469.73 μmol, 1 eq) was added to the mixture under N2 at 0 °C. The resulting mixture was stirred at 60 °Cunder N2. LCMS showed the 6,8- dichloro-5-fluoro-3,4-dimethyl-2H-2,7-naphthyridin-1-one was consumed completely and a peak (85%) with desired mass. The mixture was quenched by water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford tert-butyl (1R,4S,5S)-4-[1-[(3-chloro- 4-fluoro-5,6-dimethyl-8-oxo-7H-2,7-naphthyridin-1-yl)oxy]ethyl]-1-methyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (211 mg, 362.33 μmol, 77.14% yield, 85% purity) as white solid. MS (ES+) C24H32ClFN4O4 requires: 494, found: 495 [M+H]+. Step 8 119Attorney Docket No. MDA0094-401-PC tert-butyl (4R,7S,8S)-13-chloro-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene-20- carboxylate -fluoro-5,6-dimethyl-8-oxo-7H-2,7-naphthyridin-1-yl)oxy]ethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (211 mg, 426.28 μmol, 1 eq) in DMF (5 mL) were added DIEA (165.28 mg, 1.28 mmol, 222.75 μL, 3 eq) and CMPI (217.81 mg, 852.55 μmol, 2 eq). Then the mixture was stirred at 70 °C for 16 h. LCMS showed a peak (79%) with desired mass. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL x 2), then the organic phase was dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-13% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-chloro-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene-20-carboxylate (128 mg, 262.99 μmol, 61.70% yield, 98% purity) as colorless solid. MS (ES+) C24H30ClN4FO3 requires: 476, found: 477 [M+H]+. Step 9 tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro- 4,9,16,17-tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate 120Attorney Docket No. MDA0094-401-PC -10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16- pentaene-20-carboxylate (50 mg, 104.83 μmol, 1 eq), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (47.50 mg, 157.24 μmol, 1.5 eq) and K3PO4(3 M, 104.83 μL, 3 eq) in THF (1 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (7.63 mg, 10.48 μmol, 0.1 eq) at 25 °C under N2. Then the mixture was stirred at 60 °C for 16 h under N2. LCMS showed a peak (84%) with desired mass. The mixture was diluted with ethyl acetate (10 mL), and dried with anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-33% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (48 mg, 74.73 μmol, 71.28% yield, 96% purity) as colorless solid. MS (ES+) C31H36N6F4O3 requires: 616, found: 617 [M+H]+. Step 10 4-[(4R,7S,8S)-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-6- methyl-5-(trifluoromethyl)pyridin-2-amine 121Attorney Docket No. MDA0094-401-PC -(trifluoromethyl)-4-pyridyl]-14-fluoro-4,9,16,17-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (48 mg, 77.84 μmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 25 °C. Then the mixture was stirred at 25 °C for 20 min. LCMS showed one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)- ACN];gradient:15%-45% B over 10 min) and lyophilized to afford 4-[(4R,7S,8S)-14-fluoro- 4,9,16,17-tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-13-yl]-6-methyl-5-(trifluoromethyl)pyridin-2-amine (23.4 mg, 41.60 μmol, 53.44% yield, 100% purity, FA)as yellow solid. MS (ES+) C26H28F4N6O requires: 516, found: 517 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.54 - 8.44 (m, 1H), 6.51 - 6.18 (m, 1H), 5.08 (d, J = 14.1 Hz, 1H), 4.63-4.48 (m, 1H), 4.06 (d, J = 9.2 Hz, 1H), 3.97 (d, J = 6.4 Hz, 1H), 3.19 (d, J = 14.2 Hz, 1H), 2.89 - 2.73 (m, 1H), 2.63 - 2.47 (m, 9H), 2.12 - 1.91 (m, 2H), 1.78 - 1.65 (m, 1H), 1.59 - 1.46 (m, 6H). EXAMPLE 14122Attorney Docket No. MDA0094-401-PC 2-((5aS,6S,9R)-2-(5-amino-3-fluoro-2-(trifluoromethoxy)phenyl)-1-fluoro-5,9,14- trimethyl-5a,6,7,8,9,10-hexahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridin-13-yl)propan-2-ol

[0247] Synthesized according to the procedure of Example 13. MS (ES+) C28H30F5N5O3 requires:579, found:580 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.49 (s, 1H), 6.70 - 6.55 (m, 2H), 5.04 (d, J = 13.8 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.06 (d, J = 9.0 Hz, 1H), 3.89 (d, J = 6.2 Hz, 1H), 3.18 (d, J = 14.1 Hz, 1H), 2.83 (d, J = 9.0 Hz, 3H), 2.68 - 2.57 (m, 1H), 2.09 - 1.86 (m, 2H), 1.75 - 1.65 (m, 7H), 1.55 (d, J = 6.4 Hz, 3H), 1.50 (s, 3H). EXAMPLE 15 3-((5aS,6S,9R)-13-(2-(dim,9,14-trimethyl-5a,6,7,8,9,10- hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridin-2- yl)-5-fluoro-4-(trifluoromethoxy)aniline

[0248] Synthesized according to the procedure of Example 13. MS (ES+) C29H33F5N6O2 requires: 592, found: 593 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.67 - 6.57 (m, 2H), 4.93 (d, J = 14.1 Hz, 1H), 4.63 - 4.54 (m, 1H), 4.12 - 3.98 (m, 2H), 3.63 - 3.46 (m, 2H), 3.43 - 3.32 (m, 2H), 3.30 - 3.24 (m, 1H), 2.95 (s, 6H), 2.68 - 2.57 (m, 4H), 2.12 - 2.01 (m, 2H), 1.84 - 1.73 (m, 1H), 1.57 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H). EXAMPLE 16 123Attorney Docket No. MDA0094-401-PC H N 5-[(4R,7S,8S)-17-[2-(dimet 6-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-2,3- difluoro-4-(trifluoromethoxy)aniline

[0249] Synthesized according to the procedure of Example 13.

[0250] MS (ES+) C29H32F6N6O2 requires: 610, found: 611 [M+H]+.

[0251] 1H NMR (400 MHz, CD3OD) δ = 6.80 (dd, J = 2.1, 8.8 Hz, 1H), 5.00 -4.99 (m, 1H), 4.70 - 4.62 (m, 1H), 4.19 - 4.12 (m, 2H), 3.74 - 3.59 (m, 2H), 3.44 - 3.36 (m, 3H), 3.05 (s, 6H), 2.73 - 2.64 (m, 4H), 2.21 - 2.11 (m, 2H), 1.95 - 1.83 (m, 1H), 1.65 (s, 3H), 1.54 (d, J = 6.5 Hz, 3H). EXAMPLE 17 2-amino-4-[(4R,7S,8S,9fluoro-4,9,16-trimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen- 13-yl]-7-fluoro-benzothiophene-3-carbonitrile

[0252] Synthesized according to the procedure of Example 13. MS (ES+) C31H33F2N7OS requires: 589, found: 590 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.39 (s, 1H), 7.44 - 7.35 (m, 1H), 7.09 - 7.00 (m, 1H), 5.09 - 5.00 (m, 1H), 4.63 - 4.53 (m, 1H), 4.15 - 4.07 (m, 1H), 4.05 - 3.98 (m, 1H), 3.64 - 3.47 (m, 2H), 3.39 - 3.33 (m, 2H), 3.29 - 3.23 (m, 1H), 2.95 (s, 6H), 2.70 - 2.61 (m, 4H), 2.11 - 1.98 (m, 2H), 1.84 - 1.72 (m, 1H), 1.62 - 1.53 (m, 6H). 124Attorney Docket No. MDA0094-401-PC EXAMPLE 18 5-[(4R,7S,8S,9S)-16-chloro 4-fluoro-4,9-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13- yl]-2,3-difluoro-4-(trifluoromethoxy)aniline

[0253] Synthesized according to the procedure of Example 13. MS (ES+) C28H29ClF6N6O2 requires: 630, found: 631 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.66 - 8.48 (m, 1H), 6.83 - 6.72 (m, 1H), 5.03 (s, 1H), 4.51 - 4.42 (m, 1H), 3.98 (d, J = 9.3 Hz, 1H), 3.56 - 3.51 (m, 1H), 3.27 - 3.24 (m, 2H), 3.04 - 2.95 (m, 3H), 2.48 (s, 6H), 2.38 - 2.28 (m, 1H), 1.93 - 1.66 (m, 2H), 1.54 (d, J = 6.4 Hz, 3H), 1.50 - 1.43 (m, 1H), 1.35 (s, 3H). EXAMPLE 19 H N 3-[(4R,7S,8S,9S)-17-[2-(difluoro-9,16-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13- yl]-5-fluoro-4-(trifluoromethoxy)aniline

[0254] Synthesized according to the procedure of Example 13. MS (ES+) C30H35F5N6O2 requires: 606 found: 607[M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.49 - 8.36 (m, 1H), 6.68 - 6.56 (m, 2H), 5.18 (d, J = 14.1 Hz, 1H), 4.61 - 4.53 (m, 1H), 4.17 - 4.08 (m, 1H), 4.03 - 3.94 (m, 1H), 3.61 - 3.35 (m, 4H), 125Attorney Docket No. MDA0094-401-PC 3.21 (d, J = 13.6 Hz, 1H), 2.92 (s, 6H), 2.68 - 2.57 (m, 4H), 2.09 - 1.86 (m, 4H), 1.83 - 1.72 (m, 1H), 1.54 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H). EXAMPLE 20 3-fluoro-5-[(4R,7S,8S,9S)-1 1-methylazetidin-3-yl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13- yl]-4-(trifluoromethoxy)aniline

[0255] Synthesized according to the procedure of Example 13. MS (ES+) C29H31F5N6O2 requires:590, found: 591 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.51 (s, 1H), 6.67 - 6.54 (m, 2H), 5.08 - 5.03 (m, 1H), 4.84 - 4.81 (m, 1H), 4.64 - 4.57 (m, 2H), 4.45 - 4.38 (m, 2H), 4.25 - 4.18 (m, 1H), 4.06 - 3.99 (m, 1H), 3.80 - 3.72 (m, 1H), 3.21 - 3.15 (m, 1H), 2.93 (s, 3H), 2.48 (d, J = 7.1 Hz, 4H), 2.03 - 1.85 (m, 2H), 1.76 - 1.67 (m, 1H), 1.53 (d, J = 6.5 Hz, 3H), 1.35 (s, 3H). EXAMPLE 21 3-fluoro-5-[(4R,7S,8S, hyl)azetidin-3-yl]-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-13-yl]-4-(trifluoromethoxy)aniline Step 1 126Attorney Docket No. MDA0094-401-PC tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-17-[1-(2-methoxyethyl)azetidin-3-yl]-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylatebutoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate (100 mg, 128.73 μmol, 1 eq) in ACN (3 mL) were added N-ethyl-N- isopropyl-propan-2-amine (83.19 mg, 643.67 μmol, 112.12 μL, 5 eq) and 1-bromo-2- methoxy-ethane (89.46 mg, 643.67 μmol, 60.49 μL, 5 eq) at 20 °C, then the mixture was stirred at 20 °C for 5 h. LCMS showed a peak with the desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 100% MeOH ether gradient @ 50 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-[1-(2- methoxyethyl)azetidin-3-yl]-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (60 mg, 71.87 μmol, 55.83% yield) as a yellow solid. MS (ES+) C41H51N6F5O7requires: 834, found: 835 [M+H]+. Step 2 3-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-17-[1-(2-methoxyethyl)azetidin-3-yl]-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-13-yl]-4-(trifluoromethoxy)aniline 127Attorney Docket No. MDA0094-401-PCfluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-[1-(2-methoxyethyl)azetidin-3-yl]-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (60 mg, 71.87 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 1 mL) at 20 °C, then the mixture was stirred at 20 °C for 0.5 h. LCMS showed a peak with the desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [H2O(0.225% FA)-ACN]; gradient : 10%-30% B over 10.0 min) and lyophilized to afford 3-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-17-[1-(2- methoxyethyl)azetidin-3-yl]-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]-4- (trifluoromethoxy)aniline (26 mg, 37.82 μmol, 52.62% yield, 99% purity, FA) as a yellow solid. MS (ES+) C31H35F5N6O3requires: 634, found: 635 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.50 - 8.29 (m, 0.2H), 6.64 (dd, J = 2.6, 12.4 Hz, 1H), 6.54 - 6.51 (m, 1H), 5.05 (d, J = 14.2 Hz, 1H), 4.92 - 4.89 (m, 1H), 4.65 - 4.47 (m, 5H), 4.43 - 4.31 (m, 1H), 4.10 (d, J = 8.6 Hz, 1H), 3.99 - 3.93 (m, 1H), 3.66 (t, J = 4.9 Hz, 2H), 3.48 - 3.37 (m, 5H), 2.70 - 2.57 (m, 1H), 2.45 (d, J = 7.1 Hz, 3H), 2.12 - 1.98 (m, 2H), 1.86 - 1.72 (m, 1H), 1.61 - 1.46 (m, 6H). EXAMPLE 22 128Attorney Docket No. MDA0094-401-PC 6-[(4R,7S,8S,9S)-13-[5-am oxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-1H-pyridin-2-one Step 1 (4R,7S,8S,9S)-20-tert-butoxycarbonyl-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17-carboxylic acidfluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-formyl-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (1.3 g, 1.73 mmol, 1 eq) in 2-methylbut-2-ene (8.61 g, 122.71 mmol, 13.00 mL, 70.77 eq), dichloromethane (4 mL) and t-BuOH (13 mL) were added sodium dihydrogen phosphate hydrate (1.44 g, 10.40 mmol, 6 eq) in H2O (4 mL) and NaClO2 (313.65 mg, 3.47 mmol, 2 eq) at 0 °C. The mixture was stirred at 20 °C for 1 h. LCMS showed a peak with desired mass. The mixture was quenched with 10% of Na2SO3 aqueous solution (50 mL) and then extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 80 mL / min) to 129Attorney Docket No. MDA0094-401-PC afford (4R,7S,8S,9S)-20-tert-butoxycarbonyl-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17-carboxylic acid (1.18 g, 1.43 mmol, 82.65% yield, 93% purity) as yellow oil. MS (ES+) C36H40F5N5O8 requires:765, found:766 [M+H]+. Step 2 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-17-hydroxy-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylatebutoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 17-carboxylic acid (500 mg, 652.98 μmol, 1 eq) in DCE (5 mL) were added NaHCO3 (54.85 mg, 652.98 μmol, 25.41 μL, 1 eq) and tert-butyl hypochlorite (106.34 mg, 979.47 μmol, 1.5 eq) at 20 °C. The mixture was stirred at 60 °C for 12 h. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford the intermediate (461 mg). To a suspension of Pd / C (150 mg, 10% purity) in MeOH (12 mL) was added the intermediate (461 mg) in MeOH (4 mL) at 20 °C under N2. Then the mixture was degassed under vacuum and purged with H2(15 Psi) several times. The mixture was stirred under H2 (15 psi) at 20 °C for 0.5 h. LCMS showed the reaction was completed. The mixture was filtered and the filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-40% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- 130Attorney Docket No. MDA0094-401-PC (trifluoromethoxy)phenyl]-14-fluoro-17-hydroxy-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (327 mg, 398.94 μmol, 61.09% yield, 90% purity) as yellow oil. MS (ES+) C35H40F5N5O7requires:737, found:760 [M+Na]+. Step 3 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(trifluoromethylsulfonyloxy)- 10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaene-20-carboxylateylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-hydroxy-4,9,16-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (327 mg, 443.26 μmol, 1 eq) in dichloromethane (6 mL) were added DIEA (171.86 mg, 1.33 mmol, 231.62 μL, 3 eq) and Tf2O (250.12 mg, 886.53 μmol, 146.27 μL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 30 min under N2. LCMS showed a peak with desired mass. The mixture was quenched with H2O (10 mL) and extracted with dichloromethane (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-30% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(trifluoromethylsulfonyloxy)-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate (257 mg, 260.02 μmol, 58.66% yield, 88% purity) as yellow oil. MS (ES+) C36H39F8N5O9S requires: 869, found: 870 [M+H]+. Step 4 131Attorney Docket No. MDA0094-401-PC tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(6-oxo-1H-pyridin-2-yl)-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaene-20-carboxylatefluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17- (trifluoromethylsulfonyloxy)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (80 mg, 91.98 μmol, 1 eq) and 6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin-2-one (40.67 mg, 183.96 μmol, 2 eq) in dioxane (2 mL) and H2O (0.4 mL) were added Pd(dppf)Cl2 (13.46 mg, 18.40 μmol, 0.2 eq) and K2CO3 (38.14 mg, 275.93 μmol, 3 eq). The mixture was stirred at 100 °C for 16 h under N2. LCMS showed a peak with desired mass. The mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-60% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(6-oxo-1H-pyridin-2-yl)-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (52 mg, 60.63 μmol, 65.92% yield, 95% purity) as yellow oil. MS (ES+) C40H43F5N6O7 requires:814, found:815[M+H]+. Step 5 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-1H-pyridin-2-one 132Attorney Docket No. MDA0094-401-PCfluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(6-oxo-1H-pyridin-2-yl)- 10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaene-20-carboxylate (52 mg, 63.82 μmol, 1 eq) in dichloromethane (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 105.47 eq). The mixture was stirred at 20 °C for 30 min. LCMS showed a peak with desired mass. The mixture was concentrated to afford a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [H2O(0.225% FA)-ACN];gradient:20%-40% B over 10.0 min). The eluent was freeze-dried to afford 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-17-yl]-1H- pyridin-2-one (31.5 mg, 45.78 μmol, 71.73% yield, 96% purity, FA) as a white solid. MS (ES+) C30H27F5N6O3 requires: 614, found: 615 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.47 (s, 0.4H), 7.72 (dd, J = 6.9, 9.1 Hz, 1H), 6.67 - 6.61 (m, 4H), 5.02 (d, J = 14.1 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.10 (d, J = 8.8 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.22 (d, J = 13.8 Hz, 1H), 2.70 - 2.59 (m, 4H), 2.09 - 1.99 (m, 2H), 1.77 - 1.64 (m, 1H), 1.57 (d, J = 6.3 Hz, 3H), 1.49 (s, 3H). EXAMPLE 23133Attorney Docket No. MDA0094-401-PC 3-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-1H-pyridin-2-one

[0263] Synthesized according to the procedure of Example 22. MS (ES+) C30H27F5N6O3 requires: 614, found: 615[M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.53 (s, 0.1H), 7.79 (d, J = 6.4 Hz, 1H), 7.60 (dd, J = 2.0, 6.5 Hz, 1H), 6.72 - 6.54 (m, 3H), 5.00 - 4.95 (m, 1H), 4.65 - 4.59 (m, 1H), 4.06 (d, J = 8.8 Hz, 1H), 3.99 - 3.88 (m, 1H), 3.17 (d, J = 13.8 Hz, 1H), 2.77 - 2.64 (m, 1H), 2.49 (d, J = 8.1 Hz, 3H), 2.16 - 1.95 (m, 2H), 1.73 - 1.52 (m, 4H), 1.45 (s, 3H). EXAMPLE 24 6-[(4R,7S,8S,9S)-13-[5-amoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-5-fluoro-1H-pyridin-2-one Step 1 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-tributylstannyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate134Attorney Docket No. MDA0094-401-PC

[0264] To a solution of tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17- (trifluoromethylsulfonyloxy)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (300 mg, 344.92 μmol, 1 eq) and bis(tributyltin) (2.6 g, 4.48 mmol, 2.25 mL, 12.99 eq) in dioxane (5 mL) were added tricyclohexylphosphane (24.18 mg, 86.23 μmol, 27.96 μL, 0.25 eq), Pd2(dba)3(47.38 mg, 51.74 μmol, 0.15 eq) and LiCl (73.11 mg, 1.72 mmol, 35.35 μL, 5 eq). The mixture was stirred at 100 °C for 16 h under N2. LCMS showed a peak with desired mass. The mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-33% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17- tributylstannyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (67 mg, 61.65 μmol, 17.87% yield, 93% purity) as yellow oil. MS (ES+) C47H66F5N5O6Sn requires:1011, found:1012[M+H]+. Step 2 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-17-(3-fluoro-6-oxo-1H-pyridin-2-yl)-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate

[0265] To a solution of tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3- fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-tributylstannyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- 135Attorney Docket No. MDA0094-401-PC carboxylate (57 mg, 56.39 μmol, 1 eq) and 6-bromo-5-fluoro-1H-pyridin-2-one (32.48 mg, 169.18 μmol, 3 eq) in dioxane (2.5 mL) were added Pd(PPh3)4(13.03 mg, 11.28 μmol, 0.2 eq), LiCl (11.95 mg, 281.97 μmol, 5.78 μL, 5 eq) and CuI (1.07 mg, 5.64 μmol, 0.1 eq). The mixture was stirred at 100 °C for 16 h under N2. LCMS showed a peak with desired mass. The mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL × 2). The combined organic layers were washed with H2O (5 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to afford a residue which was purified by prep- TLC (Petroleum ether: Ethyl acetate= 1: 1) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-(3-fluoro-6-oxo- 1H-pyridin-2-yl)-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (16 mg, 12.10 μmol, 21.46% yield, 63% purity) as yellow oil. MS (ES+) C40H42F6N6O7 requires:832, found:833[M+H]+. Step 3 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-5-fluoro-1H-pyridin-2-one-3- fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-(3-fluoro-6-oxo-1H-pyridin-2-yl)-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (16 mg, 19.21 μmol, 1 eq) in dichloromethane (1 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL, 350.35 eq). The mixture was stirred at 20 °C for 20 min. LCMS showed a peak with desired mass. The mixture was concentrated to afford a residue which was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [H2O(0.225% FA)- ACN];gradient:18%-48% B over 10.0 min). The eluent was freeze-dried to afford 6- 136Attorney Docket No. MDA0094-401-PC [(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-5-fluoro-1H-pyridin-2-one (1.7 mg, 2.35 μmol, 12.26% yield, 94% purity, FA) as a yellow solid. MS (ES+) C30H26F6N6O3 requires: 632, found: 633 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.51 (s, 0.4H), 7.69 (dd, J = 8.2, 9.7 Hz, 1H), 6.71 - 6.61 (m, 3H), 5.00 - 4.98 (m, 1H), 4.58 - 4.53 (m, 1H), 4.03 (d, J = 9.0 Hz, 1H), 3.78 - 3.70 (m, 1H), 3.07 (d, J = 13.1 Hz, 1H), 2.60 - 2.47 (m, 4H), 1.99 - 1.86 (m, 2H), 1.60 - 1.52 (m, 4H), 1.38 (s, 3H). EXAMPLE 25 6-[(4R,7S,8S,9S)-13-[5-amoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]pyrazin-2-ol Step 1 (6-benzyloxypyrazin-2-yl)-tributyl-stannane

[0267] To a solution of 2-benzyloxy-6-chloro-pyrazine (1 g, 4.53 mmol, 1 eq) in Toluene (20 mL) were added Pd(PPh3)4(523.70 mg, 453.20 μmol, 0.1 eq) and bis(tributyltin) (5.26 g, 9.06 mmol, 4.54 mL, 2 eq) at 20 °C under N2. The mixture was stirred at 110 °C for 8 h. LCMS showed a peak with desired mass. The mixture was diluted with ethyl acetate (40 mL) and filtered through celite, the filtrate was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 0-4% Ethyl acetate / Commercial hexanes gradient @ 120 mL / min) to afford (6- benzyloxypyrazin-2-yl)-tributyl-stannane (310 mg, 652.28 μmol, 14.39% yield) as yellow oil. MS (ES+) C23H36N2SnO requires: 476, found 477 [M+H]+. 137Attorney Docket No. MDA0094-401-PC Step 2 tert-butyl (4R,7S,8S,9S)-17-(6-benzyloxypyrazin-2-yl)-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylatefluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17- (trifluoromethylsulfonyloxy)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (130 mg, 149.46 μmol, 1 eq) and (6- benzyloxypyrazin-2-yl)-tributyl-stannane (213.10 mg, 448.39 μmol, 3 eq) in DMF (2 mL) were added CuI (8.54 mg, 44.84 μmol, 0.3 eq), CsF (68.11 mg, 448.39 μmol, 3 eq) and Pd(PPh3)4(17.27 mg, 14.95 μmol, 0.1 eq). The mixture was stirred at 60 °C for 1 h under N2. LCMS showed a peak with desired mass. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-30% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to afford tert-butyl (4R,7S,8S,9S)-17- (6-benzyloxypyrazin-2-yl)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (110 mg, 106.85 μmol, 71.49% yield, 88% purity) as yellow oil. MS (ES+) C46H48N7F5O7requires: 905, found: 906 [M+H]+. Step 3 138Attorney Docket No. MDA0094-401-PC 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]pyrazin-2-ol Boc N H N O -(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (60 mg, 66.23 μmol, 1 eq) in AcOH (0.5 mL) was added HBr (745.00 mg, 3.04 mmol, 0.5 mL, 33% purity, 45.88 eq). The mixture was stirred at 20 °C for 2 h under N2. LCMS showed a peak with desired mass. The reaction mixture was quenched with NaHCO3(15 mL) and extracted with EtOAc (15 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um;mobile phase: [H2O(0.225% FA)-ACN]; gradient: 10%-40% B over 13.0 min) and lyophilized to afford 6- [(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]pyrazin-2-ol (15.2 mg, 22.98 μmol, 34.69% yield, 100% purity, FA) as a yellow solid. MS (ES+) C29H26F5N7O3 requires: 615, found 616 [M+H]+. 1H NMR (400 MHz, CD3OD) δ = 8.52 (s, 0.2H), 8.10 (s, 1H), 7.79 (s, 1H), 6.68 - 6.59 (m, 2H), 4.98 (d, J = 13.5 Hz, 1H), 4.56 - 4.51 (m, 1H), 4.02 (d, J = 9.0 Hz, 1H), 3.75 - 3.69 (m, 1H), 3.07 (d, J = 13.5 Hz, 1H), 2.62 (d, J = 8.1 Hz, 3H), 2.56 - 2.45 (m, 1H), 1.98 - 1.86 (m, 2H), 1.60 - 1.51 (m, 4H), 1.38 (s, 3H). EXAMPLE 26 139Attorney Docket No. MDA0094-401-PC 6-[(4R,7S,8S,9S)-13-[5-am oxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-4-methyl-piperazin-2-one Step 1 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(4-methyl-6-oxo-piperazin-2- yl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaene-20-carboxylateadded a solution of tert-butyl (4R,7S,8S,9S)-17-(6-benzyloxypyrazin-2-yl)-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate (40 mg, 44.15 μmol, 1 eq) in MeOH (1 mL). The suspension was degassed and purged with N2for 3 times and H2for 3 times. The mixture was stirred under H2(15 Psi) at 25 °C 16 h. LCMS showed no peak with desired mass. Additional Pd / C (20 mg, 18.79 μmol, 10% purity) and Pd(OH)2 (20 mg, 142.41 μmol, 3.23 eq) were added to the mixture, The suspension was degassed and purged with N2for 3 times and H2for 3 times. The mixture was stirred under H2 (45 Psi) at 25 °C 16 h. LCMS showed a peak with desired mass. The reaction mixture was diluted with MeOH (100 mL), filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (4 g 140Attorney Docket No. MDA0094-401-PC SepaFlash® Silica Flash Column, eluent of 0-100% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17- (4-methyl-6-oxo-piperazin-2-yl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (20 mg, 14.63 μmol, 33.14% yield, 61% purity) as yellow oil. MS (ES+) C40H48N7F5O7 requires: 833, found: 834 [M+H]+. Step 2 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16- trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-17-yl]-4-methyl-piperazin-2-onefluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(4-methyl-6-oxo- piperazin-2-yl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (20 mg, 23.99 μmol, 1 eq) in DCM (0.5 mL) was added TFA (767.50 mg, 6.73 mmol, 0.5 mL). The mixture was stirred at 20 °C for 15 min. LCMS showed a peak with desired mass. The reaction mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10um; mobile phase: [H2O(0.1% TFA)-ACN]; gradient: 1%-30% B over 13.0 min) and lyophilized to afford 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-17-yl]-4-methyl- piperazin-2-one (4.2 mg, 5.62 μmol, 23.42% yield, 100% purity, TFA) as an off-white solid. MS (ES+) C30H32F5N7O3requires: 633, found 634 [M+H]+. 1H NMR (400 MHz, CD3OD) δ = 6.68 - 6.57 (m, 2H), 5.58 - 5.45 (m, 1H), 5.15 - 5.00 (m, 1H), 4.65 - 4.52 (m, 1H), 4.23 - 4.11 (m, 2H), 4.02 - 3.96 (m, 1H), 3.90 - 3.69 (m, 2H), 3.58 - 141Attorney Docket No. MDA0094-401-PC 3.44 (m, 1H), 3.29 - 3.23 (m, 1H), 2.97 - 2.82 (m, 3H), 2.78 - 2.63 (m, 4H), 2.16 - 1.95 (m, 2H), 1.88 - 1.74 (m, 1H), 1.62 - 1.54 (m, 6H). EXAMPLE 27 6-[(4R,7S,8S,9S)-13-[5- thoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-17-yl]-1H- pyridin-2-one Step 1 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-17-hydroxy-4-(methoxymethyl)-9,16-dimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaene-20-carboxylatebutoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)- 9,16-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-17-carboxylic acid (0.4 g, 502.67 μmol, 1 eq) and NaHCO3 (42.23 mg, 502.67 μmol, 19.56 μL, 1 eq) in DCE (5 mL) was added tert-butyl hypochlorite (81.86 mg, 754.01 μmol, 1.5 eq). The mixture was stirred at 60 °C for 16 h. LCMS showed 142Attorney Docket No. MDA0094-401-PC the starting material was consumed completely. The mixture was filtered and the filtrate was diluted with ethyl acetate (20 mL), and washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was diluted with MeOH (2 mL) and was added to the suspension of Pd / C (80 mg, 75.17 μmol, 10% purity) in MeOH (6 mL) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2(15psi) at 25 °C for 1 hour. TLC (Plate 1 Commercial hexanes : Ethyl acetate = 1:1) showed the starting material was consumed completely and one new spot was formed. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography ( 12 g SepaFlash® Silica Flash Column, eluent of 0-25-100% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-17-hydroxy-4-(methoxymethyl)-9,16-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (270 mg, 334.10 μmol, 66.46% yield, 95% purity) as yellow solid. MS (ES+) C36H42N5F5O8 requires: 767, found: 768 [M+H]+. Step 2 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17- (trifluoromethylsulfonyloxy)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate, , , fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-hydroxy-4-(methoxymethyl)-9,16- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (270 mg, 351.68 μmol, 1 eq) in DCM (5.4 mL) were added DIEA (136.36 mg, 1.06 mmol, 183.77 μL, 3 eq) and Tf2O (198.45 mg, 143Attorney Docket No. MDA0094-401-PC 703.37 μmol, 116.05 μL, 2 eq) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. TLC (Plate 1 Commercial hexanes : Ethyl acetate = 2:1) showed the starting material was consumed completely and one new spot was fromed. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17- (trifluoromethylsulfonyloxy)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (240 mg, 250.72 μmol, 71.29% yield, 94% purity) as yellow solid. MS (ES+) C37H41N5F8O10S requires: 899, found: 900 [M+H]+. Step 3 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17- tributylstannyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate- fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17- (trifluoromethylsulfonyloxy)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (120 mg, 133.36 μmol, 1 eq) in dioxane (3 mL) was added bis(tributyltin) (386.82 mg, 666.82 μmol, 334.04 μL, 5 eq)，P(Cy)3 (7.48 mg, 26.67 μmol, 8.65 μL, 0.2 eq), LiCl (14.13 mg, 333.41 μmol, 6.83 μL, 2.5 eq) and Pd2(dba)3(12.21 mg, 13.34 μmol, 0.1 eq) at 25°C under the protection of N2. The mixture was stirred at 100 °C for 16 h under N2. LCMS showed a peak with desired mass. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, eluent of 0-16% 144Attorney Docket No. MDA0094-401-PC Ethyl acetate / Commercial hexanes gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14- fluoro-4-(methoxymethyl)-9,16-dimethyl-17-tributylstannyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (62 mg, 48.25 μmol, 36.18% yield, 81% purity) as yellow solid. MS (ES+) C48H68N5F5O7Sn requires: 1041, found: 1042 [M+H]+. Step 4 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17-(6-oxo-1H- pyridin-2-yl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylateo)-3- fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17- tributylstannyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (62 mg, 59.57 μmol, 1 eq) and 6-bromo-1H- pyridin-2-one (31.09 mg, 178.71 μmol, 3 eq) in dioxane (2 mL) were added LiCl (6.31 mg, 148.93 μmol, 3.05 μL, 2.5 eq), CuI (2.27 mg, 11.91 μmol, 0.2 eq) and Pd(PPh3)4 (6.88 mg, 5.96 μmol, 0.1 eq) under N2. The mixture was stirred at 100 °C for 16 h. LCMS showed a peak with desired mass. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-33-100% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17-(6-oxo-1H- pyridin-2-yl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (30 mg, 34.09 μmol, 57.23% yield, 96% purity) as yellow solid. 145Attorney Docket No. MDA0094-401-PC MS (ES+) C41H45N6F5O8requires: 844, found: 845 [M+H]+. Step 5 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4- (methoxymethyl)-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-17-yl]-1H- pyridin-2-one Boc O N H O N Ofluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-17-(6-oxo- 1H-pyridin-2-yl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (30 mg, 35.51 μmol, 1 eq) in DCM (0.6 mL) was added TFA (431.72 mg, 3.79 mmol, 0.3 mL) at 25 °C. The mixture was stirred at 25 °C for 15 min. LCMS showed a peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [H2O(0.1% TFA)-ACN];gradient:18%-48% B over 10.0 min) and lyophilized to afford 6-[(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4-(methoxymethyl)-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-17-yl]-1H- pyridin-2-one (6.4 mg, 8.44 μmol, 23.76% yield, 100% purity, TFA) as yellow solid. MS (ES+) C31H29F5N6O4requires: 644, found: 645 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 7.75 - 7.68 (m, 1H), 6.70 - 6.60 (m, 4H), 5.14 - 5.04 (m, 1H), 4.75 - 4.63 (m, 1H), 4.22 - 4.09 (m, 2H), 3.83 - 3.66 (m, 2H), 3.53 - 3.48 (m, 4H), 2.74 - 2.62 (m, 4H), 2.22 - 2.02 (m, 2H), 1.95 - 1.81 (m, 1H), 1.58 (d, J = 6.4 Hz, 3H). EXAMPLE 28 146Attorney Docket No. MDA0094-401-PC [(4R,7S,8S,9S)-13-[5-ami hoxy)phenyl]-14-fluoro-9,16-dimethyl-17-(1H-pyrazol-5-yl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-4-yl]methanol Step 1 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-17-(1- hydroxyethyl)-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylatefluoro-2-(trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-17- formyl-9,16-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (0.4 g, 454.55 μmol, 1 eq) in THF (4 mL) was added MeMgBr (3 M, 454.55 μL, 3 eq) at -78 °C under N2. The mixture was stirred at - 78 °C for 1 h under N2. LCMS showed a peak with desired mass. The mixture was quenched by sat. aq. NH4Cl (10 mL) at 0 °C, the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-9% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- 147Attorney Docket No. MDA0094-401-PC (trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-17-(1- hydroxyethyl)-9,16-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (340 mg, 345.30 μmol, 75.97% yield, 91% purity) as colorless oil MS (ES+) C43H58N5F5O8Si requires: 895, found: 896 [M+H]+. Step 2 tert-butyl (4R,7S,8S,9S)-17-acetyl-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylateo)-3- fluoro-2-(trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-17-(1- hydroxyethyl)-9,16-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (340 mg, 379.45 μmol, 1 eq) in DCM (6.5 mL) was added DMP (241.41 mg, 569.18 μmol, 176.34 μL, 1.5 eq) in portions at 0 °C under N2. The mixture was stirred at 25 °C for 1 h. LCMS showed a peak with desired mass. The mixture was quenched with aq. NaOH(1M，5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 0-16 ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-17-acetyl-13-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-4-[[tert- butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (320 mg, 272.03 μmol, 71.69% yield, 76% purity) as yellow solid. MS (ES+) C43H56N5F5O8Si requires: 893, found: 894 [M+H]+. 148Attorney Docket No. MDA0094-401-PC Step 3 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-17-[(E)-3- (dimethylamino)prop-2-enoyl]-14-fluoro-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylatebutoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-4-[[tert- butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (200 mg, 223.71 μmol, 1 eq) and DMFDMA (4.49 g, 37.64 mmol, 5.00 mL) was stirred at 100 °C for 16 h. LCMS showed a peak (60%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 1-33% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro- 2-(trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-17-[(E)-3- (dimethylamino)prop-2-enoyl]-14-fluoro-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (100 mg, 91.67 μmol, 40.98% yield, 87% purity) as yellow oil. MS (ES+) C46H61N6F5O8Si requires: 948, found: 949 [M+H]+. Step 4 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16- dimethyl-17-(1H-pyrazol-5-yl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate 149Attorney Docket No. MDA0094-401-PC ro-2-(trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-17-[(E)-3- (dimethylamino)prop-2-enoyl]-14-fluoro-9,16-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (100 mg, 105.36 μmol, 1 eq) and NH2NH2.H2O (26.91 mg, 526.82 μmol, 26.08 μL, 98% purity, 5 eq) in EtOH (2 mL) was stirred at 80 °C for 2 h. LCMS showed a peak (87%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-32% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-4-[[tert- butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16-dimethyl-17-(1H-pyrazol-5-yl)-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate (57 mg, 55.26 μmol, 52.45% yield, 89% purity) as yellow solid. MS (ES+) C44H56N7F5O7Si requires: 917, found: 918 [M+H]+. Step 5 [(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-9,16- dimethyl-17-(1H-pyrazol-5-yl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-4-yl]methanol150Attorney Docket No. MDA0094-401-PC

[0281] A mixture of tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro- 2-(trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16- dimethyl-17-(1H-pyrazol-5-yl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (57 mg, 62.09 μmol, 1 eq) and HCl / dioxane (2 M, 0.5 mL, 16.11 eq) was stirred at 25 °C for 0.5 h. LCMS showed a peak (87%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna C18 150*25mm* 10um;mobile phase: [H2O(0.225% FA)-ACN];gradient:20%-40% B over 10.0 min) and lyophilized to afford [(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16-dimethyl-17-(1H-pyrazol-5-yl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-4-yl]methanol (15.9 mg, 24.23 μmol, 39.03% yield, 99% purity, FA) as yellow solid. MS (ES+) C28H26F5N7O3 requires: 603, found: 604 [M+H]+.1H NMR (400 MHz,CD3OD) δ = 8.51 (s, 0.6H), 7.74 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.69 - 6.60 (m, 2H), 5.14 (d, J = 13.8 Hz, 1H), 4.65 - 4.54 (m, 1H), 4.08 (d, J = 8.8 Hz, 1H), 3.89 - 3.77 (m, 3H), 3.27 (s, 1H), 2.77 (d, J = 7.9 Hz, 3H), 2.64 - 2.53 (m, 1H), 2.06 - 1.90 (m, 2H), 1.81 - 1.69 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H). EXAMPLE 29 [(4R,7S,8S,9S)-13-[5-amihoxy)phenyl]-14-fluoro-9,16- dimethyl-17-oxazol-5-yl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-4-yl]methanol Step 1 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16- dimethyl-17-oxazol-5-yl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate 151Attorney Docket No. MDA0094-401-PCfluoro-2-(trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-17- formyl-9,16-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (100 mg, 113.64 μmol, 1 eq), K2CO3(31.41 mg, 227.28 μmol, 2 eq) in MeOH (2 mL) was added 1-(isocyanomethylsulfonyl)-4-methyl- benzene (26.62 mg, 136.37 μmol, 1.2 eq). The mixture was stirred at 60 °C for 2 h. LCMS showed a peak with desired mass. The mixture was added water (5 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5- (tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-4-[[tert- butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16-dimethyl-17-oxazol-5-yl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (0.08 g, 85.31 μmol, 75.07% yield, 98% purity) as colorless solid. MS (ES+) C44H55N6F5O8Si requires: 918 found: 919 [M+H]+. Step 2 [(4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-9,16- dimethyl-17-oxazol-5-yl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-4-yl]methanol 152Attorney Docket No. MDA0094-401-PCfluoro-2-(trifluoromethoxy)phenyl]-4-[[tert-butyl(dimethyl)silyl]oxymethyl]-14-fluoro-9,16- dimethyl-17-oxazol-5-yl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (0.08 g, 87.05 μmol, 1 eq) in HCl / dioxane (2 M, 1 mL). The mixture was stirred at 25 °C for 3 h. LCMS showed a peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [H2O(0.225% FA)- ACN];gradient:21%-41% B over 10.0 min) and lyophilized to afford [(4R,7S,8S,9S)-13-[5- amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-9,16-dimethyl-17-oxazol-5-yl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-4- yl]methanol (37.4 mg, 56.34 μmol, 64.72% yield, 98% purity, FA) as yellow solid. MS (ES+) C28H25F5N6O4 requires: 604 found: 605 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.53 (s, 0.3H), 8.40 (s, 1H), 7.75 (s, 1H), 6.68 - 6.58 (m, 2H), 5.22 (d, J = 13.4 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.07 (d, J = 9.5 Hz, 1H), 3.81 - 3.73 (m, 2H), 3.68 (d, J = 6.0 Hz, 1H), 3.15 (d, J = 13.8 Hz, 1H), 2.78 (d, J = 7.2 Hz, 3H), 2.62 - 2.52 (m, 1H), 1.94 - 1.75 (m, 2H), 1.73 - 1.62 (m, 1H), 1.57 (d, J = 6.2 Hz, 3H). EXAMPLE 30 (4R,7S,8S,9S)-13-[5-amethoxy)phenyl]-14-fluoro- N4,N4,N17,9,16-pentamethyl-10-oxa-2,12,18,20- 153Attorney Docket No. MDA0094-401-PC tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,17- dicarboxamide Step 1 (4R,7S,8S,9S)-20-tert-butoxycarbonyl-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16-dimethyl-17-(methylcarbamoyl)-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4- carboxylic acidfluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4-formyl-9,16-dimethyl-17- (methylcarbamoyl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (70 mg, 88.30 μmol, 1 eq) in 2- methylpropan-2-ol (2 mL) and 2-methylbut-2-ene (2 mL) were added sodium dihydrogen phosphate dihydrate (73.11 mg, 529.80 μmol, 6 eq) and sodium chlorite (23.96 mg, 264.90 μmol, 3 eq) in H2O (0.7 mL) at 20 °C and the mixture stirred at 20 °C for 2 h. LCMS showed a peak (44%) with the desired mass. The reaction was poured into a solution of saturated Na2S2O3(10 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (12 g SepaFlash® Silica Flash Column, eluent of 30-60% ethyl acetate / petroleum ether gradient @ 50 mL / min) to afford (4R,7S,8S,9S)-20-tert- butoxycarbonyl-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14- fluoro-9,16-dimethyl-17-(methylcarbamoyl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4-carboxylic acid (50 mg, 61.82 μmol, 70.02% yield) as a yellow solid. MS (ES+) C37H41N6F5O9 requires: 808, found: 809 [M+H]+. Step 2 154Attorney Docket No. MDA0094-401-PC tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-4-(dimethylcarbamoyl)-14-fluoro-9,16-dimethyl-17- (methylcarbamoyl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate

[0285] To a solution of (4R,7S,8S,9S)-20-tert-butoxycarbonyl-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-9,16-dimethyl-17- (methylcarbamoyl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylic acid (50 mg, 61.82 μmol, 1 eq) and N- methylmethanamine (2 M, 154.56 μL, 5 eq) in DMF (1 mL) was added DIEA (63.92 mg, 494.59 μmol, 86.15 μL, 8 eq) and HATU (47.01 mg, 123.65 μmol, 2 eq) at 20 ° C, then the reaction was stirred at 20 °C for 1 h. LCMS showed a peak (69%) with the desired mass. The reaction mixture was diluted with water (2 mL), then extracted with ethyl acetate (2 mL x 3), washed with brine (2 mL x 3), the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum which was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert- butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-4-(dimethylcarbamoyl)-14- fluoro-9,16-dimethyl-17-(methylcarbamoyl)-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (50 mg, 59.82 μmol, 96.76% yield) as a yellow solid. MS (ES+) C39H46N7F5O8 requires: 835, found: 836 [M+H]+. Step 3 (4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro- N4,N4,N17,9,16-pentamethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,17- dicarboxamide 155Attorney Docket No. MDA0094-401-PC amino)-3-fluoro-2-(trifluoromethoxy)phenyl]-4-(dimethylcarbamoyl)-14-fluoro-9,16-dimethyl-17- (methylcarbamoyl)-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (30 mg, 35.89 μmol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 1 mL) at 20 °C, then the mixture was stirred at 20 °C for 20 min. LCMS showed a peak (67%) with the desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex Luna C18150*25mm*10um; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 16%-36% B over 10.0 min) and lyophilized to afford (4R,7S,8S,9S)-13-[5-amino-3- fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-N4,N4,N17,9,16-pentamethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,17- dicarboxamide (7.2 mg, 9.12 μmol, 25.42% yield, 95% purity, TFA) as a yellow solid. MS (ES+) C29H30F5N7O4 requires: 635, found: 636 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.69 - 6.61 (m, 2H), 5.53 (d, J = 14.2 Hz, 1H), 4.64 - 4.49 (m, 1H), 4.17 (d, J = 10.3 Hz, 1H), 3.77 - 3.68 (m, 1H), 3.53 (s, 3H), 3.35 (s, 1H), 3.16 - 3.11 (m, 1H), 2.97 (s, 3H), 2.76 (s, 3H), 2.61 (d, J = 7.8 Hz, 3H), 2.06 - 1.80 (m, 3H), 1.61 (d, J = 6.2 Hz, 3H). EXAMPLE 31156Attorney Docket No. MDA0094-401-PC (4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-N4,N17,9,16- tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4,17-dicarboxamide

[0287] Synthesized according to the procedure of Example 30. MS (ES+) C28H28F5N7O4 requires: 621, found: 622 [M+H].1H NMR (400 MHz, CD3OD) δ = 8.10 (s, 1H), 6.71 - 6.59 (m, 2H), 5.26 (d, J = 14.3 Hz, 1H), 4.74 - 4.64 (m, 1H), 4.14 - 4.05 (m, 2H), 3.49 (d, J = 14.1 Hz, 1H), 3.01 (s, 3H), 2.91 - 2.80 (m, 4H), 2.67 (d, J = 7.8 Hz, 3H), 2.24 - 1.96 (m, 3H), 1.54 (d, J = 6.4 Hz, 3H). EXAMPLE 32 (4R,7S,8S)-13-[5-amino-3-nyl]-14-fluoro-17-(1-hydroxy- 1-methyl-ethyl)-N,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4- carboxamide

[0288] Synthesized according to the procedure of Example 30. MS (ES+) C29H31F5N6O4 requires: 622, found: 623 [M+H].1H NMR (400 MHz, CD3OD) δ = 6.67 - 6.56 (m, 2H), 5.29 (d, J = 13.4 Hz, 1H), 4.60 - 4.51 (m, 1H), 3.98 - 3.91 (m, 1H), 3.83 (s, 1H), 3.30 - 3.25 (m, 1H), 2.86 - 2.81 (m, 6H), 2.74 - 2.64 (m, 1H), 2.05 - 1.86 (m, 3H), 1.73 (d, J = 5.0 Hz, 6H), 1.48 (d, J = 6.5 Hz, 3H). EXAMPLE 33 157Attorney Docket No. MDA0094-401-PC (4R,7S,8S)-13-[6-amino- -4-pyridyl]-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxamide Step 1 tert-butyl (4R,7S,8S)-4-carbamoyl-13-chloro-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate6,17- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylic acid (130 mg, 263.73 μmol, 1 eq), NH4Cl (56.43 mg, 1.05 mmol, 4 eq) and DIEA (340.85 mg, 2.64 mmol, 459.37 μL, 10 eq) in DMF (5 mL) was added HATU (200.56 mg, 527.46 μmol, 2 eq) at 25 °C. Then the mixture was stirred at 25 °C for 1 h. LCMS showed a main peak with desired mass. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 10-66% ethyl acetate / petroleum ether gradient @ 60 mL / min) to afford tert-butyl (4R,7S,8S)-4-carbamoyl-13- chloro-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (180 mg, crude) as white solid. MS (ES+) C23H27ClN5FO4requires: 491, found: 492 [M+H]+. Step 2 158Attorney Docket No. MDA0094-401-PC tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-4-carbamoyl- 14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate -16,17-dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (50 mg, 101.64 μmol, 1 eq) and 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine (30.70 mg, 101.64 μmol, 1 eq) in THF (1 mL) were added K3PO4 (1.5 M, 203.28 μL, 3 eq) and Ad2nBuP Pd G3(cataCXium® A Pd G3) (7.40 mg, 10.16 μmol, 0.1 eq) under the protection of N2. Then the mixture was stirred at 60 °C for 16 h under N2. LCMS showed a peak (68%) with desired mass. The mixture was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 4-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4- pyridyl]-4-carbamoyl-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (53 mg, 70.49 μmol, 69.35% yield, 84% purity) as yellow solid. MS (ES+) C30H33N7F4O4 requires: 631, found: 632 [M+H]+. Step 3 (4R,7S,8S)-13-[6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-16,17- dimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxamide 159Attorney Docket No. MDA0094-401-PC ethyl)-4-pyridyl]-4-carbamoyl-14-fluoro-16,17-dimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (53 mg, 83.91 μmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL, 48.13 eq) at 25 °C. Then the mixture was stirred at 25 °C for 10 min. LCMS showed a peak (86%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Welch Xtimate C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:8%-38% B over 10 min) and lyophilized to afford (4R,7S,8S)-13- [6-amino-2-methyl-3-(trifluoromethyl)-4-pyridyl]-14-fluoro-16,17-dimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4- carboxamide (11.2 mg, 17.35 μmol, 20.68% yield, 100% purity, TFA). MS (ES+) C25H25F4N7O2requires: 531, found: 532 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.48 - 6.22 (m, 1H), 4.68 - 4.58 (m, 1H), 4.55 - 4.32 (m, 2H), 4.06 - 3.94 (m, 1H), 3.82 - 3.69 (m, 1H), 3.55 - 3.42 (m, 1H), 2.65 - 2.51 (m, 10H), 2.37 - 2.26 (m, 1H), 2.20 - 2.06 (m, 1H), 2.05 - 1.92 (m, 1H). EXAMPLE 34160Attorney Docket No. MDA0094-401-PC (5aS,6S,9R)-2-(5-amino-3-fluoro-2-(trifluoromethoxy)phenyl)-1-fluoro-N,5,13,14- tetramethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxamide

[0292] Synthesized according to the procedure of Example 33. MS (ES+) C27H27F5N6O3 requires: 578, found: 579 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.66 - 6.56 (m, 2H), 5.42 (d, J = 13.1 Hz, 1H), 4.49 - 4.38 (m, 1H), 3.88 (d, J = 8.9 Hz, 1H), 3.61 (d, J = 6.1 Hz, 1H), 3.08 (d, J = 12.9 Hz, 1H), 2.82 (s, 3H), 2.80 - 2.73 (m, 1H), 2.60 (s, 3H), 2.55 (d, J = 6.9 Hz, 3H), 1.93 - 1.70 (m, 3H), 1.50 (d, J = 6.4 Hz, 3H). EXAMPLE 35 (4R,7S,8S)-13-[5-amino-3henyl]-14-fluoro-N,N,9,16,17- pentamethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxamide

[0293] Synthesized according to the procedure of Example 33. MS (ES+) C28H29F5N6O3requires: 592, found: 593 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.66 - 6.55 (m, 2H), 5.53 (d, J = 13.8 Hz, 1H), 4.52 - 4.40 (m, 1H), 4.07 (d, J = 10.0 Hz, 1H), 3.61 - 3.52 (m, 4H), 3.20 - 3.08 (m, 2H), 3.03 (s, 3H), 2.59 - 2.51 (m, 6H), 2.01 - 1.74 (m, 3H), 1.56 (d, J = 6.3 Hz, 3H). EXAMPLE 36 161Attorney Docket No. MDA0094-401-PC [(4R,7S,8S)-13-[5-amin )phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaen-4-yl]-(azetidin-1-yl)methanone

[0294] Synthesized according to the procedure of Example 33. MS (ES+) C29H29F5N6O3 requires:604, found: 605 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.59 - 8.44 (m, 1H), 6.68 - 6.57 (m, 2H), 5.53 - 5.48 (m, 1H), 4.71 - 4.67 (m, 1H), 4.47 - 4.41 (m, 1H), 4.23 - 4.13 (m, 2H), 4.01 - 3.96 (m, 1H), 3.63 - 3.58 (m, 1H), 3.17 - 3.13 (m, 1H), 2.99 - 2.89 (m, 1H), 2.64 - 2.54 (m, 6H), 2.51 - 2.35 (m, 3H), 1.96 - 1.75 (m, 3H), 1.60 - 1.51 (m, 3H). EXAMPLE 37 (8aS,9S,12R)-5y)phenyl)-N-(1,3- dihydroxypropan-2-yl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide tris(2,2,2-trifluoroacetate)

[0295] Synthesized according to the procedure of Example 33. MS (ES+) C29H31F5N6O5 requires: 638, found: 639 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dt, J = 3.8, 1.8 Hz, 1H), 5.50 (d, J = 14.4 Hz, 1H), 5.22 (d, J = 14.3 Hz, 1H), 4.69 – 4.66 (m, 1H), 4.62 (dd, J = 8.9, 6.3 Hz, 1H), 4.59 (d, J = 5.7 Hz, 1H), 4.23 – 4.17 (m, 1H), 4.11 (dt, J = 11.8, 6.4 Hz, 1H), 162Attorney Docket No. MDA0094-401-PC 3.89 (dd, J = 11.6, 4.4 Hz, 1H), 3.82 (ddd, J = 11.7, 5.4, 1.5 Hz, 1H), 3.72 (dd, J = 11.2, 5.5 Hz, 1H), 3.69 – 3.65 (m, 2H), 3.59 – 3.52 (m, 1H), 2.62 (s, 1H), 2.60 (dd, J = 6.7, 4.4 Hz, 3H), 2.22 – 2.08 (m, 3H), 1.55 (d, J = 6.3 Hz, 2H), 1.46 (d, J = 6.6 Hz, 2H). EXAMPLE 38 ((8aS,9S,12R)-5-(5- phenyl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-12(13H)-yl)(3-methoxyazetidin-1-yl)methanone

[0296] Synthesized according to the procedure of Example 33. MS (ES+) C30H31F5N6O4requires: 634, found: 635 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (q, J = 2.4, 1.9 Hz, 1H), 5.57 (dd, J = 14.6, 11.3 Hz, 1H), 4.63 – 4.57 (m, 2H), 4.40 (dd, J = 11.6, 6.6 Hz, 2H), 4.19 (d, J = 9.8 Hz, 1H), 4.06 (d, J = 6.4 Hz, 1H), 3.99 – 3.93 (m, 1H), 3.37 (s, 3H), 3.34 (s, 4H), 2.65 (s, 2H), 2.63 (s, 3H), 2.60 (d, J = 6.7 Hz, 3H), 1.58 (d, J = 6.3 Hz, 3H). EXAMPLE 39 (8aS,9S,12R)-xy)phenyl)-N-(2- (dimethylamino)ethyl)-4-fluoro-N,2,3,8-tetramethyl-8a,9,10,11-tetrahydro-8H-9,12- 163Attorney Docket No. MDA0094-401-PC epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0297] Synthesized according to the procedure of Example 33. MS (ES+) C31H36F5N7O3requires: 649, found: 650 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.64 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.7, 1.2 Hz, 1H), 5.64 (d, J = 14.9 Hz, 1H), 4.64 – 4.59 (m, 1H), 4.25 (d, J = 10.0 Hz, 1H), 4.06 (d, J = 6.5 Hz, 1H), 3.94 (dt, J = 13.7, 6.5 Hz, 1H), 3.85 (dt, J = 14.7, 6.2 Hz, 1H), 3.59 (s, 3H), 3.46 – 3.43 (m, 1H), 3.00 (s, 6H), 2.65 (s, 7H), 2.62 – 2.57 (m, 4H), 1.60 (d, J = 6.2 Hz, 3H). EXAMPLE 40 (8aS,9S,12R)-5-(5-phenyl)-4-fluoro-N-(2- hydroxyethyl)-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0298] Synthesized according to the procedure of Example 33. MS (ES+) C28H29F5N6O4requires: 608, found: 609 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.8, 1.1 Hz, 1H), 5.25 (d, J = 14.2 Hz, 1H), 4.68 – 4.63 (m, 1H), 4.11 (d, J = 6.5 Hz, 1H), 4.04 (d, J = 7.8 Hz, 1H), 3.68 (t, J = 5.8 Hz, 2H), 3.52 (d, J = 14.6 Hz, 1H), 3.45 (dt, J = 9.0, 5.8 Hz, 2H), 3.34 (s, 3H), 3.04 (t, J = 3.6 Hz, 1H), 2.67 (s, 3H), 2.61 (d, J = 6.5 Hz, 3H), 1.48 (d, J = 6.5 Hz, 3H). EXAMPLE 41 164Attorney Docket No. MDA0094-401-PC ((5aS,6S,9R)-2-(5-am phenyl)-1-fluoro-5,13,14-trimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-9(10H)-yl)(3,6-diazabicyclo[3.1.1]heptan-3-yl)methanone

[0299] Synthesized according to the procedure of Example 33. MS (ES+) C31H32F5N7O3requires: 645, found: 646 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.64 (dd, J = 12.4, 2.7 Hz, 1H), 6.60 (d, J = 1.3 Hz, 1H), 4.66 – 4.58 (m, 2H), 4.55 – 4.47 (m, 2H), 4.29 – 4.15 (m, 3H), 4.14 – 4.08 (m, 1H), 4.07 – 3.95 (m, 1H), 3.56 – 3.46 (m, 1H), 3.35 (s, 1H), 3.17 – 3.04 (m, 1H), 2.70 – 2.55 (m, 7H), 2.30 – 2.18 (m, 1H), 2.13 – 2.08 (m, 2H), 2.06 – 1.98 (m, 1H), 1.63 – 1.57 (m, 3H), 0.90 (m, J = 14.7, 7.6 Hz, 1H). EXAMPLE 42 ((5aS,6S,9R)-2-(5-amiphenyl)-1-fluoro-5,13,14- trimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-9(10H)-yl)(morpholino)methanone

[0300] Synthesized according to the procedure of Example 33. MS (ES+) C30H31F5N6O4 requires: 634, found: 635 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.65 (dd, J = 12.3, 2.7 Hz, 1H), 6.61 (dd, J = 2.8, 1.2 Hz, 1H), 5.47 (d, J = 15.0 Hz, 1H), 4.61 (dq, J = 10.0, 6.2 Hz, 1H), 4.36 – 4.15 (m, 1H), 4.07 – 4.03 165Attorney Docket No. MDA0094-401-PC (m, 1H), 3.87 (s, 2H), 3.79 (d, J = 9.9 Hz, 1H), 3.66 (d, J = 10.4 Hz, 1H), 3.50 (d, J = 14.9 Hz, 1H), 2.66 (s, 8H), 2.60 (d, J = 6.6 Hz, 3H), 2.55 (s, 3H), 2.22 – 2.04 (m, 3H), 1.60 (d, J = 6.2 Hz, 3H). EXAMPLE 43 (8aS,9S,12R)-5-(5-amino- enyl)-N-ethyl-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-12(13H)-carboxamide

[0301] Synthesized according to the procedure of Example 33. MS (ES+) C28H29F5N6O3 requires: 592, found: 593 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.69 – 6.66 (m, 1H), 6.63 (d, J = 2.7 Hz, 1H), 5.24 (d, J = 14.2 Hz, 1H), 4.67 (p, J = 6.7 Hz, 1H), 4.13 (d, J = 6.7 Hz, 1H), 4.08 (d, J = 7.8 Hz, 1H), 3.53 (d, J = 14.2 Hz, 1H), 3.42 – 3.35 (m, 3H), 3.03 (ddt, J = 17.9, 12.5, 6.2 Hz, 1H), 2.63 (d, J = 6.5 Hz, 3H), 2.29 – 2.24 (m, 1H), 2.08 (dt, J = 13.5, 6.4 Hz, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 1.3 Hz, 4H), 1.25 –1.21 (m, 3H). EXAMPLE 44166Attorney Docket No. MDA0094-401-PC (8aS,9S,12R)-5-(5-amino-3-fluoro-2-(trifluoromethoxy)phenyl)-4-fluoro-N-(2-hydroxy- 2-methylpropyl)-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0302] Synthesized according to the procedure of Example 33. MS (ES+) C30H33F5N6O4requires: 637, found: 638 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.68 (dd, J = 12.4, 2.8 Hz, 1H), 6.63 (d, J = 2.7 Hz, 1H), 5.30 (d, J = 14.3 Hz, 1H), 4.69 (p, J = 6.6 Hz, 1H), 4.15 (d, J = 6.6 Hz, 1H), 4.07 (d, J = 7.6 Hz, 1H), 3.57 (d, J = 14.3 Hz, 1H), 3.37 (t, J = 1.6 Hz, 3H), 3.07 (ddd, J = 13.6, 10.0, 4.2 Hz, 1H), 2.63 (d, J = 6.5 Hz, 3H), 2.34 – 2.27 (m, 1H), 1.54 (d, J = 1.1 Hz, 1H), 1.50 (d, J = 6.4 Hz, 3H), 1.32 (d, J = 1.1 Hz, 4H), 1.26 (s, 6H). EXAMPLE 45 ((8aS,9S,12R)-5-(5-a)phenyl)-4-fluoro-2,3,8- trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-12(13H)-yl)(4-methylpiperazin-1-yl)methanone

[0303] Synthesized according to the procedure of Example 33. MS (ES+) C31H34F5N7O3requires: 647, found: 648 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.68 (dd, J = 12.3, 2.7 Hz, 1H), 6.65 (dd, J = 2.8, 1.2 Hz, 1H), 5.44 (d, J = 15.0 Hz, 1H), 4.64 (dq, J = 10.0, 6.2 Hz, 1H), 4.32 – 4.26 (m, 1H), 4.15 – 4.09 (m, 1H), 3.56 (d, J = 15.8 Hz, 2H), 3.37 (s, 1H), 3.02 (s, 3H), 2.68 (s, 6H), 2.63 (d, J = 6.6 Hz, 3H), 2.60 (s, 3H), 2.24 (q, J = 5.8, 5.2 Hz, 2H), 2.11 (t, J = 9.9 Hz, 1H), 1.63 (d, J = 6.2 Hz, 3H), 1.32 (s, 2H). EXAMPLE 46 167Attorney Docket No. MDA0094-401-PC ((8aS,9S,12R)-5-(5- phenyl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-12(13H)-yl)(3-(dimethylamino)azetidin-1-yl)methanone

[0304] Synthesized according to the procedure of Example 33. MS (ES+) C31H34F5N7O3requires: 647, found: 648 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.66 (dd, J = 12.3, 2.7 Hz, 1H), 6.62 (t, J = 1.8 Hz, 1H), 5.55 (dd, J = 14.7, 4.1 Hz, 1H), 5.17 (d, J = 8.8 Hz, 1H), 4.65 – 4.59 (m, 1H), 4.53 – 4.42 (m, 1H), 4.34 (t, J = 17.7 Hz, 2H), 4.23 (d, J = 9.7 Hz, 1H), 4.11 (d, J = 6.0 Hz, 1H), 3.47 (s, 1H), 3.37 (s, 3H), 3.28 – 3.23 (m, 1H), 2.97 (d, J = 3.4 Hz, 4H), 2.68 (s, 3H), 2.66 (s, 3H), 2.63 (d, J = 6.6 Hz, 3H), 1.60 (d, J = 6.3 Hz, 3H). EXAMPLE 47 (8aS,9S,12R)-5-(5-aminonyl)-N-(tert-butyl)-4-fluoro- 2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0305] Synthesized according to the procedure of Example 33. MS (ES+) C30H33F5N6O3requires: 621, found: 622 [M+H]+. 168Attorney Docket No. MDA0094-401-PC1H NMR (600 MHz, MeOD) δ 7.41 (s, 1H), 6.64 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.7, 1.2 Hz, 1H), 4.98 (d, J = 14.1 Hz, 1H), 4.71 (p, J = 6.6 Hz, 1H), 4.12 – 4.09 (m, 1H), 3.88 (dd, J = 6.1, 1.3 Hz, 1H), 3.52 (dd, J = 14.2, 1.3 Hz, 1H), 2.84 (ddd, J = 15.8, 8.5, 3.5 Hz, 1H), 2.65 (s, 2H), 2.61 (d, J = 6.5 Hz, 3H), 2.42 (ddd, J = 14.4, 10.1, 4.7 Hz, 1H), 2.05 – 1.99 (m, 1H), 1.43 (s, 9H), 1.38 (d, J = 6.7 Hz, 3H), 1.30 (s, 3H). EXAMPLE 48 3-((8aS,9S,12R)-5- henyl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11,12,13-hexahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12- carboxamido)propane-1-sulfonic acid

[0306] Synthesized according to the procedure of Example 33. MS (ES+) C29H31F5N6O6S requires: 687, found: 688 [M+H]+.1H NMR (600 MHz, MeOD) δ 8.57 (t, J = 5.8 Hz, 1H), 6.67 (dd, J = 12.3, 2.7 Hz, 1H), 6.62 (dd, J = 2.7, 1.2 Hz, 1H), 5.31 – 5.27 (m, 1H), 4.67 – 4.62 (m, 1H), 4.10 (d, J = 6.4 Hz, 1H), 4.07 (d, J = 8.2 Hz, 1H), 3.51 (d, J = 4.4 Hz, 1H), 3.40 (dd, J = 13.1, 6.6 Hz, 1H), 3.07 (ddd, J = 13.6, 9.7, 4.3 Hz, 1H), 2.88 (t, J = 7.4 Hz, 2H), 2.68 (s, 3H), 2.60 (d, J = 6.6 Hz, 3H), 2.06 (dd, J = 9.4, 6.7 Hz, 2H), 1.50 (d, J = 6.4 Hz, 3H), 1.29 (s, 8H). EXAMPLE 49 169Attorney Docket No. MDA0094-401-PC (8aS,9S,12R)- xy)phenyl)-N-(2-(dimethylamino)ethyl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0307] Synthesized according to the procedure of Example 33. MS (ES+) C30H34F5N7O3 requires: 635, found: 636 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.65 (dd, J = 12.3, 2.7 Hz, 1H), 6.62 – 6.60 (m, 1H), 5.30 (d, J = 14.2 Hz, 1H), 4.64 (dq, J = 8.5, 6.4 Hz, 1H), 4.13 (d, J = 7.6 Hz, 2H), 3.78 (dt, J = 15.0, 6.1 Hz, 1H), 3.68 (dt, J = 15.0, 5.9 Hz, 1H), 3.56 (d, J = 14.2 Hz, 1H), 3.40 – 3.37 (m, 2H), 3.27 (s, 2H), 3.05 (m, 1H), 2.99 (s, 6H), 2.60 (d, J = 6.5 Hz, 3H), 2.23 – 2.16 (m, 3H), 1.51 (d, J = 6.4 Hz, 3H), 1.29 (s, 1H). EXAMPLE 50 (8aS,9S,12R)-5-(5-aminohenyl)-N,N-diethyl-4-fluoro- 2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0308] Synthesized according to the procedure of Example 33. MS (ES+) C30H33F5N6O3 requires: 621, found: 622 [M+H]+. 170Attorney Docket No. MDA0094-401-PC1H NMR (600 MHz, MeOD) δ 6.64 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.8, 1.2 Hz, 1H), 5.51 (d, J = 14.9 Hz, 1H), 4.60 (dq, J = 10.0, 6.2 Hz, 1H), 4.26 – 4.22 (m, 1H), 4.09 (dq, J = 14.3, 7.0 Hz, 1H), 4.02 (d, J = 6.7 Hz, 1H), 3.85 (dq, J = 14.2, 7.0 Hz, 1H), 3.55 (dq, J = 14.1, 7.1 Hz, 1H), 3.47 (dq, J = 14.1, 6.9 Hz, 2H), 2.66 (s, 3H), 2.61 (s, 2H), 2.60 (s, 4H), 1.60 (d, J = 6.2 Hz, 3H), 1.39 (t, J = 7.0 Hz, 3H), 1.29 (s, 1H), 1.21 (t, J = 7.1 Hz, 3H). EXAMPLE 51 ((8aS,9S,12R)-5-(5-am y)phenyl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-12(13H)-yl)(thiomorpholino)methanone

[0309] Synthesized according to the procedure of Example 33. MS (ES+) C30H31F5N6O3S requires: 651, found: 652 [M+H]+.1H NMR (600 MHz, MeOD) δ6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.7, 1.2 Hz, 1H), 5.46 (d, J = 15.0 Hz, 1H), 4.64 – 4.58 (m, 1H), 4.43 (d, J = 14.1 Hz, 1H), 4.28 (d, J = 14.3 Hz, 1H), 4.24 – 4.21 (m, 1H), 4.04 (d, J = 6.3 Hz, 2H), 3.92 (d, J = 9.1 Hz, 1H), 3.50 – 3.45 (m, 1H), 2.88 (d, J = 20.8 Hz, 2H), 2.73 (d, J = 12.0 Hz, 2H), 2.65 (s, 3H), 2.60 (d, J = 6.7 Hz, 4H), 2.20 – 2.13 (m, 2H), 2.10 – 2.04 (m, 1H), 1.60 (d, J = 6.2 Hz, 3H). EXAMPLE 52171Attorney Docket No. MDA0094-401-PC (8aS,9S,12R)-5-(5-amino-3-fluoro-2-(trifluoromethoxy)phenyl)-4-fluoro-2,3,8-trimethyl- N-(thiazol-2-ylmethyl)-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0310] Synthesized according to the procedure of Example 33. MS (ES+) C30H28F5N7O3S requires: 662, found: 663 [M+H]+.1H NMR (600 MHz, MeOD) δ 7.76 (d, J = 3.3 Hz, 1H), 7.57 (d, J = 3.3 Hz, 1H), 6.64 (dd, J = 12.4, 2.7 Hz, 1H), 6.60 (dd, J = 2.8, 1.1 Hz, 1H), 5.34 (d, J = 14.2 Hz, 1H), 4.84 (s, 2H), 4.69 – 4.63 (m, 1H), 4.16 – 4.13 (m, 1H), 4.07 (d, J = 8.0 Hz, 1H), 3.56 (d, J = 14.3 Hz, 1H), 3.35 (s, 3H), 2.67 (s, 2H), 2.61 (d, J = 6.4 Hz, 3H), 2.16 – 2.10 (m, 2H), 1.55 (d, J = 6.3 Hz, 1H), 1.52 – 1.48 (m, 3H), 1.39 – 1.35 (m, 1H). EXAMPLE 53 (8aS,9S,12R)-5-(5-aminoyl)-4-fluoro-2,3,8-trimethyl- N-(tetrahydrofuran-3-yl)-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0311] Synthesized according to the procedure of Example 33. MS (ES+) C30H31F5N6O4 requires: 635, found: 636 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.64 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.7, 1.2 Hz, 1H), 5.08 (dd, J = 14.2, 1.4 Hz, 1H), 4.70 (p, J = 6.6 Hz, 1H), 4.54 – 4.47 (m, 1H), 4.14 (d, J = 6.7 Hz, 1H), 4.00 – 3.97 (m, 1H), 3.97 – 3.93 (m, 2H), 3.93 – 3.89 (m, 1H), 3.81 (tdd, J = 8.4, 6.1, 1.2 Hz, 1H), 3.71 (ddd, J = 9.3, 7.3, 3.8 Hz, 1H), 3.53 (ddd, J = 14.2, 4.2, 1.4 Hz, 1H), 3.35 (s, 1H), 2.96 – 2.89 (m, 1H), 2.61 (d, J = 6.5 Hz, 3H), 2.37 (ddd, J = 14.3, 10.1, 4.7 Hz, 1H), 2.33 – 2.26 (m, 1H), 2.18 (ddd, J = 17.0, 11.6, 4.7 Hz, 1H), 2.09 – 2.02 (m, 1H), 1.96 (dddd, J = 18.7, 7.7, 6.2, 3.8 Hz, 1H), 1.42 (d, J = 6.6 Hz, 3H). 172Attorney Docket No. MDA0094-401-PC EXAMPLE 54 (8aS,9S,12R)-5-(5-amin )-4-fluoro-2,3,8-trimethyl-N-(6-methylpyridin-3-yl)-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0312] Synthesized according to the procedure of Example 33. MS (ES+) C32H30F5N7O3 requires: 655, found: 656 [M+H]+.1H NMR (600 MHz, MeOD) δ 9.16 – 9.10 (m, 1H), 8.51 – 8.44 (m, 1H), 7.85 – 7.79 (m, 1H), 6.65 (dt, J = 12.4, 2.2 Hz, 1H), 6.61 (d, J = 3.1 Hz, 1H), 5.23 (dd, J = 14.2, 2.5 Hz, 1H), 4.75 (p, J = 6.5 Hz, 1H), 4.24 (d, J = 5.6 Hz, 1H), 4.01 (t, J = 6.3 Hz, 1H), 3.69 (dd, J = 14.2, 2.4 Hz, 1H), 3.35 (s, 1H), 3.12 – 3.06 (m, 1H), 2.74 (d, J = 9.5 Hz, 3H), 2.67 (s, 3H), 2.62 (d, J = 6.4 Hz, 3H), 2.27 (t, J = 5.2 Hz, 2H), 1.52 (d, J = 1.1 Hz, 1H), 1.43 (d, J = 6.6 Hz, 3H). EXAMPLE 55 (8aS,9S,12R)-5-(5-aminyl)-4-fluoro-2,3,8-trimethyl- N-((3-methylazetidin-3-yl)methyl)-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide 173Attorney Docket No. MDA0094-401-PC

[0313] Synthesized according to the procedure of Example 33. MS (ES+) C31H34F5N7O3requires: 647, found: 648 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.9, 1.1 Hz, 1H), 5.24 (d, J = 14.2 Hz, 1H), 4.70 – 4.64 (m, 1H), 4.15 – 4.11 (m, 2H), 4.07 – 4.03 (m, 2H), 3.73 (d, J = 11.3 Hz, 2H), 3.58 – 3.53 (m, 2H), 3.50 (d, J = 14.1 Hz, 1H), 3.34 (s, 3H), 3.07 – 3.00 (m, 3H), 2.61 (d, J = 6.6 Hz, 3H), 2.32 – 2.25 (m, 1H), 2.23 – 2.15 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H), 1.42 (s, 3H). EXAMPLE 56 ((8aS,9S,12R)-5-(5-a)phenyl)-4-fluoro-2,3,8- trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-12(13H)-yl)(2,6-diazaspiro[3.3]heptan-2-yl)methanone

[0314] Synthesized according to the procedure of Example 33. MS (ES+) C31H32F5N7O3requires: 645, found: 646 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.64 (dd, J = 12.3, 2.7 Hz, 1H), 6.60 (dd, J = 2.8, 1.1 Hz, 1H), 5.54 (d, J = 14.6 Hz, 1H), 5.02 – 4.98 (m, 1H), 4.81 (s, 1H), 4.62 – 4.57 (m, 1H), 4.43 – 4.38 (m, 1H), 4.38 – 4.28 (m, 5H), 4.19 (d, J = 9.7 Hz, 1H), 4.06 (d, J = 6.4 Hz, 1H), 3.40 (d, J = 14.6 Hz, 1H), 3.35 (s, 1H), 3.24 – 3.18 (m, 1H), 2.69 (s, 2H), 2.62 (d, J = 6.7 Hz, 3H), 2.17 – 2.12 (m, 1H), 2.11 – 2.06 (m, 1H), 1.57 (d, J = 6.2 Hz, 3H), 1.50 (d, J = 6.4 Hz, 1H), 1.38 – 1.35 (m, 1H). EXAMPLE 57 174Attorney Docket No. MDA0094-401-PC (8aS,9S,12R)-5-(5-amino yl)-4-fluoro-2,3,8-trimethyl-N-(1,1,1-trifluorobutan-2-yl)-8a,9,10,11-tetrahydro-8H-9,12- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-12(13H)- carboxamide

[0315] Synthesized according to the procedure of Example 33. MS (ES+) C30H30F8N6O3 requires: 674, found: 675 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.2, 2.7 Hz, 1H), 6.58 (s, 1H), 5.11 (dd, J = 14.0, 8.5 Hz, 1H), 4.71 (p, J = 6.3 Hz, 1H), 4.61 (dt, J = 7.9, 3.7 Hz, 1H), 4.15 (t, J = 6.8 Hz, 1H), 3.94 (dd, J = 11.6, 6.5 Hz, 1H), 3.55 (dd, J = 18.3, 14.1 Hz, 1H), 2.95 (td, J = 17.8, 16.9, 8.8 Hz, 1H), 2.65 (s, 4H), 2.61 (d, J = 6.5 Hz, 3H), 2.20 (dq, J = 12.8, 6.4, 5.9 Hz, 1H), 2.07 (d, J = 12.1 Hz, 1H), 1.97 – 1.89 (m, 1H), 1.81 – 1.72 (m, 1H), 1.41 (t, J = 6.4 Hz, 3H), 1.04 (dt, J = 14.3, 7.4 Hz, 3H). EXAMPLE 58 ((8aS,9S,12R)-5-(5-ay)phenyl)-4-fluoro-2,3,8- trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-12(13H)-yl)(3,3-dimethylazetidin-1-yl)methanone

[0316] Synthesized according to the procedure of Example 33. MS (ES+) C31H33F5N6O3 requires: 633, found: 634 [M+H]+. 175Attorney Docket No. MDA0094-401-PC1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.8, 1.1 Hz, 1H), 5.57 (d, J = 14.5 Hz, 1H), 4.59 (dq, J = 9.8, 6.2 Hz, 1H), 4.49 (d, J = 8.4 Hz, 1H), 4.30 (d, J = 8.4 Hz, 1H), 4.20 (d, J = 9.8 Hz, 1H), 4.06 (d, J = 6.4 Hz, 1H), 3.86 – 3.77 (m, 3H), 3.42 (d, J = 14.6 Hz, 1H), 3.34 (s, 1H), 3.24 – 3.18 (m, 1H), 2.61 (d, J = 2.8 Hz, 4H), 2.16 – 2.11 (m, 1H), 2.07 (td, J = 13.8, 12.3, 4.4 Hz, 2H), 1.58 (d, J = 6.2 Hz, 3H), 1.39 (d, J = 8.1 Hz, 6H). EXAMPLE 59 ((8aS,9S,12R)-5-(5- phenyl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-12(13H)-yl)(3-hydroxypyrrolidin-1-yl)methanone

[0317] Synthesized according to the procedure of Example 33. MS (ES+) C30H31F5N6O4requires: 634, found: 635 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.64 (dd, J = 12.3, 2.7 Hz, 1H), 6.61 – 6.58 (m, 1H), 5.65 (d, J = 14.7 Hz, 1H), 4.61 (dt, J = 7.7, 3.9 Hz, 1H), 4.52 – 4.44 (m, 1H), 4.26 (d, J = 10.3 Hz, 1H), 4.05 (d, J = 5.6 Hz, 1H), 3.71 – 3.67 (m, 1H), 3.63 – 3.59 (m, 1H), 3.43 (dd, J = 14.9, 7.6 Hz, 2H), 2.64 (s, 1H), 2.61 (d, J = 2.4 Hz, 3H), 2.60 (s, 2H), 2.18 – 2.12 (m, 2H), 2.12 – 2.06 (m, 2H), 1.60 (d, J = 6.2 Hz, 3H), 1.52 (d, J = 1.0 Hz, 3H). EXAMPLE 60176Attorney Docket No. MDA0094-401-PC 3-((5S,5aS,6S,9S)-9-((dimethylamino)methyl)-1-fluoro-5,13,14-trimethyl-5a,6,7,8,9,10- hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridin-2- yl)-5-fluoro-4-(trifluoromethoxy)aniline bis(2,2,2-trifluoroacetate) Step 1(trifluoromethoxy)phenyl)-1-fluoro-N,N,5,13,14-pentamethyl-5a,6,7,8-tetrahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-9(10H)-carboxamide in THF (1 ml) was added LAH and the resulting mixture was stirred at 0 °C for 0.5 h. Then the reaction was warmed to room temperature and allowed to stir for 1 hour before checked by LCMS.2 more equivalents of LAH were added and the reaction was allowed to stir for 2 hours before it was quenched. H2O (3.00 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (3 x 3.00 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A = 0.1% TFA / H2O, B = 0.1% TFA / MeCN; Gradient: B = 20 - 60%; 16 min; Column: XBridge C18, 5 μm, 50 mm x 100 mm) to give 3-((5S,5aS,6S,9S)-9-((dimethylamino)methyl)-1-fluoro-5,13,14-trimethyl- 5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridin-2-yl)-5-fluoro-4-(trifluoromethoxy)aniline bis(2,2,2-trifluoroacetate) (1.4 mg, 1.736 μmol) as yellow solid. MS (ES+) C28H31F5N6O2 requires: 578, found: 579 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.59 (dd, J = 2.8, 1.2 Hz, 1H), 5.22 (d, J = 14.0 Hz, 1H), 4.59 – 4.51 (m, 1H), 4.11 (d, J = 9.2 Hz, 1H), 3.96 (d, J = 6.6 Hz, 1H), 3.19 – 3.16 (m, 1H), 2.88 (d, J = 26.8 Hz, 1H), 2.80 (s, 6H), 2.58 (d, J = 7.7 Hz, 7H), 1.99 (s, 1H), 1.89 – 1.83 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 18.7 Hz, 2H), 0.92 – 0.86 (m, 2H). 177Attorney Docket No. MDA0094-401-PC EXAMPLE 61 isopropyl (4R,7S,8S)-13-[5 romethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylate Step 1 tert-butyl (1S,2S,5R)-3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate-2-(hydroxymethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (6 g, 24.76 mmol, 1 eq) in MeCN (120 mL) was added BnBr (4.45 g, 26.00 mmol, 3.09 mL, 1.05 eq) and K2CO3 (5.13 g, 37.14 mmol, 1.5 eq) at 20 °C, the mixture was stirred at 20 °C for 16 h. TLC (Dichloromethane : Methanol = 101) showed the tert-butyl (1S,2S,5R)-2- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate was consumed completely and one new spot was formed. The mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-80% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1S,2S,5R)-3-benzyl-2- (hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.1 g, 21.36 mmol, 86.25% yield) as yellow oil. MS (ES+) C19H28N2O3requires: 332, found: 333 [M+H]+. Step 2 tert-butyl (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 178Attorney Docket No. MDA0094-401-PC Boc Boc N (COCl)2, DMSO, TEA N .12 g, 40.37 mmol, 3.53 mL, 2.2 eq) in DCM(140 mL) was added DMSO (6.31 g, 80.74 mmol, 6.31 mL, 4.4 eq) at -70 °C under N2, then the mixture was stirred at -70 °C for 20 min, to the mixture was added tert-butyl (1S,2S,5R)- 3-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.1 g, 18.35 mmol, 1 eq) in DCM (20 mL) at -70 °C under N2, The mixture was stirred at -70 °C for 40 min, to the mixture was added TEA (14.85 g, 146.80 mmol, 20.43 mL, 8 eq) and stirred at - 70 °C for 0.5 h. LCMS showed a peak (53%) with desired desired mass. The mixture was poured into water (200 mL). The aqueous phase was extracted with DCM (100 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 15.13 mmol, 82.47% yield) as yellow oil.1H NMR (400 MHz, DMSO-d6) δ = 9.61 (d, J = 2.6 Hz, 1H), 7.37 - 7.23 (m, 5H), 4.17 - 4.09 (m, 1H), 3.77 (d, J = 13.6 Hz, 1H), 3.32 (s, 2H), 3.27 (d, J = 13.6 Hz, 1H), 3.11 - 2.98 (m, 1H), 2.22 - 2.12(m,1H), 1.94 - 1.85 (m, 1H), 1.81 - 1.63 (m, 3H), 1.38 (s, 9H). Step 3 tert-butyl (1S,2S,5R)-3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8- carboxylate,5R)-3-benzyl-2-formyl-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (5 g, 15.13 mmol, 1 eq) in THF (50 mL) was added MeMgBr (3 M, 15.13 mL, 3 eq) slowly at -78 °C under N2. The mixture was stirred at -78 °C for 2 h under N2. TLC (Petroleum ether : Ethyl acetate = 2:1 ) and LCMS showed the tert- butyl (1S,2S,5R)-3-benzyl-2-formyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was consumed completely. The mixture was quenched by sat. aq. NH4Cl (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried with anhydrous 179Attorney Docket No. MDA0094-401-PC Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 2-16% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford tert-butyl (1S,2S,5R)-3-benzyl-2-(1- hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.7 g, 9.93 mmol, 65.63% yield, 93% purity) as colorless oil. MS (ES+) C20H30N2O3requires: 346, found: 347 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.36 - 7.28 (m, 4H), 7.27 - 7.23 (m, 1H), 4.45 - 4.28 (m, 1H), 4.16 - 3.97 (m, 2H), 3.87 - 3.75 (m, 1H), 3.07 - 2.99 (m, 1H), 2.69 - 2.20 (m, 3H), 1.93 - 1.61 (m, 4H), 1.55 - 1.41 (m, 9H), 1.40 - 1.28 (m, 3H). Step 4 tert-butyl (1S,2S,5R)-3-benzyl-2-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylatebenzyl-2-(1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (3.7 g, 10.68 mmol, 1 eq) in DCM (37 mL) were added IMIDAZOLE (2.18 g, 32.04 mmol, 3 eq) and TBSCl (2.41 g, 16.02 mmol, 1.97 mL, 1.5eq) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed the tert-butyl (1S,2S,5R)-3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate remained and then the mixture was stirred at 25°C for another 16 h. LCMS showed the tert- butyl (1S,2S,5R)-3-benzyl-2-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate remained and a peak (72%) with desired mass. The mixture was concentrated in vacuum. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 2-16% ethyl acetate / petroleum ether gradient @ 150 mL / min) to afford tert-butyl (1S,2S,5R)-3-benzyl-2-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (4 g, 8.07 mmol, 75.61% yield, 93% purity) as colorless oil. MS (ES+) C26H44N2O3Si requires: 460, found: 461 [M+H]+. Step 5 O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-[1-[tert-butyl(dimethyl)silyl]oxyethyl]- 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate 180Attorney Docket No. MDA0094-401-PC -butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.5 g, 7.60 mmol, 1 eq) in THF (35 mL) were added TMEDA (2.65 g, 22.79 mmol, 3.44 mL, 3 eq) and s-BuLi (1.3 M, 17.53 mL, 3 eq) slowly at -40 °C under N2. The mixture was stirred at 0 °C for 0.5 h. The methyl carbonochloridate (2.52 g, 26.67 mmol, 2.06 mL, 3.51 eq) was added to the mixture at -78 °C under N2. The mixture was stirred at 0 °C for 1.5 h under N2. LCMS showed a peak (76%) with desired mass. The mixture was quenched by sat. aq. NH4Cl (50 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-3-6% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-[1-[tert-butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane- 1,8-dicarboxylate (3.2 g, 5.55 mmol, 73.08% yield, 90% purity) as colorless oil. MS (ES+) C28H46N2O5Si requires: 518, found: 519 [M+H]+.1H NMR (400 MHz, CDCl3) δ = 7.37 - 7.28 (m, 4H), 7.26 - 7.20 (m, 1H), 4.53 - 4.37 (m, 1H), 4.33 - 4.17 (m, 2H), 3.69 (s, 3H), 3.07 (d, J = 13.6 Hz, 1H), 2.90 (d, J = 11.4 Hz, 1H), 2.57 - 2.29 (m, 2H), 2.23 - 2.05 (m, 3H), 2.03 - 1.93 (m, 1H), 1.45 (s, 9H), 1.27 (d, J = 7.0 Hz, 3H), 0.92 - 0.90 (m, 9H), 0.11 - 0.07 (m, 6H). Step 6 O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate, , yl-4-[1-[tert- butyl(dimethyl)silyl]oxyethyl]-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (0.5 g, 963.84 μmol, 1 eq) in THF (5 mL) was added TBAF (1 M, 1.93 mL, 2 eq) at 25 °C. The mixture was stirred at 25 °C for 1 h. LCMS showed a peak (80%) with desired mass. The mixture was quenched by sat. aq. NH4Cl (10 mL) and extracted with ethyl acetate (10 mL x 3). The 181Attorney Docket No. MDA0094-401-PC combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, eluent of 0-20% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate (372 mg, 836.89 μmol, 86.83% yield, 91% purity) as colorless oil. MS (ES+) C22H32N2O5 requires: 404, found: 405 [M+H]+. Step 7 O8-tert-butyl O1-methyl (1R,4S,5S)-4-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane- 1,8-dicarboxylate d Pd(OH)2 (135mg, 192.26 μmol, 20% purity) in EtOH (5 mL) was added O8-tert-butyl O1-methyl (1R,4S,5S)-3-benzyl-4-(1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (370 mg, 914.71 μmol, 1 eq) in EtOH (1 mL) at 25 °C under N2. Then the mixture was degassed under vacuum and purged with H2 (50 Psi) several times. The mixture was stirred under H2(50 psi) at 25 °C for 16 hours. TLC (Petroleum ether : Ethyl acetate = 1:1) showed the material was consumed completely. The mixture was filtered and the filtrate was concentrated in vacuum to afford O8-tert-butyl O1-methyl (1R,4S,5S)-4-(1-hydroxyethyl)- 3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (243 mg, 772.96 μmol, 84.50% yield) as white solid.

[0326] 1H NMR (400 MHz, CDCl3) δ = 4.29 - 3.99 (m, 1H), 3.77 (s, 3H), 3.56 - 3.42 (m, 1H), 3.33 - 3.13 (m, 1H), 2.82 - 2.57 (m, 1H), 2.31-2.18 (m, 1H), 2.09 - 1.91 (m, 4H), 1.90 - 1.80 (m, 1H), 1.46 (s, 9H), 1.23 (d, J = 6.1 Hz, 3H). Step 8 O8-tert-butyl O1-methyl (1R,4S,5S)-4-[1-[(3-chloro-4-fluoro-8-hydroxy-5,6-dimethyl- 2,7-naphthyridin-1-yl)oxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate 182Attorney Docket No. MDA0094-401-PC HF (3 mL)was added O8-tert-butyl O1-methyl (1R,4S,5S)-4-(1-hydroxyethyl)-3,8- diazabicyclo[3.2.1]octane-1,8-dicarboxylate (43 mg, 136.78 μmol, 1.02 eq) at 0 °C under the protection of N2. The mixture was stirred at 0 °C for 10 min under N2. The 6,8-dichloro-5- fluoro-3,4-dimethyl-2H-2,7-naphthyridin-1-one (35.00 mg, 134.06 μmol, 1 eq) was added to the mixture at 0° C under N2. The mixture was stirred at 25 °C for 0.5 h under N2. LCMS showed a peak (39%) with desired mass. The mixture was quenched by sat. aq. NH4Cl (5 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to afford O8-tert-butyl O1-methyl (1R,4S,5S)-4-[1-[(3-chloro-4-fluoro-8-hydroxy-5,6-dimethyl-2,7-naphthyridin-1- yl)oxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-1,8-dicarboxylate (0.1 g, crude) as white solid. MS (ES+) C25H32ClN4FO6 requires: 538, found: 539 [M+H]+. Step 9 O20-tert-butyl O4-methyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 4,20-dicarboxylate, , (3-chloro-4-fluoro-8- hydroxy-5,6-dimethyl-2,7-naphthyridin-1-yl)oxy]ethyl]-3,8-diazabicyclo[3.2.1]octane-1,8- dicarboxylate (0.1 g, 185.53 μmol, 1 eq) in DMF (2 mL) were added DIEA (71.94 mg, 556.59 μmol, 96.95 μL, 3 eq) and CMPI (94.80 mg, 371.06 μmol, 2 eq). Then the mixture was stirred at 70 °C for 2 h. LCMS showed the starting material was consumed completely 183Attorney Docket No. MDA0094-401-PC and a peak (26%) with desired mass. The mixture was diluted with ethyl acetate (10 mL) and washed with brine (10 mL x 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 0-9% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O20-tert-butyl O4-methyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate (15 mg, 28.50 μmol, 15.36% yield, 99% purity) as yellow solid. MS (ES+) C25H30ClN4FO5requires: 520, found: 521 [M+H]+. Step 10 (4R,7S,8S)-20-tert-butoxycarbonyl-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4- carboxylic acidfluoro- 9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4,20-dicarboxylate (0.4 g, 767.78 μmol, 1 eq) in THF (4 mL) and MeOH (4 mL) was added LiOH·H2O (96.65 mg, 2.30 mmol, 3 eq) in H2O (2 mL). The mixture was stirred at 50 °C for 16 h. LCMS showed the starting material remained and a peak (80%) with desired mass. The mixture was concentrated in vacuum and diluted with water (10 mL), the aqueous phase was washed with ethyl acetate (20 mL x 2). The aqueous phase was adjusted to pH = 5 by aq. HCl (1M) at 0 °C. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, eluent of 3-66% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford (4R,7S,8S)-20-tert- butoxycarbonyl-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4-carboxylic acid (360 mg, 568.10 μmol, 73.99% yield, 80% purity) as yellow solid. MS (ES+) C24H28ClN4FO5 requires: 506, found: 507 [M+H]+. 184Attorney Docket No. MDA0094-401-PC Step 11 O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 4,20-dicarboxylate oro-9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylic acid (50 mg, 98.63 μmol, 1 eq) and K2CO3(136.3 mg, 986.3 μmol, 10 eq) in DMF (2 mL) was added 2-iodopropane (100.60 mg, 591.77 μmol, 59.07 μL, 6 eq) at 20 °C. The mixture was stirred at 20 °C for 16 h. LCMS showed the starting material was consumed completely and a peak (26%) with desired mass. The mixture was filtered and diluted with ethyl acetate (5 mL) and washed with brine (10 mL x 2), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-33% ethyl acetate / petroleum ether gradient @ 100 mL / min) to give O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-chloro-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate (45 mg, 69.67 μmol, 70.64% yield, 85% purity) as yellow solid. MS (ES+) C27H34ClN4FO5requires: 548, found: 549 [M+H]+. Step 12 O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate 185Attorney Docket No. MDA0094-401-PC9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4,20-dicarboxylate (45 mg, 81.96 μmol, 1 eq), 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethoxy)aniline (39.47 mg, 122.94 μmol, 1.5 eq) and K3PO4(1.5 M, 163.92 μL, 3 eq) in THF (1 mL) was added Ad2nBuP Pd G3(cataCXium® A Pd G3 ) (5.97 mg, 8.20 μmol, 0.1 eq) under N2. The mixture was stirred at 60 °C for 16 h under N2. LCMS showed the material was consumed completely and a peak (58%) with desired mass. The mixture was added water (2 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by flash silica gel chromatography (4 g SepaFlash® Silica Flash Column, eluent of 2-27% ethyl acetate / petroleum ether gradient @ 100 mL / min) to afford O20-tert-butyl O4-isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate (46 mg, 49.40 μmol, 60.27% yield, 76% purity) as yellow solid. MS (ES+) C34H38N5F5O6requires: 707, found: 708 [M+H]+. Step 13 isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro- 9,16,17-trimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-4-carboxylate 186Attorney Docket No. MDA0094-401-PC o-2-(trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4,20- dicarboxylate (46 mg, 65.00 μmol, 1 eq) in DCM (0.6 mL) was added TFA (460.50 mg, 4.04 mmol, 0.3 mL) at 20 °C. The mixture was stirred at 20 °C for 10 min. LCMS showed the starting material was consumed completely and one main peak with desired mass. The mixture was concentrated in vacuum. The residue was purified by prep-HPLC(column: Phenomenex luna C18150*25mm*10um;mobile phase: [water(FA)-ACN];gradient:24%- 54% B over 10 min) and lyophilized to afford isopropyl (4R,7S,8S)-13-[5-amino-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-9,16,17-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-4-carboxylate (19.2 mg, 31.60 μmol, 48.62% yield, 100% purity) as white solid. MS (ES+) C29H30F5N5O4requires: 607, found: 608 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.68 - 6.53 (m, 2H), 5.45 (d, J = 13.1 Hz, 1H), 5.18 - 5.07 (m, 1H), 4.48 - 4.36 (m, 1H), 3.93 (d, J = 9.3 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.12 (d, J = 13.2 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.62 - 2.48 (m, 6H), 1.90 - 1.67 (m, 3H), 1.52 (d, J = 6.4 Hz, 3H), 1.34 (dd, J = 1.3, 6.2 Hz, 6H). EXAMPLE 62187Attorney Docket No. MDA0094-401-PC methyl (5aS,6S,9R)-2-(6-amino-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-1-fluoro- 5,13,14-trimethyl-5a,6,7,8-tetrahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-9(10H)-carboxylate

[0333] Synthesized according to the procedure of Example 61. MS (ES+) C27H28F4N6O3 requires: 560, found: 561 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.30 - 8.17 (m, 1H), 6.51 - 6.19 (m, 1H), 5.45 (d, J = 13.2 Hz, 1H), 4.53 - 4.41 (m, 1H), 3.96 (d, J = 9.5 Hz, 1H), 3.86 (s, 3H), 3.69 (d, J = 4.9 Hz, 1H), 3.24 - 3.17 (m, 1H), 2.96 - 2.83 (m, 1H), 2.58 (s, 3H), 2.56-2.51 (m, 6H), 1.96 - 1.75 (m, 3H), 1.52 (d, J = 6.2 Hz, 3H). EXAMPLE 63 cyclopropyl (5aS,6S,9R)-2romethoxy)phenyl)-1-fluoro- 5,13,14-trimethyl-5a,6,7,8-tetrahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-9(10H)-carboxylate

[0334] Synthesized according to the procedure of Example 61. MS (ES+) C29H28F5N5O4 requires: 605, found: 606 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.36 - 8.27 (m, 1H), 6.68 - 6.54 (m, 2H), 5.41 (d, J = 13.2 Hz, 1H), 4.48 - 4.38 (m, 1H), 4.33 - 4.24 (m, 1H), 4.00 - 3.88 (m, 1H), 3.66 - 3.58 (m, 1H), 3.14 (d, J = 13.1 Hz, 1H), 2.88 - 2.77 (m, 1H), 2.65 - 2.49 (m, 6H), 1.91 - 1.71 (m, 3H), 1.52 (d, J = 6.4 Hz, 3H), 0.88 - 0.71 (m, 4H). EXAMPLE 64 188Attorney Docket No. MDA0094-401-PC methyl (6S,9R)-2-(5-ami oxy)phenyl)-1-fluoro-13,14-dimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxylate

[0335] Synthesized according to the procedure of Example 61. MS (ES+) C26H24F5N5O4 requires: 565, found: 566 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.68 - 6.54 (m, 2H), 4.62 - 4.44 (m, 3H), 3.94 - 3.91 (m, 1H), 3.88 (s, 3H), 3.83 - 3.77 (m, 1H), 3.45 (d, J = 13.3 Hz, 1H), 2.69 - 2.56 (m, 6H), 2.56 - 2.46 (m, 1H), 2.39 - 2.29 (m, 1H), 2.12 - 1.95 (m, 2H). EXAMPLE 65 methyl (6S,9R)-2-(6-aminol)pyridin-4-yl)-1-fluoro-13,14- dimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxylate

[0336] Synthesized according to the procedure of Example 61. MS (ES+) C26H26F4N6O3 requires: 546, found: 547 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.44 - 6.26 (m, 1H), 4.63 - 4.40 (m, 3H), 4.03 - 3.93 (m, 1H), 3.89 (s, 3H), 3.86 - 3.77 (m, 1H), 3.53 - 3.44 (m, 1H), 2.62 - 2.50 (m, 10H), 2.41 - 2.32 (m, 1H), 2.15 - 1.98 (m, 2H). EXAMPLE 66 189Attorney Docket No. MDA0094-401-PC methyl (5aS,6S,9R)-2-(5-a oxy)phenyl)-1-fluoro-5,13,14-trimethyl-5a,6,7,8-tetrahydro-5H-6,9-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-9(10H)-carboxylate

[0337] Synthesized according to the procedure of Example 61. MS (ES+) C27H26F5N5O4 requires: 579, found: 580 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.68 - 6.56 (m, 2H), 5.50 (d, J = 14.1 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.11 - 4.01 (m, 2H), 3.94 (s, 3H), 3.41 (d, J = 14.1 Hz, 1H), 3.16 - 3.05 (m, 1H), 2.67 - 2.54 (m, 6H), 2.10 - 1.98 (m, 3H), 1.55 (d, J = 6.2 Hz, 3H). EXAMPLE 67 oxetan-3-yl (5aS,6S,9Rmethoxy)phenyl)-1-fluoro- 5,13,14-trimethyl-5a,6,7,8-tetrahydro-5H-6,9- epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7-ij][2,7]naphthyridine-9(10H)-carboxylate

[0338] Synthesized according to the procedure of Example 61. MS (ES+) C29H28F5N5O5requires: 621, found: 622 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.66 - 6.56 (m, 2H), 5.67 - 5.59 (m, 1H), 5.47 - 5.41 (m, 1H), 4.98 - 4.96 (m, 2H), 4.72 - 4.67 (m, 2H), 4.49 - 4.36 (m, 1H), 3.94 (d, J = 9.3 Hz, 1H), 3.62 - 3.56 (m, 1H), 3.22 - 3.16 (m, 1H), 2.93 - 2.82 (m, 1H), 2.61 - 2.51 (m, 6H), 1.90 - 1.74 (m, 3H), 1.52 (d, J = 6.2 Hz, 3H). 190Attorney Docket No. MDA0094-401-PC EXAMPLE 68 (8aS,9S,12R)-5-(5-amino-3- henyl)-4-fluoro-2,3,8-trimethyl-8a,9,10,11-tetrahydro-8H-9,12-epiminoazepino[2',1':3,4][1,4]oxazepino[5,6,7- ij][2,7]naphthyridine-12(13H)-carboxylic acid

[0339] Synthesized according to the procedure of Example 61. MS (ES+) C26H24F5N5O4requires: 565, found: 566 [M+H]+.1H NMR (600 MHz, MeOD) δ 6.63 (dd, J = 12.4, 2.7 Hz, 1H), 6.58 (s, 1H), 5.55 (d, J = 14.3 Hz, 1H), 4.63 – 4.58 (m, 1H), 4.12 – 4.06 (m, 2H), 2.65 (s, 9H), 2.59 (d, J = 6.6 Hz, 3H), 1.54 (d, J = 6.4 Hz, 3H). EXAMPLE 69 (4R,7S,8S,9S)-13-[5-amino-xy)phenyl]-14-fluoro-N,4,9,16- tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-17-carboxamide Step 1 tert-butyl (1R,4S,5S)-4-[(1S)-1-[(3-chloro-4-fluoro-5-methyl-8-oxo-6-vinyl-7H-2,7- naphthyridin-1-yl)oxy]ethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 191Attorney Docket No. MDA0094-401-PC thyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (8.61 g, 31.86 mmol, 1 eq) in THF (100 mL) was added NaH (3.19 g, 79.64 mmol, 60% purity, 2.5 eq) at 0 °C under N2 and the mixture was stirred at 0 °C for 10 min. To the mixture was added 6,8-dichloro-5-fluoro-4-methyl-3-vinyl- 2H-2,7-naphthyridin-1-one (8.7 g, 31.86 mmol, 1 eq) the mixture was stirred at 45 °C for 1 hour. LCMS showed benzyl N-[2-[tert-butyl(dimethyl)silyl]oxy-1-(6,8-dichloro-5-fluoro-1- oxo-2H-2,7-naphthyridin-3-yl)ethyl]carbamate was consumed and a main peak with desired mass. To the mixture was added saturated NH4Cl (50 mL) and extracted with EtOAc (50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (45 g SepaFlash® Silica Flash Column, eluent of 0-100% ethyl acetate / petroleum ether gradient @ 50 mL / min) to afford tert-butyl (1R,4S,5S)-4-[(1S)-1-[(3-chloro-4-fluoro-5-methyl-8-oxo-6-vinyl-7H-2,7- naphthyridin-1-yl)oxy]ethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (14.6 g, 28.80 mmol, 90.39% yield) as a yellow solid. MS (ES+) C25H32ClFN4O requires: 506, found: 507 [M+H]+. Step 2 tert-butyl (4R,7S,8S,9S)-13-chloro-14-fluoro-4,9,16-trimethyl-17-vinyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaene-20- carboxylate192Attorney Docket No. MDA0094-401-PC

[0341] To a solution of tert-butyl (1R,4S,5S)-4-[(1S)-1-[(3-chloro-4-fluoro-5-methyl-8- oxo-6-vinyl-7H-2,7-naphthyridin-1-yl)oxy]ethyl]-1-methyl-3,8-diazabicyclo[3.2.1]octane-8- carboxylate (14.6 g, 28.80 mmol, 1 eq) in DMF (140 mL) was added DIPEA (14.89 g, 115.19 mmol, 20.06 mL, 4 eq) and CMPI (14.71 g, 57.59 mmol, 2 eq), and the mixture was stirred at 70 °C for 1 hour. LCMS showed a main peak with desired mass. To the mixture was added water (70 mL) and extracted with EtOAc (70 mL x 3), the combined organic phase was washed with brine(200 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, eluent of 0-15% ethyl acetate / petroleum ether gradient @ 80 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-chloro-14-fluoro-4,9,16-trimethyl-17- vinyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16- pentaene-20-carboxylate (12.4 g, 25.36 mmol, 88.06% yield) as colorless oil. MS (ES+) C25H30ClFN4O3 requires: 488, found: 489 [M+H]+. Step 3 tert-butyl (4R,7S,8S,9S)-13-chloro-14-fluoro-17-formyl-4,9,16-trimethyl-10-oxa- 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylate CF3O Boc Boc O H217-vinyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11,13,15(19),16-pentaene-20-carboxylate (12.4 g, 25.36 mmol, 1 eq) in dioxane (120 mL) and H2O (40 mL) were added NaIO4 (27.12 g, 126.79 mmol, 7.03 mL, 5 eq) and K2OsO4•2H2O (934.36 mg, 2.54 mmol, 0.1 eq), the mixture was stirred at 20 °C for 2 hour. TLC(Commercial hexanes: Ethyl acetate= 3:1) showed reactant was consumed and new spot formed. To the mixture was added water (20 mL) and extracted with EtOAc (20 mL x 3), the combined organic phase was washed with saturated Na2S2O3(50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by 193Attorney Docket No. MDA0094-401-PC flash silica gel chromatography (10 g SepaFlash® Silica Flash Column, eluent of 0-30% Ethyl acetate / Commercial hexanes gradient @ 60 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-chloro-14-fluoro-17-formyl-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (7 g, 14.26 mmol, 56.22% yield) as yellow solid. MS (ES+) C24H28ClFN4O4requires: 490, found: 491 [M+H]+. Step 4 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-17-formyl-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylatetrimethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-20-carboxylate (4 g, 8.15 mmol, 1 eq) in THF (80 mL) were added CataCXium A Pd G3(593.35 mg, 814.74 μmol, 0.1 eq), K3PO4(1.5 M, 16.29 mL, 3 eq) and tert-butyl N-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (trifluoromethoxy)phenyl]carbamate (5.15 g, 12.22 mmol, 1.5 eq) under N2, the mixture was stirred at 60 °C for 2.5 hours. LCMS showed reactant was consumed and one peak with desired mass. The reaction mixture was diluted with EtOAc (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, eluent of 0-100% Ethyl acetate / Commercial hexanes gradient @ 100 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14- fluoro-17-formyl-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (5.7 g, 6.16 mmol, 75.59% yield, 81% purity) as yellow solid. 194Attorney Docket No. MDA0094-401-PC MS (ES+) C36H40F5N5O7requires: 749, found: 750 [M+H]+. Step 5 (4R,7S,8S,9S)-20-tert-butoxycarbonyl-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17-carboxylic acidfluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-17-formyl-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20-carboxylate (5.7 g, 6.16 mmol, 1 eq) in t-BuOH (30 mL) and 2-methylbut-2-ene (30 mL) was added a solution of NaH2PO4 (5.10 g, 36.95 mmol, 6 eq) and NaClO2 (1.67 g, 18.47 mmol, 3 eq) in H2O (10 mL) at 0 °C, the mixture was stirred at 20 °C for 1 hour. LCMS showed reactant was consumed and main peak with desired mass. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3), the combined organic phase was washed with saturated Na2S2O3(100 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (45 g SepaFlash® Silica Flash Column, eluent of 0-100% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to afford (4R,7S,8S,9S)-20-tert-butoxycarbonyl-13-[5-(tert-butoxycarbonylamino)- 3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17-carboxylic acid (4.3 g, 5.62 mmol, 91.19% yield) as yellow solid. MS (ES+) C36H40F5N5O8 requires: 765, found: 766 [M+H]+. Step 6 tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)-3-fluoro-2- (trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(methylcarbamoyl)-10-oxa- 195Attorney Docket No. MDA0094-401-PC 2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-20- carboxylatebutoxycarbonylamino)-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 17-carboxylic acid (3.8 g, 4.96 mmol, 1 eq), HATU (3.77 g, 9.93 mmol, 2 eq) and DIPEA (3.21 g, 24.81 mmol, 4.32 mL, 5 eq) in DMF (40 mL) was added methanamine hydrochloride (1.01 g, 14.89 mmol, 3 eq), the mixture was stirred at 20 °C for 0.5 h. LCMS showed reactant of carboxylic acid was consumed and main peak with desired mass. To the mixture was added water (20 mL) and extracted with EtOAc (20 mL x 3), the combined organic phase was washed with brine(50 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (25 g SepaFlash® Silica Flash Column, eluent of 0-60% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to afford tert-butyl (4R,7S,8S,9S)-13-[5-(tert-butoxycarbonylamino)- 3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(methylcarbamoyl)-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate (3.8 g, 4.88 mmol, 98.33% yield) as a yellow solid. MS (ES+) C37H43F5N6O7 requires: 778, found: 779 [M+H]+. Step 7 (4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-N,4,9,16- tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-17-carboxamide 196Attorney Docket No. MDA0094-401-PCfluoro-2-(trifluoromethoxy)phenyl]-14-fluoro-4,9,16-trimethyl-17-(methylcarbamoyl)-10- oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene- 20-carboxylate (3.8 g, 4.88 mmol, 1 eq), TFA (58.33 g, 511.56 mmol, 38.00 mL, 104.84 eq) in DCM (40 mL) was added TFA (58.33 g, 511.56 mmol, 38.00 mL, 104.84 eq), the mixture was stirred at 20 °C for 0.25 h. LCMS showed reactant was consumed and main peak with desired mass. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC (column: Phenomenex luna C18 (250*70mm,10 um); mobile phase: [H2O(0.225% FA)-ACN]; gradient:20%-50% B over 22.0 min), the eluent was freeze dried over to afford (4R,7S,8S,9S)-13-[5-amino-3-fluoro-2-(trifluoromethoxy)phenyl]- 14-fluoro-N,4,9,16-tetramethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17-carboxamide (2368.8 mg, 3.79 mmol, 77.73% yield, 100% purity, FA) as a white solid. MS (ES+) C27H27F5N6O3 requires: 578, found: 579 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.45 (s, 1H), 6.72 - 6.57 (m, 2H), 5.02 (d, J = 14.3 Hz, 1H), 4.66 - 4.56 (m, 1H), 4.11 (d, J = 8.9 Hz, 1H), 4.04 (d, J = 5.7 Hz, 1H), 3.25 (d, J = 14.3 Hz, 1H), 2.97 (s, 3H), 2.75 - 2.67 (m, 1H), 2.63 (d, J = 7.9 Hz, 3H), 2.12 - 1.98 (m, 2H), 1.80 - 1.69 (m, 1H), 1.58 - 1.52 (m, 6H). EXAMPLE 70 197Attorney Docket No. MDA0094-401-PC 4-((5aS,6S,9R)-1-fluoro-9 5a,6,7,8,9,10-hexahydro-5H-6,9-epiminoazepino[2’,1 :3,4][1,4]oxazepino[5,6,7-ij][2,7]pyridine198dine-2-yl)-6- methyl-5-(trifluoromethyl)pyridine-2-amine

[0347] Synthesized according to the procedure of Example 69. MS (ES+) C30H31F5N6O3 requires:618, found:619[M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.51 (s, 1H), 6.67 - 6.57 (m, 2H), 4.99 (d, J = 13.9 Hz, 1H), 4.56 - 4.46 (m, 1H), 4.03 (d, J = 9.3 Hz, 1H), 3.78 (d, J = 6.0 Hz, 1H), 3.09 (d, J = 13.9 Hz, 1H), 2.67 - 2.55 (m, 4H), 2.03 - 1.81 (m, 2H), 1.64 - 1.57 (m, 1H), 1.55 (d, J = 6.3 Hz, 3H), 1.51 (s, 3H), 1.43 (s, 3H), 0.91 - 0.82 (m, 2H), 0.80 - 0.71 (m, 2H). EXAMPLE 71 4-((5aS,6S,9R)-1-fluoro-9--5a,6,7,8,9,10-hexahydro-5H- 6,9-epiminoazepino[2’,1’:3,4][1,4]oxazepino[5,6,7-ij][2,7]pyridine198dine-2-yl)-6- methyl-5-(trifluoromethyl)pyridine-2-amine

[0348] Synthesized according to the procedure of Example 69. MS (ES+) C30H33F5N6O3 requires:620, found:621[M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.51 (s, 1H), 6.67 - 6.58 (m, 2H), 4.99 (d, J = 13.9 Hz, 1H), 4.56 - 4.46 (m, 1H), 4.04 (d, J = 9.4 Hz, 1H), 3.79 (d, J = 6.0 Hz, 1H), 3.11 (d, J = 13.9 Hz, 1H), 2.70 - 2.60 (m, 4H), 2.04 - 1.83 (m, 2H), 1.66 - 1.59 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.49 (s, 9H), 1.44 (s, 3H). 198Attorney Docket No. MDA0094-401-PC EXAMPLE 72 (4R,7S,8S,9S)-13-[5-amino ro-phenyl]-14-fluoro-N,4,9,16-tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-17-carboxamide

[0349] Synthesized according to the procedure of Example 69. MS (ES+) C27H28F4N6O3 requires: 560, found: 561 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.73 - 6.28 (m, 3H), 5.04 (d, J = 14.5 Hz, 1H), 4.63 (dd, J = 6.4, 8.8 Hz, 1H), 4.19 - 4.07 (m, 2H), 3.30 - 3.27 (m, 1H), 2.98 (s, 3H), 2.83 - 2.70 (m, 1H), 2.64 (d, J = 7.9 Hz, 3H), 2.19 - 2.00 (m, 2H), 1.86 - 1.73 (m, 1H), 1.64 - 1.52 (m, 6H). EXAMPLE 73 (4R,7S,8S,9S)-13-[5-amino-3hyl)phenyl]-14-fluoro-N,4,9,16- tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-17-carboxamide

[0350] Synthesized according to the procedure of Example 69. MS (ES+) C28H29F5N6O2 requires: 576, found 577 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.59 - 6.53 (m, 2H), 5.05 (d, J = 14.2 Hz, 1H), 4.69 - 4.60 (m, 1H), 4.12 (d, J = 8.3 Hz, 2H), 3.50 - 3.38 (m, 2H), 3.29 - 3.25 (m, 1H), 2.97 (s, 3H), 2.82 199Attorney Docket No. MDA0094-401-PC - 2.71 (m, 1H), 2.63 (d, J = 8.3 Hz, 3H), 2.15 - 2.03 (m, 2H), 1.85 - 1.74 (m, 1H), 1.58 (s, 3H), 1.55 (d, J = 6.4 Hz, 3H). EXAMPLE 74 (4R,7S,8S,9S)-13-[5 phenyl]-14-fluoro-N-(2-hydroxy-2-methyl-propyl)-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide

[0351] Synthesized according to the procedure of Example 69. MS (ES+) C30H33F5N6O4 requires: 636, found: 637 [M+H]+.1H NMR (400 MHz,CD3OD) δ = 6.68 - 6.58 (m, 2H), 5.00 (d, J = 13.1 Hz, 1H), 4.51 - 4.40 (m, 1H), 3.96 (d, J = 9.6 Hz, 1H), 3.53 - 3.42 (m, 2H), 3.36 (d, J = 13.3 Hz, 1H), 2.94 (d, J = 13.3 Hz, 1H), 2.69 (d, J = 8.1 Hz, 3H), 2.50 - 2.40 (m, 1H), 1.89 - 1.77 (m, 1H), 1.76 - 1.66 (m, 1H), 1.54 (d, J = 6.3 Hz, 3H), 1.48 - 1.38 (m, 1H), 1.36 - 1.26 (m, 9H). EXAMPLE 75 (4R,7S,8S,9S)-13-[5-am)phenyl]-14-fluoro-4,9,16- trimethyl-N-tetrahydrofuran-3-yl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide 200Attorney Docket No. MDA0094-401-PC

[0352] Synthesized according to the procedure of Example 69. MS (ES+) C30H31F5N6O4requires: 634, found 635 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.70 - 6.60 (m, 2H), 5.06 (dd, J = 3.4, 14.6 Hz, 1H), 4.68 - 4.58 (m, 2H), 4.20 - 4.10 (m, 2H), 4.01 - 3.92 (m, 2H), 3.91 - 3.76 (m, 2H), 3.37 - 3.33 (m, 1H), 2.86 - 2.75 (m, 1H), 2.65 (d, J = 7.6 Hz, 3H), 2.43 - 2.30 (m, 1H), 2.19 - 1.93 (m, 3H), 1.89 - 1.75 (m, 1H), 1.62 - 1.54 (m, 6H). EXAMPLE 76 (4R,7S,8S,9S)-13-(2-ami hen-4-yl)-14-fluoro-N,4,9,16-tetramethyl-10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa- 1(18),11(19),12,14,16-pentaene-17-carboxamide

[0353] Synthesized according to the procedure of Example 69. MS (ES+) C29H27F2N7O2S requires:575, found:576[M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.52 (s, 1H), 7.41 (dd, J = 5.2, 8.4 Hz, 1H), 7.08 - 6.99 (m, 1H), 5.07 (d, J = 13.8 Hz, 1H), 4.58 - 4.49 (m, 1H), 4.05 (d, J = 9.4 Hz, 1H), 3.81 (d, J = 6.4 Hz, 1H), 3.15 - 3.07 (m, 1H), 2.97 (s, 3H), 2.67 - 2.56 (m, 4H), 2.03 - 1.83 (m, 2H), 1.66 - 1.54 (m, 4H), 1.46 (s, 3H). EXAMPLE 77 tert-butyl (4R,7S,8S, y y mino)-3-cyano-7-fluoro- benzothiophen-4-yl]-14-fluoro-4,9,16-trimethyl-17-[(1-methylcyclopropyl)carbamoyl]- 201Attorney Docket No. MDA0094-401-PC 10-oxa-2,12,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16- pentaene-20-carboxylate

[0354] Synthesized according to the procedure of Example 69. MS (ES+) C32H31F2N7O2S requires:615, found:616[M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.51 (s, 1H), 7.40 (dd, J = 5.1, 8.4 Hz, 1H), 7.08 - 7.00 (m, 1H), 5.07 (d, J = 13.6 Hz, 1H), 4.56 - 4.47 (m, 1H), 4.06 (d, J = 9.5 Hz, 1H), 3.84 - 3.76 (m, 1H), 3.09 (d, J = 13.6 Hz, 1H), 2.69 - 2.59 (m, 4H), 2.02 - 1.80 (m, 2H), 1.63 - 1.56 (m, 4H), 1.51 (s, 3H), 1.44 (s, 3H), 0.91 - 0.83 (m, 2H), 0.80 - 0.71 (m, 2H). EXAMPLE 78 (4R,7S,8S,9S)-13-[5-am)phenyl]-14-fluoro-4,9,16- trimethyl-N-[(1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide

[0355] Synthesized according to the procedure of Example 69. MS (ES+) C31H31F5N6O4 requires:646, found:647[M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.66 - 6.58 (m, 2H), 4.97 - 4.93 (m, 1H), 4.50 - 4.40 (m, 1H), 4.08 - 4.00 (m, 2H), 3.95 (d, J = 9.3 Hz, 1H), 3.85 (d, J = 8.4 Hz, 1H), 3.80 (d, J = 8.4 Hz, 1H), 3.51 (d, J = 6.5 Hz, 1H), 2.95 (d, J = 13.3 Hz, 1H), 2.61 (d, J = 7.9 Hz, 3H), 2.49 - 2.37 (m, 1H), 1.91 - 1.79 (m, 2H), 1.78 - 1.69 (m, 1H), 1.53 (d, J = 6.3 Hz, 3H), 1.50 - 1.39 (m, 1H), 1.33 (s, 3H), 1.11 (dd, J = 5.4, 8.6 Hz, 1H), 1.06 - 0.98 (m, 1H). EXAMPLE 79 202Attorney Docket No. MDA0094-401-PC (4R,7S,8S,9S)-13-(2 en-4-yl)-14-fluoro-N-(2-hydroxy-2-methyl-propyl)-4,9,16-trimethyl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide

[0356] Synthesized according to the procedure of Example 69. MS (ES+) C32H33F2N7O3S requires:633, found:634[M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.57 - 8.48 (m, 1H), 7.41 (dd, J = 5.1, 8.4 Hz, 1H), 7.04 (t, J = 8.9 Hz, 1H), 5.10 (d, J = 13.6 Hz, 1H), 4.57 - 4.46 (m, 1H), 4.05 (d, J = 9.6 Hz, 1H), 3.71 (d, J = 6.1 Hz, 1H), 3.52 - 3.47 (m, 1H), 3.37 (d, J = 13.4 Hz, 1H), 3.07 (d, J = 13.1 Hz, 1H), 2.72 (d, J = 8.0 Hz, 3H), 2.67 - 2.55 (m, 1H), 1.99 - 1.77 (m, 2H), 1.63 - 1.51 (m, 4H), 1.43 (s, 3H), 1.30 (s, 6H). EXAMPLE 80 (4R,7S,8S,9S)-13-[5-am)phenyl]-14-fluoro-4,9,16- trimethyl-N-[(1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide

[0357] Synthesized according to the procedure of Example 69. MS (ES+) C31H31F5N6O4 requires: 646, found: 647 [M+H]+. 203Attorney Docket No. MDA0094-401-PC1H NMR (400 MHz, CD3OD) δ = 8.50 (s, 1H), 6.69 - 6.55 (m, 2H), 5.00 (d, J = 14.0 Hz, 1H), 4.60 - 4.50 (m, 1H), 4.15 - 3.97 (m, 3H), 3.91 (d, J = 6.5 Hz, 1H), 3.86 - 3.76 (m, 2H), 3.18 (d, J = 14.0 Hz, 1H), 2.68 - 2.57 (m, 4H), 2.08 - 1.85 (m, 3H), 1.74 - 1.62 (m, 1H), 1.55 (d, J = 6.4 Hz, 3H), 1.49 (s, 3H), 1.13 - 1.07 (m, 1H), 1.03 - 0.98 (m, 1H). EXAMPLE 81 (4R,7S,8S,9S)-13-[5-a phenyl]-14-fluoro-4,9,16-trimethyl-N-tetrahydropyran-4-yl-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide

[0358] Synthesized according to the procedure of Example 69. MS (ES+) C31H33F5N6O4 requires: 648, found 649 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.69 - 6.57 (m, 2H), 5.05 (d, J = 14.1 Hz, 1H), 4.60 - 4.55 (m, 1H), 4.21 - 4.08 (m, 2H), 4.04 - 3.94 (m, 3H), 3.63 - 3.52 (m, 2H), 3.22 (d, J = 14.3 Hz, 1H), 2.79 - 2.69 (m, 1H), 2.64 (d, J = 7.9 Hz, 3H), 2.11 - 1.92 (m, 4H), 1.76 - 1.60 (m, 3H), 1.57 (d, J = 6.3 Hz, 3H), 1.52 (s, 3H). EXAMPLE 82 (4R,7S,8S,9S)-13-[5-amy)phenyl]-14-fluoro-4,9,16- trimethyl-N-[(3R)-tetrahydrofuran-3-yl]-10-oxa-2,12,18,20- 204Attorney Docket No. MDA0094-401-PC tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide

[0359] Synthesized according to the procedure of Example 69. MS (ES+) C30H31F5N6O4requires: 634, found 635 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 6.68 - 6.59 (m, 2H), 5.02 (d, J = 14.0 Hz, 1H), 4.67 - 4.61 (m, 1H), 4.59 - 4.52 (m, 1H), 4.07 (d, J = 9.3 Hz, 1H), 4.02 - 3.92 (m, 2H), 3.91 - 3.82 (m, 2H), 3.81 - 3.75 (m, 1H), 3.14 (d, J = 13.6 Hz, 1H), 2.71 - 2.58 (m, 4H), 2.41 - 2.29 (m, 1H), 2.05 - 1.86 (m, 3H), 1.69 - 1.59 (m, 1H), 1.56 (d, J = 6.3 Hz, 3H), 1.47 (s, 3H). EXAMPLE 83 (4R,7S,8S,9S)-13-[5-aphenyl]-14-fluoro-4,9,16- trimethyl-N-[(3S)-tetrahydrofuran-3-yl]-10-oxa-2,12,18,20- tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene-17- carboxamide

[0360] Synthesized according to the procedure of Example 69. MS (ES+) C30H31F5N6O4 requires: 634, found: 635 [M+H]+.1H NMR (400 MHz, CD3OD) δ = 8.46 (s, 1H), 6.68 - 6.58 (m, 2H), 5.03 (d, J = 14.0 Hz, 1H), 4.67 - 4.60 (m, 1H), 4.59 - 4.52 (m, 1H),...

Claims

Attorney Docket No. MDA0094-401-PC CLAIMS What is claimed is:

1. A compound of Formula I (I) or a pharmaceutically acce ereof, wherein 1J is chosen from N and CH; X is chosen from CH2, O, S, and NR7; R1is chosen from aryl and heteroaryl, either of which may be optionally substituted with one or more R12; each R2is chosen from halo, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, cyano, -C(O)N(R8)2, alkylamino, dialkylamino, - C(O)OR8, -C(O)R8, and haloalkyl, wherein alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino, dialkylamino, and haloalkyl may be optionally substituted with one or more R15; R3is chosen from alkyl, cycloalkyl, alkynyl, halo, and cyano, wherein alkyl, cycloalkyl, and alkynyl may be optionally substituted with one or more R9; R4is chosen from hydrogen, alkyl, alkoxy, cyano and halo; R5is chosen from hydrogen, alkyl, alkoxy, and halo; R6is chosen from hydrogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, -C(O)OR10, -S(O)(NH)-alkyl, alkylthio, and halo, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, and alkylthio may be optionally substituted with one or more groups chosen from R11; R7is chosen from hydrogen and alkyl; each R8is independently chosen from hydrogen, alkyl, heterocycloalkyl, heteroaryl, and cycloalkyl, any of which may be optionally substituted by one or 357Attorney Docket No. MDA0094-401-PC more R13OR two R8may combine to form a heterocycloalkyl optionally substituted by one or more R16; each R9is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy; R10is independently chosen from hydrogen and alkyl; each R11is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, amidoalkyl, alkylcycloalkyl, halocycloalkyl, halocycloalkylalkyl, hydroxycycloalkylalkyl, alkylheterocycloalkyl, cyanoheterocycloalkyl, perdeuteroalkyl, cyano, halo, haloalkyl, oxo, amino, alkylamino, dialkylamino, and hydroxy; each R12is independently chosen from alkyl, amino, cyanocycloalkyloxy, cyano, halo, haloalkyl, and haloalkoxy; each R13is independently chosen from hydroxy, halo, alkylamino, dialkylamino, -SO3H, heterocycloalkyl, heteroaryl, and cycloalkyl, wherein heterocycloalkyl, heteroaryl, and cycloalkyl may be substituted with one or more R17; each R15is independently chosen from halo, alkoxy, deuteroalkoxy, perdeuteroalkoxy, alkyl, aryl, cyano, heteroaryl, heterocycloalkyl, alkylamino, dialkylamino, hydroxy, oxo, and -SO3H; each R16and R17is independently chosen from alkyl, alkoxy, amino, cyano, halo, and hydroxy; and n is 1, 2, or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt or tautomer thereof, wherein J1is N.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt or tautomer thereof, wherein X is O.

4. The compound of any one of claims 1–3, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is chosen from phenyl and pyridinyl, either of which may be optionally substituted with 1, 2, or 3 R12.

5. The compound of claim 4, or a pharmaceutically acceptable salt or tautomer thereof, wherein each R12is independently chosen from fluoro, -NH2, methyl, trifluoromethyl, and trifluoromethoxy.

6. The compound of claim 4, or a pharmaceutically acceptable salt or tautomer thereof, wherein R1is 358Attorney Docket No. MDA0094-401-PC , wherein J2is chosen from C 18R is chosen from haloalkyl and haloalkoxy; and R19is chosen from halo and alkyl.

7. The compound of claim 6, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is CH.

8. The compound of claim 6, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is N.

9. The compound of any one of claims 6-8, or a pharmaceutically acceptable salt or tautomer thereof, wherein R18is chosen from trifluoromethyl, -CH2CF3, and trifluoromethoxy.

10. The compound of any one of claims 6-8, or a pharmaceutically acceptable salt or tautomer thereof, wherein R19is chosen from fluoro and methyl.

11. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is chosen from methyl and cyclopropyl, either of which may be optionally substituted by one R9.

12. The compound of claim 11, or a pharmaceutically acceptable salt or tautomer thereof, wherein R9is chosen from cyano and hydroxy.

13. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or tautomer thereof, wherein R5is fluoro.

14. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or tautomer thereof, wherein R6is chosen from amido and heterocycloalkyl, any of which may be optionally substituted by one R11.

15. The compound of claim 14, or a pharmaceutically acceptable salt or tautomer thereof, wherein R11is chosen from alkyl and oxo.

16. The compound of any one of claims 1–10 or 14-15, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is methyl and R5is fluoro.

17. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is chosen from hydrogen and alkyl. 359Attorney Docket No. MDA0094-401-PC 18. The compound of claim 17, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is alkyl.

19. The compound of claim 18, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is methyl.

20. The compound of one of the preceding claims, or a pharmaceutically acceptable salt or tautomer thereof, wherein n is 1.

21. The compound of claim 1, or a pharmaceutically acceptable salt or tautomer thereof, wherein J1is N; X is O; ; ,360Attorney Docket No. MDA0094-401-PC , ,R3is chosen from methyl, chlor ; R4 is chosen from H and -CH3;R5is fluoro; , ,361Attorney Docket No. MDA0094-401-PC , nd22. The compound of claim 1, having the structure of Formula IA A) or a pharmaceutically ac whereinJ2is chosen from CH and N; each R2is chosen from halo, alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, cyano, -C(O)N(R8)2, alkylamino, dialkylamino, - C(O)OR8, -C(O)R8, and haloalkyl, wherein alkyl, alkoxy, aryl, heteroaryl, cycloalkyl, alkoxyalkyl, hydroxyalkyl, alkylamino, dialkylamino, and haloalkyl may be optionally substituted with one or more R15; R3is chosen from alkyl, cycloalkyl, alkynyl, halo, and cyano, wherein alkyl, cycloalkyl, and alkynyl may be optionally substituted with one or more R9; R4is chosen from hydrogen, alkyl, alkoxy, cyano and halo; R6is chosen from hydrogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, -C(O)OR10, -S(O)(NH)-alkyl, alkylthio, and halo, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, amido, aryl, heteroaryl, alkoxy, amino, and alkylthio may be optionally substituted with one or more groups chosen from R11; 362Attorney Docket No. MDA0094-401-PC each R8is independently chosen from hydrogen, alkyl, heterocycloalkyl, heteroaryl, and cycloalkyl, any of which may be optionally substituted by one or more R13OR two R8may combine to form a heterocycloalkyl optionally substituted by one or more R16; each R9is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, cyano, halo, and hydroxy; R10is independently chosen from hydrogen and alkyl; each R11is independently chosen from alkyl, cycloalkyl, heterocycloalkyl, alkoxy, alkoxyalkyl, hydroxyalkyl, amidoalkyl, alkylcycloalkyl, halocycloalkyl, halocycloalkylalkyl, hydroxycycloalkylalkyl, alkylheterocycloalkyl, cyanoheterocycloalkyl, perdeuteroalkyl, cyano, halo, haloalkyl, oxo, amino, alkylamino, dialkylamino, and hydroxy; each R13is independently chosen from hydroxy, halo, alkylamino, dialkylamino, -SO3H, heterocycloalkyl, heteroaryl, and cycloalkyl, wherein heterocycloalkyl, heteroaryl, and cycloalkyl may be substituted with one or more R17; each R15is independently chosen from halo, alkoxy, deuteroalkoxy, perdeuteroalkoxy, alkyl, aryl, cyano, heteroaryl, heterocycloalkyl, alkylamino, dialkylamino, hydroxy, oxo, and -SO3H; each R16and R17is independently chosen from alkyl, alkoxy, amino, cyano, halo, and hydroxy; R18is chosen from haloalkyl and haloalkoxy; and R19is chosen from halo and alkyl.

23. The compound of claim 22, or a pharmaceutically acceptable salt or tautomer thereof, wherein R2is alkyl.

24. The compound of claim 23, or a pharmaceutically acceptable salt or tautomer thereof, wherein R2is methyl.

25. The compound of any one of claims 22 to 24, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is alkyl.

26. The compound of claim 25, or a pharmaceutically acceptable salt or tautomer thereof, wherein R3is methyl.

27. The compound of any one of claims 22 to 26, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is alkyl.

28. The compound of claim 27, or a pharmaceutically acceptable salt or tautomer thereof, wherein R4is methyl. 363Attorney Docket No. MDA0094-401-PC 29. The compound of any one of claims 22 to 28, or a pharmaceutically acceptable salt or tautomer thereof, wherein R6is chosen from amido and heterocycloalkyl, any of which may be optionally substituted by one R11.

30. The compound of claim 29, or a pharmaceutically acceptable salt or tautomer thereof, wherein R11is chosen from alkyl and oxo.

31. The compound of claim 30, or a pharmaceutically acceptable salt or tautomer thereof, wherein R11is methyl.

32. The compound of claim 29, or a pharmaceutically acceptable salt or tautomer thereof, nd 33.e salt or tautomer thereof, wherein R18is trifluoromethyl, -CH2CF3, and trifluoromethoxy.

34. The compound of any one of claims 22 to 33, or a pharmaceutically acceptable salt or tautomer thereof, wherein R19is fluoro and methyl.

35. The compound of any one of claims 22 to 34, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is CH.

36. The compound of any one of claims 22 to 34, or a pharmaceutically acceptable salt or tautomer thereof, wherein J2is N.

37. The compound of claim 1, having a structure chosen from the compound of Examples 1-1 to 168-1, or a pharmaceutically acceptable salt or tautomer thereof,.

38. The compound of claim 1, having a structure chosen from the compound of Examples 1-168, or a pharmaceutically acceptable salt or tautomer thereof,.

39. The compound of claim 1, having a structure chosen from ,364Attorney Docket No. MDA0094-401-PC nda pharmaceutically acceptable salt or tautomer40. A pharmaceutical formulation comprising a compound of any one of claims 1–39, or a pharmaceutically acceptable salt or tautomer thereof, together with a pharmaceutically acceptable carrier.

41. The pharmaceutical formulation of claim 40, formulated for oral administration.

42. The pharmaceutical formulation of claim 40 or 41, additionally comprising another therapeutic agent.

43. A method of inhibition of NRAS, KRAS, or HRAS, comprising contacting NRAS, KRAS, or HRAS with a compound of any one of claims 1–39, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of any one of claims 40–42.

44. A method of treatment of an NRAS-, KRAS-, or HRAS-mediated disease, comprising the administration of a therapeutically effective amount of a compound of any one of 365Attorney Docket No. MDA0094-401-PC claims 1–39, or a pharmaceutically acceptable salt or tautomer thereof, or a pharmaceutical composition of any one of claims 40–42, to a subject in need thereof.

45. The method of claim 43 or 44, wherein the NRAS is NRAS G12D.

46. The method of claim 43 or 44, wherein the KRAS is KRAS G12D.

47. The method of claim 43 or 44, wherein the HRAS is HRAS G12D.

48. The method of claim 43, wherein the NRAS, KRAS, or HRAS-mediated disease is cancer.

49. The method of claim 48, wherein the cancer is chosen from Melanoma, Malignant Solid Tumors, Colorectal Carcinoma, Non-Small Cell Lung Carcinoma, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, Colorectal Adenocarcinoma, Multiple Myeloma, Non-Hodgkin Lymphoma, Pancreatic Carcinoma, Cutaneous Melanoma, Ovarian Carcinoma, Pancreatic Ductal Adenocarcinoma, Acute Lymphoblastic Leukemia, Thyroid Gland Carcinoma, Glioma, Neurofibromatosis, Poorly Differentiated Thyroid Gland Carcinoma, Myelodysplastic Syndrome With Excess Blasts, Juvenile Myelomonocytic Leukemia, Histiocytic And Dendritic Cell Neoplasm, Head And Neck Squamous Cell Carcinoma, Small Cell Lung Carcinoma, Low Grade Glioma, Squamous Cell Lung Carcinoma, Breast Carcinoma, Chronic Myelomonocytic Leukemia, Thyroid Gland Undifferentiated (Anaplastic) Carcinoma, Embryonal Rhabdomyosarcoma, Thyroid Gland Follicular Carcinoma, T-Cell Acute Lymphoblastic Leukemia, Mucosal Melanoma, Low Grade Ovarian Serous Adenocarcinoma, Thyroid Gland Papillary Carcinoma, Refractory Anemia With Excess Blasts, Myeloid Neoplasm, Myelodysplastic / Myeloproliferative Neoplasm, Mucinous Carcinoma, Rectal Carcinoma, Colon Carcinoma, Malignant Peripheral Nerve Sheath Tumor, Cholangiocarcinoma, Endometrial Carcinoma, Mantle Cell Lymphoma, Secondary Myelodysplastic Syndrome, Therapy-Related Myelodysplastic Syndrome, Lymphoma, Neuronal And Mixed Neuronal-Glial Tumors, Ganglioglioma, Soft Tissue Sarcoma, Bladder Carcinoma, Esophageal Carcinoma, Sarcoma, Thymic Carcinoma, Lung Adenocarcinoma, Lung Carcinoma, Uveal Melanoma, Head And Neck Carcinoma, Diffuse Glioma, Squamous Cell Carcinoma, Chronic Myeloid Leukemia, Adenocarcinoma of the Gastroesophageal Junction, Glioblastoma, Neuroblastoma, Astrocytic Tumor, Hepatocellular Carcinoma, Pancreatic Adenocarcinoma, Diffuse Large B-Cell Lymphoma, Anaplastic Astrocytoma, Gastric Adenocarcinoma, Gastric Carcinoma, Prostate 366Attorney Docket No. MDA0094-401-PC Carcinoma, Renal Cell Carcinoma, B-Cell Acute Lymphoblastic Leukemia, Double- Hit Lymphoma, Dysembryoplastic Neuroepithelial Tumor, Gangliocytoma, Low- Grade Neuroepithelial Tumor, Peripheral T-Cell Lymphoma, Pilocytic Astrocytoma, Pilomyxoid Astrocytoma, Rhabdoid Tumor, and Schwannoma. 367

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