Macrocycles as ras inhibitors

Abstract

The present invention provides macrocyclic compounds, their use for selectively inhibiting the activity of RAS mutants, and pharmaceutical compositions comprising said compounds, for example for the treatment of various diseases, including cancer.

Description

Technical Field

[0001] This invention provides the use of macrocyclic compounds for selectively inhibiting the activity of RAS mutants, and pharmaceutical compositions comprising said compounds as treatments for various diseases, including cancer. Background Technology

[0002] Rat sarcoma (RAS) gene mutations are a driver of several deadly cancers. The three typical RAS genes—Kirsten-RAS (KRAS), neuroblastoma-RAS (NRAS), and harvest-RAS (HRAS)—are mutated in approximately 19% of cancer patients. Prior, IA, Cancer Research, 2020, 80 (14): pp. 2969-74 The retinoid process (RAS) and its downstream pathways control a variety of biological activities, such as cell proliferation, survival, and migration. Therefore, RAS mutations genetically drive multiple types of cancer, including non-small cell lung cancer (NSCLC), pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), melanoma, and some hematologic malignancies. Moore, AR, Nature Reviews Drug Discovery, 2020, 19: Pages 533-52 ].

[0003] Essentially, RAS GTPase cycles between two switchable states: an inactive form bound to guanosine diphosphate (GDP) (RAS OFF) and an active form bound to guanosine triphosphate (GTP) (RAS ON). Fey, D. et al. Semin Cell Dev Biol., 2016, 58, 96-107 In the RAS ON state, RAS has a high affinity for many effectors, enabling it to perform its functions. Common mutations in the RAS gene disrupt its internal cycle and lock RAS into a permanent GTP-binding conformation, thereby continuously activating downstream pathways.

[0004] The significant challenges of RAS-targeted therapy stem from the smooth, globular protein structure and the picomolar binding strength between RAS and GTP, both of which contribute to the difficulty in drug development of RAS. Yang, H., Cancer Communication, 2023, 43 (1): Pages 42-74 ] For this "undruggable" target, pioneering research primarily employed allele-specific strategies. For example, utilizing KRAS... G12C The nucleophilicity of cysteine ​​in mutants has been extensively studied, and covalent small molecule inhibitors have ultimately led to FDA approval of sotorasib and adagrasib.

[0005] Despite significant progress made with these subtype-specific inhibitors, rapidly acquired resistance may limit their further therapeutic potential. Reactivation of the RAS pathway via different mechanisms (particularly through compensation in the NRAS and HRAS) could lead to resistance to the KRAS.G12C Inhibit the development of primary drug resistance [ Noritaka, T., Cancer Discovery, 2021, 11: Pages 1913-22 Furthermore, non-G12C mutations account for a significant proportion of RAS alterations in various cancers. Unmet medical needs have spurred the development of pan-RAS therapies. Summary of the Invention

[0006] This article provides compounds having the following formula (I). (I) Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, wherein: X is -O-, -S-, or -CH2-; where when X is -CH2-, hydrogen can be released by R. 2 replace; n1 is 0, 1, or 2; n2 is 1, 2, or 3; n3 can be 0, 1, 2, 3 or 4; R 1 Independently selected from hydrogen, halogen, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 3-8 Cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a and -CONR 1a R 1b ; R 1a and R 1b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 2 yes Partial substituents; R 2 Each is independently selected from hydrogen, halogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl, -OR2a -NR 2a R 2b -COR 2a -CO2R 2a and -CONR 2a R 2b ; R 2a and R 2b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 3 Independently selected from hydrogen, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl and substituted or unsubstituted 5 to 12-membered heteroaryl, -COR 3a -CO2R 3a and -CONR 3a R 3b ; R 3a and R 3b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 4 Independently selected from substituted or unsubstituted -C 1-3 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 5 Independently selected from hydrogen, halogen, substituted or unsubstituted -C 1-3 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 6 Independently selected from hydrogen and substituted or unsubstituted -C 1-3 alkyl; R7 R 8 and R 9 Each is independently selected from hydrogen, halogen, substituted or unsubstituted -C. 1-6 Alkyl groups and -CN; R 10a and R 10b Each is independently selected from hydrogen and substituted or unsubstituted -C. 1-3 Alkyl; or R 10a and R 10b Together with the atoms they are attached to, they form 3 to 6 substituted or unsubstituted rings, which contain 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 11a R 11b R 12a R 12b R 13a and R 13b Each is independently selected from hydrogen, halogen, and substituted or unsubstituted -C. 1-3 alkyl.

[0007] In one embodiment, the compound is selected from Table 1.

[0008] In one embodiment, this document provides a method for treating cancer in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound provided herein, or its N-oxide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a deuterated analog thereof.

[0009] In one embodiment, this document provides a method for treating a subject with RAS protein-related conditions, the method comprising administering to the subject a therapeutically effective amount of the compound provided herein, or its N-oxide, or a pharmaceutically acceptable salt thereof, or its stereoisomer, tautomer, or deuterated analog thereof. Detailed Implementation

[0010] One object of the present invention is to provide compounds and derivatives that act as RAS inhibitors, as well as methods for their preparation and uses.

[0011] Aspect 1. A compound of formula (I): (I) Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue, wherein: X is -O-, -S-, or -CH2-; n1 is 0, 1, or 2; n2 is 1, 2, or 3; n3 can be 0, 1, 2, 3 or 4; m is 1, 2, or 3; R 1 Selected from hydrogen, halogen, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 3-8 Cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a and -CONR 1a R 1b ; R 1a and R 1b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 2 Each is independently selected from hydrogen, halogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl, -OR 2a -NR 2a R 2b -COR 2a -CO2R 2a and -CONR 2a R 2b ; R 2a and R 2b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 3 Selected from hydrogen, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl and substituted or unsubstituted 5 to 12-membered heteroaryl, -COR3a -CO2R 3a and -CONR 3a R 3b ; R 3a and R 3b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 4 Selected from substituted or unsubstituted -C 1-3 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 5 Selected from hydrogen, halogen, substituted or unsubstituted -C 1-3 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 6 Selected from hydrogen and substituted or unsubstituted -C 1-3 alkyl; R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, substituted or unsubstituted -C. 1-6 Alkyl groups and -CN; R 10a and R 10b Each is independently selected from hydrogen and substituted or unsubstituted -C. 1-3 Alkyl; or R 10a and R 10b Together with the atoms they are attached to, they form 3 to 6 substituted or unsubstituted rings, which contain 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 11a R 11b R 12a R 12b R 13a and R 13b Each is independently selected from hydrogen, halogen, and substituted or unsubstituted -C. 1-3 alkyl.

[0012] In one implementation, R1 Selected from hydrogen, halogens, -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a and -CONR 1a R 1b Wherein -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally selected from at least one of R 1c Substituents of the substituents; R 1a and R 1b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 1d replace; R 1c and R 1d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkynyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxo and -CN, wherein the -C 1-6 Alkyl, -C 2-6 alkynyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 1j Replace; or Two Rs 1c Together with the atoms they are attached to and any intermediate atoms, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-6 Alkyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1j Selected from halogens, -C 1-6 Alkyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; wherein the -C 1-6 Alkyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted by at least one substituent selected from -NH2, -OH, or alkynyl.

[0013] In one embodiment, the compound is of formula (Ia): (Ia).

[0014] In one embodiment, the compound is of formula (II): (II).

[0015] In one embodiment, the compound is of formula (III): (III).

[0016] In one embodiment, the compound is of formula (IIIa): (IIIa).

[0017] In one embodiment, the compound is of formula (IV): (IV).

[0018] In one embodiment, the compound is of formula (V): (V).

[0019] In one embodiment, the compound is of formula (Va): (Va).

[0020] In one embodiment, the compound is of formula (VI): (VI).

[0021] In one embodiment, the compound is of formula (VIa): (VIa).

[0022] In one embodiment, the compound is of formula (VII): (VII)

[0023] In one embodiment, the compound is of formula (VIII): (VIII)

[0024] The compound as described in aspect 1, or the compound as described in any of the foregoing embodiments, wherein the compound is a p-isomer or an M-isomer. The compound as described in aspect 1, or the compound as described in any of the foregoing embodiments, wherein the compound is an M-isomer.

[0025] In one embodiment, the compound is of formula (IXa): (IXa).

[0026] In one embodiment, the compound is of formula (IXb): (IXb).

[0027] In one embodiment, the compound is of formula (Xa): (Xa); Wherein ring A is a 5- to 6-membered heterocyclic group containing one or two heteroatoms selected from N and O. R 1c As specified in aspect 2; n4 can be 1, 2, 3, or 4.

[0028] In one embodiment, the compound is of formula (Xb): (Xb) Wherein ring A is a 5- to 6-membered heterocyclic group containing one or two heteroatoms selected from N and O. R 1c As specified in aspect 2; n4 can be 1, 2, 3, or 4.

[0029] In one embodiment, the compound is of formula (XIa): (XI).

[0030] In one embodiment, the compound is of formula (XIb): (XIb).

[0031] In one embodiment, the compound is of formula (XIc): (XIc).

[0032] In one embodiment, the compound is of formula (XId): (XId).

[0033] In one embodiment, the compound is of formula (XIe): (XIe).

[0034] In one embodiment, the compound is of formula (XIIa): (XIIa).

[0035] In one embodiment, the compound is of formula (XIIb): (XIIb).

[0036] In one embodiment, the compound is of formula (XIIc): (XIIc).

[0037] In one embodiment, the compound is of formula (XIId): (XIId).

[0038] In one embodiment, the compound is of formula (XIIe): (XIIe).

[0039] Aspect 2. A compound of formula (I): (I) Or its N-oxide, or its pharmaceutically acceptable salt, or its stereoisomer, or its tautomer, or its deuterated analogue, wherein: X is -O-, -S-, or -CH2-; n1 is 0, 1, or 2; n2 is 0, 1, 2, 3 or 4; n3 can be 0, 1, 2, 3 or 4; m is 1, 2, or 3; R 1 Independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a and -CONR 1a R 1b Wherein -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally selected from at least one of R 1c Substituents of the substituents; R 1a and R 1b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 1d replace; R 1c and R 1d Each is independently selected from hydrogen, halogen, -C 1-6Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxo and -CN, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; or Two Rs 1c Together with the atoms they are attached to and any intermediate atoms, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-6 Alkoxy, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 2 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 3-6cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 2a -NR 2a R 2b -COR 2a -CO2R 2a and -CONR 2a R 2b Wherein -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally selected from at least one of R 2c Substituents of the substituents; R 2a and R 2b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 2c Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 2d -COR 2d -CO2R 2d -CONR 2d R 2e -NR 2d R 2e -NR 2d COR 2e -NR 2d CO2R 2e Oxygenated and -CN; R 2d and R 2e Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 3 Selected from hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -COR 3a -CO2R 3a and -CONR 3a R 3b Wherein -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 3c replace; R 3a and R 3b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 3d Replace; or R 3a and R 3b Together with the nitrogen atoms to which they are attached, they form 3 to 8-membered unsaturated or saturated rings, which are optionally substituents R. 3d replace; R 3c and R 3d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 3e -COR 3e -CO2R 3e -CONR 3e R 3f -NR3e R 3f -NR 3e COR 3f -NR 3e CO2R 3f , oxidized and -CN; wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 3e and R 3f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 4 Selected from -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 6-membered heteroaryl group is optionally selected from at least one of R 4a Substituents of the substituents; R 4a Independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 4b -COR 4b -CO2R 4b -CONR 4b R 4c -NR 4b R4c -NR 4b COR 4c -NR 4b CO2R 4c Oxygenated and -CN; R 4b and R 4c Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 5 Selected from hydrogen, halogens, -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 6-membered heteroaryl groups is optionally substituent R. 5a replace; R 5a Independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 5b -COR 5b -CO2R 5b -CONR 5b R 5c -NR 5b R 5c -NR 5b COR 5c -NR 5b CO2R 5c Oxygenated and -CN; R 5b and R 5c Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 6 Selected from hydrogen and -C 1-3 Alkyl, wherein the -C 1-3 Alkyl groups are optionally selected from at least one halogen, -C 1-6 Substituents in the group consisting of alkoxy groups and -OH groups; R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl and -CN, wherein the -C 1-6 Alkyl groups are optionally selected from at least one halogen, -C 1-6 Substituents in the group consisting of alkoxy groups and -OH groups; R 10a and R 10b Each is independently selected from hydrogen and -C. 1-3 Alkyl; wherein the -C 1-3 The alkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or R 10a and R 10b Together with the atoms they are attached to, they form 3 to 6 substituted or unsubstituted rings, which contain 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 11a R 11b R 12a R 12b R 13a and R 13b Each is independently selected from hydrogen, halogen, and -C. 1-3 Alkyl, wherein the -C 1-3 Alkyl groups are optionally surrounded by at least one element selected from hydrogen, halogen, -OH, and -C. 1-3 Substitution of alkoxy groups.

[0040] Aspect 3. The compound as described in any of the preceding aspects, wherein X is -O-.

[0041] Aspect 4. The compound as described in any of the preceding aspects, wherein n1 + n2 ≤ 3.

[0042] In one implementation, n1 is 0 and n2 is 2.

[0043] In one implementation, n1 is 0 and n2 is 2; and yes , , or ,in This refers to the position where the phenyl group is attached, and This refers to the position where it connects to the pyrrole group.

[0044] Aspect 5. The compound as described in any of the preceding aspects, wherein R 1 Selected from hydrogen, halogens, -C 1-6 Alkyl, -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 aryl and 5 to 10-membered heteroaryl, wherein the -C 1-6 Alkyl, -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituent R. 1c replace; R 1c Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 10-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxidized and -CN; wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 aryl and 5 to 10-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

[0045] In one implementation, R 1 Selected from hydrogen, -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 aryl and 5 to 10-membered heteroaryl, wherein the -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituent R. 1c replace; R 1c Each is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 10-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f Oxygenated and -CN; R 1e and R 1f Each is independently selected from hydrogen and -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 Aryl and 5 to 10 heteroaryl compounds.

[0046] In one implementation, R 1 for Where ring A is a 5- to 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O; R 1c Each is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 10-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxidized and -CN; wherein the -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituted by at least one substituent selected from halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2 and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 Aryl and 5- to 10-membered heteroaryl groups; n4 can be 1, 2, 3, or 4.

[0047] In one implementation, R 1 for Where Y is -O- or -NH-; R 1c -C 1-3 Alkyl or -C3-C6 cycloalkyl, wherein the -C 1-3 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituted by at least one substituent selected from halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2 and oxo; n4 can be 1, 2, 3, or 4.

[0048] In one implementation, R 1 for The atoms of -(CH2)- and -NH- can be R 1c replace; n4 is 1, 2, or 3; R 1c The group is methyl, ethyl, propyl, or cyclopropyl, wherein each of the methyl, ethyl, propyl, and cyclopropyl groups is optionally substituted by at least one substituent selected from: halogen, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo.

[0049] In one implementation, R 1 for The atoms of -(CH2)- and -NH- can be R 1c Replace; R 1c The group is methyl, ethyl, propyl, or cyclopropyl, wherein each of the methyl, ethyl, propyl, and cyclopropyl groups is optionally substituted by at least one substituent selected from: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; n4 is 1.

[0050] In one implementation, R 1 for , or ; n4 can be 1, 2, 3, or 4; R 1cThe group is methyl, ethyl, propyl, or cyclopropyl, wherein each of the methyl, ethyl, propyl, and cyclopropyl groups is optionally substituted by at least one substituent selected from: halogen, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo.

[0051] In one implementation, R 1 for ; n4 is 1, 2, or 3; R 1c It is methyl, ethyl, or propyl, wherein each of the methyl, ethyl, and propyl groups is optionally substituent R. 1j replace; R 1j The group is selected from halogens, -C3-C6 cycloalkyl groups, and 3- to 6-membered heterocyclic groups, wherein each of the -C3-C6 cycloalkyl groups and 3- to 6-membered heterocyclic groups is optionally substituted by at least one substituent selected from: halogens, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo.

[0052] In one implementation, R 1 Selected from -C 1-6 Alkyl, wherein the -C 1-6 The alkyl group is optionally substituent for at least one R group. 1c replace; R 1c Each is independently selected from -C3-C6 cycloalkyl and 3 to 6-membered heterocyclic groups; wherein each of the -C3-C6 cycloalkyl and 3 to 6-membered heterocyclic groups is optionally substituted by at least one substituent selected from: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

[0053] In one implementation, R 1 Selected from -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituent for at least one R group. 1c replace; R 1c Each is independently selected from 5- to 6-membered heterocyclic groups containing 1-2 heteroatoms selected from N and O.

[0054] In one implementation, R 1 for , ( or ), , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0055] Aspect 6. The compound as described in any of the preceding aspects, wherein R 2 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the -C 1-6 Alkyl, -C 3-6 Each of the cycloalkyl group and the 3- to 6-membered heterocyclic group is optionally substituent R. 2c replace; R 2c Each is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -OR 2d -COR 2d -CO2R 2d-CONR 2d R 2e -NR 2d R 2e -NR 2d COR 2e -NR 2d CO2R 2e Oxygenated and -CN; R 2d and R 2e Each is independently selected from hydrogen and -C 1-3 Alkyl and -C3-C6 cycloalkyl, wherein the -C 1-3 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -CN, -OH, -NH2, and oxo.

[0056] In one implementation, R 2 Each is independently selected from hydrogen, methyl, ethyl, and propyl.

[0057] In one implementation, R 2 Each is independently selected from hydrogen, methyl, ethyl, and propyl, and n3 is 1 or 2.

[0058] Aspect 7. The compound as described in any of the preceding aspects, wherein R 3 Independently selected from hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, -COR 3a -CO2R 3a and -CONR 3a R 3b Wherein -C 1-6 Alkyl and -C 3-6 Each of the cycloalkyl groups is optionally substituent R. 3c replace; R 3a and R 3b Each is independently selected from -C 1-6 Alkyl, -C3-C6 cycloalkyl and 3 to 12-membered heterocyclic groups, wherein the -C 1-6 Each of the alkyl, -C3-C6 cycloalkyl, and 3- to 12-membered heterocyclic groups is optionally substituented by at least one R group. 3d Replace; or R 3a and R 3b Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered unsaturated or saturated rings, which are optionally substituents R. 3d replace; R3c and R 3d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, and -CN; wherein the -C 1-6 Each of the alkyl group, -C3-C6 cycloalkyl group, and 3- to 6-membered heterocyclic group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

[0059] In one implementation, R 3 Independently selected from hydrogen, -COR 3a -CO2R 3a and -CONR 3a R 3b ; R 3a and R 3b Each is independently selected from -C 1-6 Alkyl, -C3-C6 cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the -C 1-6 Each of the alkyl, -C3-C6 cycloalkyl, and 3- to 6-membered heterocyclic groups is optionally substituented by at least one R group. 3d Replace; or R 3a and R 3b Together with the nitrogen atoms to which they are attached, they form 3 to 6-membered unsaturated or saturated rings, which are optionally substituents R. 3d replace; R 3d Each is independently selected from halogens, -C 1-3 Alkyl, -C3-C6 cycloalkyl and -CN, wherein the -C 1-3 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -CN, -OH, -NH2, and oxo.

[0060] In one implementation, R 3 Independently selected from hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, -COR 3a -CO2R 3a and -CONR 3a R 3b Wherein -C 1-6 Alkyl and -C 3-6 Each of the cycloalkyl groups is optionally substituent R.3c replace; R 3a and R 3b Each is independently selected from -C 1-6 Alkyl, -C3-C6 cycloalkyl and 3 to 12-membered heterocyclic groups, wherein the -C 1-6 Each of the alkyl, -C3-C6 cycloalkyl, and 3- to 12-membered heterocyclic groups is optionally substituented by at least one R group. 3d replace; R 3c and R 3d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, and -CN; wherein the -C 1-6 Each of the alkyl group, -C3-C6 cycloalkyl group, and 3- to 6-membered heterocyclic group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

[0061] In one implementation, R 3 Independently selected from hydrogen, -COR 3a -CO2R 3a and -CONR 3a R 3b ; R 3a and R 3b Each is independently selected from -C 1-6 Alkyl, -C3-C6 cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the -C 1-6 Each of the alkyl, -C3-C6 cycloalkyl, and 3- to 6-membered heterocyclic groups is optionally substituented by at least one R group. 3d replace; R 3d Each is independently selected from halogens, -C 1-3 Alkyl, -C3-C6 cycloalkyl and -CN, wherein the -C 1-3 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -CN, -OH, -NH2, and oxo.

[0062] In one implementation, R 3 For H, , ( , , or ), ( , , or ), ( or ), ( , , or ), ( or ), ( or ), , , , , , , , , , ( , , or ), , ( , , or ), ( , , or ), ( , , or )or ( , , or ).

[0063] Aspect 8. The compound as described in any of the preceding aspects, wherein R 4 Selected from -C 1-3 Alkyl, -C 3-6 cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the -C 1-3 Alkyl, -C 3-6 Each of the cycloalkyl group and the 3- to 6-membered heterocyclic group is optionally substituent R. 4a replace; R 4a Independently selected from hydrogen, halogen, -C1-3 Alkyl, -C3-C6 cycloalkyl, -OR 4b NR 4b R 4c Oxygenated and -CN; R 4b and R 4c Each is independently selected from hydrogen and -C 1-6 Alkyl and -C3-C6 cycloalkyl.

[0064] In one implementation, R 4 Selected from -C 1-3 Alkyl and -C 3-6 Cycloalkyl.

[0065] In one implementation, R 4 Selected from methyl, ethyl, and propyl.

[0066] Aspect 9. The compound as described in any of the preceding aspects, wherein R 5 Selected from hydrogen, halogens, -C 1-3 Alkyl and -C 3-6 cycloalkyl, wherein the -C 1-3 Alkyl and -C 3-6 Each of the cycloalkyl groups is optionally substituent R. 5a replace; R 5a Independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -OR 5b -NR 5b R 5c Oxygenated and -CN; R 5b and R 5c Each is independently selected from hydrogen and -C 1-6 Alkyl and -C3-C6 cycloalkyl, wherein the -C 1-8 The alkyl group and the -C3-C6 cycloalkyl group are optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

[0067] In one implementation, R 5 Selected from hydrogen, halogens, -C 1-3 Alkyl and -C 3-6 Cycloalkyl.

[0068] In one implementation, R 5 Selected from methyl, ethyl, and propyl.

[0069] In one implementation, R 4 It is methyl and R 5 It is a methyl group.

[0070] In one implementation scheme Part of .

[0071] Aspect 10. The compound as described in any of the preceding aspects, wherein R 6 Selected from hydrogen and -C 1-3 alkyl.

[0072] In one implementation, R 6 It is hydrogen.

[0073] Aspect 11. The compound as described in any of the preceding aspects, wherein R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl groups and -CN.

[0074] In one implementation, R 7 R 8 and R 9 Each is hydrogen.

[0075] Aspect 12. The compound as described in any of the preceding aspects, wherein R 10a and R 10b Each is independently selected from hydrogen and -C. 1-3 alkyl.

[0076] In one implementation, R 10a and R 10b At least one of them is -C 1-3 alkyl.

[0077] In one implementation, R 10a and R 10b Both are methyl groups.

[0078] In one implementation, R 10a and R 10b Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, or cyclopentyl groups.

[0079] Aspect 13. The compound as described in any of the preceding aspects, wherein R 11a R 11b R 12a R 12b R 13a and R 13b Each is independently selected from hydrogen, halogen, and -C. 1-3 alkyl.

[0080] In one implementation, R 11a R 11b R 12a R 12b R 13a and R 13b Each is hydrogen.

[0081] Aspect 14. The compound as described in any of the preceding aspects, wherein the compound is selected from the mixtures in Table 1: Table 1.

[0082] Aspect 15. A pharmaceutical composition comprising the compound or its N-oxide, a pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analog, as described in any of the preceding aspects, and a pharmaceutically acceptable excipient.

[0083] Aspect 16. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of any one of Aspects 1-14, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, or the pharmaceutical composition of Aspect 15.

[0084] Aspect 17. The method as described in aspect 16, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, stomach cancer, esophageal cancer, ovarian cancer, or uterine cancer.

[0085] Aspect 18. A method for treating a subject with RAS protein-related disease, the method comprising administering to the subject a therapeutically effective amount of any one of Aspects 1-14, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, or the pharmaceutical composition of Aspect 15.

[0086] definition The following terms have the meanings indicated throughout this specification: Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0087] The following terms have the meanings indicated throughout this specification: As used herein (including the appended claims), unless the context clearly indicates otherwise, the singular forms of words such as “a / an” and “the” include their corresponding plural referents.

[0088] Unless the context clearly specifies otherwise, the term “or” is used to mean the term “and / or” and is used interchangeably with the term “and / or”.

[0089] The term "alkyl" includes alkyl groups selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 18 carbon atoms (such as 1 to 12, further such as 1 to 10, even further such as 1 to 8, or 1 to 6, or 1 to 4). Alkyl groups containing 1 to 6 carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-6 Examples of alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl or n-propyl (“n-Pr”), 2-propyl or isopropyl (“i-Pr”), 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), 1,1-dimethylethyl or tert-butyl (“t-Bu”), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl. Unless otherwise defined, "C" 1-8 "alkyl" includes hydrocarbon groups selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 8 carbon atoms; "C" 1-8 "alkyl" also includes hydrocarbon groups (C) selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 6 carbon atoms. 1-6 Alkyl groups or hydrocarbon groups containing 1 to 4 carbon atoms (C1-4 alkyl).

[0090] The term "propyl" includes 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr").

[0091] The term “butyl” includes 1-butyl or n-butyl (“n-Bu”), 2-methyl-1-propyl or isobutyl (“i-Bu”), 1-methylpropyl or sec-butyl (“s-Bu”), and 1,1-dimethylethyl or tert-butyl (“t-Bu”).

[0092] The term "pentyl" includes 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, and 2-methyl-1-butyl. The term "pentyl" further includes... , ( or ), , , ( or ), , and .

[0093] The term "hexyl" includes 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl.

[0094] The term "alkylene" refers to a divalent alkyl group produced by removing two hydrogen atoms from an alkane. Alkylenes include, but are not limited to, methylene, ethylene, and propylene.

[0095] The term "halogen" includes fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0096] The term "H" or "hydrogen" disclosed herein includes hydrogen ( 1 H) and non-radioactive isotope deuterium ( 2 H). In a preferred embodiment, hydrogen is hydrogen (H). 1 H).

[0097] The term "alkenyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups comprising at least one C=C double bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alkenyl (e.g., C...) 2-6Examples of alkenyl groups include, but are not limited to, ethenyl (or vinyl), propenyl, propenyl-2-alkenyl, 2-methylpropenyl, butenyl, butenyl-2-alkenyl, butenyl-3-alkenyl, butenyl-1,3-dienyl, 2-methylbutenyl-1,3-dienyl, hexenyl-1-alkenyl, hexenyl-2-alkenyl, hexenyl-3-alkenyl, hexenyl-4-alkenyl, and hexenyl-1,3-dienyl.

[0098] The term "alkenyl" refers to a divalent alkenyl group produced by removing two hydrogens from an olefin. Alkenyl groups include, but are not limited to, vinylene and butene.

[0099] The term "alkynyl" includes hydrocarbon groups selected from straight-chain and branched hydrocarbon groups comprising at least one C≡C triple bond and 2 to 18 (such as 2 to 8, further such as 2 to 6) carbon atoms. Alynyl (e.g., C...) 2-6 Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl (propynyl), 1-butynyl, 2-butynyl and 3-butynyl.

[0100] The term "ethynyl group" refers to a divalent ethynyl group produced by removing two hydrogens from an alkyne. Ethyynyl groups include, but are not limited to, ethynylene groups.

[0101] The term "cycloalkyl" includes hydrocarbon groups selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused, bridged, or screwed cycloalkyl groups.

[0102] For example, cycloalkyl groups can contain 3 to 12 (such as 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4) carbon atoms. Even further, for example, cycloalkyl groups can be selected from monocyclic groups containing 3 to 12 (such as 3 to 10, further such as 3 to 8, 3 to 6) carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. In particular, saturated monocyclic cycloalkyl groups (e.g., C16, C26, C36, C46, ​​C56, C6 ... 3-8 Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In a preferred embodiment, the cycloalkyl group is a monocyclic ring (abbreviated as C16) containing 3 to 6 carbon atoms. 3-6Cycloalkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged in a fused bicyclic arrangement selected from the [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or arranged in a bridged bicyclic arrangement selected from bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Other examples of bicyclic cycloalkyl groups include those bicyclic arrangements selected from the [5,6] and [6,6] ring systems.

[0103] The term "spirocycloalkyl" includes cyclic structures containing carbon atoms and formed by at least two rings sharing an atom.

[0104] The term “fused cycloalkyl” includes bicyclic cycloalkyl groups as defined herein, which are saturated and formed by two or more rings sharing two adjacent atoms.

[0105] The term "bridged cycloalkyl" includes a cyclic structure containing carbon atoms and formed by two rings sharing two non-adjacent atoms. The term "7- to 10-membered bridged cycloalkyl" includes a cyclic structure containing 7 to 12 carbon atoms and formed by two rings sharing two non-adjacent atoms.

[0106] Examples of fused cycloalkyl, fused cycloalkenyl, or fused cycloalkynyl groups include, but are not limited to, bicyclo[1.1.0]butyl, bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl, naphthane, and benzo3 to 8-membered cycloalkyl, benzoC 4-6 Cycloalkenyl, 2,3-dihydro-1H-indenyl, 1H-indenyl, 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl, etc. A preferred embodiment is an 8- to 9-membered fused ring; in the above examples, this refers to a cyclic structure containing 8 to 9 ring atoms.

[0107] The term "aryl" used alone or in combination with other terms includes groups selected from the following: 5- and 6-membered carbon-ring aromatic rings, for example, phenyl; Bicyclic systems, such as 7- to 12-membered bicyclic systems, wherein at least one ring is a carbocyclic and aromatic, such as naphthyl and indanyl; and, Tricyclic systems, such as 10- to 15-membered tricyclic systems, in which at least one ring is a carbocyclic ring and an aromatic ring, such as a fluorene ring.

[0108] The terms "aromatic ring" and "aryl" are used interchangeably throughout this disclosure. In some embodiments, the monocyclic or bicyclic aromatic ring has 5 to 10 cyclic carbon atoms (i.e., C64, C16, C2 ... 5-10Aryl). Examples of monocyclic or bicyclic aromatic rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthraceneyl, phenanthrene, etc. In some embodiments, the aromatic ring is a naphthyl ring (naphth-1-yl or naphth-2-yl) or a benzene ring. In some embodiments, the aromatic ring is a phenyl ring.

[0109] Specifically, the term "bicyclic fused aryl" includes bicyclic aryl rings as defined herein. A typical bicyclic fused aryl is naphthalene.

[0110] The term "heteroaryl" includes groups selected from the following: A 5-, 6-, or 7-membered aromatic monocyclic ring comprising at least one heteroatom selected from nitrogen (N), sulfur (S), and oxygen (O), for example, 1 to 4 (or in some embodiments, 1 to 3, in some embodiments, 1 to 2) heteroatoms, with the remaining ring atoms being carbon. A 7- to 12-membered bicyclic ring comprising at least one heteroatom, such as 1 to 4, or in some embodiments 1 to 3, or in other embodiments 1 or 2 heteroatoms selected from N, O, and S, wherein the remaining ring atoms are carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and The 11- to 14-membered tricyclic ring contains at least one heteroatom selected from N, O, and S, for example, 1 to 4, or 1 to 3 in some embodiments, or 1 or 2 heteroatoms in other embodiments, the remaining ring atoms being carbon, and at least one ring being aromatic and at least one heteroatom being present in the aromatic ring.

[0111] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group is no greater than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is no greater than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different. The nitrogen atom in one or more rings of the heteroaryl group can be oxidized to form an N-oxide.

[0112] Specifically, the term "bicyclic fused heteroaryl" includes 7- to 12-membered, preferably 7- to 10-membered, more preferably 9- or 10-membered fused bicyclic heteroaryl rings as defined herein. Typically, bicyclic fused heteroaryl groups are 5 / 5, 5 / 6, 6 / 6, or 6 / 7-membered bicyclic rings. The groups can be attached to the remainder of the molecule via either ring.

[0113] "Heterocyclic group", "heterocyclic" or "heterocyclic" are interchangeable and include non-aromatic heterocyclic groups containing one or more heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridging and spirocyclic groups, i.e. containing monocyclic heterocyclic groups, bridging heterocyclic groups, spirocyclic groups and fused heterocyclic groups.

[0114] The term "at least one substituent" disclosed herein includes, for example, 1 to 4 (such as 1 to 3, further such as 1 or 2) substituents, provided that they conform to the theory of valence. For example, "at least one substituent F" disclosed herein includes 1 to 4 (such as 1 to 3, further such as 1 or 2) substituents F.

[0115] The term "divalent" refers to a linking group capable of forming covalent bonds with two other moieties. For example, "divalent cycloalkyl" refers to a cycloalkyl group obtained by removing two hydrogens from the corresponding cycloalkane to form a linking group. The terms "divalent aryl," "divalent heterocyclic," or "divalent heteroaryl" should be understood in a similar manner.

[0116] The compounds disclosed herein may contain asymmetric centers, axes, or planes and therefore may exist as enantiomers. "Enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other. Where the compounds disclosed herein have two or more asymmetric centers, they may also exist as diastereomers. Enantiomers and diastereomers belong to a broader class of stereoisomers. This is intended to include all such possible stereoisomers in the form of substantially pure, separated enantiomers, racemic mixtures thereof, and mixtures of diastereomers. This is intended to include all stereoisomers of the compounds disclosed herein and / or their pharmaceutically acceptable salts. Unless otherwise specifically indicated, reference to one isomer applies to any possible isomer. All possible isomers are included unless the isomer composition is specified.

[0117] The term "axial chirality" refers to the stereoisomerism resulting from the non-planar arrangement of four groups in pairs around a chiral axis. It is exemplified by the transisomerism of propadiene abC=C=Ccd (or abC=C=Cab) and ortho-substituted biphenyls.

[0118] The configuration of molecular entities with axial chirality is determined by stereo descriptors. R a and S a (or M or P ) specified.

[0119] In the context of the compounds disclosed herein (e.g., compounds of formula (VIII)), the term "M-isomer" refers to compounds consisting of: (IXa) or its equivalents represent the configuration.

[0120] In the context of the compounds disclosed herein (e.g., compounds of formula (VIII)), the term "P-isomer" refers to compounds consisting of: (IXb) or its equivalents represent the configuration.

[0121] In this article, “restricted rotation isomer” refers to a subclass of conformational isomers that can be isolated as a separate chemical species and are caused by restricted rotation or rotational barriers around a single bond.

[0122] Unless otherwise stated, when the compounds disclosed herein contain alkene double bonds, such double bonds are intended to include both E and Z geometric isomers.

[0123] When the compounds disclosed herein contain a disubstituted ring system, the substituents found on such ring systems can be employed... Cis and trans form. Cis The formal meaning refers to the fact that both substituents are located above the positions of the two substituents on the carbon atom, while opposite Mode "Will" means that they are located on opposite sides. For example, a disubstituted cyclic system can be a cyclohexyl ring or a cyclobutyl ring.

[0124] Separating the reaction products from each other and / or from the starting materials may be advantageous. The desired products of each step or series of steps are separated and / or purified (hereinafter, separated) to the desired degree of homogeneity using techniques commonly used in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve many methods, including, for example: reversed-phase and normal-phase chromatography; size exclusion chromatography; ion exchange chromatography; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus; small-scale analytical chromatography; simulated moving bed (“SMB”) chromatography and preparative thin-layer or thick-layer chromatography, as well as small-scale thin-layer and rapid chromatography techniques. Those skilled in the art can select and apply the techniques most likely to achieve the desired separation.

[0125] "Diarrhetinic isomers" refer to stereoisomers of compounds having two or more chiral centers that are not mirror images of each other. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher's acid chloride) to convert the enantiomer mixture into a diastereomer mixture, separating the diastereomers, and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0126] A single stereoisomer (e.g., a substantially pure enantiomer) can be obtained by resolving a racemic mixture using a method such as forming diastereomers using an optically active resolving agent. Eliel, E. and Wilen, S. Stereochemistry of Organic Compounds. New York: John Wiley & Sons, Inc., 1994; Lochmuller, CH et al. "Chromatographic resolution of enantiomers: Selective “Review.” J. Chromatogr., 113(3) (1975): pp. 283-302 The racemic mixtures of the chiral compounds of the present invention can be separated and isolated by any suitable method, the method comprising: (1) forming ionic diastereomeric salts with the chiral compounds and separating them by stepwise crystallization or other methods; (2) forming diastereomeric compounds with chiral derivatizing agents, separating the diastereomeric compounds and converting them into pure stereoisomers; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See also: Wainer, Irving W. (Editor of Drug) Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993 .

[0127] Some of the compounds disclosed herein may have different hydrogen bonding sites, referred to as tautomers. For example, compounds including a carbonyl -CH2C(O)- group (ketone form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Where applicable, both single ketone and enol forms, as well as mixtures thereof, are also intended to be included.

[0128] A "prodrug" is an active agent derivative that needs to be converted in vivo to release the active agent. In some implementations, this conversion is enzymatic. Prodrugs are typically (but not necessarily) pharmacologically inactive before being converted into the active agent.

[0129] "Pharmaceutically acceptable salts" refer to those salts that, within reasonable medical judgment, are suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, etc., and in proportion to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compounds disclosed herein, or individually by reacting a free base functional group with a suitable organic acid or by reacting an acidic group with a suitable base. The term also includes salts of stereoisomers (such as enantiomers and / or diastereomers), tautomers, and prodrugs of the compounds of the present invention.

[0130] Furthermore, if the compounds disclosed herein are obtained as acid addition salts, the free base can be obtained by alkalizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize that various synthetic methods are available for preparing non-toxic, pharmaceutically acceptable addition salts without excessive experimentation.

[0131] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms “administration,” “administering,” “treating,” and “treatment” herein mean contact between an exogenous drug, therapeutic agent, diagnostic agent, or composition and an animal, human, subject, cell, tissue, organ, or biological fluid. Cellular treatment encompasses contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid contacts the cell. The terms “administration” and “treatment” also mean, for example, in vitro and ex vivo treatment of cells by means of a reagent, diagnostic agent, conjugated compound, or by means of another cell. The term “subject” herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0132] The term "effective amount" or "therapeutic effective amount" refers to an amount of active ingredient (such as a compound) sufficient to achieve such treatment for a disease, condition, or symptom when administered to a subject to treat at least one clinical symptom of the disease, condition, or symptom. The term "therapeutic effective amount" can vary depending on the compound, the disease, condition, and / or the symptoms of the disease or condition, the severity of the disease, condition, and / or the age and / or weight of the subject being treated. In any given case, an appropriate amount may be obvious to those skilled in the art or may be determined by routine experiments. In some embodiments, "therapeutic effective amount" is the amount of at least one compound disclosed herein and / or at least one stereoisomer, tautomer, or prodrug and / or at least one pharmaceutically acceptable salt thereof that effectively "treats" a subject's disease or condition as defined herein. In the case of combination therapies, the term "therapeutic effective amount" refers to the total amount of the combination of substances used to effectively treat the disease, condition, or symptom.

[0133] The term “disease” refers to any illness, discomfort, ailment, symptom, or indication, and is interchangeable with the terms “symptom” or “illness”.

[0134] Throughout this specification and the appended claims, unless the context otherwise requires, the term "comprise" and its variations (such as "comprises / comprising") are intended to specify the presence of the following feature but do not exclude the presence or addition of one or more other features. When used herein, the term "comprise" may be replaced by the terms "containing," "including," or sometimes "having."

[0135] Throughout this specification and the appended claims, the term "C" is used. n-m The indicator includes a range of endpoints, where n and m are integers and indicate the number of carbon atoms. Examples include C. 1-8 C 1-6 wait.

[0136] The illustrations in this document show substituents bonded to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, fused cyclic, spirocyclic groups) via interatomic bonds. Unless otherwise stated, these substituents are intended to indicate that the substituent can bond to the cyclic group at any cyclic position through which the substituent bond passes, provided that such substitution produces a stable compound. Thus, for example, the substituent R in formula (I) of this document... 2 yes The substituents are partial substituents, not the substituents of the aromatic ring fused with this partial substituent in formula (I). Therefore, for example, the substituent R in formula (I) 2 Can be used with the parentheses Partial carbon atom bonding, or when X is CH2, bonding with the carbon atoms of X.

[0137] Unless otherwise expressly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0138] Example General Synthesis The compounds disclosed herein (including their salts) can be prepared using known organic synthetic techniques and can be synthesized according to any of the many possible synthetic routes.

[0139] The reactions used to prepare the compounds disclosed herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents are substantially unreactive with the starting materials, intermediates, or products at temperatures during which the reaction takes place (e.g., temperatures within the boiling point range of the solvent). A given reaction can be carried out in a single solvent or a mixture of solvents.

[0140] The selection of appropriate protecting groups can be readily determined by those skilled in the art. In the synthetic scheme, some protecting / deprotecting steps are not shown and may be introduced before, after, or between any steps. Depending on the reaction conditions, the protecting groups shown in the synthetic scheme may or may not be used. The order of the reactions may vary and provide similar results.

[0141] The reaction can be monitored using any suitable method known in the art, such as NMR, UV, HPLC, LC-MS, and TLC. Compounds can be purified using a variety of methods, including preparative HPLC and silica gel chromatography. Unless otherwise specified, preparative HPLC uses a buffered acetonitrile / water system, and silica gel chromatography (including column chromatography and preparative TLC) uses PE / EtOAc, EtOAc / MeOH, or DCM / MeOH systems as the mobile phase. NMR spectra are recorded using a Bruker or Varian instrument with a preset pulse sequence.

[0142] Option I For example, compound (I) can be formed as shown in scheme I. Compounds (i) and (ii) can be coupled via indole to give compound (iii). Compound (iii) can undergo functional group transformation to give compound (iv). Compound (iv) can be coupled with compound (v) via boration of an aryl halide and subsequent metal-catalyzed coupling to give compound (vi). Compound (vi) can be converted to compound (vii) via successive deprotection and macrocyclization. Compound (vii) can undergo deprotection and amidation to give compound (viii) [i.e., formula (I)].

[0143] Option II For example, compound (I) can be formed as shown in scheme I. Compounds (i) and (ii) can be coupled via indole to give compound (iii). Compound (iii) can undergo functionalization to give compound (iv). Compound (iv) can undergo CH functionalization to give compound (v). Compound (v) can be coupled with the corresponding reaction chaperone via metal-catalytic coupling to give compound (vi). Compound (vi) can be coupled with compound (vii) via boration of an aryl halide and subsequent metal-catalytic coupling to give compound (viii). Compound (viii) can be converted to compound (ix) via successive deprotection and macrocyclization. Compound (ix) can undergo deprotection and amidation to give compound (x) [i.e., formula (VIII)].

[0144] abbreviation

[0145] Intermediate 1: 5-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-2,2-dimethyl-5-oxovalerate n-BuLi (2.5 M in hexane, 80 mL, 200 mmol) was added dropwise to a mixture of iPrMgCl (2 M in THF, 120 mL) under N2 at -10 °C. The mixture was stirred at -10 °C for 30 min, and then 3-bromo-2-[(1S)-1-methoxyethyl]pyridine (43.2 g, 200 mmol) was added dropwise to THF (300 mL) at -10 °C. The mixture was warmed to -5 °C and stirred for 1 h. Then, 3,3-dimethyloxane-2,6-dione (28.4 g, 200 mmol) was added dropwise to THF (200 mL) at -5 °C. The mixture was warmed to 0 °C and stirred for 1.5 h. HCl (4 N in dioxane) was added at 0 °C to adjust the pH of the mixture to approximately 5. The mixture was diluted with ice water (500 mL) and extracted with EA (3 x 800 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (EA) to give intermediate 1 (13.5 g, 24%). LC-MS (M+H) + = 280.1.

[0146] Intermediate 2. (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl-2-yl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylic acid methyl ester Step 1: (2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}methyl propionate 1,2-Dibromoethane (5.71 g, 30.4 mmol) was added dropwise to a suspension of Zn powder (49.7 g, 760 mmol) in THF (500 mL). The suspension was stirred at 90 °C for 30 min and then cooled to 25 °C. TMSCl (1.65 g, 15.2 mmol) was added, and the suspension was stirred at 25 °C for 30 min. Methyl (2R)-2-(tert-butoxycarbonylamino)-3-iodopropionate (50.0 g, 152 mmol) was added dropwise to a solution of (500 mL) THF, and the suspension was stirred at 35 °C for 1 h. 2,4-Dibromothiazole (73.8 g, 304 mmol) and Pd(PPh3)2Cl2 (10.7 g, 15.2 mmol) were added to the mixture, and the mixture was stirred at 70 °C for 16 h. The reaction mixture was poured into water (500 mL). The aqueous phase was extracted with EA (200 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO₂, PE:EA = 50:1 to 5:1) to give the title compound (5.0 g, 9%). LC-MS (M+Na) + = 387.0 / 388.9.

[0147] Step 2: (2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionic acid LiOH was added to a solution of (2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}methyl propionate (2.0 g, 5.48 mmol) in THF (16 mL) and H2O (4 mL). . H₂O (230 mg, 5.48 mmol). The mixture was stirred at 25 °C for 1 h. The aqueous phase was extracted with DCM (30 mL x 2). HCl (2 M, aqueous solution) was added to the mixture to adjust the pH to approximately 5. The mixture was poured into water (10 mL), and the aqueous phase was extracted with EA (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (1.0 g, 52%). LC-MS (M+Na) + = 373.0 / 374.9.

[0148] Step 3: (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl-2-yl)-2-{[(tert-butoxy)carbonyl]amino}propane Methyl acyl]-1,2-diazinane-3-carboxylate Cs₂CO₃ (11.8 g, 36.3 mmol) and MeI (3.88 g, 27.2 mmol) were added to a solution of (3S)-1,2-bis(tert-butoxycarbonyl)hexahydropyridazine-3-carboxylic acid (6.0 g, 18.2 mmol) in MeCN (60 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into water (100 mL). The aqueous phase was extracted with EA (80 mL x 2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and TFA (1.99 g, 17.4 mmol) was added. The mixture was stirred at 25 °C for 1 h. The mixture was concentrated under reduced pressure. The residue was dissolved in THF (50 mL), and (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid (3.2 g, 9.11 mmol) was added, followed by T4P (50%, 9.85 g, 13.7 mmol) and Et3N (4.61 g, 45.56 mmol). The mixture was stirred at 25 °C for 1 h. The reaction mixture was poured into water (50 mL). The aqueous phase was extracted with EA (20.0 mL x 2). The combined organic phases were washed with brine (50.0 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE:EA = 50:1 to 3:1) to give intermediate 2 (3.0 g, 69%). 1 H NMR (400 MHz, DMSO- d6 δ = 7.69 (s, 1H), 6.68 (d, J = 8.8 Hz, 1H), 5.34 (d, J = 9.4 Hz, 1H), 5.29 - 5.17 (m, 1H), 3.85 - 3.71 (m, 1H), 3.66 (s, 3H), 3.60 (d, J = 5.9 Hz, 1H), 3.30 - 3.25 (m, 1H), 3.11 (dd, J = 14.7, 8.9 Hz, 1H), 1.85 (dd, J = 6.8, 3.4 Hz, 1H), 1.72 - 1.50 (m, 3H), 1.42 - 1.23 (m, 10H). LC-MS(M+H) + = 477.0 / 479.0.

[0149] Examples 1 and 2: N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9, 13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl] tert-butyl carbamate; N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Trin-1(28),2,5(31),19,25(29),26-hexen-7-yl]tert-butyl carbamate and Step 1: 7-Bromo-3,4-dihydro-2H-1,4-benzoxazine-4-amine A solution of NaNO2 (9.33 g, 135 mmol) in H2O (50 mL) was added to a solution of 7-bromo-3,4-dihydro-2H-1,4-benzoxazine (24.0 g, 112 mmol) in EtOH (120 mL). The mixture was cooled to 0 °C, and concentrated HCl (12.2 mL) was added dropwise at 0 °C with vigorous stirring. The mixture was stirred at 0 °C for 30 min. At 0 °C, a solution of NaOH (45.1 g, 1.12 mol) in H2O (120 mL) was added to the mixture, followed by solid Na2S2O4 (85%, 69.2 g, 338.1 mmol). The mixture was heated to reflux for 2 h, then cooled to room temperature, diluted with H2O (500 mL), and extracted with EA (2 x 700 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 1:2) to give the title compound (11.0 g, 42%). LC-MS (M+H) + = 229.1 / 231.1.

[0150] Step 2: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic) [6.3.1.0 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionic acid TsOH was added to a mixture of 7-bromo-3,4-dihydro-2H-1,4-benzoxazine-4-amine (9.0 g, 39.3 mmol) and 5-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-2,2-dimethyl-5-oxovaleric acid (intermediate 1, 11.0 g, 39.4 mmol) in toluene (500 mL) at room temperature. . H2O (15.0 g, 78.9 mmol). The mixture was stirred at 100 °C for 16 h under N2 atmosphere, then cooled to room temperature. Toluene was removed under vacuum. The mixture was diluted with EA (400 mL), washed with H2O (150 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (MeOH:EA = 1:100) to give the title compound (6.6 g, 36%). LC-MS (M+H) + = 473.1 / 475.1.

[0151] Step 3: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic) [6.3.1.0 4,12 Ethyl dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic[6.3.1.0] 4,12 [A solution of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionic acid (6.57 g, 13.9 mmol) in DMF (100 mL) was mixed with Cs₂CO₃ (6.79 g, 20.8 mmol), followed by dropwise addition of EtI (3.24 g, 20.8 mmol) at 0 °C under N₂ atmosphere. The mixture was stirred at room temperature for 2 h, diluted with EA (300 mL), washed with brine (3 x 80 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 1:4) to give the title compound (6.8 g, 98%). LC-MS (M+H) + = 501.1 / 503.1.

[0152] Step 4: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic) [6.3.1.0 4,12 [Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylprop-1-ol] Under a nitrogen atmosphere at 0°C, 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] was subjected to oxidation. 4,12 Ethyl dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionate (6.8 g, 13.6 mmol) was added to a solution of LiBH4 (1.48 g, 67.9 mmol) in THF (100 mL). The mixture was heated to 60 °C and stirred for 16 h, cooled to room temperature, and then quenched with pre-cooled (0 °C) aqueous NH4Cl solution (80 mL). The mixture was extracted with EA (2 x 150 mL), and the combined organic layers were washed with brine (2 x 60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EA:MeOH = 200:1) to give the title compound (5.3 g, 85%). LC-MS (M+H) + = 459.1 / 461.1.

[0153] Step 5: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic) [6.3.1.0 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate Under a nitrogen atmosphere at 0°C, the 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic[6.3.1.0] group was subjected to oxidation. 4,12 A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylprop-1-ol (5.3 g, 11.5 mmol) and Et3N (2.33 g, 23.1 mmol) in DCM (80 mL) was added in portions with DMAP (140 mg, 1.15 mmol) and Ac2O (1.41 g, 13.8 mmol). The mixture was stirred at room temperature for 4 hours and then concentrated under reduced pressure. The residue was diluted with EA (200 mL), washed with 1 N HCl (40 mL), saturated NaHCO3 (60 mL), and brine (60 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 1:4) to give the title compound (4.5 g, 78%). LC-MS (M+H) + = 501.1 / 503.1.

[0154] Step 6: 3-(2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2- Dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl]- 2,2-Dimethylpropylacetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic[6.3.1.0] 4,12 Pd(dppf)Cl2 was added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (500 mg, 1 mmol) in toluene (10 mL). . DCM (82 mg, 0.1 mmol) and KOAc (294 mg, 3.0 mmol). The resulting mixture was stirred at 90 °C for 4 h under a N2 atmosphere. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using EA to give the title compound (460 mg, 84%). LC-MS (M+H) + = 549.3.

[0155] Step 7: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- [1-Methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraene-] 6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylic acid methyl ester To 3-(2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 K3PO4 (534 mg, 2.52 mmol) and Pd(dtbpf)Cl2 (55 mg, 0.084 mmol) were added to a mixture of toluene (9 mL), dioxane (3 mL), and H2O (3 mL). The resulting solution was stirred at 70 °C for 2 h under N2 atmosphere and then cooled to room temperature. The reaction mixture was diluted with EA (50 mL), washed with H₂O (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography using EA to give the title compound (395 mg, 57%). LC-MS (M+H) + = 819.4.

[0156] Step 8: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (6.3.1.0)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 ]twelve [C-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid To (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic[6.3.1.0] 4,12 Methyl methyl dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (395 mg, 0.48 mmol) was added to a solution of THF (5 mL) and H2O (5 mL) with LiOH (58 mg, 2.4 mmol). The resulting mixture was stirred at room temperature for 2 h. THF was removed under vacuum. The pH of the aqueous phase was acidified to 5 with 1 N HCl at 0 °C. The mixture was extracted with DCM (2 x 15 mL), and the organic phase was dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (370 mg, 99%). LC-MS (M+H) + = 763.4.

[0157] Step 9: N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl 8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexen-7-yl] tert-butyl carbamate; N-[(7S, 13S,19P)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24- Dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28), 2,5(31),19,25(29),26-hexen-7-yl]tert-butyl carbamate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [370 mg, 0.49 mmol]-1,3-thiazolyl-2-yl]-1,2-diazinane-3-carboxylic acid was prepared in a solution of MeCN (40 mL) with DIEA (2.53 g, 19.6 mmol), EDCI (2.82 g, 14.7 mmol), and HOBt (655 mg, 4.86 mmol). The mixture was stirred overnight at room temperature, then concentrated, diluted with DCM (150 mL), and washed with 1 N HCl (30 mL), H2O (20 mL), and brine (20 mL). The organic phase was concentrated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH = 20:1) to give two trans-restricted isomers.

[0158] Example 1 (110 mg, 30%) 1H NMR (400 MHz, DMSO- d6 ) δ 8.72 (d, J = 4.0 Hz,1H), 8.13 (s, 1H), 7.77 (s, 2H), 7.52 – 7.46 (m, 1H), 7.31 (d, J = 4.0 Hz, 1H),7.16 (s, 1H), 5.21 (t, J = 8.0 Hz, 1H), 5.04 (d, J = 12.0 Hz, 1H), 4.65 – 4.57(m, 2H), 4.49 – 4.43 (m, 1H), 4.32 – 4.25 (m, 1H), 4.24 – 4.15 (m, 2H), 3.75– 3.67 (m, 1H), 3.62 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 12.0 Hz, 1H), 3.28 (s,3H), 3.20 – 3.10 (m, 2H), 2.98 – 2.91 (m, 1H), 2.77 – 2.69 (m, 1H), 2.41–2.35 (m, 1H), 2.13 – 2.06 (m, 1H), 1.81 – 1.71 (m, 2H), 1.54 – 1.44 (m, 1H),1.37 (s, 9H), 1.36 – 1.33 (m, 3H), 1.27 – 1.21 (m, 1H), 0.92 (s, 3H), 0.34(s, 3H). LC-MS (M+H) + = 745.3.

[0159] Example 2 (60 mg, 16%), 1 H NMR (400 MHz, DMSO- d6 ) δ 8.73 (d, J = 4.0 Hz,1H), 8.16 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.49 – 7.45 (m, 1H),7.31 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 5.22 (t, J = 8.0 Hz, 1H), 5.03 (d,J = 12.0Hz, 1H), 4.57 – 4.50 (m, 1H), 4.45 – 4.37 (m, 1H), 4.24 – 4.14 (m, 3H), 4.05 – 3.98 (m, 1H), 3.71 – 3.66 (m, 1H), 3.63 (d, J = 12.0 Hz, 1H), 3.55 (d, J = 12.0Hz, 1H), 3.21 – 3.16 (m, 2H), 3.14 (s, 3H), 3.05 – 3.00 (m, 1H), 2.79 – 2.70(m, 1H), 2.38 – 2.33 (m, 1H), 2.15 – 2.08 (m, 1H), 1.81 – 1.72 (m, 2H), 1.54 – 1.45 (m, 1H), 1.38 (s, 9H), 1.28 – 1.21 (m, 1H), 1.17 – 1.14 (m, 3H), 0.93 (s, 3H), 0.45 (s, 3H). LC-MS(M+H) + = 745.3.

[0160] Example 3: (7S,13S,19M)-7-amino-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21 ,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21 ,26A mixture of tert-butyl carbamate (60 mg, 0.08 mmol) in HCl / dioxane (4 M, 4 mL) was stirred at room temperature for 1 h and concentrated under vacuum. The residue was diluted with DCM (20 mL), washed with an aqueous solution of NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC to obtain Example 3 (50 mg, 96%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.72 (d, J = 4.0 Hz, 1H), 8.10 (s, 1H), 7.78 – 7.73 (m, 2H), 7.52 –7.44 (m, 1H), 7.16 (s, 1H), 4.96 (d, J = 12.0 Hz, 1H), 4.65 – 4.53 (m, 2H), 4.47 – 4.40 (m, 2H), 4.29 – 4.20 (m, 2H), 4.17 – 4.08 (m, 1H), 3.76 – 3.68(m, 1H), 3.62 (d, J = 12.0 Hz, 1H), 3.56 (d, J = 12.0 Hz, 1H), 3.25 (s, 3H), 3.23– 3.18 (m, 1H), 2.92 (d, J = 16.0 Hz, 1H), 2.80 – 2.70 (m, 2H), 2.43 – 2.38 (m,1H), 2.12 – 2.04 (m, 1H), 1.85 – 1.64 (m, 3H), 1.55 – 1.44 (m, 2H), 1.36 (d, J = 8.0 Hz, 3H), 0.88 (s, 3H), 0.36 (s, 3H). LC-MS(M+H) + = 645.3.

[0161] Example 4: (7S,13S,19P)-7-amino-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .019,27 .0 21 ,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21 ,26 A mixture of tert-butyl carbamate (60 mg, 0.08 mmol) in HCl / dioxane (4 M, 4 mL) was stirred at room temperature for 1 h and concentrated under vacuum. The residue was diluted with DCM (20 mL), washed with an aqueous solution of NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the residue. The residue was purified by preparative HPLC to obtain Example 4 (50 mg, 96%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.73 (d, J = 4.0 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.73(s, 1H), 7.51 – 7.45 (m, 1H), 7.16 (s, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.56 –4.49 (m, 1H), 4.45– 4.38 (m, 1H), 4.32 – 4.23 (m, 2H), 4.20 – 4.10 (m, 2H),4.05 – 3.97 (m, 1H), 3.71 – 3.66 (m, 1H), 3.63 (d, J = 12.0 Hz, 1H), 3.54 (d, J=12.0 Hz, 1H), 3.25 (s, 3H), 3.06 – 3.00 (m, 1H), 2.77 – 2.67 (m, 2H), 2.66 –2.63 (m, 1H), 2.33 – 2.29 (m, 1H), 2.16 – 2.09 (m, 1H), 1.85 – 1.74 (m, 3H), 1.54 – 1.46 (m, 1H), 1.16 (d, J = 8.0 Hz, 3H), 0.91 (s, 3H), 0.44 (s, 3H). LC-MS(M+H) + = 645.3.

[0162] Example 5: (1S,2S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2 ,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide] At 0°C, the (7S,13S,19M)-7-amino-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21 ,26A solution of 3,1-carbo-1 (28),2,5 (31),19,25 (29),26-hexene-8,14-dione (50 mg, 0.08 mmol) in DMF (4 mL) was supplemented with DIEA (516 mg, 4.0 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (16 mg, 0.16 mmol), and HATU (61 mg, 0.16 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with EA (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC to give Example 5 (15.2 mg, 27%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.72 (d, J = 4.0 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.12 (s, 1H), 7.78 – 7.72 (m, 2H), 7.52 – 7.47(m, 1H), 7.16 (s, 1H), 5.55 (t, J = 8.0 Hz, 1H), 5.05 (d, J = 12.0 Hz, 1H), 4.65– 4.56 (m, 2H), 4.49 – 4.42 (m, 1H), 4.31 – 4.14 (m, 3H), 3.76 – 3.67 (m,1H), 3.63 – 3.54 (m, 2H), 3.31 – 3.26 (m, 1H), 3.27 (s, 3H), 3.15 – 3.07 (m,1H), 2.94 (d, J = 16.0 Hz, 1H), 2.78 – 2.68 (m, 1H), 2.39 (d, J = 16.0 Hz, 1H),2.13– 2.05 (m, 1H), 1.82 – 1.73 (m, 2H), 1.53 – 1.43 (m, 2H), 1.35 (d, J = 6.0Hz, 3H), 1.07 – 1.01 (m, 1H), 1.04 (s, 3H), 0.91 (s, 3H), 0.85 – 0.80 (m,1H), 0.55 – 0.49 (m, 1H), 0.33 (s, 3H). LC-MS(M+H) += 727.3.

[0163] Example 6: (1S,2S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2 ,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide] At 0°C, the (7S,13S,19P)-7-amino-20-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21 ,26 A solution of 60 mg (0.09 mmol) of 1,2,5,19,25,29,26-hexene-8,14-dione in DMF (4 mL) was mixed with DIEA (580 mg, 4.5 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (19 mg, 0.18 mmol), and HATU (69 mg, 0.18 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with EA (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC to give Example 6 (16 mg, 24%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.73 (d, J = 4.0 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.16 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.75 (s,1H), 7.50 – 7.45 (m, 1H), 7.16 (s, 1H), 5.54 (t, J=8.0 Hz, 1H), 5.04 (d, J =12.0Hz, 1H), 4.57 – 7.50 (m, 1H), 4.44 – 4.37 (m, 1H), 4.25 – 4.13 (m, 3H), 4.05 – 3.98 (m, 1H), 3.70 – 3.63 (m, 2H), 3.56 – 3.51 (m, 1H), 3.30 – 3.28 (m, 1H), 3.14 (s, 3H), 3.13 – 3.08 (m, 1H), 3.02 (d, J = 12.0 Hz, 1H), 2.79 –2.69 (m, 1H), 2.38 – 2.30 (m, 1H), 2.15 – 2.08 (m, 1H), 1.82 – 1.73 (m, 2H), 1.56 – 1.45 (m, 2H), 1.15 (d, J = 6.0 Hz, 3H), 1.08 – 1.00 (m, 4H), 0.92 (s, 3H), 0.86 – 0.81 (m, 1H), 0.56 – 0.50 (m, 1H), 0.44 (s, 3H). LC-MS(M+H) + =727.3.

[0164] Example 7: N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [Trin-1(28),2,5(31),19,25(29),26-hexen-7-yl]tert-butyl carbamate Step 1: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) pentane-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraene-3-] 2,2-dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic[6.3.1.0] 4,12A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (2 g, 3.98 mmol) and BPD (1.72 g, 6.8 mmol) in THF (40 mL) was supplemented with dtbpy (182 mg, 0.68 mmol) and chloro(1,5-cyclooctadiene)iridium(I) dimer (188 mg, 0.28 mmol). The mixture was stirred overnight at 75 °C under N2 atmosphere and then cooled to room temperature. The mixture was diluted with EA (100 mL), washed with H2O (40 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound (1.9 g, 76%). LC-MS (M-pinacol + 2H2O + H) + = 545.1 / 547.1.

[0165] Step 2: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}- 9-oxa-1-azatricyclic [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Et3N (703 mg, 6.96 mmol) and Cu(OAc)2 (1.27 g, 6.96 mmol) were added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (1.9 g, 3.03 mmol) and 1-methylpiperazine (1.74 g, 17.4 mmol) in MeCN (40 mL). The resulting mixture was stirred overnight at room temperature under an O2 atmosphere and then diluted with EA (150 mL) and H2O (50 mL). The solids were filtered off, and the filter cake was washed with EA (2 x 50 mL). The organic layer of the filtrate was separated and washed successively with H2O (50 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound (1.06 g, 58%). LC-MS (M+H) + = 599.3 / 601.3.

[0166] Step 3: 3-(2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-6-(4, 4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 [2,4-D12] (12), 5,7-Tetraen-3-yl)-2,2-Dimethylpropylacetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Pd(dppf)Cl2 was added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (1.0 g, 1.67 mmol) and BPD (847 mg, 3.33 mmol) in toluene (25 mL). . DCM (140 mg, 0.17 mmol) and KOAc (491 mg, 5.0 mmol). The resulting mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (760 mg, 70%). LC-MS (M+H) + = 647.4.

[0167] Step 4: (3S)-1-[(2S)-3-{4-[(2M)-3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2- [(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl}-2-{[(tert-butoxy)carbonyl]amino}propionyl Methyl 1,2-diazinane-3-carboxylate; (3S)−1−[(2S)−3−{4−[(2P)−3−[3−(acetoxy)−2,2−dimethylpropyl]−2−{2−[(1S)−1− Methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 ]twelve [carbon-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl}-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2- Methyl diazine-3-formate and To 3-(2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12K3PO4 (363 mg, 1.71 mmol) and Pd(dtbpf)Cl2 (37 mg, 0.057 mmol) were added to a mixture of toluene (8 mL), dioxane (2 mL), and H2O (2 mL). The resulting solution was stirred at 70 °C for 2 h under a N2 atmosphere. The reaction mixture was diluted with EA (50 mL), washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give a pair of trans-isomers. The trans-isomers were further separated by SFC to give two fractions: P1 (M-isomer, 110 mg, 21%) and P2 (P-isomer, 30 mg, 6%). The analytical chiral SFC conditions were as follows: Column: YMC Cellulose-C; Column size: 4.6 x 100 mm, 5 μm; Mobile phase: 4 mM methanol NH3:CO2, 1:9 to 1:1 within 3 min, 1:1 within 2 min, 1:1 to 1:9 within 0.1 min, 1:9 within 1.9 min; Flow rate: 2.0 mL / min; Temperature: 35 °C; Back pressure: 1500 psi. P1: Analytical SFC tR = 3.33 min. LC-MS (M+H) + = 917.5. P2: Analytical SFC tR = 4.38 min. LC-MS (M+H) + = 917.5.

[0168] Step 5: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[(2M)-3-(3-hydroxy-2,2- (dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1- Azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2- Diazine-3-carboxylic acid To (3S)-1-[(2S)-3-{4-[(2M)-3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12Methyl methyl [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazinane-3-carboxylate (from the P1,M-isomer in step 4, 110 mg, 0.12 mmol) was added to a solution of THF (4 mL) and H2O (4 mL) with LiOH (15 mg, 0.6 mmol). The mixture was stirred for 1 h. THF was removed under reduced pressure, and the pH of the aqueous phase was adjusted to 5 with 1 N HCl at 0 °C. The resulting solution was extracted with DCM (2 x 15 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (95 mg, 92%). LC-MS (M+H) + = 861.5.

[0169] Step 6: N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridine pyridyl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]amino tert-butyl formate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[(2M)-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [95 mg, 0.11 mmol]-1,3-thiazolyl-2-yl]-1,2-diazinane-3-carboxylic acid (95 mg, 0.11 mmol) was added to a solution of [15 mL]-1,3-thiazolyl-2-yl]-1,2-diazinane-3-carboxylic acid in MeCN, along with DIEA (569 mg, 4.4 mmol), EDCI (636 mg, 3.3 mmol), and HOBt (149 mg, 1.1 mmol). The mixture was stirred overnight at room temperature and concentrated under reduced pressure. The residue was diluted with DCM (40 mL) and washed with 1 N HCl (10 mL), H2O (15 mL), and brine (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to give Example 7 (30 mg, 32%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.42 (d, J = 2.9Hz, 1H), 8.11 (s, 1H), 7.75 (s, 1H), 7.31 (d, J= 8.9 Hz, 1H), 7.18 – 7.15 (m,1H), 7.14 (s, 1H), 5.21 (t, J = 8.0 Hz, 1H), 5.04 (d, J = 12.0 Hz, 1H), 4.64 –4.54 (m, 2H), 4.35 – 4.27 (m, 2H), 4.24 – 4.15 (m, 2H), 3.75 – 3.66 (m, 1H), 3.61 (d, J = 12.0 Hz, 1H), 3.54 (d, J = 12.0 Hz, 1H), 3.25 – 3.12 (m, 9H), 2.92(d, J = 16.0 Hz, 1H), 2.78 – 2.69 (m, 1H), 2.45 – 2.40 (m, 5H), 2.20 (s, 3H), 2.12 – 2.06 (m, 1H), 1.82 – 1.74 (m, 2H), 1.53 – 1.47 (m, 1H), 1.37 (s, 9H), 1.31 (d, J = 6.0 Hz, 3H), 1.25 – 1.21 (m, 1H), 0.93 (s, 3H), 0.36 (s, 3H). LC-MS(M+H) + = 843.5.

[0170] Example 8: (7S,13S,19M)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .19,13 .0 19,27 .0 21,26 A mixture of tert-butyl carbamate (30 mg, 0.036 mmol) in HCl / dioxane (4 M, 3 mL) was stirred at room temperature for 1 h and concentrated under vacuum. The residue was diluted with DCM (20 mL), washed with an aqueous solution of NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 8 (25 mg, 94%). 1 H NMR (400 MHz, DMSO-) d6 ) δ 8.42 (s, 1H), 8.10 (s, 1H), 7.71 (s, 1H), 7.17 (s, 1H),7.13 (s, 1H), 4.90 (d, J = 12.0 Hz, 1H), 4.63 – 4.52 (m, 2H), 4.35 – 4.24 (m,4H), 4.18 – 4.09 (m, 1H), 3.74 – 3.67 (m, 1H), 3.62 (d, J = 12.0 Hz, 1H), 3.55(d, J = 12.0 Hz, 1H), 3.29 – 3.23 (m, 5H), 3.21 (s, 3H), 3.19 – 3.15 (m, 1H), 2.95 – 2.89 (m, 1H), 2.74 – 2.67 (m, 2H), 2.45 – 2.40 (m, 5H), 2.20 (s, 3H), 2.10 – 2.05 (m, 1H), 1.82 – 1.66 (m, 3H), 1.51 – 1.46 (m, 1H), 1.32 (d, J = 6.0Hz, 3H), 0.91 (s, 3H), 0.37 (s, 3H). LC-MS(M+H) + = 743.5.

[0171] Example 9: (1S,2S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide] At 0°C, the (7S,13S,19M)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 A solution of 25 mg (0.034 mmol) of 1,2,5,19,25,29,26-hexene-8,14-dione in DMF (4 mL) was mixed with DIEA (217 mg, 1.68 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (6.7 mg, 0.067 mmol), and HATU (25.5 mg, 0.067 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EA (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC to give Example 9 (5 mg, 18%). 1 H NMR (400 MHz, DMSO- d6 ) δ 8.52 (d, J =12.0 Hz, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.74 (s, 1H),7.18 – 7.15 (m, 1H),7.14 (s, 1H), 5.53 (t, J = 8.0 Hz, 1H), 5.05 (d, J= 12.0 Hz,1H), 4.63 – 4.51 (m, 2H), 4.35 – 4.26 (m, 2H), 4.25 – 4.15 (m, 2H), 3.74 –3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 3.28 – 3.19 (m, 8H), 3.15 – 3.07 (m, 1H), 2.96 – 2.87 (m, 1H), 2.76 – 2.69 (m, 1H), 2.45 – 2.40 (m, 5H), 2.20 (s, 3H), 2.12 – 2.05 (m, 1H), 1.82 – 1.74 (m, 2H), 1.51 – 1.44 (m, 1H), 1.31 (d, J = 6.0Hz, 3H), 1.09 – 0.98 (m, 1H), 1.04 (s, 3H), 0.92 (s, 3H), 0.86 – 0.79 (m,1H), 0.57 – 0.46 (m, 1H), 0.36 (s, 3H). LC-MS(M+H) + = 825.5.

[0172] Example 10: (1S,2S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide] Step 1: (3S)−1−[(2S)−2−{[(tert-butoxy)carbonyl]amino}−3−{4−[(2P)−3−(3−hydroxy−2,2− (dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1- Azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2- Diazine-3-carboxylic acid The title compound (25 mg, 83%) was prepared in a manner similar to step 5 of Example 7, by (3S)-1-[(2S)-3-{4-[(2P)-3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Methyl methyl [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazinane-3-carboxylate (P2, P-isomer from step 4 of Example 7) was prepared by LC-MS (M+H). + = 861.5.

[0173] Step 2: N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridine pyridyl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]amino tert-butyl formate The title compound (10 mg, 41%) was prepared in a manner similar to that in step 6 of Example 7, by (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[(2P)-3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + =843.5.

[0174] Step 3: (7S,13S,19P)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1- pyridin-3-yl-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (8 mg, 91%) was prepared in a manner similar to that in step 1 of Example 8, from N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26Preparation of tert-butyl carbamate from 1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + =743.5.

[0175] Step 4: (1S,2S)−N−[(7S,13S,19P)−20−{2−[(1S)−1−methoxyethyl]−5−(4−methylpiperyl) Azine-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetramethyl Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl]-2-methylcyclopropane-1-formamide Example 10 (0.4 mg, 4%) was prepared in a similar manner to step 1 of Example 9, from (7S,13S,19P)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione. 1 H NMR (400 MHz, DMSO- d6 ) δ 8.52(d, J = 9.0 Hz, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 7.74 (s, 1H), 7.38 (s, 1H),7.14 (s, 1H), 5.53 (t, J = 8.0 Hz, 1H), 5.03 (d, J= 12.0 Hz, 1H), 4.54 – 4.48(m, 1H), 4.43 – 4.37 (m, 1H), 4.25 – 4.15 (m, 2H), 4.09 – 3.97 (m, 2H), 3.70– 3.62 (m, 2H), 3.57 – 3.51 (m, 1H), 3.27 – 3.11 (m, 6H), 3.10 (s, 3H), 3.02 – 2.96 (m, 1H), 2.81 – 2.70 (m, 1H), 2.44 – 2.38 (m, 5H), 2.21 – 2.07 (m,4H), 1.82 – 1.75 (m, 2H), 1.51 – 1.44 (m, 2H), 1.23 – 1.20 (m, 2H), 1.15 –1.12 (m, 3H), 1.04 (s, 3H), 0.93 (s, 3H), 0.86 – 0.80 (m, 2H), 0.54 – 0.49(m, 3H). LC-MS(M+H) + = 825.5.

[0176] Example 11: (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] At 0°C, the (7S,13S,19M)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26A solution of 60 mg (0.08 mmol) of 1,2,5,19,25,29,26-hexene-8,14-dione in DMF (4 mL) was supplemented with DIEA (516 mg, 4.0 mmol), (1r,1S,2R)-2,3-dimethylcyclopropane-1-carboxylic acid (18 mg, 0.16 mmol), and HATU (61 mg, 0.16 mmol). The mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with EA (30 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC to give Example 11 (14.5 mg, 18%). 1 H NMR (400MHz, DMSO- d6 ) δ 8.44 – 8.37 (m, 2H), 8.11 (s, 1H), 7.75 (s, 1H), 7.16 (s,1H), 7.14 (s, 1H), 5.53 (t, J = 8.0 Hz, 1H), 5.04 (d, J = 12.0 Hz, 1H), 4.64 –4.52 (m, 2H), 4.33 – 4.26 (m, 2H), 4.24 – 4.14 (m, 2H), 3.75 – 3.66 (m, 1H),3.63 – 3.54 (m, 2H), 3.26 – 3.20 (m, 8H), 3.15 – 3.07 (m, 1H), 2.91 (d, J =12.0 Hz, 1H), 2.76 – 2.69 (m, 1H), 2.45 – 2.40 (m, 5H), 2.20 (s, 3H), 2.11 –2.05 (m, 1H), 1.80 – 1.72 (m, 2H), 1.55 – 1.44 (m, 1H), 1.31 (d, J = 6.0 Hz,3H), 1.15 – 1.12 (m, 3H), 1.06 (d, J = 5.4 Hz, 3H), 1.04 (d, J = 5.2 Hz, 3H), 0.92 (s, 3H), 0.37 (s, 3H). LC-MS(M+H) + = 839.4.

[0177] Examples 12, 13, and 14: (1S,2S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17,22-trimethyl-8,14-dioxa-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide; (1S,2S)‐N‐[(7S,13S)‐20‐{2‐[(1S)‐1‐methoxyethyl]‐5‐(4‐methylpiperazin‐1‐yl)pyridin‐3‐yl}‐17,17,22‐trimethyl‐8,14‐dioxa‐15,24‐dioxa‐4‐thia‐9,21,30,31‐tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide; (1S,2S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide] and and Step 1: 1-(5-chloro-2-nitrophenoxy)prop-2-one At 20 °C, K₂CO₃ (23.89 g, 172.86 mmol), NaI (4.32 g, 28.81 mmol), and 1-bromoprop-2-one (17.8 g, 130 mmol) were added to a solution of 5-chloro-2-nitrophenol (10 g, 57.6 mmol) in acetone (100 mL). The mixture was stirred at 60 °C for 4 hours. The solution was filtered, and the filter cake was washed with DCM (100 mL x 3). The filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO₂, PE / EA = 1 / 0 to 2 / 1) to give the title compound (8.6 g, 64%). LC-MS (M+H) + = 230.0.

[0178] Step 2: 7-Chloro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine Under a nitrogen atmosphere, Pt / C (1%, 45.0 g, 2.1 mmol) was added to a solution of 1-(5-chloro-2-nitrophenoxy)prop-2-one (45 g, 196 mmol) in dioxane (500 mL) and isopropanol (500 mL). The suspension was degassed and purged with H2. The mixture was stirred with H2 at 100 °C for 24 h. The solution was filtered, and the filter cake was washed with MeOH (500 mL x 3). The filtrate was concentrated under vacuum. The residue was purified by column chromatography (SiO2, PE / EA = 1 / 0 to 0 / 1) to give the title compound (25 g, 69%). 1 H NMR (400 MHz, DMSO- d6 ) δ 6.72 - 6.63 (m, 2H), 6.56 - 6.51 (m,1H), 5.97 (s, 1H), 4.17 - 4.09 (m, 1H), 3.61 (dd, J = 8.0, 10.4 Hz, 1H), 3.40 -3.34 (m, 1H), 1.07 (d, J = 6.4 Hz, 3H). LC-MS (M+H) + = 184.0.

[0179] Step 3: 7-Chloro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-4-amine A solution of NaNO2 (11.2 g, 162.3 mmol) in H2O (50 mL) was added to a solution of 7-chloro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine (25.0 g, 136 mmol) in EtOH (120 mL). The reaction mixture was cooled to 0 °C, and concentrated HCl (14.7 mL, 176.4 mmol) was added dropwise at 0 °C with vigorous stirring. The reaction mixture was then stirred at 0 °C for 30 min. At 0 °C, a solution of NaOH (54.4 g, 1.36 mol) in H2O (140 mL) was added to the mixture, followed by solid Na2S2O4 (85%, 83.5 g, 407.9 mmol), and the mixture was heated to reflux for 2 h. The reaction mixture was cooled to room temperature, diluted with 600 mL of H₂O, extracted with EA (2 x 800 mL), washed with 200 mL of brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 2:1) to give the title compound (12 g, 44%). LC-MS (M+H) + = 199.1 / 201.1.

[0180] Step 4: 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-nitrogen Miscellaneous tricyclic rings [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionic acid TsOH was added to a mixture of 7-chloro-3-methyl-3,4-dihydro-2H-1,4-benzoxazine-4-amine (5.66 g, 28.5 mmol) and 5-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-2,2-dimethyl-5-oxovaleric acid (intermediate 1, 7.94 g, 28.5 mmol) in toluene (300 mL) at room temperature. . H2O (13.5 g, 71.3 mmol). The mixture was stirred at 80 °C for 16 h under a N2 atmosphere, then cooled to room temperature. Toluene was removed under vacuum. The reaction mixture was diluted with EA (400 mL), washed with H2O (150 mL) and brine (100 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (MeOH:EA = 1:100) to give the title compound (1.9 g, 15%). LC-MS (M+H) + = 443.3.

[0181] Step 5: 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-nitrogen Miscellaneous tricyclic rings [6.3.1.0] 4,12 Ethyl dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionate To 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclic[6.3.1.0] 4,12 [1.9 g, 4.3 mmol] Cs₂CO₃ (2.1 g, 6.4 mmol) was added to a solution of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionic acid in DMF (50 mL). Then, EtI (998 mg, 6.4 mmol) was added dropwise at 0 °C under a N₂ atmosphere. The mixture was stirred at room temperature for 2 h. The mixture was then diluted with EA (150 mL), washed with brine (2 x 50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 1:4) to give the title compound (2.0 g, 99%). LC-MS (M+H) + = 471.3.

[0182] Step 6: 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-nitrogen Miscellaneous tricyclic rings [6.3.1.0] 4,12 [Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylprop-1-ol] Under a nitrogen atmosphere at 0°C, 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclo[6.3.1.0] was subjected to oxidation. 4,12 Ethyl dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionate (2.0 g, 4.25 mmol) was added to a solution of LiBH4 (464 mg, 21.3 mmol) in THF (50 mL). The mixture was heated to 60 °C for 16 h and then cooled to room temperature. The reaction mixture was quenched with pre-cooled (0 °C) aqueous NH4Cl solution (40 mL). The mixture was extracted with EA (2 x 80 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (1.5 g, 82%). LC-MS (M+H) + = 429.3.

[0183] Step 7: 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-nitrogen Miscellaneous tricyclic rings [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate Under a nitrogen atmosphere at 0°C, the 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclo[6.3.1.0] group was subjected to oxidation. 4,12A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylprop-1-ol (1.3 g, 3.04 mmol) and Et3N (614 mg, 6.07 mmol) in DCM (20 mL) was added fractionally with DMAP (37 mg, 0.3 mmol) and Ac2O (372 mg, 3.6 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated. The residue was diluted with EA (80 mL), washed with 1 N HCl (15 mL), saturated NaHCO3 (30 mL), and brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 1:4) to give the title compound (1.2 g, 86%). LC-MS (M+H) + = 471.3.

[0184] Step 8: 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) pentane-2-yl)pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Twelve carbon-2,4(12),5,7-] Tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclic[6.3.1.0] 4,12 A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (1.2 g, 2.5 mmol) and HBpin (920 mg, 7.2 mmol) in THF (30 mL) was supplemented with dtbpy (130 mg, 0.48 mmol) and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (160 mg, 0.24 mmol). The resulting mixture was then placed in a sealed tube. N The mixture was stirred overnight at 80°C under a certain atmosphere, and then cooled to room temperature. The resulting mixture was diluted with EA (100 mL), washed with H₂O (40 mL) and brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (1.0 g, 83%). LC-MS (M-pinacol + 2H₂O + H₂) + =515.3.

[0185] Step 9: 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}- 11-Methyl-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethyl] Propyl acetate To 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Et3N (591 mg, 5.85 mmol) and Cu(OAc)2 (710 mg, 3.9 mmol) were added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (1.0 g, 2.12 mmol) and 1-methylpiperazine (973 mg, 9.73 mmol) in MeCN (25 mL). The resulting mixture was stirred overnight at room temperature under an O2 atmosphere. The mixture was diluted with EA (100 mL). The solids were filtered off, and the filter cake was washed with EA (2 x 50 mL). The combined organic layers were washed with H2O (50 mL) and brine (40 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give the title compound (520 mg, 43%). LC-MS (M+H) + = 569.5.

[0186] Step 10: 3-(2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}11-methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 ]ten Dicarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-chloro-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Pd2(dba)3 (76 mg, 0.083 mmol), Xphos (119 mg, 0.25 mmol), and KOAc (488 mg, 4.98 mmol) were added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (470 mg, 0.83 mmol) and BPD (841 mg, 3.31 mmol) in dioxane (15 mL). The mixture was stirred at 80 °C for 30 h under N2 atmosphere and then cooled to room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (270 mg, 49%). LC-MS (M+H) + = 661.5.

[0187] Step 11: (3S)−1−[(2S)−3−(4−{3−[3−(acetoxy)−2,2−dimethylpropyl]−2−{2−[(1S)− 1-Methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclic[6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] [Aminopropionyl]-1,2-diazinane-3-carboxylic acid methyl ester; To 3-(2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-11-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 K3PO4 (261 mg, 1.23 mmol) and Pd(dtbpf)Cl2 (27 mg, 0.041 mmol) were added to a mixture of toluene (4.5 mL), dioxane (1.5 mL), and H2O (1.5 mL). The mixture was stirred at 70 °C for 2 h under a N2 atmosphere and then cooled to room temperature. The reaction mixture was diluted with EA (40 mL), washed with H₂O (20 mL) and brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (280 mg, 73%). LC-MS (M+H) + = 931.6.

[0188] Step 12: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (1S)-1-methoxyethyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-11-methyl-9-oxy Hetero-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]- 1,2-Diazinane-3-carboxylic acid To (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Methyl methyl dodecanoyl-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (280 mg, 0.3 mmol) was added to a solution of THF (5 mL) and H2O (5 mL) with LiOH. .H₂O (36 mg, 1.5 mmol). The resulting mixture was stirred for 1 h. THF was removed under reduced pressure. The pH of the aqueous phase was adjusted to approximately 5 with 1 NHCl at 0 °C. The mixture was extracted with DCM (2 x 15 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (240 mg, 92%). LC-MS (M+H) + = 875.5.

[0189] Step 13: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridine- 3-yl}-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]amino tert-butyl formate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-11-methyl-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [100 mg, 0.11 mmol]-1,3-thiazolyl-2-yl]-1,2-diazinane-3-carboxylic acid was added to a solution of [DCM] (20 mL) with DIEA (568 mg, 4.4 mmol), EDCI (634 mg, 3.3 mmol), and HOBt (232 mg, 1.72 mmol). The mixture was stirred overnight at room temperature, then diluted with DCM (30 mL) and washed with 1 N HCl (10 mL), H2O (15 mL), and brine (10 mL). The solution was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (50 mg, 53%). LC-MS (M+H) + = 857.5.

[0190] Step 14: (1S,2S)−N−[(7S,13S,19M)−20−{2−[(1S)−1−methoxyethyl]−5−(4−methylpiperyl) (azinyl-1-yl)pyridyl-3-yl}-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30, 31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26- [Hexen-7-yl]-2-methylcyclopropane-1-formamide; (1S,2S)‐N‐[(7S,13S)‐20‐{2‐[(1S)‐1‐methoxyethyl]‐5‐(4‐methylpiperazin‐1‐yl)pyridine pyridyl-3-yl-17,17,22-trimethyl-8,14-dioxa-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane Ring [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]- 2-Methylcyclopropane-1-formamide; (1S,2S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(4- Methylpiperazine-1-yl)pyridin-3-yl}-17,17,22-trimethyl-8,14-dioxo-15,24-dioxa-4-thia-9, 21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17,22-trimethyl-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 A mixture of tert-butyl carbamate (50 mg, 0.058 mmol) in HCl / dioxane (4 N, 4 mL) was stirred at room temperature for 1 h and concentrated under vacuum. The residue was diluted with DCM (20 mL), washed with an aqueous solution of NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was redissolved in DMF (3 mL), followed by the addition of DIEA (322 mg, 2.5 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (10 mg, 0.10 mmol), and HATU (38 mg, 0.10 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h, diluted with EA (20 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC and then by preparative HPLC to obtain Examples 12, 13 (as a pair of mixtures) and 14.

[0191] Example 12 (5.5 mg, 12%) 1 H NMR (400 MHz, DMSO- d6 ) δ 8.49 (d, J = 12.0 Hz, 1H), 8.40 (d, J = 4.0 Hz, 1H), 8.07 (s, 1H), 7.71 (s, 1H), 7.16 (d, J = 4.0 Hz,1H), 7.12 (s, 1H), 5.48 (t, J = 12.0 Hz, 1H), 5.00 (d, J= 12.0 Hz, 1H), 4.66 –4.59 (m, 1H), 4.56 – 4.51 (m, 1H), 4.45 – 4.41 (m, 1H), 4.28 – 4.22 (m, 1H),4.20 – 4.12 (m, 2H), 3.57 – 3.53 (m, 1H), 3.52 – 3.48 (m, 2H), 3.26 – 3.18(m, 8H), 3.11 – 3.04 (m, 1H), 2.93 – 2.87 (m, 1H), 2.72 – 2.66 (m, 1H), 2.41– 2.39 (m, 5H), 2.16 (s, 3H), 2.09 – 2.03 (m, 1H), 1.79 – 1.72 (m, 2H), 1.46– 1.41 (m, 2H), 1.27 (d, J = 6.0 Hz, 3H), 1.01 – 0.95 (m, 1H), 1.01 (s, 3H),0.91 (s, 3H), 0.85 (d, J = 6.6 Hz, 1H), 0.82 – 0.78 (m, 1H), 0.52 – 0.47 (m,1H), 0.29 (s, 3H). LC-MS (M+H) + = 839.5.

[0192] Example 13 (1.7 mg, 4%), 1 1H NMR (400 MHz, DMSO- d6 ) δ 8.48 (d, J = 12.0 Hz,1H), 8.43 (d, J = 4.0 Hz, 1H), 8.38 (d, J = 4.0 Hz, 1H), 8.27 (d, J = 8.0 Hz, 1H),8.12 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.60 (s, 1H), 7.35 (d, J = 4.0 Hz,1H), 7.28 (d, J= 4.0 Hz, 1H), 7.11 (s, 1H), 7.05 (s, 1H) , 6.03 – 5.46 (m,1H), 5.35 – 4.97 (m, 1H), 4.47 – 4.24 (m, 3H) , 3.78 – 3.53 (m, 3H), 3.22 –2.99 (m, 8H), 2.91 – 2.88 (m, 2H), 2.84 – 2.80 (m, 2H) , 2.16 (s, 3H), 1.78 –1.59 (m, 4H), 1.46 – 1.41 (m, 4H), 1.22 – 1.17 (m, 2H), 1.13 – 1.09 (m, 2H),1.03 – 0.94 (m, 7H), 0.91 (s, 1H), 0.82 (br s, 2H) 0.71 – 0.65 (m, 2H), 0.82– 0.78 (m, 1H), 0.52 – 0.47 (m, 1H), 0.39 – 0.31 (m, 3H). LC-MS (M+H) + = 839.5.

[0193] Example 14 (0.7 mg, 1%), 1 H NMR (400 MHz, DMSO- d6 ) δ 8.48 (d, J = 12.0 Hz,1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.70 (s, 1H), 7.33 (s, 1H), 7.11 (s, 1H),5.51 (d, J = 12.0 Hz, 1H), 4.98 (d, J= 12.0 Hz, 1H), 4.46 – 4.41 (m, 1H), 4.33 –4.26 (m, 2H), 4.21 – 4.12 (m, 2H), 4.01 – 3.96 (m, 1H), 3.58 – 3.54 (m, 1H) ,3.47 – 3.43 (m, 1H), 3.22 – 3.09 (m, 8H), 2.40 – 2.38 (m, 4H), 2.15 (s, 3H), 1.79 – 1.71 (m, 3H), 1.47 – 1.41 (m, 3H), 1.23 – 1.20 (m, 2H), 1.19 – 1.17(m, 3H), 1.00 (s, 3H), 0.88 (s, 3H), 0.86 – 0.83 (m, 3H), 0.82 – 0.78 (m,1H), 0.51 – 0.46 (m, 1H), 0.34 (s, 3H). LC-MS(M+H) + = 839.5.

[0194] Example 15: (1R,5S,6R)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [31-C-1(28),2,5(31),19,25(29),26-Hexen-7-yl]-3-oxabicyclo[3.1.0]hexane-6-formamide Step 1: (3S)−1−[(2S)−3−(4−{3−[3−(acetoxy)−2,2−dimethylpropyl]−2−{2−[(1S)− 1-Methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 ]twelve C-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2- Methyl diazine-3-formate To 3-(2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12[1.21 g, 1.86 mmol] and (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (888 mg, 1.86 mmol) were added to a mixture of toluene (15 mL), dioxane (5 mL), and water (5 mL) with K3PO4 (1.18 g, 5.57 mmol) and Pd(dtbpf)Cl2 (121 mg, 0.186 mmol). The solution was stirred at 70 °C for 3 h under nitrogen atmosphere. The mixture was cooled to room temperature and diluted with EA (100 mL), washed with water (30 mL) and brine (30 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (1.6 g, 94%). LC-MS (M+H) + = 917.5.

[0195] Step 2: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-aza Three Rings [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl}propionyl]-1,2-diazine Alkyl-3-carboxylic acid The title compound (1.4 g, 93%) was prepared in a manner similar to step 5 of Example 7, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 861.5.

[0196] Step 3: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridine- 3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]amino tert-butyl formate The title compound (760 mg, 56%) was prepared in a manner similar to that in step 6 of Example 7, by (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + =843.5.

[0197] Step 4: (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazine-1-yl)pyridine pyridyl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1] 2,5 .1 9 ,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (660 mg, 99%) was prepared in a similar manner to that in Example 8, from N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of tert-butyl carbamate from 1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 743.5.

[0198] Step 5: (1R,5S,6R)−N−[(7S,13S,19M)−20−{2−[(1S)−1−methoxyethyl]−5−(4−methyl Piperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- Tetraazahexane [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ] 31-carbon-1(28),2,5(31),19,25(29),26-hexane [Al-7-yl]-3-oxabicyclo[3.1.0]hexane-6-formamide To (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9, 13 .0 19,27 .0 21,26A solution of 1,2,5,19,25,29,26-hexene-8,14-dione (15 mg, 0.02 mmol) in DMF (2 mL) was supplemented with DIEA (129 mg, 1.0 mmol), (1R,5S,6r)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid (5.2 mg, 0.04 mmol), and HATU (15 mg, 0.04 mmol). The mixture was stirred at room temperature for 1 h, then diluted with EA (15 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) and preparative HPLC to give Example 15 (2.3 mg, 14%). LC-MS (M+H) + = 853.7.

[0199] 1 H NMR (400 MHz, DMSO- d6 ) δ 8.51 (d, J = 8.9 Hz, 1H), 8.39 (d, J = 2.9Hz, 1H), 8.08 (s, 1H), 7.71 (s, 1H), 7.13 (d, J = 2.7 Hz, 1H), 7.11 (s, 1H),5.56 – 5.54 (m, 1H), 5.04 – 4.98 (m, 1H), 4.60 – 4.49 (m, 2H), 4.31 – 4.23(m, 2H), 4.21 – 4.12 (m, 2H), 3.81 – 3.75 (m, 2H), 3.72 – 3.65 (m, 1H), 3.61 – 3.52 (m, 4H), 3.24 – 3.20 (m, 5H), 3.18 (s, 3H), 3.10 – 3.03 (m, 1H), 2.91– 2.85 (m, 1H), 2.74–2.65 (m, 1H), 2.42 – 2.39 (m, 5H), 2.17 (s, 3H), 2.09 – 2.01 (m, 1H), 1.92 – 1.82 (m, 2H), 1.78 – 1.69 (m, 2H), 1.62 – 1.58 (m,1H), 1.51 – 1.42 (m, 1H), 1.29 (d, J= 6.0 Hz, 3H), 0.89 (s, 3H), 0.35 (s, 3H).

[0200] Examples of trans-reactive isomers -16 and 16: (1S,2S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide and (1S,2S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2-methylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-9-oxy Hetero-1-azatricyclic [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (350 mg, 0.56 mmol) and morpholine (243 mg, 2.79 mmol) in MeCN (10 mL) was supplemented with TEA (170 mg, 1.7 mmol) and Cu(OAc)₂ (203 mg, 1.11 mmol). The mixture was stirred at room temperature under an oxygen atmosphere for 4 h, and then diluted with EA (50 mL) and water (50 mL). The solids were filtered off, and the filter cake was washed with EA (2 x 50 mL). The organic phase was separated and washed with water (50 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (210 mg, 64%). LC-MS (M+H) + = 586.3 / 588.3.

[0201] Step 2: 3-(2-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-6-(4,4,5,5- Tetramethyl-1,3,2-dioxoboropentan-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 [Decadecyl carbon-2,4(12),5, 7-Tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 Pd(dppf)Cl2 was added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (210 mg, 0.36 mmol) and BPD (182 mg, 0.71 mmol) in toluene (8 mL). . DCM (30 mg, 0.037 mmol) and KOAc (105 mg, 1.07 mmol). The mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EA (40 mL), washed with brine (20 mL), filtered through Na₂SO₄, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give the title compound (200 mg, 88%). LC-MS (M+H) + = 634.5.

[0202] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- 1-Methoxyethyl]-5-(morpholino-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Carbon-2,4-12 (12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine Methyl alkyl-3-carboxylate To 3-(2-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [A mixture of (2S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2,2-dimethylpropyl acetate (200 mg, 0.32 mmol) and (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate (153 mg, 0.32 mmol)] in a mixture of dioxane (5 mL) and H2O (0.5 mL) was supplemented with K3PO4 (204 mg, 0.96 mmol) and Pd(dtbpf)Cl2 (21 mg, 0.032 mmol). The mixture was stirred at 70 °C for 3 h under nitrogen and then cooled to room temperature. The mixture was diluted with EA (40 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum.] The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (160 mg, 56%). LC-MS (M+H) + = 904.5.

[0203] Step 4: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (1S)-1-methoxyethyl]-5-(morpholino-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazine-3- Formic acid To (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12Methyl methyl dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (160 mg, 0.18 mmol) was added to a solution of THF (2.5 mL) and water (2.5 mL) with LiOH (35 mg, 1.44 mmol). The mixture was stirred at room temperature for 3 h. The mixture was then diluted with water (30 mL) and washed with EA (10 mL). The aqueous phase was acidified to pH 5 with 1 N HCl (aqueous solution) at 0 °C. The mixture was extracted with EA (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (130 mg, 87%). LC-MS (M+H) + = 848.5.

[0204] Step 5: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}- 17,17-Dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2 ,5 .1 9,13 .0 19,27 .0 21,26 [Trin-1(28),2,5(31),19,25(29),26-hexen-7-yl]tert-butyl carbamate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [130 mg, 0.15 mmol]-1,3-thiazolyl-2-yl]-1,2-diazinane-3-carboxylic acid was added to a solution in DCM (20 mL) with DIEA (791 mg, 6.13 mmol), EDCI (864 mg, 4.5 mmol), and HOBt (304 mg, 2.25 mmol). The mixture was stirred at room temperature for 20 h and then washed with 1 N hydrochloric acid (15 mL), water (10 mL), and brine (10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (75 mg, 60%). LC-MS (M+H) + = 830.5.

[0205] Step 6: (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridine-3- [23.3.1.1]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane 2,5 .1 9, 13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-17,17-dimethyl-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 A mixture of tert-butyl carbamate (75 mg, 0.09 mmol) in HCl / dioxane (4 M, 3 mL) was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was diluted with DCM (10 mL) and washed with a saturated aqueous solution of NaHCO3 (5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (60 mg, 91%). LC-MS (M+H) + = 730.5.

[0206] Step 7: (1S,2S)−N−[(7S,13S,19P)−20−{2−[(1S)−1−methoxyethyl]−5−(morpholin−4−yl) pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2- Methylcyclopropane-1-formamide and (1S,2S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(methoxyethyl) (Lin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetra- Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl]-2-methylcyclopropane-1-formamide To (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19, 27 .0 21,26A solution of 60 mg (0.08 mmol) of 1-(28),2,5(31),19,25(29),26-hexene-8,14-dione in DMF (3 mL) was mixed with DIEA (530 mg, 4.1 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (16 mg, 0.16 mmol), and HATU (61 mg, 0.16 mmol). The mixture was stirred at room temperature for 1 h and then diluted with EA (15 mL). The mixture was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (DCM:MeOH = 10:1) to give a pair of trans-restricted isomers. The transisomers were further separated by preparative HPLC to obtain transisomer-16 (P-isomer, 3.7 mg, 6%) and Example 16 (M-isomer, 13.2 mg, 20%).

[0207] Transisomer-16: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.47 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 2.9 Hz, 1H), 8.12 (s, 1H), 7.70 (s, 1H), 7.37 (d, J = 2.9 Hz, 1H),7.11 (s, 1H), 5.58 – 5.47 (m, 1H), 5.02 – 4.93 (m, 1H), 4.54 – 4.44 (m, 2H),4.41 – 4.33 (m, 2H), 4.23 – 4.12 (m, 2H), 4.05 – 3.93 (m, 2H), 3.74 – 3.59(m, 7H), 3.55 – 3.48 (m, 1H), 3.23 – 3.05 (m, 7H), 3.01 – 2.94 (m, 1H), 2.76– 2.67 (m, 1H), 2.38 – 2.33 (m, 2H), 2.15 – 2.04 (m, 1H), 1.80 – 1.72 (m, 2H), 1.48 – 1.41 (m, 2H), 1.11 (d, J= 8.0 Hz, 3H), 1.01 (s, 3H), 0.90 (s, 3H), 0.83 – 0.78 (m, 1H), 0.52 – 0.50 (m, 1H), 0.48 (s, 3H). LC-MS (M+H) + = 812.7.

[0208] Example 16: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.46 (d, J = 8.0 Hz, 1H), 8.40 (d, J = 2.9 Hz, 1H), 8.08 (s, 1H), 7.70 (s, 1H), 7.15 (d, J = 2.9 Hz, 1H), 7.11 (s, 1H), 5.50 – 5.48 (m, 1H), 5.03 – 4.97 (m, 1H), 4.59 – 4.49 (m, 2H), 4.32 – 4.23 (m, 2H), 4.23 – 4.11 (m, 2H), 3.74 – 3.64 (m, 5H), 3.60 – 3.51 (m, 2H), 3.25 – 3.23 (m, 2H), 3.21 – 3.16 (m, 6H), 3.12 – 3.04 (m, 1H), 2.92 – 2.85 (m, 1H), 2.75 – 2.66 (m, 1H), 2.42 – 2.38 (m, 1H), 2.10 – 2.01 (m, 1H), 1.79 – 1.68 (m, 2H), 1.52 – 1.40 (m, 2H), 1.29 (d, J = 6.0 Hz, 3H), 1.19 – 0.91 (m, 1H) 1.01 (s, 3H), 0.90 (s, 3H), 0.81 (s, 1H), 0.52 – 0.46 (m, 1H), 0.34 (s, 3H). LC-MS (M+H) + = 812.7.

[0209] Examples of trans-reactive isomers -17 and 17: (1R,2R,3S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Transisomer-17 (P-isomer, 8.8 mg, 12%) and Example 17 (M-isomer, 20.3 mg, 28%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(morpholin-4-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0210] Transisomer-17: 1 H NMR (400 MHz, DMSO, d6 ) δ 8.42 – 8.33 (m, 2H), 8.12(s, 1H), 7.71 (s, 1H), 7.38 (d,J = 2.9 Hz, 1H), 7.11 (s, 1H), 5.54 – 5.47 (m,1H), 5.00 – 4.97 (m, 1H), 4.53 – 4.44 (m, 1H), 4.41 – 4.34 (m, 1H), 4.21 –4.11 (m, 2H), 4.05 – 3.97 (m, 2H), 3.73 – 3.60 (m, 6H), 3.54 – 3.48 (m, 1H),3.22 – 3.07 (m, 9H), 3.00 – 2.93 (m, 1H), 2.76 – 2.67 (m, 1H), 2.41 – 2.33(m, 2H), 2.11 – 2.04 (m, 1H), 1.78 – 1.71 (m, 2H), 1.52 – 1.41 (m, 1H), 1.21– 1.11 (m, 5H), 1.05 – 1.00 (m, 6H), 0.90 (s, 3H), 0.48 (s, 3H). LC-MS (M+H) + =826.7 Example 17: 1 H NMR (400 MHz, DMSO, d6 ) δ 8.40 (d, J = 2.9 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.08 (s, 1H), 7.72 (s, 1H), 7.15 (d, J = 2.9 Hz, 1H), 7.11 (s,1H). 5.53 – 5.46 (m, 1H), 5.04 – 4.97 (m, 1H), 4.61 – 4.50 (m, 2H), 4.33 –4.23 (m, 2H), 4.21 – 4.10 (m, 2H), 3.74 – 3.63 (m, 5H), 3.61 – 3.51 (m, 2H),3.25 – 3.16 (m, 8H), 3.11 – 3.04 (m, 1H), 2.91 – 2.85 (m, 1H), 2.73 – 2.64(m, 1H), 2.42 – 2.38 (m, 1H), 2.08 – 2.01 (m, 1H), 1.78 – 1.64 (m, 2H), 1.52– 1.40 (m, 1H), 1.29 (d, J= 6.0 Hz, 3H), 1.14 – 1.01 (m, 3H), 1.05 – 0.99 (m, 6H), 0.89 (s, 3H), 0.34 (s, 3H). LC-MS(M+H) + = 826.7 Examples of trans-reactive isomers -18 and 18: (1R,2R,3S)-N-[(7S,13S,19P)-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19 ,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-{6-bromo-2-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridine-3-} [6.3.1.0]-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl]-2,2-dimethylpropyl Acetate The title compound (400 mg, 64%) was prepared in a manner similar to that in step 1 of Example 16, by 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Prepared from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and 1-cyclopropylpiperazine. LC-MS (M+H) + = 625.3 / 627.3.

[0211] Step 2: 3-{2-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-6- (4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Carbon-12, 4(12),5,7-tetraen-3-yl}-2,2-dimethylpropyl acetate The title compound (170 mg, 79%) was prepared in a manner similar to step 2 of Example 16, from 3-{6-bromo-2-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of [amount] of dodeca-2,4(12),5,7-tetraen-3-yl]-2,2-dimethylpropyl acetate and BPD. LC-MS (M+H) + = 673.5.

[0212] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-[5-(4-cyclopropyl] [(1S)-1-methoxyethyl]pyridin-3-yl]-9-oxa-1-azatricyclic [6.3.1.0] 4,12 ]ten Dicarbon-2,4(12),5,7-tetraen-6-yl}-1,3-thiazo-2-yl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1, 2-Diazinane-3-carboxylic acid methyl ester The title compound (180 mg, 76%) was prepared in a manner similar to that in step 3 of Example 16, by 3-{2-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 943.7.

[0213] Step 4: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(4-{2-[5-(4-cyclopropylpiperazine- 1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-aza Three Rings [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl)propionyl]-1,2-diazine Alkyl-3-carboxylic acid The title compound (130 mg, 77%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-9-oxa-1-azatricyclo[6.3.1.0] 4,12Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 887.5.

[0214] Step 5: N-[(7S,13S)-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridine [Pyridine-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]amino] tert-butyl formate The title compound (70 mg, 55%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(4-{2-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of 1,2-diazinane-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl)propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + =869.5.

[0215] Step 6: (7S,13S)-7-amino-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl] [pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2, 5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (60 mg, 97%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + =769.5.

[0216] Step 7: (1R,2R,3S)−N−[(7S,13S,19P)−20−[5−(4−cyclopropylpiperazine−1−yl)−2−[(1S)−1− [Methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30, 31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26- [Hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-[5-(4-cyclopropane-1-formamide)] Propylpiperazine-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15, 24-Dioxa-4-thia-9,21,30,31-tetraazahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 31-carbon-1 (28),2,5(31),19,25(29),26-[hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide Transtransisomer-18 (P-isomer, 4.4 mg, 6%) and Example 18 (M-isomer, 14.6 mg, 22%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-[5-(4-cyclopropylpiperazin-1-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0217] Transisomer-18: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.41 – 8.35 (m, 2H), 8.12(s, 1H), 7.71 (s, 1H), 7.34 (d, J = 2.9 Hz, 1H), 7.11 (s, 1H), 5.55 – 5.47 (m,1H), 5.02 – 4.95 (m, 1H), 4.53 – 4.95 (m, 1H), 4.42 – 4.34 (m, 1H), 4.20 –4.12 (m, 2H), 4.03 – 3.94 (m, 2H), 3.66 – 3.60 (m, 2H), 3.54 – 3.47 (m, 2H), 3.21 – 3.13 (m, 6H), 3.06 (s, 3H), 2.98 – 2.94 (m, 1H), 2.73 – 2.69 (m, 1H),2.65 – 2.60 (m, 3H), 2.37 – 2.33 (m, 2H), 2.12 – 2.06 (m, 1H), 1.78 – 1.71(m, 2H), 1.63 – 1.58 (m, 1H), 1.50 – 1.44 (m, 1H), 1.17 – 1.09 (m, 6H), 1.05– 0.99 (m, 6H), 0.89 (s, 3H), 0.47 (s, 3H), 0.41 – 0.36 (m, 2H), 0.31 – 0.27 (m, 2H). LC-MS(M+H) + = 865.7.

[0218] Example 18: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.40 – 8.34 (m, 2H), 8.07 (s,1H), 7.71 (s, 1H), 7.12 (d, J = 2.9 Hz, 1H), 7.11 (s, 1H), 5.53 – 5.46 (m, 1H), 5.03 – 4.97 (m, 1H), 4.59 – 4.50 (m, 2H), 4.30 – 4.23 (m, 2H), 4.20 – 4.11(m, 2H), 3.72 – 3.62 (m, 1H), 3.59 – 3.50 (m, 2H), 3.23 – 3.17 (m, 8H), 3.10 – 3.04 (m, 1H), 2.92 – 2.85 (m, 1H), 2.72 – 2.60 (m, 5H), 2.42 – 2.35 (m,1H), 2.08 – 2.00 (m, 1H), 1.78 – 1.69 (m, 2H), 1.64 – 1.57 (m, 1H), 1.51 –1.42 (m, 1H), 1.28 (d, J = 6.1 Hz, 3H), 1.15 – 1.01 (m, 3H), 1.05 – 0.98 (m, 6H), 0.88 (s, 3H), 0.42 – 0.36 (m, 2H), 0.33 (s, 3H), 0.31 – 0.26 (m, 2H). LC-MS(M+H) + = 865.7.

[0219] Examples of trans-reactive isomers -19 and 19: (1R,2R,3S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(oxan-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26[[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(oxan-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 4-Methyl-N'-(oxane-4-yl)benzene-1-sulfonylhydrazine A mixture of oxane-4-one (300 mg, 3 mmol) and 4-methylbenzene-1-sulfonylhydrazine (558 mg, 3 mmol) in anhydrous MeOH (9 mL) was stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure to give the title compound (800 mg, 99%). LC-MS (M+H) + = 269.0.

[0220] Step 2: (5-{3-[3-(acetoxy)-2,2-dimethylpropyl]-6-bromo-9-oxa-1-azatricyclic] [6.3.1.0 4,12 [1S-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic[6.3.1.0] 4,12A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (6.0 g, 12.0 mmol) and BPD (9.2 g, 72 mmol) in THF (80 mL) was supplemented with dtbpy (643 mg, 2.4 mmol) and chloro(1,5-cyclooctadiene)iridium(I) dimer (794 mg, 1.2 mmol). The mixture was stirred overnight at 75 °C under nitrogen and then cooled to room temperature. The mixture was diluted with EA (200 mL) and washed with water (50 mL) and brine (50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography (MeCN: 0.5% FA aqueous solution, 0:100 to 55:45) to give the title compound (4.8 g, 73%). LC-MS (M+H) + =545.1 / 547.1.

[0221] Step 3: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(oxane-4-yl)pyridin-3-yl}-9-oxy Hetero-1-azatricyclic [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (5‐{3‐[3‐(acetoxy)‐2,2‐dimethylpropyl]‐6‐bromo‐9‐oxa‐1‐azatricyclo[6.3.1.0] 4 ,12 A mixture of dodeca-2,4(12),5,7-tetraen-2-yl}-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid (272 mg, 0.5 mmol) and 4-methyl-N'-(oxane-4-ylidene)benzene-1-sulfonylhydrazine (402 mg, 1.5 mmol), Cs₂CO₃ (489 mg, 1.5 mmol) in 1,4-dioxane (10 mL) was stirred overnight at 110 °C under nitrogen. The mixture was cooled to room temperature and diluted with brine (100 mL). The mixture was extracted with EA (50 mL x 3). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (80 mg, 27%). LC-MS (M+H) + = 585.4 / 587.4.

[0222] Step 4: 3-(2-{2-[(1S)-1-methoxyethyl]-5-(oxane-4-yl)pyridin-3-yl}-6-(4,4,5,5- Tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 [Twelve carbon-2,4(12),5, 7-Tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (78 mg, 90%) was prepared in a manner similar to step 2 of Example 16, by 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(oxane-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate. LC-MS (M+H) + = 633.5.

[0223] Step 5: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- 1-Methoxyethyl]-5-(oxane-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Carbon-2,4-12 (12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine Methyl alkyl-3-carboxylate The title compound (67 mg, 60%) was prepared in a manner similar to step 3 of Example 16, by 3-(2-{2-[(1S)-1-methoxyethyl]-5-(oxan-4-yl)pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 903.7.

[0224] Step 6: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (2-[(1S)-1-methoxyethyl]-5-(oxane-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic) [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazine-3- Formic acid The title compound (55 mg, 98%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(oxane-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + =847.6.

[0225] Step 7: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(oxane-4-yl)pyridin-3-yl}- 17,17-Dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1] 2 ,5 .1 9,13 .0 19,27 .0 21,26 [Trin-1(28),2,5(31),19,25(29),26-hexen-7-yl]tert-butyl carbamate The title compound (36 mg, 66%) was prepared in a manner similar to that in step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(oxan-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + = 829.7.

[0226] Step 8: (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(oxane-4-yl)pyridine-3- [23.3.1.1]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane 2,5 .1 9, 13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (30 mg, 95%) was prepared in a manner similar to step 6 of Example 16, from N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(oxan-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 729.5.

[0227] Step 9: (1R,2R,3S)−N−[(7S,13S,19P)−20−{2−[(1S)−1−methoxyethyl]−5−(oxane-4− pyridin-3-yl-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraaza Sixth Ring Road [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-7- [2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxy] [[ ...][[[[[[[[[[][[[[[[[[][[[[[[[][[[[[[[[][[[[[][[[[[[[[][[[][[[[[[[][[[ 9,21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29), [2,6-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide Transisomer-19 (P-isomer, 2.7 mg, 8%) and Example 19 (M-isomer, 9 mg, 27%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(oxan-4-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .19,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0228] Transisomer-19: 1 H NMR (400 MHz, DMSO- d 6) δ = 8.60 (d, J = 1.8 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 7.85 – 7.64 (m, 2H), 7.12 (s, 1H), 5.51(t, J = 9.0 Hz, 1H), 4.98 (d, J = 12.0 Hz, 1H), 4.59 – 4.35 (m, 2H), 4.12 (dt, J = 12.8 Hz, 9.3 Hz, 3H), 4.04 – 3.87 (m, 3H), 3.63 (d, J = 10.4 Hz, 2H), 3.52 –3.34 (m, 3H), 3.19 – 3.24 (m, 1H), 3.15 – 3.05 (m, 4H), 2.93 – 3.02 (m,1 H),2.91 – 2.67 (m, 2H), 2.30 (d, J = 14.4 Hz, 1H), 2.08 (d, J = 9.8 Hz, 1H), 1.81–1.62 (m, 6H), 1.53 – 1.40 (m, 1H), 1.16 – 0.95 (m, 12H), 0.88 (s, 3H), 0.41 (s, 3H). LC-MS(M+H) + = 825.7.

[0229] Example 19: 1 H NMR (400 MHz, DMSO- d 6) δ = 8.61 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.58 (d, J =2.2 Hz, 1H), 7.12(s, 1H), 5.51 (t, J = 9.2 Hz, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.58 (s, 2H), 4.38(q, J = 6.0 Hz, 1H), 4.30 – 4.12 (m, 3H), 3.99 – 3.85 (m, 2H), 3.75 – 3.64 (m,1H), 3.58 – 3.35 (m, 4H), 3.25 – 3.21 (m, 4H), 3.12 – 3.03 (m, 1H), 2.95 – 2.67 (m, 3H), 2.40 – 2.36 (m, 1H), 2.08 – 2.01 (m, 1H), 1.79 – 1.63 (m, 6H), 1.54 – 1.41 (m, 1H), 1.31 (d, J = 6.0 Hz, 3H), 1.19 – 0.95 (m, 9H), 0.86 (s,3H), 0.29 (s,3H). LC-MS(M+H) + = 825.7.

[0230] Examples of trans-reactive isomers -20 and 20: (1R,2R,3S)-N-[(7S,13S,19P)-20-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19 ,27 .0 21,26[[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: N'-(1-cyclopropylpiperazine-4-ylidene)-4-methylbenzene-1-sulfonylhydrazine The title compound (1.2 g, 98%) was prepared in a similar manner to step 1 of Example 19, from 1-cyclopropylpiperidin-4-one and 4-methylbenzene-1-sulfonylhydrazine. LC-MS (M+H) + = 308.2.

[0231] Step 2: 3-{6-bromo-2-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridine-3-} [6.3.1.0]-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl]-2,2-dimethylpropyl Acetate The title compound (120 mg, 38%) was prepared in a manner similar to step 3 of Example 18, by (5-{3-[3-(acetoxy)-2,2-dimethylpropyl]-6-bromo-9-oxa-1-azatricyclic [6.3.1.0]). 4,12 Prepared from dodecacarbon-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid and N'-(1-cyclopropylpiperidin-4-ylidene)-4-methylbenzene-1-sulfonylhydrazine. LC-MS (M+H) + = 624.4 / 626.4.

[0232] Step 3: 3-{2-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-6- (4,4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Carbon-12, 4(12),5,7-tetraen-3-yl}-2,2-dimethylpropyl acetate The title compound (58 mg, 45%) was prepared in a manner similar to step 2 of Example 16, from 3-{6-bromo-2-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Preparation of [amount] of dodeca-2,4(12),5,7-tetraen-3-yl]-2,2-dimethylpropyl acetate and BPD. LC-MS (M+H) + =672.7.

[0233] Step 4: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-[5-(1-cyclopropyl] [(1S)-1-methoxyethyl]pyridin-3-yl]-9-oxa-1-azatricyclic [6.3.1.0] 4,12 ]ten Dicarbon-2,4(12),5,7-tetraen-6-yl}-1,3-thiazo-2-yl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1, 2-Diazinane-3-carboxylic acid methyl ester The title compound (40 mg, 49%) was prepared in a manner similar to step 3 of Example 16, from 3-{2-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 942.7.

[0234] Step 5: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(4-{2-[5-(1-cyclopropylpiperazine- 4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-aza Three Rings [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl)propionyl]-1,2-diazine Alkyl-3-carboxylic acid The title compound (30 mg, 80%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 886.7.

[0235] Step 6: N-[(7S,13S)-20-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridine [Pyridine-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]amino] tert-butyl formate The title compound (20 mg, 68%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-(4-{2-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12Preparation of 1,2-diazinane-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl)propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + =868.7.

[0236] Step 7: (7S,13S)-7-amino-20-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl] [pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2, 5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (15 mg, 85%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + =768.6.

[0237] Step 8: (1R,2R,3S)−N−[(7S,13S,19P)−20−[5−(1−cyclopropylpiperazine−4−yl)−2−[(1S)−1− [Methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30, 31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26- [Hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-[5-(1-cyclopropane-1-formamide)] Propylpiperazine-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15, 24-Dioxa-4-thia-9,21,30,31-tetraazahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 31-carbon-1 (28),2,5(31),19,25(29),26-[hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide Transtransisomer-20 (P-isomer, 2.2 mg, 13%) and Example 20 (M-isomer, 4.5 mg, 27%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-[5-(1-cyclopropylpiperazin-4-yl)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0238] Transisomer-20: 1 H NMR (400 MHz, DMSO- d6) δ = 8.58 (d, J = 2.0 Hz, 1H),8.36 (d, J = 8.8 Hz, 1H), 8.11 (s, 1H), 7.80 – 7.62 (m, 2H), 7.13 (s, 1H), 5.50(t, J = 9.0 Hz, 1H), 5.28 (t, J = 4.8, 1H), 4.98 (d, J = 12.2 Hz, 1H), 4.52 – 4.34(m, 2H), 4.22 – 4.05 (m, 3H), 4.02 – (s, 1H), 3.67 – 3.44 (m, 5H), 3.09 (s,3H), 2.98 (d, J = 6.9 Hz, 3H), 2.72 – 2.65 (m, 1H), 2.34 – 2.18 (m, 2H), 2.09(s, 1H), 2.00 – 1.91 (m, 3H), 1.76 – 1.66 (m, 3H), 1.63 – 1.53 (m, 3H), 1.12– 0.94 (m, 12H), 0.80 (t, J = 6.7 Hz, 3H), 0.46 – 0.21 (m, 7H). LC-MS (M+H) + =864.8.

[0239] Example 20: 1 H NMR (400 MHz, DMSO- d 6) δ = 8.59 (d, J = 2.0 Hz, 1H), 8.35(d, J = 8.8 Hz, 1H), 8.08 (s, 1H), 7.72 (s, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.12(s, 1H), 5.51 (t, J = 9.0, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.57 (s, 2H), 4.46 –4.35 (m, 1H), 4.29 – 4.08 (m, 3H), 3.72 – 3.50 (m, 6H), 3.10 – 2.95 (m, 5H),2.88 (d, J =14.2 Hz, 1H), 2.73 – 2.62 (m, 3H), 2.17 – 2.18 (m, 2 H) 2.04 (d, J = 9.8 Hz, 1H), 1.78 – 1.72 (m, 3H), 1.58 – 1.42 (m, 4H), 1.30 (d, J = 6.0 Hz, 3H), 1.13 – 0.97 (m, 9H), 0.83 (s, 3H), 0.41 – 0.19 (m, 7H). LC-MS(M+H) + =864.8.

[0240] Example 21: (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-{4-[(morpholin-4-yl)methyl]phenyl}pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] Step 1: 4-[(4-iodophenyl)methyl]morpholine K₂CO₃ (1242 mg, 6 mmol) was added to a mixture of 1-(bromomethyl)-4-iodobenzene (891 mg, 3 mmol) and morpholine (261 mg, 3 mmol) in MeCN (9 mL). The mixture was stirred at room temperature for 1 h. The mixture was then diluted with brine (30 mL) and extracted with DCM (50 mL x 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (900 mg, 99%). LC-MS (M+H) + = 304.1.

[0241] Step 2: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(morpholino-4-yl)methyl]phenyl}pyridine pyridyl-3-yl-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethyl] propyl acetate (5‐{3‐[3‐(acetoxy)‐2,2‐dimethylpropyl]‐6‐bromo‐9‐oxa‐1‐azatricyclo[6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-2-yl}-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid (327 mg, 0.6 mmol), 4-[(4-iodophenyl)methyl]morpholine (364 mg, 1.2 mmol), Pd(dppf)Cl2 . A mixture of CH₂Cl₂ (48 mg, 0.02 mmol) and K₃PO₄ (381 mg, 1.8 mmol) in dioxane (8 mL) and water (2 mL) was stirred at 70 °C for 3 h under nitrogen. The mixture was cooled to room temperature, diluted with brine (50 mL), and then extracted by DCM (50 mL × 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (228 mg, 56%). LC-MS (M+H) + = 676.3 / 678.4.

[0242] Step 3: {2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(3S)-3-(methoxycarbonyl)-1,2-di] [[1-yl]-3-oxopropyl]-1,3-thiazolyl-4-yl]boronic acid Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl-2-yl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (2.87 g, 6 mmol), BPD (3.81 g, 15 mmol), KOAc (1.76 g, 18 mmol) and Pd(dppf)Cl2 were added. . A mixture of CH₂Cl₂ (490 mg, 0.6 mmol) in dioxane (50 mL) was stirred in a sealed tube at 130 °C under nitrogen for 10 h. The mixture was cooled to room temperature, diluted with brine (100 mL), and extracted with EtOAc (100 mL x 2). The organic layer was washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by reversed-phase rapid chromatography (MeCN: 0.5% FA aqueous solution, 0:100 to 30:70) to give the title compound (2.1 g, 79%). LC-MS (M+H) + = 443.3.

[0243] Step 4: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- 1-Methoxyethyl]-5-{4-[(morpholino-4-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(morpholino-4-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 A mixture of 2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (228 mg, 0.34 mmol), {2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(3S)-3-(methoxycarbonyl)-1,2-diazinyl]-3-oxopropyl]-1,3-thiazolyl-4-yl}boronic acid (301 mg, 0.68 mmol), K3PO4 (215 mg, 1.02 mmol), and Pd(dtpf)Cl2 (22 mg, 0.034 mmol) in dioxane (8 mL) and water (1 mL) was stirred at 70 °C for 3 h under nitrogen. The mixture was cooled to room temperature, diluted with brine (50 mL), and extracted with DCM (50 mL x 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography to give the title compound (302 mg, 90%). LC-MS (M+H) + = 994.8.

[0244] Step 5: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (1S)-1-methoxyethyl]-5-{4-[(morpholino-4-yl)methyl]phenyl}pyridin-3-yl}-9-oxy Hetero-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]- 1,2-Diazinane-3-carboxylic acid To (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(morpholino-4-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Methyl methyl dodecanoyl-2,4(12),5,7-tetraen-6-yl)-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazinane-3-carboxylate (302 mg, 0.3 mmol) was added to a mixture of THF (10 mL) and water (10 mL) with LiOH. .H₂O (63 mg, 1.5 mmol). The mixture was stirred at room temperature for 8 h. The mixture was then diluted with water (30 mL). The mixture was acidified to pH approximately 5 with hydrochloric acid (1 N). The mixture was extracted with EtOAc (50 mL x 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated under vacuum to give the title compound (241 mg, 85%). LC-MS (M+H) + = 938.7.

[0245] Step 6: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-{4-[(morpholin-4-yl)methyl]benzene pyridin-3-yl-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraaza Sixth Ring Road [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl] tert-butyl carbamate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(morpholino-4-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [241 mg, 0.26 mmol]-1,3-thiazolyl-2-yl propionyl]-1,2-diazinane-3-carboxylic acid (241 mg, 0.26 mmol) was added to a solution in anhydrous DCM (40 mL) with DIEA (671 mg, 5.2 mmol), followed by HOBt (351 mg, 2.6 mmol) and EDCI (749 mg, 3.9 mmol). The mixture was stirred at room temperature for 16 h. The mixture was then diluted with brine (50 mL) and extracted with DCM (50 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (93 mg, 39%). LC-MS (M+H) + = 920.7.

[0246] Step 7: (1R,2R,3S)−N−[(7S,13S,19M)−20−{2−[(1S)−1−methoxyethyl]−5−{4−[(methoxyethyl] [Lin-4-yl]methyl]phenyl}pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9 21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29), [2,6-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-{4-[(morpholin-4-yl)methyl]phenyl}pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .19,13 .0 19,27 .0 21,26 A mixture of tert-butyl carbamate (93 mg, 0.10 mmol) in 4 N HCl / 1,4-dioxane (3 mL) was stirred for 0.5 h. The mixture was then concentrated under vacuum. The residue was dissolved in DMF (3 mL), followed by the addition of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (23 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol), and DIEA (129 mg, 1.0 mmol). The mixture was stirred at room temperature for 1 h. The mixture was diluted with brine (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give Example 21 (42 mg, 46%). 1 H NMR (400 MHz, DMSO- d 6) δ = 9.02 (s, 1H), 8.36 (d, J = 8.8Hz, 1H), 8.11 (s, 1H), 7.97 (s, 1H), 7.78 – 7.67 (m, 3H), 7.40 (d, J = 8.0 Hz,2H), 7.14 (s, 1H), 5.51 (t, J = 9.2 Hz, 1H), 5.01 (d, J = 12.2 Hz, 1H), 4.65 –4.42 (m, 3H), 4.32 – 4.09 (m, 3H), 3.80 – 3.40 (m, 9H), 3.25 (s, 3H), 3.11 –3.03 (m, 1H), 2.92 (d, J = 14.2 Hz, 1H), 2.74 – 2.65 (m, 1H), 2.38 – 2.27(m,5H), 2.04 (d, J = 10.0 Hz, 1H), 1.73 (s, 2H), 1.50 – 1.32 (m, 4H), 1.17 – 0.95 (m, 9H), 0.87 (s, 3H), 0.37 (s, 3H). LC-MS(M+H) + = 916.8.

[0247] Examples of trans-reactive isomers -22 and 22: (1R,2R,3S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionic acid TsOH was added to a mixture of 6-bromo-1,2,3,4-tetrahydroquinoline-1-amine (2.62 g, 11.7 mmol) and 5-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-2,2-dimethyl-5-oxovaleric acid (3.1 g, 11.1 mmol) in toluene (150 mL) at room temperature. . H₂O (4.2 g, 22.2 mmol). The mixture was stirred at 100 °C for 16 h under a nitrogen atmosphere, then cooled to room temperature. The mixture was concentrated under vacuum. The residue was diluted with EA (200 mL) and washed with water (80 mL) and brine (80 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was used directly in the next step without further purification. LC-MS (M+H) + = 471.1 / 473.1.

[0248] Step 2: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4 ,12 Ethyl dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4,12 Crude (11.1 mmol) of 2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionic acid (crude, 11.1 mmol) was added to a solution of Cs₂CO₃ (5.38 g, 16.5 mmol) in DMF (50 mL), followed by dropwise addition of EtI (2.57 g, 16.5 mmol) at 0 °C under a nitrogen atmosphere. The mixture was stirred at room temperature for 2 h, diluted with EA (200 mL), and washed with brine (2 x 80 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 1:4) to give the title compound (5.1 g, 92% by two steps). LC-MS (M+H) + = 499.3 / 501.3.

[0249] Step 3: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4 ,12 [Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylprop-1-ol] Under a nitrogen atmosphere at 0°C, 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclo[6.3.1.0] was subjected to oxidation. 4,12 Ethyl dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropionate (5.1 g, 10.2 mmol) was added fractionally to a solution of LiBH4 (536 mg, 25.5 mmol) in THF (80 mL). The mixture was heated to 60 °C and stirred for 16 h. The mixture was then cooled to room temperature and quenched with a pre-cooled (0 °C) aqueous solution of NH4Cl (100 mL). The mixture was extracted with EA (2 x 150 mL). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was used directly in the next step without further purification. LC-MS (M+H) + =457.3 / 459.3.

[0250] Step 4: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate Under nitrogen atmosphere at 0°C, 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4,12DMAP (124 mg, 1.02 mmol) and Ac2O (1.25 g, 12.2 mmol) were added in portions to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylprop-1-ol (crude, 10.2 mmol) and Et3N (2.06 g, 20.4 mmol) in DCM (70 mL). The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was diluted with DCM (60 mL) and washed with hydrochloric acid (1 N, 40 mL), saturated NaHCO3 (60 mL), and brine (60 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE:EA = 1:4) to give the title compound (4.1 g, 80% by two steps). LC-MS (M+H) + = 499.3 / 501.3.

[0251] Step 5: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboron) pentane-2-yl)pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4,12 A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (2.3 g, 4.6 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborane (3.55 g, 27.8 mmol) in THF (35 mL) was supplemented with dtbpy (247 mg, 0.92 mmol) and di-μ-methoxybis(1,5-cyclooctadiene)diiridium(I) (305 mg, 0.46 mmol). The mixture was stirred in a sealed tube at 80 °C under a nitrogen atmosphere for 16 h, and then cooled to room temperature. The mixture was poured into ice water (200 mL) with stirring. The mixture was then extracted with EA (200 mL), washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was ground in MeOH (20 mL), and the solid was collected to give the title compound (1.7 g, 59%). LC-MS (M+H) + = 625.3 / 627.3.

[0252] Step 6: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}- 1-Azatricyclic [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12 A mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (1 g, 1.6 mmol) and 1-methylpiperazine (802 mg, 8 mmol) in MeCN (30 mL) was supplemented with TEA (485 mg, 4.8 mmol) and Cu(OAc)₂ (582 mg, 3.2 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The mixture was then diluted with EA (100 mL) and water (100 mL). The solids were filtered off and the filter cake was washed with EA (2 x 30 mL). The organic phase was separated and washed with water (50 mL) and brine (60 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give the title compound (465 mg, 49%). LC-MS (M+H) + = 597.3 / 599.3.

[0253] Step 7: 3-(2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-6-(4, 4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-azatricyclic [6.3.1.0] 4,12 [Twelve carbon-2,4(12),5,7-] Tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12 Pd(dppf)Cl2 was added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (465 mg, 0.78 mmol) and BPD (495 mg, 1.95 mmol) in toluene (10 mL). . DCM (64 mg, 0.078 mmol) and KOAc (229 mg, 2.34 mmol). The mixture was stirred at 90 °C for 4 h under nitrogen. The mixture was cooled to room temperature, diluted with EA (40 mL), and washed with brine (20 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 15:1) to give the title compound (430 mg, 86%). LC-MS (M+H) + = 645.5.

[0254] Step 8: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- 1-Methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12 Carbon-2,4-12 (12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine Methyl alkyl-3-carboxylate To 3-(2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-azatricyclic [6.3.1.0] 4,12 [A mixture of methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (320 mg, 0.67 mmol) was prepared in a mixture of toluene (9 mL), dioxane (3 mL), and water (5 mL) with K3PO4 (424 mg, 2.01 mmol) and Pd(dtbpf)Cl2 (44 mg, 0.067 mmol). The solution was stirred at 70 °C for 3 h under nitrogen and then cooled to room temperature. The mixture was diluted with EA (50 mL) and washed with water (20 mL) and brine (20 mL).] The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (330 mg, 54%). LC-MS (M+H) + = 915.5.

[0255] Step 9: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (1S)-1-methoxyethyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazine-3- Formic acid To (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12Methyl methyl dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (330 mg, 0.36 mmol) was added to a solution of THF (4 mL) and water (4 mL) with LiOH (87 mg, 3.6 mmol). The resulting mixture was stirred at room temperature for 3 h. The mixture was diluted with water (30 mL) and EA (10 mL). The aqueous phase was acidified to pH about 5 with 1 N hydrochloric acid at 0 °C. The mixture was extracted with EA (3 x 40 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (180 mg, 58%). LC-MS (M+H) + = 859.5.

[0256] Step 10: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridine- 3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2 ,5 .1 9,13 .0 19,27 .0 21,26 [Trin-1(28),2,5(31),19,25(29),26-hexen-7-yl]tert-butyl carbamate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12 [180 mg, 0.21 mmol]-1,3-thiazolyl-2-yl]-1,2-diazinane-3-carboxylic acid was added to a solution in DCM (40 mL) with DIEA (1.08 g, 8.4 mmol), EDCI (1.21 g, 6.3 mmol), and HOBt (424 mg, 3.14 mmol). The mixture was stirred at room temperature for 20 h and then washed with 1 N hydrochloric acid (20 mL), water (20 mL), and brine (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (140 mg, 80%). LC-MS (M+H) + = 841.5.

[0257] Step 11: (1R,2R,3S)−N−[(7S,13S,19P)−20−{2−[(1S)−1−methoxyethyl]−5−(4−methyl) Piperazine-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazine Hexacyclic rings [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-7- [2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxy] [[ ...][[[[[[[[[[[][[[[[[[[][[[[[[[[][[[[[[[][[[[[[[][[[[[][[[[[[][[[[[[ Hetero-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19, 25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide The N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2, 5 .1 9,13 .0 19,27 .0 21,26 A mixture of tert-butyl carbamate (140 mg, 0.17 mmol) in HCl / dioxane (4 M, 3 mL) was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was diluted with DCM (20 mL), washed with saturated NaHCO3 (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the residue (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2, 5 .1 9,13 .0 19,27 .0 21,26 [The residues were obtained as 1(28), 2,5(31), 19, 25(29), 26-hexene-8,14-dione, and were used without further purification. LC-MS (M+H)] + = 741.5.

[0258] To (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(4-methylpiperazin-1-yl)pyridin-3-yl}-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19, 27 .0 21,26A solution of 1,2,5,19,25,29,26-hexene-e-8,14-dione (120 mg, 0.16 mmol) in DMF (4 mL) was supplemented with DIEA (1.1 g, 8.5 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (39 mg, 0.34 mmol), and HATU (129 mg, 0.34 mmol). The mixture was stirred at room temperature for 2 h, then diluted with EA (40 mL) and washed with brine (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give a pair of trans-restricted isomers. The transisomers were further separated by preparative HPLC to obtain transisomer-22 (P-isomer, 9.3 mg, 7%) and Example 22 (M-isomer, 16 mg, 12%).

[0259] Transisomer-22: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.40 – 8.35 (m, 2H) , 8.31(s, 1H), 7.67 (s, 1H), 7.38 (s, 1H), 7.31 (d, J = 2.9 Hz, 1H), 5.54 – 5.47 (m,1H), 5.01 – 4.96 (m, 1H), 4.20 – 4.13 (m, 2H), 3.91 – 3.82 (m, 2H), 3.67 –3.62 (m, 1H), 3.55 – 3.51 (m, 2H), 3.45 – 3.42 (m, 1H), 3.22 – 3.13 (m, 7H), 3.03 (s, 3H), 2.99 – 2.96 (m, 1H), 2.95 – 2.90 (m, 3H), 2.74 – 2.68 (m, 1H),2.41 – 2.38 (m, 4H), 2.32 – 2.28 (m, 1H), 2.11– 2.05 (m, 1H), 1.99 – 1.91 (m,1H), 1.78 – 1.71 (m, 2H), 1.51 – 1.43 (m, 1H), 1.14 – 1.07 (m, 6H), 1.05 –1.01 (m, 7H), 0.89 (s, 3H), 0.50 (s, 3H). LC-MS(M+H) += 837.5.

[0260] Example 22: 1 H NMR 1 H NMR (400 MHz, DMSO- d6 ) δ 8.39 (d, J = 2.9 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.27 (s, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 7.09 (d, J =2.9 Hz, 1H), 5.52 (t, J = 9.0 Hz, 1H), 5.01 (d, J = 12.1 Hz, 1H), 4.48 – 4.04 (m,4H), 3.60 – 3.52 (m, 2H), 3.50 – 3.42 (m, 2H), 3.24 – 3.15 (m, 7H), 3.08 (dd, J = 14.7, 9.2 Hz, 1H), 3.02 – 2.93 (m, 1H), 2.89 – 2.81 (m, 2H), 2.73 – 2.65(m, 1H), 2.42 – 2.36 (m, 5H), 2.25 – 1.98 (m, 6H), 1.83 – 1.62 (m, 2H), 1.57 – 1.39 (m, 1H), 1.28 (d, J = 6.1 Hz, 3H), 1.18 – 0.98 (m, 9H), 0.86 (s, 3H), 0.35 (s, 3H). LC-MS(M+H) + = 837.5.

[0261] Examples of trans-reactive isomers -23 and 23: (1R,2R,3S)-N-[(7S,13S,19P)-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26[[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl [6.3.1.0]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate To 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 A mixture of (2R,6S)-2,6-dimethylpropyl acetate (450 mg, 0.72 mmol) and (2R,6S)-2,6-dimethylmorpholine (413 mg, 3.59 mmol) in MeCN (15 mL) was supplemented with TEA (218 mg, 2.16 mmol) and Cu(OAc)₂ (262 mg, 1.44 mmol). The resulting mixture was stirred at room temperature under an oxygen atmosphere for 4 h. The mixture was diluted with EA (50 mL) and water (50 mL). The solids were filtered off and the filter cake was washed with EA (2 x 50 mL). The organic phase was separated, washed with water (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (270 mg, 61%). LC-MS (M+H) + = 614.3 / 616.3.

[0262] Step 2: 3-(2-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridine pyridyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate To 3-(6-bromo-2-{5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 Pd(dppf)Cl2 was added to a mixture of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (270 mg, 0.44 mmol) and BPD (224 mg, 0.88 mmol) in dioxane (8 mL). . DCM (36 mg, 0.044 mmol) and KOAc (129 mg, 1.32 mmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 12 hours. The mixture was cooled to room temperature, diluted with EA (50 mL), and washed with brine (40 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 15:1) to give the title compound (160 mg, 55%). LC-MS (M+H) + = 662.5.

[0263] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2R, [6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate To 3-(2-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12K3PO4 (153 mg, 0.72 mmol) and Pd(dtbpf)Cl2 (16 mg, 0.024 mmol) were added to a mixture of dioxane (5 mL) and water (0.5 mL). The solution was stirred at 70 °C for 3 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with EA (40 mL), washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give the title compound (110 mg, 49%). LC-MS (M+H) + = 932.5.

[0264] Step 4: (3S)−1−[(2S)−2−{[(tert-butoxy)carbonyl]amino}−3−[4−(2−{5−[(2R,6S)−2,6− [dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9- Oxa-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl 1,2-diazinyl-3-carboxylic acid To (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Methyl methyl dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (110 mg, 0.12 mmol) was added to a solution of THF (2.5 mL) and water (2.5 mL) with LiOH (28 mg, 1.18 mmol). The resulting mixture was stirred at room temperature for 3 h. The mixture was then diluted with water (30 mL) and washed with EA (10 mL). The aqueous phase was acidified to pH about 5 with 1 N hydrochloric acid at 0 °C. The resulting solution was extracted with EA (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (70 mg, 67%). LC-MS (M+H) + = 876.5.

[0265] Step 5: N-[(7S,13S)-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxy [[ ...][[[[[[[[[[[][[[[[[[[[][[[[[[[[[][[[[[[[[][[[[[[][[[[[[[][[[[][[[[[[][[[ Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl] tert-butyl carbamate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(2-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid (70 mg, 0.08 mmol) was added to a solution in DCM (20 mL) with DIEA (413 mg, 3.2 mmol), EDCI (461 mg, 2.4 mmol), and HOBt (162 mg, 1.2 mmol). The mixture was stirred at room temperature for 20 h and then washed with 1 N hydrochloric acid (10 mL), water (10 mL), and brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1) to give the title compound (25 mg, 36%). LC-MS (M+H) + = 858.5.

[0266] Step 6: 7S,13S)-7-amino-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methyl [Oxyethyl]pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The N-[(7S,13S)-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26A mixture of tert-butyl carbamate (25 mg, 0.029 mmol) in HCl / dioxane (4 M, 3 mL) was stirred at room temperature for 1 h and then concentrated under vacuum. The residue was diluted with DCM (10 mL), washed with saturated NaHCO3 (5 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (20 mg, 91%). LC-MS (M+H) + = 758.5.

[0267] Step 7: (1R,2R,3S)−N−[(7S,13S,19P)−20−{5−[(2R,6S)−2,6−dimethylmorpholin−4−]− 2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29), 26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20- {5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl 8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-methyl] amide To (7S,13S)-7-amino-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 A solution of 20 mg (0.026 mmol) of 31-C-1(28),2,5(31),19,25(29),26-hexene-8,14-dione in DMF (2 mL) was mixed with DIEA (187 mg, 1.45 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (7 mg, 0.061 mmol), and HATU (22 mg, 0.058 mmol). The mixture was stirred at room temperature for 1 h, then diluted with EA (15 mL) and washed with brine (10 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give a pair of trans-restricted isomers. The transisomers were further separated by preparative HPLC to obtain transisomer-23 (P-isomer, 3.03 mg, 14%) and Example 23 (M-isomer, 9.2 mg, 41%).

[0268] Transisomer-23: 1 H NMR (400 MHz, DMSO- d6) δ 8.42 – 8.33 (m, 2H), 8.12(s, 1H), 7.72 (s, 1H), 7.37 (d, J = 2.9 Hz, 1H), 7.11 (s, 1H), 5.55 – 5.47 (m,1H), 5.02 – 4.96 (m, 1H), 4.54 – 4.46 (m, 1H), 4.42 – 4.34 (m, 1H), 4.21 –4.13 (m, 2H), 4.07 – 3.98 (m, 2H), 3.72 – 3.59 (m, 7H), 3.54 – 3.48 (m, 1H),3.23 – 3.12 (m, 1H), 3.08 (s, 3H), 2.99 – 2.93 (m, 1H), 2.75 – 2.68 (m, 1H),2.40 – 2.26 (m, 3H), 2.26 – 2.19 (m, 1H), 2.11 – 2.04 (m, 1H), 1.79 – 1.72(m, 2H), 1.48 – 1.42 (m, 1H), 1.18 – 1.08 (m, 11H), 1.05 – 1.00 (m, 6H), 0.90(s, 3H), 0.46 (s, 3H). LC-MS (M+H) + = 854.5.

[0269] Example 23: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.39 (d, J = 2.8 Hz, 1H), 8.37 (d, J = 9.7 Hz, 2H), 8.08 (s, 1H), 7.72 (s, 1H), 7.16 (d, J = 2.9 Hz, 1H), 7.11 (s,1H), 5.50 (t, J = 9.1 Hz, 1H), 5.01 (d, J = 12.1 Hz, 1H), 4.74 – 4.46 (m, 2H),4.45 – 3.99 (m, 4H), 3.73 – 3.60 (m, 5H), 3.56 (q, J = 11.0 Hz, 2H), 3.25 (m,1H), 3.18 (s, 3H), 3.08 (dd, J= 14.6, 9.2 Hz, 1H), 2.89 (d, J = 14.2 Hz, 1H),2.80 – 2.64 (m, 1H), 2.41 – 2.35 (m, 1H), 2.33 – 2.23 (m, 2H), 2.09 – 2.01(m, 1H), 1.81 – 1.62 (m, 2H), 1.57 – 1.39 (m, 1H), 1.29 (d, J = 6.1 Hz, 3H), 1.12 – 0.95 (m, 15H), 0.89 (s, 3H), 0.35 (s, 3H). LC-MS(M+H) + = 854.5.

[0270] Examples of trans-reactive isomers -24 and 24: (1R,2R,3S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and (1R,2R,3S)‐N‐[(7S,13S,19M)‐20‐{2‐[(1S)‐1‐methoxyethyl]‐5‐[4‐(2,2,2‐trifluoroethyl)piperazin-1‐yl]pyridin-3‐yl}‐17,17‐dimethyl-8,14‐dioxo-15,24‐dioxa-4‐thia-9,21,30,31‐tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1- [6.3.1.0]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate The title compound (240 mg, 75%) was prepared in a manner similar to that in step 1 of Example 16, by 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Prepared from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and 1-(2,2,2-trifluoroethyl)piperazine. LC-MS (M+H) + = 667.3 / 669.3.

[0271] Step 2: 3-(2-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine-1-yl]pyridine pyridyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (130 mg, 51%) was prepared in a manner similar to step 2 of Example 16, from 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of [amount] from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and BPD. LC-MS (M+H) + = 715.5.

[0272] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- 1-Methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate The title compound (170 mg, 95%) was prepared in a manner similar to step 3 of Example 16, by 3-(2-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 985.5.

[0273] Step 4: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] propyl)-2-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-9-Oxa-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl}propionyl 1,2-diazinyl-3-carboxylic acid The title compound (130 mg, 75%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 929.5.

[0274] Step 5: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazine] Azine-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetra- Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl] tert-butyl carbamate The title compound (60 mg, 51%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl}propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + = 911.5.

[0275] Step 6: (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl) Piperazine-1-yl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (50 mg, 91%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .019 ,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 811.5.

[0276] Step 7: (1R,2R,3S)−N−[(7S,13S,19P)−20−{2−[(1S)−1−methoxyethyl]−5−[4−(2,2, 2-Trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29), 26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20- {2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-17,17-dimethyl 8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-methyl] amide Transtransisomer-24 (P-isomer, 4.3 mg, 8%) and Example 24 (M-isomer, 11 mg, 20%) were prepared in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0277] Transisomer-24: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.42 – 8.33 (m, 2H), 8.12(s, 1H), 7.71 (s, 1H), 7.35 (d, J= 2.9 Hz, 1H), 7.11 (s, 1H), 5.55 – 5.47 (m,1H), 5.02 – 4.95 (m, 1H), 4.53 – 4.49 (m, 1H), 4.42 – 4.34 (m, 1H), 4.21 –4.12 (m, 2H), 4.06 – 3.97 (m, 2H), 3.66 – 3.59 (m, 2H), 3.55 – 3.49 (m, 1H),3.22 – 3.15 (m, 8H), 3.07 (s, 3H), 2.99 – 2.93 (m, 1H), 2.75 – 2.69 (m, 5H),2.39 – 2.35 (m, 1H), 2.12 – 2.03 (m, 1H), 1.79 – 1.70 (m, 2H), 1.52 – 1.43(m, 1H), 1.20 – 1.09 (m, 6H), 1.05 – 1.01 (m, 6H), 0.90 (s, 3H), 0.47 (s,3H). LC-MS (M+H) + = 907.7.

[0278] Example 24: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.41 – 8.34 (m, 2H), 8.08 (s,1H), 7.72 (s, 1H), 7.14 (d, J = 2.9 Hz, 1H), 7.11 (s, 1H), 5.53 – 5.46 (m, 1H),5.03 – 4.97 (m, 1H), 4.60 – 4.49 (m, 1H), 4.31 – 4.24 (m, 2H), 4.21 – 4.12(m, 2H), 3.71 – 3.62 (m, 1H), 3.60 – 3.51 (m, 2H), 3.27 – 3.17 (m, 10H), 3.10– 3.04 (m, 1H), 2.90 – 2.85 (m, 1H), 2.78 – 2.65 (m, 6H), 2.42 – 2.37 (m,1H), 2.09 – 2.02 (m, 1H), 1.79 – 1.67 (m, 2H), 1.52 – 1.41 (m, 1H), 1.28 (d, J= 8.0 Hz, 3H), 1.15 – 1.07 (m, 3H), 1.05 – 0.66 (m, 6H), 0.89 (s, 3H), 0.33 (s, 3H). LC-MS(M+H) + = 907.7.

[0279] Example 25: (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] Step 1: 1-[(4-iodophenyl)methyl]-4-methylpiperazine K₂CO₃ (1242 mg, 6.0 mmol) was added to a mixture of 1-(bromomethyl)-4-iodobenzene (891 mg, 3.0 mmol) and 1-methylpiperazine (300 mg, 3.0 mmol) in MeCN (9 mL). The mixture was stirred at room temperature for 1 h. The mixture was then diluted with brine (15 mL) and extracted with DCM (15 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound (920 mg, 97%). LC-MS (M+H) + = 317.1.

[0280] Step 2: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]benzene [6.3.1.0] pyridine-3-yl-9-oxa-1-azatricyclic 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate The title compound (140 mg, 68%) was prepared in a manner similar to step 2 of Example 21, by reacting 1-[(4-iodophenyl)methyl]-4-methylpiperazine and (5-{3-[3-(acetoxy)-2,2-dimethylpropyl]-6-bromo-9-oxa-1-azatricyclo[6.3.1.0]). 4,12 Preparation of 1,4(12),5,7-tetraen-2-yl}-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid. LC-MS (M+H)+ = 689.4.

[0281] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- 1-Methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate The title compound (92 mg, 45%) was prepared in a manner similar to step 4 of Example 21, from 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 The mixture was prepared from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and {2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(3S)-3-(methoxycarbonyl)-1,2-diazinyl-1-yl]-3-oxopropyl]-1,3-thiazolyl-4-yl}boronic acid. LC-MS (M+H) + = 1007.9.

[0282] Step 4: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyridin-3-yl}- 9-oxa-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl}propionyl 1,2-diazinyl-3-carboxylic acid The title compound (70 mg, 80%) was prepared in a manner similar to step 5 of Example 21, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 951.8.

[0283] Step 5: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazine-1-yl)methyl] [[B]phenyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetra- Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl] tert-butyl carbamate The title compound (30 mg, 44%) was prepared in a manner similar to that in step 6 of Example 21, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + = 933.7.

[0284] Step 6: (1R,2R,3S)−N−[(7S,13S,19M)−20−{2−[(1S)−1−methoxyethyl]−5−{4−[(4− [Methylpiperazine-1-yl]methyl[phenyl]pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thio Hetero-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19, 25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide Example 25 (6 mg, 23%) was prepared in a similar manner to step 7 of Example 21, from N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-{4-[(4-methylpiperazin-1-yl)methyl]phenyl}pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19, 27 .0 21,26 [Tart-butyl carbamate] was prepared by amide coupling of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid. The mixture was separated by SFC (column: YMC Cellulose-C; column size: 20 x 250 mm, 5 μm; mobile phase: isocratic, 6 mM methanol NH3:CO2, 45:55; flow rate: 40 mL / min; temperature: 35 °C; back pressure: 100 bar. tR = 11.03 min).

[0285] 1 H NMR (400 MHz, DMSO- d 6) δ = 9.02 (d, J = 2.2 Hz, 1H), 8.37 (d, J = 9.0Hz, 1H), 8.11 (s, 1H), 7.97 (d, J= 2.0 Hz, 1H), 7.86 – 7.60 (m, 3H), 7.38 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 5.51 (t, J = 9.2 Hz, 1H), 5.01 (d, J = 12.0 Hz, 1H),4.65 – 4.40 (m, 3H), 4.22 (m, 3H), 3.82 – 3.42 (m, 5H), 3.27 – 3.22 (m, 4H),3.13 – 3.03 (m, 1H), 2.92 (d, J = 14.4 Hz, 1H), 2.72 - 2.66 (m, 1H), 2.37 -2.27 (m, 9H), 2.12 - 2.02 (m, 4H), 1.73 (s, 2H), 1.48 -1.33 (m, 4H), 1.22 -1.07 (m, 3H), 1.01 - 0.96 (m, 6H), 0.87 (s, 3H), 0.37 (s, 3H). LC-MS(M+H) + =929.8.

[0286] Examples of trans-reactive isomers -26 and 26: (1R,2R,3S)-N-[(7S,13S,19P)-20-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21 ,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19,27 .021,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(2-{5-[(9aS)-octahydropyrazine[2,1-c][1,4]oxazine-8-yl]-2-[(1S)-1-methoxy] [6.3.1.0]pyridin-3-yl}-6-bromo-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraene-] 3-yl)-2,2-dimethylpropyl acetate The title compound (430 mg, 70%) was prepared in a manner similar to that in step 1 of Example 16, by 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 [Prepared from] dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and (9aS)-octahydropyrazine[2,1-c][1,4]oxazine. LC-MS (M+H) + = 641.3.

[0287] Step 2: 3-(2-{5-[(9aS)-octahydropyrazine[2,1-c][1,4]oxazine-8-yl]-2-[(1S)-1-methoxy] [[4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl]-9-oxa-1-azatricyclic] [6.3.1.0 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (220 mg, 48%) was prepared in a manner similar to step 2 of Example 16, by 3-(2-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-bromo-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of [amount] from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and BPD. LC-MS (M+H) + = 689.5.

[0288] Step 3: (3S)-1-[(2S)-3-[4-(2-{5-[(9aS)-octahydropyrazine[2,1-c][1,4]oxazine-8- [3-(acetoxy)-2-[(1S)-1-methoxyethyl]pyridin-3-yl]-3-[3-(acetoxy)-2,2-dimethylpropyl]-9-oxa-1- Azatricyclic [6.3.1.0] 4,12 ]dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazolyl]-2-{[(tert-butoxy [[carbonyl]amino]propionyl]-1,2-diazinyl-3-carboxylate methyl ester The title compound (160 mg, 52%) was prepared in a manner similar to that in step 3 of Example 16, by 3-(2-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 959.5.

[0289] Step 4: (3S)-1-[(2S)-3-[4-(2-{5-[(9aS)-octahydropyrazine[2,1-c][1,4]oxazine-8- [1S]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatri Ring [6.3.1.0] 4,12 [dodecyl-2,4(12),5,7-tetraen-6-yl)-1,3-thiazolyl]-2-{[(tert-butoxy)carbonyl] [aminopropionyl]-1,2-diazinyl-3-carboxylic acid The title compound (130 mg, 66%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-[4-(2-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-[3-(acetoxy)-2,2-dimethylpropyl]-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl [[(tert-butoxy)carbonyl]-1,3-thiazolyl]-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate. LC-MS (M+H) + = 903.5.

[0290] Step 5: N-[(7S,13S)-20-{5-[(9aS)-octahydropyrazine[2,1-c][1,4]oxazine-8-yl]-2- [(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9, 21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29),2,6-hexen-7-yl]tert-butyl carbamate The title compound (35 mg, 36%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-3-[4-(2-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12Preparation of 1,2-diazine-3-carboxylic acid from [[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylic acid. LC-MS (M+H) + = 885.5.

[0291] Step 6: (7S,13S)-20-{5-[(9aS)-octahydropyrazine[2,1-c][1,4]oxazine-8-yl]-2-[(1S)- [1-Methoxyethyl]pyridin-3-yl]-7-amino-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetra- Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 8,14-Diketone The title compound (30 mg, 97%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2 ,5 .1 9,13 .0 19,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 785.5.

[0292] Step 7: (1R,2R,3S)‐N‐[(7S,13S,19P)‐20‐{5‐[(9aS)‐octahydropyrazine[2,1‐c][1,4]] [Oxazine-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-di Oxa-4-thia-9,21,30,31-tetraazahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ] [28),2,5(31),19,25(29),26-hexen-7-yl]2,3-dimethylcyclopropane-1-formyl Amines and (1R,2R,3S)-N-[(7S,13S,19M)-20-{5-[(9aS)-octahydropyrazine[2,1-c][1,4]oxazine-8-yl]- 2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ] [[28,2,5(31),19,25(29),26-hexen-7-yl]2,3-dimethylcyclopropane-1-carboxamide] Transtransisomer-26 (P-isomer, 3.4 mg, 10%) and Example 26 (M-isomer, 10 mg, 30%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-20-{5-[(9aS)-octahydropyrazino[2,1-c][1,4]oxazin-8-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-7-amino-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0293] Transisomer-26: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.40 – 8.33 (m, 2H), 8.12(s, 1H), 7.72 (s, 1H), 7.36 (d, J = 2.9 Hz, 1H), 7.11 (s, 1H), 5.55 – 5.47 (m,1H), 5.03 – 4.97 (m, 1H), 4.53 – 4.45 (m, 1H), 4.40 – 4.33 (m, 1H), 4.21 –4.13 (m, 1H), 4.05 – 3.97 (m, 1H), 3.78 – 3.69 (m, 2H), 3.68 – 3.57 (m, 3H), 3.53 – 3.44 (m, 2H), 3.26 – 3.20 (m, 1H), 3.12 – 3.05 (m, 5H), 2.99 – 2.93(m, 1H), 2.77 – 2.72 (m, 2H), 2.65 – 2.60 (m, 1H), 2.40 – 2.22 (m, 4H), 2.20 – 2.11 (m, 2H), 2.10 – 2.03 (m, 1H), 1.97 – 1.90 (m, 1H), 1.79 – 1.70 (m,2H), 1.49 – 1.40 (m, 1H), 1.21– 1.17 (m, 3H), 1.13– 1.08 (m, 6H), 1.05 – 0.99(m, 6H), 0.90 (s, 3H), 0.46 (s, 3H). LC-MS(M+H) + = 881.5.

[0294] Example 26: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.41 – 8.33 (m, 2H), 8.08 (s,1H), 7.72 (s, 1H), 7.13 (d, J= 2.9 Hz, 1H), 7.11 (s, 1H), 5.53 – 5.46 (m, 1H), 5.03 – 4.97 (m, 1H), 4.60 – 4.49 (m, 2H), 4.30 – 4.23 (m, 2H), 4.21 – 4.12(m, 2H), 3.76 – 3.44 (m, 8H), 3.26 – 3.23 (m, 2H), 3.18 (s, 3H), 3.13 – 3.05(m, 2H), 2.91 – 2.85 (m, 1H), 2.81 – 2.74 (m, 2H), 2.70 – 2.63 (m, 2H), 2.41– 2.29 (m, 4H), 2.09 – 2.00 (m, 1H), 1.78 – 1.70 (m, 2H), 1.51 – 1.38 (m,1H), 1.29 (d, J = 8.0 Hz, 3H), 1.20 – 1.09 (m, 3H), 1.04 – 1.00 (m, 6H), 0.89 (s, 3H), 0.34 (s, 3H). LC-MS(M+H) + = 881.5.

[0295] Examples of trans-reactive isomers -27 and 27: (1R,2R,3S)-N-[(7S,13S,19P)-20-{5-[(2S,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and] (1R,2R,3S)‐N‐[(7S,13S,19M)‐20‐{5‐[(2S,6S)‐2,6‐dimethylmorpholin-4‐yl]‐2‐[(1S)‐1‐methoxyethyl]pyridin-3‐yl}‐17,17‐dimethyl-8,14‐dioxo-15,24‐dioxa-4‐thia-9,21,30,31‐tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26[[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{5-[(2S,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl [6.3.1.0]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate The title compound (320 mg, 54%) was prepared in a manner similar to that in step 1 of Example 16, by 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation by (2S,6S)-2,6-dimethylpropyl acetate and (2S,6S)-2,6-dimethylmorpholine. LC-MS (M+H) + = 614.3.

[0296] Step 2: 3-(2-{5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridine pyridyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (300 mg, 87%) was prepared in a manner similar to step 2 of Example 16, by 3-(6-bromo-2-{5-[(2S,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of [amount] from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and BPD. LC-MS (M+H) + = 662.5.

[0297] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2S, [6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate The title compound (330 mg, 78%) was prepared in a manner similar to step 3 of Example 16, by 3-(2-{5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 932.5.

[0298] Step 4: (3S)−1−[(2S)−2−{[(tert-butoxy)carbonyl]amino}−3−[4−(2−{5−[(2S,6S)−2,6− [dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9- Oxa-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl 1,2-diazinyl-3-carboxylic acid The title compound (250 mg, 81%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 876.5.

[0299] Step 5: N-[(7S,13S)-20-{5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxy [[ ...][[[[[[[[[[[][[[[[[[[[][[[[[[[[[][[[[[[[[][[[[[[][[[[[[[][[[[][[[[[[][[[ Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl] tert-butyl carbamate The title compound (200 mg, 82%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(2-{5-[(2S,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + = 858.5.

[0300] Step 6: (7S,13S)-7-amino-20-{5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1- [Methoxyethyl]pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (170 mg, 96%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-{5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 758.5.

[0301] Step 7: (1R,2R,3S)−N−[(7S,13S,19P)−20−{5−[(2S,6S)−2,6−dimethylmorpholin−4−]− 2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29), 26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20- {5-[(2S,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl 8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-methyl] amide Transisomer-27 (P-isomer, 6.8 mg, 4%) and Example 27 (M-isomer, 27.2 mg, 14%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{5-[(2S,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0302] Transisomer-27: 1 H NMR (400 MHz, DMSO- d6) δ 8.38 – 8.32 (m, 2H), 8.13(s, 1H), 7.72 (s, 1H), 7.54 – 7.38 (m, 1H), 7.12 (s, 1H), 5.54 – 5.48 (m,1H), 5.00 – 4.95 (m, 1H), 4.54 – 4.48 (m, 1H), 4.42 – 4.34 (m, 1H), 4.21 –3.98 (m, 6H), 3.68 – 3.62 (m, 2H), 3.53 – 3.49 (m, 1H), 3.22 – 3.06 (m, 6H),3.00 – 2.93 (m, 3H), 2.75 – 2.66 (m, 1H), 2.49 – 2.47 (m, 1H), 2.37 – 2.32(m, 2H), 2.09 – 2.05 (m, 1H), 1.80 – 1.71 (m, 2H), 1.52 – 1.45 (m, 1H), 1.17– 1.10 (m, 11H), 1.04 – 1.00 (m, 6H), 0.90 (s, 3H), 0.47 (s, 3H). LC-MS (M+H) + = 854.5.

[0303] Example 27: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.38 – 8.32 (m, 2H), 8.08 (s,1H), 7.71 (s, 1H), 7.16 (s, 1H), 7.10 (s, 1H), 5.54 – 5.45 (m, 1H), 5.03 –4.96 (m, 1H), 4.61 – 4.46 (m, 2H), 4.32 – 3.97 (m, 6H), 3.71 – 3.61 (m, 1H),3.58 – 3.50 (m, 2H), 3.25 – 3.21 (m, 3H), 3.18 (s, 3H), 3.11 – 3.04 (m, 1H),2.97 – 2.86 (m, 3H), 2.74 – 2.65 (m, 1H), 2.47 – 2.32 (m, 1H), 2.08 – 2.00(m, 1H), 1.78 – 1.67 (m, 2H), 1.51 – 1.41(m, 1H), 1.29 (d, J= 8.0 Hz, 3H), 1.15 – 1.09 (m, 9H), 1.04 – 0.99 (m, 6H), 0.89 (s, 3H), 0.34 (s, 3H). LC-MS(M+H) + = 854.5.

[0304] Examples of trans-reactive isomers -28 and 28: (1R,2R,3S)-N-[(7S,13S,19P)-20-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and (1R,2R,3S)‐N‐[(7S,13S,19M)‐20‐{5‐[(2R,6R)‐2,6‐dimethylmorpholin-4‐yl]‐2‐[(1S)‐1‐methoxyethyl]pyridin-3‐yl}‐17,17‐dimethyl-8,14‐dioxo-15,24‐dioxa-4‐thia-9,21,30,31‐tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{5-[(2R,6R)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl [6.3.1.0]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate The title compound (270 mg, 46%) was prepared in a manner similar to that in step 1 of Example 16, by 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12Preparation by (2R,6R)-2,6-dimethylpropyl acetate and (2R,6R)-2,6-dimethylmorpholine. LC-MS (M+H) + = 614.3 / 616.3.

[0305] Step 2: 3-(2-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridine pyridyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (250 mg, 86%) was prepared in a manner similar to step 2 of Example 16, by 3-(6-bromo-2-{5-[(2R,6R)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of [amount] from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and BPD. LC-MS (M+H) + = 662.5.

[0306] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2R, 6R)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate The title compound (170 mg, 48%) was prepared in a manner similar to step 3 of Example 16, by 3-(2-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 932.5.

[0307] Step 4: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(2-{5-[(2R,6R)-2,6- [dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9- Oxa-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl 1,2-diazinyl-3-carboxylic acid The title compound (110 mg, 69%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 876.5.

[0308] Step 5: N-[(7S,13S)-20-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxy [[ ...][[[[[[[[[[[][[[[[[[[[][[[[[[[[[][[[[[[[[][[[[[[][[[[[[[][[[[][[[[[[][[[ Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl] tert-butyl carbamate The title compound (45 mg, 42%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(2-{5-[(2R,6R)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + = 858.5.

[0309] Step 6: (7S,13S)-7-amino-20-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1- [Methoxyethyl]pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (35 mg, 88%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 758.5.

[0310] Step 7: (1R,2R,3S)−N−[(7S,13S,19P)−20−{5−[(2R,6R)−2,6−dimethylmorpholin−4−]− 2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29), 26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20- {5-[(2R,6R)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl 8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-methyl] amide Transisomer-28 (P-isomer, 4.3 mg, 11%) and Example 28 (M-isomer, 11 mg, 28%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{5-[(2R,6R)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0311] Transisomer-28: 1 H NMR (400 MHz, DMSO- d6) δ 8.38 – 8.32 (m, 2H), 8.13(s, 1H), 7.72 (s, 1H), 7.54 – 7.38 (m, 1H), 7.12 (s, 1H), 5.54 – 5.48 (m,1H), 5.00 – 4.95 (m, 1H), 4.54 – 4.48 (m, 1H), 4.42 – 4.34 (m, 1H), 4.21 –3.98 (m, 6H), 3.68 – 3.62 (m, 2H), 3.53 – 3.49 (m, 1H), 3.22 – 3.06 (m, 6H),3.00 – 2.93 (m, 3H), 2.75 – 2.66 (m, 1H), 2.49 – 2.47 (m, 1H), 2.37 – 2.32(m, 2H), 2.09 – 2.05 (m, 1H), 1.80 – 1.71 (m, 2H), 1.52 – 1.45 (m, 1H), 1.17– 1.10 (m, 11H), 1.04 – 1.00 (m, 6H), 0.90 (s, 3H), 0.47 (s, 3H). LC-MS (M+H) + = 854.5.

[0312] Example 28: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.38 – 8.32 (m, 2H), 8.08 (s,1H), 7.71 (s, 1H), 7.13 – 7.09 (m, 2H), 5.54 – 5.45 (m, 1H), 5.03 – 4.96 (m,1H), 4.61 – 4.46 (m, 2H), 4.32 – 3.97 (m, 6H), 3.71 – 3.61 (m, 1H), 3.58 –3.50 (m, 2H), 3.25 – 3.21 (m, 3H), 3.17 (s, 3H), 3.11 – 3.04 (m, 1H), 3.00 –2.85 (m, 3H), 2.74 – 2.65 (m, 1H), 2.43 – 2.32 (m, 1H), 2.08 – 2.00 (m, 1H),1.78 – 1.67 (m, 2H), 1.51 – 1.41(m, 1H), 1.29 (d, J= 8.0 Hz, 3H), 1.15 – 1.09 (m, 9H), 1.04 – 0.99 (m, 6H), 0.88 (s, 3H), 0.34 (s, 3H). LC-MS(M+H) + = 854.5.

[0313] Examples of trans-reactive isomers -29 and 29: (1R,2R,3S)-N-[(7S,13S,19P)-20-{5-[(2S,5R)-2,5-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{5-[(2S,5R)-2,5-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{5-[(2S,5R)-2,5-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl [6.3.1.0]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate The title compound (130 mg, 35%) was prepared in a manner similar to step 1 of Example 16, by (5-{3-[3-(acetoxy)-2,2-dimethylpropyl]-6-bromo-9-oxa-1-azatricyclic [6.3.1.0]). 4,12 Prepared from dodecacarbon-2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid and (2S,5R)-2,5-dimethylmorpholine. LC-MS (M+H) + = 614.4.

[0314] Step 2: 3-(2-{5-[(2S,5R)-2,5-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridine pyridyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (120 mg, 86%) was prepared in a manner similar to step 2 of Example 16, by 3-(6-bromo-2-{5-[(2S,5R)-2,5-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate. LC-MS (M+H) + = 662.7.

[0315] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2S, 5R)-2,5-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate The title compound (120 mg, 71%) was prepared in a manner similar to step 3 of Example 16, by 3-(2-{5-[(2S,5R)-2,5-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate. LC-MS (M+H) + = 932.7.

[0316] Step 4: (3S)−1−[(2S)−2−{[(tert-butoxy)carbonyl]amino}−3−[4−(2−{5−[(2S,5R)−2,5− [dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9- Oxa-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl 1,2-diazinyl-3-carboxylic acid The title compound (98 mg, 87%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2S,5R)-2,5-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 876.7.

[0317] Step 5: N-[(7S,13S)-20-{5-[(2S,5R)-2,5-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxy [[ ...][[[[[[[[[[[][[[[[[[[[][[[[[[[[[][[[[[[[[][[[[[[][[[[[[[][[[[][[[[[[][[[ Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl] tert-butyl carbamate The title compound (40 mg, 42%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(2-{5-[(2S,5R)-2,5-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + = 858.6.

[0318] Step 6: (7S,13S)-7-amino-20-{5-[(2S,5R)-2,5-dimethylmorpholin-4-yl]-2-[(1S)-1- [Methoxyethyl]pyridin-3-yl]-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (35 mg, 99%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-{5-[(2S,5R)-2,5-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 758.5.

[0319] Step 7: (1R,2R,3S)−N−[(7S,13S,19P)−20−{5−[(2S,5R)−2,5−dimethylmorpholin−4−]− 2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia- 9,21,30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25 (29), 26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20- {5-[(2S,5R)-2,5-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19 ,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-methyl] amide Transisomer-29 (P-isomer, 9.6 mg, 24%) and Example 29 (M-isomer, 22 mg, 55%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{5-[(2S,5R)-2,5-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0320] Transisomer-29: 1 H NMR (400 MHz, DMSO- d 6) δ =8.49 – 8.26 (m, 2H), 8.13(s, 1H), 7.78 – 7.57 (m, 2H), 7.13 (s, 1H), 5.51 (t, J = 9.2 Hz, 1H), 4.98 (d, J = 12.0 Hz, 1H), 4.62 – 4.30 (m, 2H), 4.22 – 4.05 (m, 4 H), 3.85 – 3.42 (m,5H), 3.29 – 2.97 (m, 9H), 2.82 – 2.64 (m, 2 H), 2.36 – 2.26 (m, 1H), 2.08 (d, J = 10.6 Hz, 1H), 1.72 (s, 2H), 1.52 – 1.38 (m, 1H), 1.16 – 0.77 (m, 21H), 0.45 (s, 3H). LC-MS(M+H) + = 854.7.

[0321] Example 29: 1 H NMR (400 MHz, DMSO- d 6) δ = 8.46 (d, J = 2.4 Hz, 1H), 8.35 (d,J = 8.7 Hz, 1H), 8.08 (s, 1H), 7.72 (s, 1H), 7.33 (s, 1H), 7.12 (s, 1H), 5.51 (t, J = 9.2, 1H), 4.99 (d, J = 12.0 Hz, 1H), 4.57 (s, 2H), 4.35 – 4.07 (m,4H), 3.88 – 3.69 (m, 3H), 3.59 – 3.50 (m, 2H), 3.28 – 3.17 (m, 7H), 3.10 –3.01 (m, 1H), 2.89 (d, J = 14.5 Hz, 1H), 2.73 – 2.63 (m, 2H), 2.37 – 2.33 (m,1H), 2.12 – 2.00(m, 1H), 1.77 – 1.68 (m, 2H), 1.52 – 1.41 (m, 1H), 1.31 (d, J = 6.0 Hz, 3H), 1.14 – 0.82 (m, 18H), 0.32 (s, 3H). LC-MS(M+H) + = 854.7.

[0322] Examples of trans-reactive isomers -30 and 30: (1R,2R,3S)-N-[(7S,13S,19P)-20-{5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2 ,5 .1 9,13 .0 19,27.0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl [6.3.1.0]pyridin-3-yl}-1-azatricyclic[6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethyl] Propyl acetate The title compound (330 mg, 61%) was prepared in a manner similar to that in step 1 of Example 16, by 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridin-3-yl}-1-azatricyclo[6.3.1.0] 4,12 Preparation by (2R,6S)-2,6-dimethylpropane (2R,6S)-2,6-dimethylmorpholine. LC-MS (M+H) + = 612.3.

[0323] Step 2: 3-(2-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridine pyridyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentyl-2-yl)-1-azatricyclic [6.3.1.0] 4,12 ]twelve C2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (300 mg, 84%) was prepared in a manner similar to step 2 of Example 16, by 3-(6-bromo-2-{5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12 Preparation of [amount] from dodecacarbon-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate and BPD. LC-MS (M+H) + = 660.5.

[0324] Step 3: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2R, 6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic[6.3.1.0 4 ,12 [dodecyl-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl] Methyl 1,2-diazinyl-3-carboxylate The title compound (300 mg, 71%) was prepared in a manner similar to step 3 of Example 16, by 3-(2-{5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-azatricyclo[6.3.1.0] 4,12Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + =930.5.

[0325] Step 4: (3S)−1−[(2S)−2−{[(tert-butoxy)carbonyl]amino}−3−[4−(2−{5−[(2R,6S)−2,6− [dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-1- Azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl]-1,2- Diazine-3-carboxylic acid The title compound (200 mg, 71%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-1-azatricyclic [6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 874.5.

[0326] Step 5: N-[(7S,13S)-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxy [[ ...][[[[[[[[[[[][[[[[[[[[[][[[[[[[[][[[[[[[][[[[[[[][[[[[[[][[[[][[[[[[][[[[ Ring [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [C31-1(28),2,5(31),19,25(29),26-hexene-7-yl]ammonium tert-butyl carbamate The title compound (150 mg, 77%) was prepared in a manner similar to step 5 of Example 16, from (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[4-(2-{5-[(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-3-(3-hydroxy-2,2-dimethylpropyl)-1-azatricyclic [6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl)-1,3-thiazo-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + = 856.5.

[0327] Step 6: (7S,13S)-7-amino-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1- [Methoxyethyl]pyridin-3-yl]-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (130 mg, 98%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21 ,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + = 756.5.

[0328] Step 7: (1R,2R,3S)−N−[(7S,13S,19P)−20−{5−[(2R,6S)−2,6−dimethylmorpholin−4−]− 2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15-oxa-4-thia-9,21, 30,31-Tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29), 26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{5- [(2R,6S)-2,6-dimethylmorpholino-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-8, 14-Dioxo-15-oxa-4-thia-9,21,30,31-tetraazahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]thirty One-carbon-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide Transisomer-30 (P-isomer, 6.3 mg, 4%) and Example 30 (M-isomer, 15 mg, 10%) were prepared in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{5-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2-[(1S)-1-methoxyethyl]pyridin-3-yl}-17,17-dimethyl-15-oxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0329] Transisomer-30: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.41 – 8.35 (m, 2H), 8.32(s, 1H), 7.67 (s, 1H), 7.38 (s, 1H), 7.34 (d, J= 2.9 Hz, 1H), 5.55 – 5.48 (m,1H), 5.06 – 4.98 (m, 1H), 4.22 – 4.13 (m, 2H), 3.97 – 3.82 (m, 2H), 3.70 –3.63 (m, 5H), 3.55 – 3.49 (m, 1H), 3.45 – 3.39 (m, 1H), 3.23 – 3.22 (m, 1H),3.13 – 3.09 (m, 1H), 3.05 (s, 3H), 2.99 – 2.09 (m, 3H), 2.75 – 2.66 (m, 1H),2.50 – 2.48 (m, 1H), 2.35 – 2.26 (m, 4H), 2.24 – 2.18 (m, 1H), 2.12 – 2.04(m, 1H), 1.78 – 1.69 (m, 2H), 1.50 – 1.40 (m, 1H), 1.18 – 1.08 (m, 11H), 1.04– 1.00 (m, 6H), 0.89 (s, 3H), 0.48 (s, 3H). LC-MS (M+H) + = 852.5.

[0330] Example 30: 1 H NMR (400 MHz, DMSO- d6 ) δ 8.39 (d, J = 2.9 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.28 (s, 1H), 7.67 (s, 1H), 7.39 (s, 1H), 7.12 (d, J = 2.9 Hz,1H), 5.52 (t, J = 9.0 Hz, 1H), 5.02 (d, J = 12.1 Hz, 1H), 4.40 – 3.99 (m, 4H),3.87 – 3.53 (m, 6H), 3.50 – 3.43 (m, 1H), 3.26 – 3.22 (m, 1H), 3.17 (s, 3H),3.09 (dd, J= 14.7, 9.2 Hz, 1H), 3.04 – 2.94 (m, 1H), 2.91 – 2.80 (m, 2H), 2.76 – 2.66 (m, 1H), 2.40 – 2.35 (m, 1H), 2.34 – 2.23 (m, 2H), 2.21 – 2.14 (m,1H), 2.11 – 1.98 (m, 2H), 1.76 – 1.71 (m, 2H), 1.55 – 1.38 (m, 1H), 1.29 (d, J = 6.1 Hz, 3H), 1.13 – 0.96 (m, 15H), 0.87 (s, 3H), 0.37 (s, 3H). LC-MS(M+H) + =852.5.

[0331] Examples of trans-reactive isomers -31 and 31: (1R,2R,3S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and] (1R,2R,3S)‐N‐[(7S,13S,19M)‐20‐{2‐[(1S)‐1‐methoxyethyl]‐5‐(1‐methylpiperidin-4‐yl)pyridin-3‐yl}‐17,17‐dimethyl-8,14‐dioxo-15,24‐dioxa-4‐thia-9,21,30,31‐tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 4-Methyl-N'-(1-methylpiperidin-4-ylidene)benzene-1-sulfonylhydrazine The title compound (1.2 g, 98%) was prepared from 1-methylpiperidin-4-one and 4-methylbenzene-1-sulfonylhydrazine in a manner similar to that in step 1 of Example 19. LC-MS (M+H) + = 282.2.

[0332] Step 2: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}- 9-oxa-1-azatricyclic [6.3.1.0] 4,12 Dodecano-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (100 mg, 98%) was prepared in a manner similar to step 3 of Example 19, by reacting 4-methyl-N'-(1-methylpiperidin-4-ylidene)benzene-1-sulfonylhydrazine and (5-{3-[3-(acetoxy)-2,2-dimethylpropyl]-6-bromo-9-oxa-1-azatricyclo[6.3.1.0]). 4,12 Preparation of 1,4(12),5,7-tetraen-2-yl}-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid. LC-MS (M+H) + = 598.3 / 600.4.

[0333] Step 3: 3-(2-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-6-(4, 4,5,5-Tetramethyl-1,3,2-dioxoboronyl-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Carbon-2,4-12 (12), 5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate The title compound (94 mg, 87%) was prepared in a manner similar to step 4 of Example 19, from 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4 ,12 Preparation of dodeca-2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate. LC-MS (M+H) + =646.6.

[0334] Step 4: (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)- 1-Methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 ]twelve C-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2- Methyl diazine-3-formate The title compound (102 mg, 77%) was prepared in a manner similar to step 3 of Example 16, by 3-(2-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-9-oxa-1-azatricyclo[6.3.1.0] 4,12Methyl (3S)-1-[(2S)-3-(4-bromo-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazine-3-carboxylate was prepared by LC-MS (M+H). + = 916.7.

[0335] Step 5: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] 2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-9-oxa-1-aza Three Rings [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl}propionyl]-1,2-diazine Alkyl-3-carboxylic acid The title compound (53 mg, 56%) was prepared in a manner similar to step 4 of Example 16, from (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of methyl 1,2-diazine-3-carboxylate from [[(tert-butoxy)carbonyl]amino]propionyl]-1,2-diazine-3-carboxylate. LC-MS (M+H) + = 860.6.

[0336] Step 6: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridine- 3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]amino] tert-butyl formate The title compound (25 mg, 48%) was prepared in a manner similar to step 5 of Example 16, by (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12 Preparation of 1,2-diazine-3-carboxylic acid from [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl]propionyl]-1,2-diazinane-3-carboxylic acid. LC-MS (M+H) + =842.6.

[0337] Step 7: (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridine pyridyl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1] 2,5 .1 9 ,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene-8,14-dione The title compound (22 mg, 99%) was prepared in a manner similar to step 6 of Example 16, by N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of tert-butyl carbamate from [C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]. LC-MS (M+H) + =742.5.

[0338] Step 8: (1R,2R,3S)−N−[(7S,13S,19P)−20−{2−[(1S)−1−methoxyethyl]−5−(1−methyl Piperidin-4-yl)pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31- Tetraazahexane [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ] 31-carbon-1(28),2,5(31),19,25(29),26-hexane [Alken-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1- [Methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl]-17,17-dimethyl-8,14-dioxo-15,24-dioxo 4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5 (31), 19, 25(29), 26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide Transtransisomer-31 (P-isomer, 4.5 mg, 18%) and Example 31 (M-isomer, 12 mg, 48%) were processed in a manner similar to step 7 of Example 16, from (7S,13S)-7-amino-20-{2-[(1S)-1-methoxyethyl]-5-(1-methylpiperidin-4-yl)pyridin-3-yl}-17,17-dimethyl-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1]. 2,5 .1 9,13 .0 19,27 .0 21,26 Preparation of 31-carbon-1(28),2,5(31),19,25(29),26-hexene-8,14-dione and (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid.

[0339] Transisomer-31: 1 H NMR (400 MHz, DMSO- d 6) δ = 8.59 (d, J = 2.0 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.12 (s, 1H), 7.78 – 7.63 (m, 2H), 7.12 (s, 1H), 5.51(t, J = 9.2 Hz, 1H), 4.98 (d, J =12.0 Hz, 1H), 4.54 – 4.34 (m, 2H), 4.22 – 3.95(m, 4H), 3.66 - 3.47 (m, 3H), 3.26 – 3.21 (m, 1H), 3.14 – 3.04 (m, 4H), 2.97(d, J = 14.4, 1H), 2.85 – 2.67 (m, 3H), 2.59 – 2.51 (m, 1H), 2.30 (d, J = 13.2Hz, 1H), 2.20 – 2.05 (m, 4H), 1.92 (t, J = 10.8 Hz, 2H), 1.78 - 1.62 (m, 6H),1.51 – 1.41 (m, 1H), 1.18 – 0.98 (m, 12H), 0.88 (s, 3 H), 0.41 (s, 3H). LC-MS(M+H) + = 838.8.

[0340] Example 31: 1 H NMR (400 MHz, DMSO- d 6) δ = 8.59 (d, J = 2.0 Hz, 1H), 8.35(d, J = 8.8 Hz, 1H), 8.09 (s, 1H), 7.72 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.12(s, 1H), 5.51 (t, J = 9.0 Hz, 1H), 5.00 (d, J = 12.0 Hz, 1H), 4.58 (s, 2H), 4.38(q, J = 6.0 Hz, 1H), 4.30 – 4.12 (m, 3H), 3.75 – 3.51 (m, 3H), 3.29 – 3.19 (m,4H), 3.08 (dd, J =14.8 Hz, 9.2 Hz, 1H), 2.92 – 2.78 (m, 3H), 2.74 – 2.56 (m,2H), 2.37 – 2.34 (m, 1H), 2.16 – 2.02 (m, 4H), 2.00 – 1.84 (m, 2H), 1.81 –1.59 (m, 6H), 1.47 – 1.41 (m, 1H), 1.30 (d, J = 6.0 Hz, 3H), 1.13 – 0.96 (m,9H), 0.86 (s, 3H), 0.28 (s, 3H). LC-MS(M+H) + = 838.8.

[0341] Examples of trans-reactive isomers -32 and 32: (1R,2R,3S)-N-[(7S,13S,19P)-20-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S,19M)-20-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-oxa-4-thia-9,21,30,31-tetraazahexacyclo[23.3.1.1]] 2,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide] and Step 1: 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazine-1- [6.3.1.0]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [Dodeca-2,4(12),5,7-tetraen-3-yl)-2,2- Dimethylpropyl acetate To (5‐{3‐[3‐(acetoxy)‐2,2‐dimethylpropyl]‐6‐bromo‐9‐oxa‐1‐azatricyclic[6.3.1.0 4 ,12 [2R,6S)-1,2,6-trimethylpiperazine (256 mg, 2 mmol), Cu(OAc)₂ (182 mg, 1 mmol), and TEA (152 mg, 1.5 mmol) were added to a solution of 2,4(12),5,7-tetraen-2-yl]-6-[(1S)-1-methoxyethyl]pyridin-3-yl)boronic acid (272 mg, 0.50 mmol) in MeCN (10 mL). The mixture was stirred overnight at room temperature under O₂. The mixture was then diluted with 50 mL of brine. The solids were filtered off, and the filter cake was washed with DCM:MeOH (10:1, 300 mL). The organic layer was separated and dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (80 mg, 25%). LC-MS (M+H) + = 627.5.

[0342] Step 2: (3S)−1−[(2S)−3−(4−{3−[3−(acetoxy)−2,2−dimethylpropyl]−2−{2−[(1S)− 1-Methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl] Methyl aminopropionyl]-1,2-diazinane-3-carboxylate 3-(6-bromo-2-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclo[6.3.1.0] 4,12A mixture of 2,4(12),5,7-tetraen-3-yl)-2,2-dimethylpropyl acetate (80 mg, 0.13 mmol), {2-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-[(3S)-3-(methoxycarbonyl)-1,2-diazinyl]-3-oxopropyl]-1,3-thiazolyl-4-yl}boronic acid (115 mg, 0.26 mmol), K3PO4 (83 mg, 0.39 mmol), and Pd(dtpf)Cl2 (10 mg, 0.013 mmol) in dioxane (4 mL) and water (0.5 mL) was stirred at 70 °C for 3 h under N2. The mixture was then diluted with brine (50 mL) and extracted by DCM (50 mL x 3). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (86 mg, 72%). LC-MS (M+H) + = 945.7.

[0343] Step 3: (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethyl] (2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl]- 9-oxa-1-azatricyclic [6.3.1.0] 4,12 [dodecano-2,4(12),5,7-tetraen-6-yl]-1,3-thiazolyl-2-yl}propionyl 1,2-diazinyl-3-carboxylic acid To (3S)-1-[(2S)-3-(4-{3-[3-(acetoxy)-2,2-dimethylpropyl]-2-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 Methyl methyl dodecano-2,4(12),5,7-tetraen-6-yl}-1,3-thiazolyl)-2-{[(tert-butoxy)carbonyl]amino}propionyl]-1,2-diazinane-3-carboxylate (86 mg, 0.091 mmol) was added to a mixture of THF (5 mL) and water (5 mL) with LiOH. . H₂O (20 mg, 0.455 mmol). The mixture was stirred at room temperature for 8 h. The mixture was then diluted with 30 mL of water. The mixture was acidified to pH approximately 5 with hydrochloric acid (1 N). The resulting mixture was extracted with EA (30 mL x 3). The organic layer was separated, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue (60 mg, 77%) was used without further purification. LC-MS (M+H) + = 889.9.

[0344] Step 4: N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazine] Azine-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetra- Azahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31),19,25(29),26-hexene- 7-yl] tert-butyl carbamate To (3S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-3-{4-[3-(3-hydroxy-2,2-dimethylpropyl)-2-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-9-oxa-1-azatricyclic [6.3.1.0] 4,12 [60 mg, 0.067 mmol]-1,3-thiazolyl-2-yl propionyl]-1,2-diazinane-3-carboxylic acid was added to a solution in anhydrous DCM (20 mL) with DIEA (173 mg, 1.34 mmol), followed by HOBt (90.5 mg, 0.67 mmol) and EDCI (194 mg, 1.01 mmol). The mixture was stirred at room temperature for 16 h. The mixture was then diluted with 30 mL of brine and extracted with DCM (30 mL x 3). The organic layer was washed with brine (30 mL x 3), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound (30 mg, 51%). LC-MS (M+H) + = 871.6.

[0345] Step 5: (1R,2R,3S)−N−[(7S,13S,19P)−20−{2−[(1S)−1−methoxyethyl]−5−[(3R, [5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4- Thiaza-9,21,30,31-tetraazahexacyclic [23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26 ]C31-1(28),2,5(31), 19,25(29),26-hexen-7-yl]-2,3-dimethylcyclopropane-1-formamide and (1R,2R,3S)-N-[(7S,13S, 19M)‐20‐{2‐[(1S)‐1‐methoxyethyl]‐5‐[(3R,5S)‐3,4,5‐trimethylpiperazin‐1‐yl]pyridin‐3‐yl}‐ 17,17-Dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane [23.3.1.1] 2 ,5 .1 9,13 .0 19,27 .0 21,26 [[C31-1(28),2,5(31),19,25(29),26-hexen-7-yl]-2,3-dimethylcyclohexane] Propane-1-formamide N-[(7S,13S)-20-{2-[(1S)-1-methoxyethyl]-5-[(3R,5S)-3,4,5-trimethylpiperazin-1-yl]pyridin-3-yl}-17,17-dimethyl-8,14-dioxo-15,24-dioxa-4-thia-9,21,30,31-tetraazahexane[23.3.1.1] 2,5 .1 9,13 .0 19,27 .0 21,26A solution of tert-butyl carbamate (30 mg, 0.034 mmol) in HCl / 1,4-dioxane (4 N, 3 mL) was stirred for 0.5 h. The mixture was then concentrated under vacuum. The residue was dissolved in DMF (3 mL), followed by the addition of (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (7.3 mg, 0.064 mmol), HATU (24 mg, 0.064 mmol), and DIEA (41.3 mg, 0.32 mmol). The mixture was stirred at room temperature for 1 h. The mixture was then diluted with brine (30 mL) and extracted with EA (30 mL x 2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under vacuum. The residues were purified by preparative HPLC to obtain transisomer-32 (P-isomer, 6.6 mg, 24%) and Example 32 (M-isomer, 7.5 mg, 27%).

[0346] Transisomer-32: 1 H NMR (400 MHz, DMSO- d 6) δ = 8.48 – 8.27(m, 2 H), 8.13(s, 1H), 7.71 (s, 1H), 7.36 (d, J = 2.8, 1H), 7.11 (s, 1H), 5.52 (t, J = 9.2,1H), 4.99 (d, J = 12.0, 1H), 4.55 – 4.32 (m, 2H), 4.24 – 3.97 (m, 4H), 3.75 –3.47 (m, 5 H), 3.18 – 2.92 (m, 5 H), 2.75 – 2.66 (m, 1H), 2.38 – 2.33 (m,3H), 2.22 – 2.06 (m, 5H), 1.82 – 1.67 (m, 2H), 1.53 – 1.36 (m, 2H), 1.24 –0.73 (m, 22H), 0.47 (s, 3H). LC-MS(M+H) + = 867.8.

[0347] Example 32: 1 H NMR (400 MHz, DMSO- d 6) δ 8.39 (d, J= 2.8 Hz, 1H), 8.36 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 1.2 Hz, 1H), 7.71 (s, 1H), 7.14 (d, J = 2.9 Hz, 1H),7.11 (s, 1H), 5.50 (t, J = 9.1 Hz, 1H), 5.00 (d, J = 12.1 Hz, 1H), 4.62 – 4.43(m, 2H), 4.38 – 4.01 (m, 4H), 3.80 – 3.63 (m, 3H), 3.56 (q, J = 10.9 Hz, 2H),3.27 – 3.22 (m, 3H), 3.18 (s, 3H), 3.08 (dd, J = 14.6, 9.2 Hz, 1H), 2.89 (d, J =14.2 Hz, 1H), 2.79 – 2.64 (m, 1H), 2.40 – 2.36 (m, 1H), 2.22 – 2.16 (m, 2H), 2.13 (s, 3H), 2.09 – 2.02 (m, 1H), 1.84 – 1.62 (m, 2H), 1.53 – 1.39 (m, 1H),1.29 (d, J = 6.1 Hz, 3H), 1.17 – 0.96 (m, 15H), 0.89 (s, 3H), 0.34 (s, 3H). LC-MS(M+H) + = 867.8.

[0348] Test Implementation Examples Method 1: pERK inhibition in AsPC-1 (KRAS G12D) cells. The AsPC-1 cell line (a pancreatic cancer cell line carrying the KRAS G12D mutation) was used in this study. Cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin, and streptomycin (Thermo Fisher) at 37°C in a humid atmosphere with 5% CO2 in the air. Cells were revived from cryopreserved cells within 30 passages of purchased progenitor cells. 30,000 cells per well were seeded into 96-well plates and incubated overnight. Cells were treated with a 10-spot dilution series of test compounds, with final compound concentrations ranging from 0 to 10 μM. Two hours after compound treatment, cells were lysed, and the pERK1 / 2 (THR202 / TYR204) levels in cell lysates were detected using an HTRF kit (Cisbio) according to the following protocol. In short, transfer a total of 16 μL of cell lysate from each well of the 96-well plate to a 384-well white assay plate. Mix the lysate from each well with 2 μL of Eu. 3+ - Anti-pERK1 / 2 antibody labeled with the cavitation compound (donor) and 2 μL of anti-pERK1 / 2 antibody labeled with D2 (receptor) (Cisbio) were incubated overnight in the dark at room temperature. When the donor and receptor were brought close together, laser excitation of the donor triggered fluorescence resonance energy transfer to the receptor, which then emitted fluorescence at a wavelength of 655 nm. The FRET signal was measured using a Pherastar FSX reader (BMG Labtech). IC50 analysis was performed using Dotmatics fitting of a curve showing the percentage of inhibition versus the logarithm of the compound concentration disclosed herein. 50 Measurements were taken. The results are reported in Table 2.

[0349] Table 2: pERK inhibition assay, IC50 50 (nM)

[0350] Based on the following rules, the activities in Table 2 are classified into "A", "B" and "C" according to the corresponding values:

[0351] Method 2: pERK inhibition in SW620 (KRAS G12V) cells This study used the SW620 cell line (a colorectal cancer cell line carrying the KRAS G12V mutation). Cells were maintained in RPMI 1640 supplemented with 10% fetal bovine serum (Thermo Fisher), 50 units / mL penicillin and streptomycin (Thermo Fisher) at 37°C in a humid atmosphere with 5% CO2 in the air. Cells were revived from cryopreserved cells within 30 passages of the purchased original cells. 40,000 cells per well were seeded into 96-well plates and incubated overnight. Cells were treated with a 10-point dilution series of the compounds disclosed herein, resulting in final compound concentrations from 0 to 10 μM. Two hours after compound treatment, cells were lysed, and pERK1 / 2 (THR202 / TYR204) levels in the cell lysates were detected using an HTRF kit (Cisbio) according to the following protocol. Briefly, a total of 16 μL of cell lysate from each well of the 96-well plate was transferred to a 384-well white assay plate. The lysate from each well was mixed with 2 μL of Eu. 3+ -- Antiphosphorylated ERK1 / 2 antibody labeled with a cavitation compound (donor) and 2 μL of anti-pERK1 / 2 antibody labeled with D2 (receptor) (Cisbio) were incubated overnight in the dark at room temperature. When the donor and receptor were brought close together, laser excitation of the donor triggered fluorescence resonance energy transfer to the receptor, which then emitted fluorescence at a wavelength of 655 nm. FRET signals were measured using a PHERAstar FSX reader (BMG Labtech). IC50 analysis was performed using Dotmatics fitting of a curve showing the percentage of inhibition versus the logarithm of the compound concentrations disclosed herein. 50 Measurement.

[0352] Table 3: pERK inhibition assay, IC50 of the compounds disclosed in this paper 50 (nM).

[0353] Based on the following rules, the activities in Table 3 are classified as “A”, “B” and “C” according to the corresponding values.

[0354] The foregoing descriptions of embodiments and certain implementations should be considered illustrative and not limiting of the invention as defined by the claims. It will be readily understood that various variations and combinations of the above features may be utilized without departing from the invention as set forth in the claims. All such variations are intended to be included within the scope of the invention. All references cited herein are incorporated herein by reference in their entirety. It should be understood that any prior art publication cited herein does not constitute an admission that such publication is part of common general knowledge in any country.

Claims

1. A compound of formula (I): (I) Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue, wherein: X is -O-, -S-, or -CH2-; n1 is 0, 1, or 2; n2 is 1, 2, or 3; n3 can be 0, 1, 2, 3 or 4; m is 1, 2, or 3; R 1 Selected from hydrogen, halogen, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 3-8 Cycloalkyl, substituted or unsubstituted 3- to 10-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a and -CONR 1a R 1b ; R 1a and R 1b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 2 Each is independently selected from hydrogen, halogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl, substituted or unsubstituted 5 to 12-membered heteroaryl, -OR 2a -NR 2a R 2b -COR 2a -CO2R 2a and -CONR 2a R 2b ; R 2a and R 2b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 3 Selected from hydrogen, substituted or unsubstituted -C 1-6 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 aryl and substituted or unsubstituted 5 to 12-membered heteroaryl, -COR 3a -CO2R 3a and -CONR 3a R 3b ; R 3a and R 3b Each is independently selected from hydrogen, substituted or unsubstituted -C. 1-6 Alkyl, substituted or unsubstituted -C3-C6 cycloalkyl, substituted or unsubstituted 3- to 12-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 4 Selected from substituted or unsubstituted -C 1-3 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 5 Selected from hydrogen, halogen, substituted or unsubstituted -C 1-3 Alkyl, substituted or unsubstituted -C 3-6 cycloalkyl, substituted or unsubstituted 3- to 6-membered heterocyclic groups, substituted or unsubstituted -C6-C 12 Aryl and substituted or unsubstituted 5 to 12-membered heteroaryl groups; R 6 Selected from hydrogen and substituted or unsubstituted -C 1-3 alkyl; R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, substituted or unsubstituted -C. 1-6 Alkyl groups and -CN; R 10a and R 10b Each is independently selected from hydrogen and substituted or unsubstituted -C. 1-3 Alkyl; or R 10a and R 10b Together with the atoms they are attached to, they form 3 to 6 substituted or unsubstituted rings, which contain 0 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; R 11a R 11b R 12a R 12b R 13a and R 13b Each is independently selected from hydrogen, halogen, and substituted or unsubstituted -C. 1-3 alkyl.

2. The compound of claim 1, wherein: R 1 Selected from hydrogen, halogens, -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a and -CONR 1a R 1b Wherein -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally selected from at least one of R 1c Substituents of the substituents; R 1a and R 1b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 1d replace; R 1c and R 1d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 2-6 alkynyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxo and -CN, wherein the -C 1-6 Alkyl, -C 2-6 alkynyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 1j Replace; or Two Rs 1c Together with the atoms they are attached to and any intermediate atoms, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-6 Alkyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1j Selected from halogens, -C 1-6 Alkyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; wherein the -C 1-6 Alkyl, -C 2-6 alkynyl group, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl and 5- to 12-membered heteroaryl groups is optionally substituted by at least one substituent selected from -NH2, -OH, or alkynyl.

3. The compound of claim 1, wherein: R 1 Selected from hydrogen, halogens, -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1a -NR 1a R 1b -COR 1a -CO2R 1a and -CONR 1a R 1b Wherein -C 1-6 Alkyl, -C 3-8 cycloalkyl, 3 to 8-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally selected from at least one of R 1c Substituents of the substituents; R 1a and R 1b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 1d replace; R 1c and R 1d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxo and -CN, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; or Two Rs 1c Together with the atoms they are attached to and any intermediate atoms, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-6 Alkoxy, C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 2 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 2a -NR 2a R 2b -COR 2a -CO2R 2a and -CONR 2a R 2b Wherein -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 2c replace; R 2a and R 2b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 2c Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 2d -COR 2d -CO2R 2d -CONR 2d R 2e -NR 2d R 2e -NR 2d COR 2e -NR 2d CO2R 2e Oxygenated and -CN; R 2d and R 2e Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 3 Selected from hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -COR 3a -CO2R 3a and -CONR 3a R 3b Wherein -C 1-6 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 3c replace; R 3a and R 3b Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 3d replace; R 3c and R 3d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 3e -COR 3e -CO2R 3e -CONR 3e R 3f -NR 3e R 3f -NR 3e COR 3f -NR 3e CO2R 3f , oxidized and -CN; wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 3e and R 3f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-8 Alkyl, -C3-C8 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 4 Selected from -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 6-membered heteroaryl group is optionally selected from at least one of R 4a Substituents of the substituents; R 4a Independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 4b -COR 4b -CO2R 4b -CONR 4b R 4c -NR 4b R 4c -NR 4b COR 4c -NR 4b CO2R 4c Oxygenated and -CN; R 4b and R 4c Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 5 Selected from hydrogen, halogens, -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-3 Alkyl, -C 3-6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5 to 12 heteroaryl groups is optionally substituent R. 5a replace; R 5a Independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 aryl, 5- to 12-membered heteroaryl, -OR 5b -COR 5b -CO2R 5b -CONR 5b R 5c -NR 5b R 5c -NR 5b COR 5c -NR 5b CO2R 5c Oxygenated and -CN; R 5b and R 5c Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 aryl and 5 to 12-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 12-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 12-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 6 Selected from hydrogen and -C 1-3 Alkyl, wherein the -C 1-3 Alkyl groups are optionally selected from at least one halogen, -C 1-6 Substituents in the group consisting of alkoxy groups and -OH groups; R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl and -CN, wherein the -C 1-6 Alkyl groups are optionally selected from at least one halogen, -C 1-6 Substituents in the group consisting of alkoxy groups and -OH groups; R 10a and R 10b Each is independently selected from hydrogen and -C. 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or R 10a and R 10b Together with the atoms they are attached to, they form 3 to 6-membered rings, which contain 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and are optionally substituted by at least one substituent selected from halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2 and oxo; R 11a R 11b R 12a R 12b R 13a and R 13b Each is independently selected from hydrogen, halogen, and -C. 1-3 Alkyl, wherein the -C 1-3 Alkyl groups are optionally surrounded by at least one element selected from hydrogen, halogen, -OH, and -C. 1-3 Substitution of alkoxy groups.

4. The compound according to any one of claims 1-3, wherein the compound is of formula (II). (II), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

5. The compound according to any one of claims 1-3, wherein the compound is of formula (III). (III), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

6. The compound according to any one of claims 1-3, wherein the compound is of formula (IV). (IV), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

7. The compound according to any one of claims 1-3, wherein the compound is of formula (V). (V)， Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

8. The compound according to any one of claims 1-3, wherein the compound is of formula (VI). (WE), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

9. The compound according to any one of claims 1-3, wherein the compound is of formula (VII). (VII), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

10. The compound according to any one of claims 1-3, wherein the compound is of formula (VIII). (VIII), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

11. The compound according to any one of claims 1-3, wherein the compound is of formula (IXa) or (Ixb). (IXa) or (IXb), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

12. The compound of claim 2 or 3, wherein the compound is of formula (Xa) or (Xb). (Far) or (Xb), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue, wherein: Ring A is a 5- to 6-membered heterocyclic group containing one or two heteroatoms selected from N and O; and n4 can be 1, 2, 3, or 4.

13. The compound of claim 12, wherein the compound is of formula (XIa), (XIb), (XIc), (XId), or (XIe): (XIa)、 (XIb), (XIc)、 (XId)、 (XIe), Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

14. The compound of claim 12, wherein the compound is of formula (XIIa), (XIIb), (XIIc), (XIId), or (XIIe): (XIIa), (XIIb)、 (XIIc)、 (XIId)、 (12th century) Or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analogue.

15. The compound according to any one of claims 1-5, wherein X is -O-.

16. The compound according to any one of claims 1-9, wherein n1 + n2 ≤ 3.

17. The compound of claim 16, wherein n1 is 0 and n2 is 2.

18. The compound according to any one of claims 1-9, wherein yes , , or ,in This refers to the position where the phenyl group is attached, and This refers to the position where it connects to the pyrrole group.

19. The compound according to any one of claims 1-11, wherein R 1 Selected from hydrogen, halogens, -C 1-6 Alkyl, -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 aryl and 5 to 10-membered heteroaryl, wherein the -C 1-6 Alkyl, -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituent R. 1c replace; R 1c Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 10-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxidized and -CN; wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 12-membered heteroaryl, -CN, -OH, -NH2, and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 aryl and 5 to 10-membered heteroaryl, wherein the -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

20. The compound of claim 19, wherein R 1 Selected from hydrogen, -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 aryl and 5 to 10-membered heteroaryl, wherein the -C 3-6 cycloalkyl, 5- to 6-membered heterocyclic, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituent R. 1c replace; R 1c Each is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 10-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f Oxygenated and -CN; R 1e and R 1f Each is independently selected from hydrogen and -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 Aryl and 5 to 10 heteroaryl compounds.

21. The compound according to any one of claims 1-11, wherein R 1 for Where ring A is a 5- to 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from N and O; R 1c Each is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5- to 10-membered heteroaryl, -OR 1e -COR 1e -CO2R 1e -CONR 1e R 1f -NR 1e R 1f -NR 1e COR 1f -NR 1e CO2R 1f , oxidized and -CN; wherein the -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Each of the aryl group and the 5- to 10-membered heteroaryl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituted by at least one substituent selected from halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2 and oxo; R 1e and R 1f Each is independently selected from hydrogen and -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 10-membered heterocyclic groups, -C6-C 12 Aryl and 5- to 10-membered heteroaryl groups; n4 can be 0, 1, 2, 3, or 4.

22. The compound of claim 21, wherein R 1 for Where Y is -O- or -N(H)-; R 1c -C 1-3 Alkyl or -C3-C6 cycloalkyl, wherein the -C 1-3 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and the rings are optionally substituted by at least one substituent selected from halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2 and oxo; n4 can be 1, 2, 3, or 4.

23. The compound of claim 22, wherein R 1 for ; n4 can be 1, 2, 3, or 4; R 1c The group is methyl, ethyl, propyl, or cyclopropyl, wherein each of the methyl, ethyl, propyl, and cyclopropyl groups is optionally substituted by at least one substituent selected from: halogen, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo.

24. The compound of claim 21, wherein R 1 for , or ; n4 can be 1, 2, 3, or 4; R 1c The group is methyl, ethyl, propyl, or cyclopropyl, wherein each of the methyl, ethyl, propyl, and cyclopropyl groups is optionally substituted by at least one substituent selected from: halogen, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo; or Two identical or adjacent R 1c Together with the atoms they are attached to, they form 3 to 6-membered unsaturated or saturated rings, the rings containing 0 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the rings are optionally substituted by at least one substituent selected from: halogens, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo.

25. The compound of claim 1 or 2, wherein R 1 for ; n4 is 1, 2, or 3; R 1c It is methyl, ethyl, or propyl, wherein each of the methyl, ethyl, and propyl groups is optionally substituent R. 1j replace; R 1j The group is selected from halogens, -C3-C6 cycloalkyl groups, and 3- to 6-membered heterocyclic groups, wherein each of the -C3-C6 cycloalkyl groups and 3- to 6-membered heterocyclic groups is optionally substituted by at least one substituent selected from: halogens, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, -CN, -OH, -NH2, and oxo.

26. The compound of claim 23 or 24, wherein R 1c The group is methyl, ethyl, propyl, or cyclopropyl, wherein each of the methyl, ethyl, propyl, and cyclopropyl groups is optionally substituted by at least one substituent selected from: halogen, -C 1-3 Alkoxy, C3-C6 cycloalkyl, -CN, -OH, -NH2 and oxo; and n4 is 1.

27. The compound according to any one of claims 1-2, wherein R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

28. The compound according to any one of claims 1-27, wherein R 2 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the -C 1-6 Alkyl, -C 3-6 Each of the cycloalkyl group and the 3- to 6-membered heterocyclic group is optionally substituent R. 2c replace; R 2c Each is independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -OR 2d -COR 2d -CO2R 2d -CONR 2d R 2e -NR 2d R 2e -NR 2d COR 2e -NR 2d CO2R 2e Oxygenated and -CN; R 2d and R 2e Each is independently selected from hydrogen and -C 1-3 Alkyl and -C3-C6 cycloalkyl, wherein the -C 1-3 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-3 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -CN, -OH, -NH2, and oxo.

29. The compound of claim 28, wherein R 2 Each is independently selected from hydrogen, methyl, ethyl, and propyl.

30. The compound according to any one of claims 1-29, wherein R 2 Each is independently selected from hydrogen, methyl, ethyl, and propyl; and n3 is either 1 or 2.

31. The compound according to any one of claims 1-30, wherein R 3 Independently selected from hydrogen, -C 1-6 Alkyl, -C 3-6 cycloalkyl, -COR 3a -CO2R 3a and -CONR 3a R 3b Wherein -C 1-6 Alkyl and -C 3-6 Each of the cycloalkyl groups is optionally substituent R. 3c replace; R 3a and R 3b Each is independently selected from -C 1-6 Alkyl, -C3-C6 cycloalkyl and 3 to 12-membered heterocyclic groups, wherein the -C 1-6 Each of the alkyl, -C3-C6 cycloalkyl, and 3- to 12-membered heterocyclic groups is optionally substituented by at least one R group. 3d replace; R 3c and R 3d Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, and -CN; wherein the -C 1-6 Each of the alkyl group, -C3-C6 cycloalkyl group, and 3- to 6-membered heterocyclic group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

32. The compound of claim 31, wherein R 3 Independently selected from hydrogen, -COR 3a -CO2R 3a and -CONR 3a R 3b ; R 3a and R 3b Each is independently selected from -C 1-6 Alkyl, -C3-C6 cycloalkyl and 3 to 6-membered heterocyclic groups, wherein the -C 1-6 Each of the alkyl, -C3-C6 cycloalkyl, and 3- to 6-membered heterocyclic groups is optionally substituented by at least one R group. 3d replace; R 3d Each is independently selected from halogens, -C 1-3 Alkyl, -C3-C6 cycloalkyl and -CN, wherein the -C 1-3 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -CN, -OH, -NH2, and oxo.

33. The compound of claim 32, wherein R 3 For H, , , , , , , , , , , , , , , , , , , , , or .

34. The compound according to any one of claims 1-33, wherein R 4 Selected from -C 1-3 Alkyl, -C 3-6 cycloalkyl groups and 3 to 6-membered heterocyclic groups, wherein the -C 1-3 Alkyl, -C 3-6 Each of the cycloalkyl group and the 3- to 6-membered heterocyclic group is optionally substituent R. 4a replace; R 4a Independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, -OR 4b NR 4b R 4c Oxygenated and -CN; R 4b and R 4c Each is independently selected from hydrogen and -C 1-6 Alkyl and -C3-C6 cycloalkyl.

35. The compound of claim 34, wherein R 4 Selected from -C 1-3 Alkyl and -C 3-6 Cycloalkyl.

36. The compound of claim 35, wherein R 4 It is independently selected from methyl, ethyl and propyl.

37. The compound according to any one of claims 1-36, wherein R 5 Selected from hydrogen, halogens, -C 1-3 Alkyl and -C 3-6 cycloalkyl, wherein the -C 1-3 Alkyl and -C 3-6 Each of the cycloalkyl groups is optionally substituent R. 5a replace; R 5a Independently selected from hydrogen, halogen, -C 1-3 Alkyl, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -OR 5b -NR 5b R 5c Oxygenated and -CN; R 5b and R 5c Each is independently selected from hydrogen and -C 1-6 Alkyl and -C3-C6 cycloalkyl, wherein the -C 1-6 Each of the alkyl group and the -C3-C6 cycloalkyl group is optionally substituted by at least one substituent selected from the following: halogen, -C 1-6 Alkoxy, -C3-C6 cycloalkyl, 3- to 6-membered heterocyclic groups, -C6-C 12 Aryl, 5 to 12-membered heteroaryl, -CN, -OH, -NH2 and oxo.

38. The compound of claim 37, wherein R 5 Selected from hydrogen, halogens, -C 1-3 Alkyl and -C 3-6 Cycloalkyl.

39. The compound of claim 38, wherein R 5 It is independently selected from methyl, ethyl and propyl.

40. The compound according to any one of claims 1-39, wherein R 4 It is methyl and R 5 It is a methyl group.

41. The compound according to any one of claims 1-7 and 15-40, wherein R 6 Selected from hydrogen and -C 1-3 alkyl.

42. The compound of claim 41, wherein R 6 It is hydrogen.

43. The compound according to any one of claims 1-42, wherein R 7 R 8 and R 9 Each is independently selected from hydrogen, halogen, -C 1-6 Alkyl groups and -CN.

44. The compound of claim 43, wherein R 7 R 8 and R 9 Each is hydrogen.

45. The compound according to any one of claims 1-8 and 15-44, wherein R 10a and R 10b Each is independently selected from hydrogen and -C. 1-3 Alkyl; or R 10a and R 10b Together with the atoms they are attached to, they form cyclopropyl, cyclobutyl, or cyclopentyl groups.

46. ​​The compound according to any one of claims 1-8 and 15-45, wherein R 10a and R 10b -C 1-3 alkyl.

47. The compound of claim 45 or 46, wherein R 10a and R 10b Both are methyl groups.

48. The compound according to any one of claims 1-6 and 15-47, wherein R 11a R 11b R 12a R 12b R 13a and R 13b Each is independently selected from hydrogen, halogen, and -C. 1-3 alkyl.

49. The compound of claim 48, wherein R 11a R 11b R 12a R 12b R 13a and R 13b Each is hydrogen.

50. A compound or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue thereof, wherein the compound is selected from: 。 51. A pharmaceutical composition comprising the compound of any one of claims 1-50 or its N-oxide, a pharmaceutically acceptable salt, stereoisomer, tautomer or deuterated analog, and a pharmaceutically acceptable excipient.

52. A method of treating cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of any one of claims 1-50, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, or the pharmaceutical composition of claim 511.

53. The method of claim 52, wherein the cancer is pancreatic cancer, colorectal cancer, lung cancer, stomach cancer, esophageal cancer, ovarian cancer, or uterine cancer.

54. A method of treating a subject with RAS protein-related disease, the method comprising administering to the subject a therapeutically effective amount of any one of claims 1-50, or its N-oxide, pharmaceutically acceptable salt, stereoisomer, tautomer, or deuterated analogue, or the pharmaceutical composition of claim 51.

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