Macrocyclic compounds as ras inhibitors for the treatment of cancer

Abstract

Related to macrocyclic compounds and therapeutic uses thereof. Disclosed a compound of formula (I), or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt, and their use for the preparation of a medicament of treatment of cancer. Provided herein are useful compounds for the inhibition of RAS mutant and the compound shows good inhibitory activity against RAS.

Description

TECHNICAL FIELD The present invention belongs to the field of medicine, and specifically, relates to macrocyclic compounds with stereoisomers, pharmaceutically acceptable salts, solvates, eutectic or deuterated compounds, and their used in the treatment of RAS protein-mediated related diseases BACKGROUND The RAS protein (including KRAS4A, KRAS4B, HRAS, and NRAS) is a small, membrane-bound guanine nucleotide-binding protein that acts as a molecular switch by cycling between an active GTP-bound state and an inactive GDP-bound state. When RAS binds to GEF family proteins such as S0S1, its conformation changes, reducing its affinity for GDP and causing its dissociation from GDP and binding to GTP in the high concentration in the environment, thus becoming active. In normal cells, activation of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) promotes the exchange of GDP and GTP in RAS, activating RAS, which plays a key role in regulating cell survival, proliferation, and differentiation through multiple cascading reactions, including the PI3K-AKT-mT0R, RAF-MEK-ERK, and RALGDS-RAL pathways. Mutations in RAS are often driving forces for carcinogenesis and tumor development, as they disrupt the guanine exchange cycle and lock RAS in the activated state, continuously activating downstream signaling pathways and leading to the development of tumors. RAS mutations occur in approximately 19% of all cancers and play an important role in tumor occurrence and progression. Among them, KRAS is the most commonly mutated subtype, followed by NRAS and HRAS. KRAS mutations commonly occur in pancreatic ductal adenocarcinoma, lung adenocarcinoma, and colorectal adenocarcinoma, while NRAS mutations have a relatively higher frequency in hematologic malignancies such as chronic myeloid leukemia and acute myeloid leukemia, as well as in malignant melanoma, thyroid cancer, and laryngeal cancer. HRAS mutations are less common in human cancers, but have a relatively higher mutation rate in head and neck squamous cell carcinoma, bladder cancer, salivary gland carcinoma, and oral cancer. In May 2021, the FDA approved AMG510 of Amgen, making it the first approved KRAS-targeted drug of the world for the treatment of patients with locally advanced or advanced non-small cell lung cancer harboring mutations in the KRAS G12C gene, this also marked a major breakthrough in the treatment of KRAS G12C mutations. In December 2022, MRTX849 of Mirati therapeutics was also successfully approved for marketing in United States, which was the second marketed oral inhibitor in the world that specifically optimizes the KRAS G12C mutant. The approval of these two drugs marked a successful breakthrough in KRAS, the most difficult druggable target in history, and has become a milestone achievement. However, in the current clinical research, mutations of various subtypes of RAS protein (KRAS, NRAS and HRAS) was reflected in pan-tumor species, and the treatment of a single mutation could not improve the objective remission rate of patients. At present, there are no highly effective inhibitors to meet various clinical needs, and the emergence of RAS molecular glue is expected to successfully solve this problem. The RAS molecular glue can simultaneously bind to highly activated RAS (RAS-ON) proteins and a ubiquitously expressed protein in cells, forming a tricomplex to occupy binding sites for RAS interacting proteins such as S0S1 and RAFI, keeping RAS protein in a locked state alone, unable to activate downstream signaling pathways, thereby blocking RAS signaling pathway transmission and inhibiting tumor growth. Therefore, there is an urgent clinical need to develop an inhibitor of RAS molecular glue type with good activity and high druggability. SUMMARY OF THE INVENTION Provided herein are Ras inhibitors as molecular glues. The approach described herein entails formation of a high affinity three-component complex between a synthetic ligand and two intracellular proteins which do not interact under normal physiological conditions: The target of interest (e.g. Ras), and a widely expressed cytosolic chaperone in cells (e.g. cyclophilin A). More specifically, in some embodiments, the Ras molecular glues described herein induce a new binding pocket in Ras by forming a three-component complex with high-affinity between the Ras protein and the cytosolic chaperone, cyclophilin A. Without being bound by theory, the inventors believe that one way the inhibitory effect on Ras is effected by compounds of the invention and the three-component complexes they form is by steric occlusion of the interaction site between Ras and downstream effector molecules, such as RAF and PI3K, which are required for propagating the oncogenic signal. In the first aspect, the present invention provides a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I); wherein n is 0, 1, 2, or 3; A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; B is selected from optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; G is optionally substituted Ci_6 alkylene; R8 and R9 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci_3 alkyl, or R8 and R9 combine with the atoms to which they are attached to form an optionally substituted C3_6 cycloalkyl or a carbonyl; R10 and R11 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci_3 alkyl, or R10 and R11 combine with the atoms to which they are attached to form an optionally substituted C3_g cycloalkyl or a carbonyl; R12 and R13 are each independently selected from hydrogen, deuterium, halogen, hydroxy, optionally substituted Ci_3 alkyl, -O(Ci_g alkyl), -S(Ci_g alkyl) or -N(Ci_g alkyl)(Ci_g alkyl); furthermore, the Ci_g alkyl may be further optionally substituted; Ra is optionally substituted C3_g cycloalkyl, optionally substituted C3_g heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; Rb is selected from hydrogen, Ci-g alkyl, Ci^ alkoxyl, Ci-g haloalkyl, Ci.ghaloalkoxyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3.g heterocycloalkyl (or 4 to 7- membered heterocycloalkyl); or provided that when n exceeds 1, any two of RB combine with the atoms to which they are attached to form a 3 to 6-membered ring, wherein the ring can be optionally substituted with halogen, hydroxy, and Ci_3 alkyl; X1 is N or C; X2 is N or -CRa-; X3 is N or -CRb-; X4 is N or -CRC-; X5 is N or C; X6 is S, O, N, or -CH-; Ra, Rb, and Rc are each independently hydrogen, halogen, cyano, Ci-3 alkyl, Ci-3 alkoxyl, Ci-3 haloalkyl, Ci-3 haloalkoxyl, C3.g cycloalkyl, or C3.g heterocycloalkyl (or 4 to 7-membered heterocycloalkyl); R3 is absent, or selected from hydrogen, Ci-g alkyl, or Ci-g haloalkyl, provided that when X6 is O or S, R3 is absent; E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-g alkyl, optionally substituted Ci-g alkoxyl, Ci-g aminoalkyl, Ci-g hydroxyalkyl, or -NReRf; wherein Re and Rf are independently selected from hydrogen, or optionally substituted Ci-g alkyl; R4 is hydrogen, optionally substituted Ci-g alkyl, optionally substituted Ci-g heteroalkyl, optionally substituted C3.io cycloalkyl, optionally substituted C3.io cycloalkenyl, optionally substituted C3.io heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally R6 Rl^Ny substituted 5 to 10-membered heteroaryl, or ' ; R5 is hydrogen, Ci-g alkyl or C3.g cycloalkyl, furthermore, the Ci-g alkyl or C3.g cycloalkyl may be further optionally substituted; or R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl; wherein L is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rg is optionally substituted C i-6 alkyl; R6 is hydrogen, or optionally substituted Ci_6 alkyl; R7 is optionally substituted Ci_6 alkyl, optionally substituted Ci_6 heteroalkyl, optionally substituted C3_io cycloalkyl, optionally substituted C3_i0 heterocycloalkyl (or 3 to 10-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6 and R7 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl. In the second aspect, the present invention provides a pharmaceutical composition comprising the compound according to the first aspect the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In the third aspect, the present invention provides a use of the compound according to the first aspect the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof in the preparation of a medicament used for the treatment of cancer. DESCRIPTION OF THE DRAWINGS Fig.l The reference compound and the representative Compound A significantly inhibited the interaction of RAFI with active RASMutailt protein or RASWT protein. Fig. 2 The reference compound and the representative Compound A significantly inhibited the cell viability of KRAS mutant cells. Fig. 3 Tumor volume changes and tumor growth inhibition ratio (TGI) after administrating vehicle or test articles to female Balb / c nude mice bearing HPAC PDAC tumors. Data endpoints represent mean ± SEM. p.o.: oral administration; QD: once a day; mpk: mg / kg. Fig. 4 Tumor volume changes and tumor growth inhibition ratio (TGI) after administrating vehicle or test articles to female Balb / c nude mice bearing PK59 PDAC tumors. Data endpoints represent mean ± SEM. p.o.: oral administration; QD: once a day; mpk: mg / kg. Fig. 5 Tumor volume changes and tumor growth inhibition ratio (TGI) after administrating vehicle or test articles to male Balb / c nude mice bearing HPAC PDAC tumors. Data endpoints represent mean ± SEM. p.o.: oral administration; QD: once a day; mpk: mg / kg. Fig. 6 Tumor volume changes and tumor growth inhibition ratio (TGI) after administrating vehicle or test articles to male Balb / c nude mice bearing LU99 NSCLC tumors. Data endpoints represent mean ± SEM. p.o.: oral administration; QD: once a day; mpk: mg / kg. Fig. 7 and Fig. 8 Bioluminescence signal changes tumor growth inhibition ratio (TGI) after administrating vehicle or test articles to female BALB / c nude mice bearing NCI-H1373-luc intracranial tumors. Data endpoints represent mean ± SEM. EMBODIMENTS FOR CARRYING OUT THE INVENTION After extensive and in-depth research, the inventors have unexpectedly developed a kind of novel compounds that can effectively inhibit the interaction of RAFI with active RASMutant protein or RASWT 5 protein and proliferation of KRAS-related tumor cells. In addition, some compounds of the present invention also showed significantly improved activity than the positive control compounds (such as compound Ref. 1) in animal model studies, even though the compounds of the present invention showed similar activities to in the positive control compounds in vitro studies. The present invention is completed on this basis. 10 In one aspect, the present invention provides a compound of formula (I): (I) or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt, wherein the variables are as described above. In some embodiments, R8, R9, R10, R11, R12 and R13 is Ho 15 In some embodiments, the compound of formula (I) is a compound of formula (1-1) (1-1) wherein X1, X2, X3, X4, X5, X6, A, B, E, G, RA, RB, R3, R4, R5 and n are as defined in formula I. In some embodiments, B is optionally substituted In some embodiments, B is optionally substituted In some embodiments, In some embodiments, RA is In some embodiments, R1 is selected from the group con sisting of hydrogen, Ci-g alkyl, Ci-g alkoxyl, Ci.g haloalkyl, Ci.g haloalkoxyl, Ci-g hydroxyalkyl, Ci-g aminoalkyl, optionally substituted C3.g cycloalkyl, optionally substituted Cvg heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2 alkylcnc-Cvg cycloalkyl, optionally substituted -C1-2 alkylcnc-Cvg heterocycloalkyl, optionally substituted -C1-2 alkylene-5 to 8-membered aryl, optionally substituted -C1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic heteroaryl (preferably, R1 is selected from the group consisting of hydrogen, Ci-g alkyl, Ci-g alkoxyl, Ci-g haloalkyl, Ci-g haloalkoxyl, Ci-g hydroxyalkyl, Ci.g aminoalkyl, optionally substituted C3.g cycloalkyl, optionally substituted CVg hctcrocyclo-alkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, and optionally substituted 8 to 10-membered fused bicyclic heteroaryl); furthermore, the Ci-g alkyl, Ci-g alkoxyl, Ci-g haloalkyl, Ci.g haloalkoxyl, Ci-ghydroxyalkyl (preferably the Ci.g alkyl) may be further optionally substituted. In some embodiments, R1 is optionally substituted -Ci^alkylcnc-Cvgcycloalkyl. optionally substituted -Ci-2 alkylene-Cs-g heterocycloalkyl, optionally substituted -C1-2 alkylene-5 to 8-membered aryl, optionally substituted -C1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic heteroaryl; preferably, is optionally substituted -C1-2 alkylcnc-Cvg cycloalkyl, optionally substituted -Ci-2 alkylene-C3_g heterocycloalkyl; more preferably, optionally substituted -methylene-C3_g heterocycloalkyl. In some embodiments, “C3_g heterocycloalkyl” is selected from heterocycloalkyl for R1 as defined in formula VI, VII or VIII. In some embodiments, in R1, when the Ci_g alkyl, Ci_g alkoxyl, Ci_g haloalkyl, Ci_g haloalkoxyl, or Ci_g hydroxyalkyl (preferably, the Ci_g alkyl) is further substituted, the substituent is selected from the group consisting of Ci_g alkyl, Ci_g alkoxyl, Ci_g haloalkyl, Ci_g haloalkoxyl, Ci_g hydroxyalkyl, Ci_g aminoalkyl, optionally substituted C3_g cycloalkyl, optionally substituted C3_g heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; preferably, the substituent is selected from the group consisting of optionally substituted C3.g cycloalkyl, optionally substituted C3.g heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; more preferably, the substituent is optionally sub stituted C3_g heterocycloalkyl. In some embodiments, in R1, optionally substituted means unsubstituted or being substituted with one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of deuterium, halogen, Ci_g alkyl, Ci_6hydroxyalkyl, Ci_g deuteroalkyl, C3_g cycloalkyl, C3_gheterocycloalkyl, -CONR'R" (e.g., -CON(Ci_6al-0 II .                                                    . .. N=S— kyl)2), -S(O)2R (e.g., - S(O)2(Ci_6 alkyl)), and -S(O)(=N-R1)R11 (e.g., / I ). In some embodiments, in R1, optionally substituted means unsubstituted or being substituted with one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of deuterium, halogen, Ci^ alkyl, Ci-6 hydroxy alkyl, and Ci-g deuteroalkyl. In some embodiments, R1 is -(CH2)-R1, and R1 is as defined in formula VI, VII, or VIII. In some embodiments, RM and RN are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, Ci^ alkyl, Ci^alkoxyl, Ci-g haloalkyl, Ci-g haloalkoxyl, Ci^ hydroxyalkyl, Ci-g aminoalkyl, optionally substituted C3.g cycloalkyl, optionally substituted C3.g heterocycloalkyl; furthermore, the Ci-g alkyl, Ci.galkoxyl, Ci-ghaloalkyl, Ci.g haloalkoxyl, Ci-g hydroxyalkyl may be further optionally substituted. In some embodiments, RM and RN are each independently selected from hydrogen, and Ci-g alkyl. In some embodiments, Y is -CH- or N; preferably, Y is N. In some embodiments, R2 is optionally substituted Ci-g alkoxy, or optionally substituted Ci-g alkyl; preferably, R2 is optionally substituted Ci_g alkyl. In some embodiments, in R2, optionally substituted means unsubstituted or being substituted with one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of deuterium, Ci.g alkoxy, Ci.g deuteroalkoxy, and Ci_g haloalkoxy. A In some embodiments of the present disclosure, B is H , R is optionally substituted phenyl or optionally substituted 6-membered heteroaryl; in some embodiments, the compound of formula (I) is a compound of formula (II): R1 (II) or a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; G is optionally substituted Ci_6 alkylene; Yis -CH- orN; R8 and R9 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci_3 alkyl, or R8 and R9 combine with the atoms to which they are attached to form an optionally substituted C3_g cycloalkyl or a carbonyl; R10 and R11 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci-3 alkyl, or R10 and R11 combine with the atoms to which they are attached to form an optionally substituted C3.g cycloalkyl or a carbonyl; R12 and R13 are each independently selected from hydrogen, deuterium, halogen, hydroxy, optionally substituted Ci-3 alkyl, -O(Ci.g alkyl), -S(Ci-6 alkyl) or -N(Ci-6 alkyl)(Ci.g alkyl); furthermore, the Ci-6 alkyl may be further optionally substituted;Y is -CH- or N; X1 is N or C; X2 is N or -CRa-; X3 is N or -CRb-; X4 is N or -CRC-; X5 is N or C; X6 is S, O, N, or -CH-; Ra, Rb, and Rc are each independently hydrogen, halogen, cyano, Ci-3 alkyl, Ci-3 alkoxyl, Ci-3 haloal-kyl, Ci.3 haloalkoxyl, C3.g cycloalkyl, or C3.g heterocycloalkyl (or 3 to 6-membered heterocycloalkyl); R1 is selected from hydrogen, Ci^ alkyl, Ci-6 alkoxyl, Ci^ haloalkyl, Ci-6 haloalkoxyl, Ci^ hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3.g cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the Ci-g alkyl, Ci-g alkoxyl, Ci-g haloalkyl, Ci-g haloalkoxyl, and Ci.g hydroxyalkyl may be further optionally substituted; R2 is optionally substituted Ci-g alkoxy, or optionally substituted Ci-g alkyl; Rm and Rn are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-g alkyl, Ci-g alkoxyl, Ci-g haloalkyl, Ci-g haloalkoxyl, Ci-g hydroxyalkyl, Ci-g aminoalkyl, optionally substituted C3.g cycloalkyl, optionally substituted C3.g heterocycloalkyl (or 4 to 7-membered heterocycloalkyl); furthermore, the Ci-g alkyl, Ci-g alkoxyl, Ci.g haloalkyl, Ci.g haloalkoxyl, and Ci.ghydroxyalkyl may be further optionally substituted; R3 is absent, or selected from hydrogen, Ci-g alkyl, or Ci.g haloalkyl, provided that when X6 is O or S, R3 is absent; E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci_g alkyl, optionally substituted Ci_g alkoxyl, Ci_g aminoalkyl, Ci_g hydroxyalkyl, or -NReRf; wherein Re and Rf are each independently selected from hydrogen, or optionally substituted Ci_g alkyl; R4 is hydrogen, optionally substituted Ci_g alkyl, optionally substituted Ci_g heteroalkyl, optionally substituted C3_i0 cycloalkyl, optionally substituted C3_i0 cycloalkenyl, optionally substituted C3_i0 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally R6 Rl^Ny substituted 5 to 10-membered heteroaryl, or * ; R5 is hydrogen, Ci^ alkyl or C3.g cycloalkyl, furthermore, the Ci.g alkyl or C3.g cycloalkyl may be further optionally substituted; or R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl. wherein L is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rg is optionally substituted Ci_g alkyl; R6 is hydrogen, or optionally substituted Ci_g alkyl; R7 is optionally substituted Ci_g alkyl, optionally substituted Ci_g heteroalkyl, optionally substituted C3_io cycloalkyl, optionally substituted C3_i0 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6 and R7 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl. In some embodiments, X1 is C, and / or X2is -CRa-(preferably -CH-), and / or X3is -CRb-(preferably -CH-), and / or X4 is -CRc-(preferably -CH-), and / or X5 is -C-. In some embodiments, Ra, Rb, and Rc are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-3 alkyl, Ci-3 alkoxyl, Ci-3 haloalkyl, and Ci-3 haloalkoxyl; preferably, Ra, Rb, and Rc are each independently hydrogen, or Ci-3 alkyl. In some embodiments of the present disclosure, X1, X2, X3, X4 and X5 are -CH-, RM and RN are hydrogen. 8    9     10    11     12          13 In some embodiments of the present disclosure, R , R , R , R , R and R are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci-3 alkyl; preferably, R8, R9, R10, R11, R12 and R13 are each independently hydrogen. In some embodiments, the compound of formula (II) is a compound of formula (II-1) (H-1) wherein X1, X2, X3, X4, X5, X6, A, B, E, G, Y, RM, RN, R1, R3, R4, R5 and n are as defined in formula In some embodiments, the compound of formula (II) is a compound of formula (III) or a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; G is optionally substituted Ci_6 alkylene; Yis -CH- orN; X6 is S, O, N, or -CH-; Ra and Rb are each independently hydrogen, halogen, cyano, Ci_3 alkyl, Ci_3 alkoxyl, Ci_3 haloalkyl, Ci_3 haloalkoxyl, C3_6 cycloalkyl, or C3_6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl); R1 is selected from hydrogen, Ci_6 alkyl, Ci_6 alkoxyl, Ci_6 haloalkyl, Ci_6 haloalkoxyl, Ci_6 hydroxyalkyl, Ci_6 aminoalkyl, optionally substituted C3_6 cycloalkyl, optionally substituted C3_6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, and Ci-6 hydroxyalkyl may be further optionally substituted; R2 is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl; R3 is absent, or selected from hydrogen, Ci-6 alkyl, or Ci^ haloalkyl, provided that when X6 is O or S, R3 is absent; E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci_6 alkyl, optionally substituted Ci_6alkoxyl, Ci_6 aminoalkyl, Ci_6 hydroxyalkyl, or -NReRf; wherein Re and Rf are independently selected from hydrogen, or optionally substituted Ci_6 alkyl; R4 is hydrogen, optionally substituted Ci_6 alkyl, optionally substituted Ci_6 heteroalkyl, optionally substituted C3_i0 cycloalkyl, optionally substituted C3_i0 cycloalkenyl, optionally substituted C3_i0 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally R6 substituted 5 to 10-membered heteroaryl, or ' ; R5 is hydrogen, Ci_6 alkyl or C3_6 cycloalkyl, furthermore, the Ci_6 alkyl or C3_6 cycloalkyl may be further optionally substituted; or R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl; wherein L is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rg is optionally substituted Ci-6 alkyl; R6 is hydrogen, or optionally substituted Ci-6 alkyl; R7 is optionally substituted Ci^ alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-io cycloalkyl, optionally substituted C3.io heterocycloalkyl (or 3 to 10-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6 and R7 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl. Furthermore, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, C3_3 heterocycloalkyl (or 4 to 6-membered heterocycloalkyl), C3.g heterocycloalkyl (or 4 to 7- membered heterocycloalkyl), 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, Ci-6 heteroalkyl, C3.io heterocycloalkyl, 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl or 4 to 11-membered bicyclic heterocycloalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1 to 4. In some embodiments of the present disclosure, the compound of formula (III) is a compound of formula (IVa) or formula (IVb): or a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; G is optionally substituted Ci-6 alkylene; Yis -CH- orN; X6 is S, O, N, or -CH-; Ra and Rb are each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, C1-3 haloalkoxyl, C3.6 cycloalkyl, C3.6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl); R1 is selected from hydrogen, Ci^ alkyl, C1-6 alkoxyl, Ci^ haloalkyl, C1-6 haloalkoxyl, Ci^ hydroxyalkyl, C1-6 aminoalkyl, optionally substituted C3.6 cycloalkyl, optionally substituted C3.6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the C1-6 alkyl, C1-6 alkoxyl, C1-6haloalkyl, Ci-6 haloalkoxyl, Ci^ hydroxyalkyl may be further optionally substituted; In some embodiments, R1 is optionally substituted Ci_6 alkyl; preferably, in R1, the Ci_6 alkyl is further substituted, the substituent is selected from optionally substituted C3_6 cycloalkyl, optionally substituted C3_6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; more preferably, the substituent is optionally substituted C3_6 heterocycloalkyl; more preferably, R1 is \— / R2 is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl; R3 is absent, or selected from hydrogen, Ci-6 alkyl, or Ci^ haloalkyl, provided that when X6 is O or S, R3 is absent; E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci^alkoxyl, Ci-6 aminoalkyl, Ci^ hydroxyalkyl, or -NReRf; wherein Re and Rf are independently selected from hydrogen, or optionally substituted Ci-6 alkyl; R4 is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C340 cycloalkyl, optionally substituted C340 cycloalkenyl, optionally substituted C340 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally R6 substituted 5 to 10-membered heteroaryl, or ' ; R5 is hydrogen, Ci^ alkyl or C3.6 cycloalkyl, furthermore, the Ci^ alkyl or C3.6 cycloalkyl may be further optionally substituted; or R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl; preferably, the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl; more preferably, the ring is selected from optionally substituted 3 to 10-membered cycloalkyl; wherein L is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rg is optionally substituted Ci-6 alkyl; R6 is hydrogen, or optionally substituted Ci-6 alkyl; R7 is optionally substituted Ci^ alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3.10 cycloalkyl, optionally substituted C3.10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6 and R7 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl. Furthermore, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, €3.5 heterocycloalkyl, C3.6 heterocycloalkyl(or 3 to 6-membered heterocycloalkyl), 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, Ci_6 heteroalkyl, C340 heterocycloalkyl (or 3 to 10-membered heterocycyoalkyl), 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl or 4 to 11-membered bicyclic heteroalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1 to 4. In some embodiments, R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl; preferably, is optionally substituted 3 to 6-membered cycloalkyl such as optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl or optionally substituted cyclohexyl, more preferably, optionally substituted 3-membered cycloalkyl i.e., optionally substituted cyclopropyl. In some embodiments of the present disclosure, the 5 to 6-membered heterocycloalkylene contains one or two heteroatoms; preferably the heteroatom is each independently selected from N, O and S. In some embodiments of the present disclosure, A is optionally substituted 5 to 6-membered heterocycloalkylene, the heteroatom is independently selected from one or two of N, O and S, and the number of In some embodiments of the present disclosure, A is optionally substituted 5 to 6-membered arylene; In some embodiments of the present disclosure, the 5 to 6-membered heteroarylene contains one, two or three (preferably one or two) heteroatoms; preferably the heteroatom is each independently selected from N, O and S. In some embodiments of the present disclosure, A is optionally substituted 5 to 6-membered heteroarylene, the heteroatom is independently selected from one or two ofN, O and S, and the number of the heteroatom is independently 1 to 3. In some embodiments of the present disclosure, A is optionally substituted 5-membered heteroarylene, the heteroatom is independently selected from N, O and S, and the number of the heteroatom is independently 1 to 2; preferably, one of the heteroatom is N, and the other, if present, is O or S. In some embodiments of the present disclosure, B is selected from the group consisting of optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11-membered bicyclic alkylene, and optionally substituted 4 to 11-membered bicyclic heteroalkylene. In some embodiments of the present disclosure, G is optionally substituted Ci_6 alkylene; preferabaly, G is optionally substituted -C(Ci_3alkyl)2-. In some embodiments, in G, optionally substituted means unsubstitued or being substituted with one or more deuterium. In some embodiments, G is In some embodiments of the present disclosure, Y is N. In some embodiments of the present disclosure, X6 is N. In some embodiments of the present disclosure, R1 is Ci_g alkyl, Ci_g alkoxyl, Ci_g haloalkyl, Ci_g haloalkoxyl, Ci_g hydroxyalkyl, Ci_g aminoalkyl, optionally substituted C3_g cycloalkyl, or optionally substi tuted C3_g heterocycloalkyl (or 3 to 6-membered heterocycloalkyl). In some embodiments of the present disclosure, R1 is Ci_g alkyl and the Ci_g alkyl is further substituted with optionally substituted C3.g cycloalkyl, optionally substituted C3.g heterocycloalkyl. In some embodiments of the present disclosure, R1 is Ci alkyl; and the Ci alkyl is further substituted with optionally substituted C3.g heterocycloalkyl, wherein the heterocycloalkyl is saturated and the heterocycloalkyl is attached to the rest of the molecule via the N atom on the ring. In some embodiments of the present disclosure, R1 is Ci alkyl; and the Ci alkyl is further substituted with optionally substituted C3.g heterocycloalkyl, wherein the heterocycloalkyl is saturated and the heterocycloalkyl is attached to the rest of the molecule via the N atom on the ring.and the C3.g heterocycloalkyl is 5 to 7 menbered heterocycloalkyl and has 1 to 2 heteroatoms. 10 HO In some embodiments of the present disclosure, R1 is optionally substituted 4 to 5-membered het- eroalkyl and 4 to 5-membered heteroaryl. In some embodiments of the present disclosure, R1 is optionally substituted 5 to 8-membered aryl, op tionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl, the heteroatom is independently In some embodiments of the present disclosure, R2 is optionally substituted Ci^ alkyl or optionally substituted Ci^ alkoxy. _kl In some embodiments, R2 is O , preferably, 0   , D         or F In some embodiments of the present disclosure, R3is Ci_6 alkyl. In some embodiments, R3is Ci_6 deu terated alkyl. In some embodiments, R3 is In some embodiments of the present disclosure, R3 is Ci_g haloalky. In some embodiments, R3 is cf3—| In some embodiments of the present disclosure, E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-g alkyl, optionally substituted Ci.galkoxyl, Ci-g aminoalkyl, Ci.ghydroxyalkyl, or -NReRf; wherein Re and Rf are independently selected from hydrogen, or optionally substituted Ci-g alkyl; preferably, E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy or Ci-g alkyl. In some embodiments of the present disclosure, Rd is halogen; In some embodiments, Rd is -F, -Cl, -Br or -I; preferably, -F. In some embodiments of the present disclosure, Rd is Ci-g alkyl; In some embodiments, Rd is In some embodiments of the present disclosure, Rd is Ci.ghaloalkyl; In some embodiments, Rd is -CF3. In some embodiments of the present disclosure, Rd is Ci-g alkoxyl; O-| In some embodiments, Rd is / In some embodiments of the present disclosure, Rd is Ci-g aminoalkyl; In some embodiments, Rd is s |     HN—I HN—I HN—|   HN—|        1   — / 1 /    , ---, /        , or \   . In some embodiments of the present disclosure, Re or Rf is Ci-g alkyl; In some embodiments, Re or Rf is independently selected from or \_| /    ; and preferably the other is hydrogen. In some embodiments, L is selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rg is optionally substituted Ci_g alkyl. In some embodiments, R4 is hydrogen, optionally substituted Ci_g alkyl, optionally substituted Ci_g heteroalkyl, optionally substituted C3_i0 cycloalkyl, optionally substituted C3_i0 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to R6 Rl .Nx 10-membered heteroaryl, or - R6 Rl^Ny preferably, R4 is hydrogen, optionally substituted Ci^ alkyl, or ' . In some embodiments, R6 is hydrogen, or optionally substituted Ci_6 alkyl; preferably, hydrogen, or Ci_6 alkyl. In some embodiments, R7is optionally substituted Ci_6 alkyl, optionally substituted Ci_6 heteroalkyl, optionally substituted C340 cycloalkyl, optionally substituted C340 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; preferably, R7is Ci-6 alkyl, optionally substituted C340 cycloalkyl. In some embodiments of the present disclosure, R4 is hydrogen, optionally substituted Ci^ alkyl, optionally substituted Ci^ heteroalkyl, optionally substituted C340 cycloalkyl, optionally substituted C340 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, op- R6 tionally substituted 5 to 10-membered heteroaryl, or        * ; wherein R6 is hydrogen, or optionally sub stituted Ci-6 alkyl; R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C340 cycloalkyl, optionally substituted C340 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl. In some embodiments, in R4, optionally substituted means unsubstituted or being substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, and Ci-6 alkyl. In some embodiments of the present disclosure, R4 is hydrogen, Ci-6 alkyl, 3 to 6-membered heterocycloalkyl, R6 Rl^Ny 3 to 6-membered cycloalkyl, 6 to 10-membered aryl, 5 to 10-membered heteroaryl, or ' , wherein R6 is hydrogen, or Ci-6 alkyl; R7 is Ci^ alkyl, 3- to 10-membered heterocycloalkyl; wherein the 3 to 10-membered heterocycloalkyl is optionally substituted by Ci^ alkyl, 6 to 10-membered aryl, -CO-O-C3.6 cycloalkyl or -CO-O-C4.6 alkyl; the 3 to 6-membered cycloalkyl is optionally substituted by hydroxyl, cyano, halogen, or Ci-6 alkyl; in 3 to 10-membered heterocycloalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1 to 3; more prefera- R6 Rl^Ny bly, R4 is hydrogen, Ci-6 alkyl, or ' . wherein R6 is hydrogen, or Ci-6 alkyl; R7 is Ci-6 alkyl, 3 to 10-membered heterocycloalkyl. In some embodiments, in R4, C340 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl) contains 1 or 2 heteroatoms selected from the group consisting of N, O and S. In some embodiments of the present disclosure, R4 is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C340 cycloalkyl, optionally substituted C340heterocycloalkyl, the heteroatom is N, O or S, and the number of the heteroatom is independently 1 to 2. In some embodi- In some embodiments of the present disclosure, R4 is optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl. In some embodiments, R4 is is optionally substituted Cm alkyl. In some em- In some embodiments of the present disclosure, R5 bodiments, R5 is In some embodiments of the present disclosure, R5 is optionally substituted C3.6 cycloalkyl. In some embodiments, R5 is In some embodiments, in the ring formed by R4, R5 and the atoms to which they are attached, the het erocycloalkyl or the bicyclic heterocycloalkyl contains 1, 2 or 3 heteroatom selected from the group con sisting ofN, O and S. In some embodiments of the present disclosure, R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl, the heteroatom is N, O or S, and the number of the heteroatom is independently 1 to 3, preferably, the ring is «,          ’, 0^ , or '—'     . In some embodiments, R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl; preferably, the ring is optionally substituted 3 to 4-membered cycloalkyl; more preferably, the ring is cy optionally substituted clopropyl; preferably, wherein optionally substituted means unsubstituted or being substituted with one or more substituents selected from the group consisting of Cm alkyl, C1-4 deuteroalkyl, cyano, Cm hydroxyalkyl, and CMhaloalkyl. In some embodiments of the present disclosure, R6 is optionally substituted Cm alkyl; In some em-_| bodiments, R6 is ’ or /     . In some embodiments, R7 is optionally substituted C3.10 cycloalkyl, or optionally substituted C3.10 heterocycloalkyl. In some embodiments, in R7, substituents for C3.10 heterocycloalkyl are selected from the group consisting of halogen, Cm alkyl, 6 to 10-membered aryl, -CO-O-C3.6 cycloalkyl, -C0-0-Cm alkyl, -CO-C3.6 cycloalkyl, -CO-Cm alkyl, -CO-Cm alkenyl, and -CO-Cm alkynyl, and / or substituents for C3.10 cycloalkyl are selected from the group consisting of hydroxyl, cyano, halogen, or Cm alkyl. In some embodiments, in R7, substituents for C3.10 heterocycloalkyl are selected from the group con sisting of Ci_6 alkyl, 6 to 10-membered aryl, -CO-O-C3_6 cycloalkyl and -CO-O-Ci_g alkyl, and / or substitu ents for C3_io cycloalkyl are selected from the group consisting of hydroxyl, cyano, halogen, or Ci_g alkyl. In some embodiments, in R7, C3_i0 heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of N, O and S. In some embodiments, R7 is optionally substituted C3_i0 cycloalkyl, optionally substituted C3_i0 heter ocycloalkyl; preferably, the C3_i0 heterocycloalkyl optionally substituted by Ci_g alkyl, C6-io aryl , -CO-O-C3_6 cycloalkyl or -CO-O-Ci_g alkyl; the C3_i0 cycloalkyl optionally substituted by hydroxyl, cyano, halogen, or Ci-g alkyl; in C3.io heterocycloalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1 to 3. In some embodiments of the present disclosure, R7 is Ci-g alkyl. In some embodiments, R7 is In some embodiments, R7 is optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments, in R7, the 3 to 6-membered heterocycloalkyl contains 1 or 2 heteroatom se lected from N, O or S; preferably, is In some embodiments of the present disclosure, R7 is 3 to 6-membered heterocycloalkyl, preferably, the heteroatom is N, O or S, and the number of the heteroatom is independently 1 to 2. In some embodi- In some embodiments, R7 is optionally substituted C3_g cycloalkyl. In some embodiments, in R7, the C3-6 cycloalkyl is In some embodiments of the present disclosure, R7 is C3.g cycloalkyl; In some embodiments, R7 is In some embodiments, R7 is optionally substituted Cg.ioaryl. In some embodiments, in R7, the Cg-io aryl is               . In some embodiments of the present disclosure, R7 is Cg.ioaryl. In some embodiments, R7 is In some embodiments, R7 is optionally substituted Ci-g alkyl or optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments, in R7, substituents for the 3 to 6-membered heterocycloalkyl is selected from -C(O)R1 or-NHC(O)R1; wherein R'is selected from the group consisting of Ci-g alkyl, -C2-galkenyl, Ckgal-kynyl; wherein the alkyl, alkenyl, or alkynyl is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atom in the group being substituted with substituents selected from the group consisting of D, halogen, -CN, -OH, Ci-g alkyl, Ci.ghaloalkyl, Ci-g deuteroalkyl, Ci_ghydroxyalkyl, Ci-g aminoalkyl, alkylamino. In some embodiments, in R7, substituents for the 3 to 6-membered heterocycloalkyl is selected from 6 to 10-membered aryl or -CO-O-Ci.g alkyl. In some embodiments, in R7, the 3- to 6-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N and O. In some embodiments of the present disclosure, R7is Ci_6 alkyl or 3 to 6-membered heterocycloalkyl; the 3 to 6-membered heterocycloalkyl optionally substituted by 6 to 10-membered aryl or -CO-O-Ci_6 alkyl; in 3 to 6-membered heterocycloalkyl, the heteroatom is independently selected from one or two ofN and O, and the number of the heteroatom is independently 1 to 2. In some embodiments of the present disclosure, L, R6 and R7 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl. In some embodiments, substituents for the ring formed by L, R6 and R7 combined with the atoms to which they are attached is -C(0)R1; wherein R1 is selected from the group consisting of Ci-6 alkyl, -Cz-galkenyl, C2-6 alkynyl, C3.10 cycloalkyl, and 3 to 10-membered heterocycloalky; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalky is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atom in the group being substituted with substituents selected from the group consisting of D, halogen, Ci^ alkyl, Ci-6 haloalky 1, C1-6 deuteroalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, alkylamino, and C3.6 cycloalkyl. In some embodiments of the present disclosure, the “halogen” is F, Cl, Br or I; preferably, F. In some embodiments of the present disclosure, the compound of formula (IVa) is a compound of 5 formula (V): R1 (V) or a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein the variables are as described above. In some embodiments, X1, X2, X3, X4, X5, X6, A, B, E, G, L, Y, Ra, Rb, Rc, RA, RB, RM, RN, R1, R2, R3, 10   R4, R5, R6, R7 and n are each independently corresponding groups in specific compound shown below or compounds of examples 1 to 30. The present invention also has some schemes derived from any combination of the above-mentioned variables. In another aspect, the present invention also provides, but is not limited to, the following compounds, 15 In some compounds of Formulas above, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic num-10   ber, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of Formulas above and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain 15 therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates. In some embodiments of the present disclosure, the compound of formula (V) is a compound of formula (VI): (VI) or a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof 10 15 or a solvate of the pharmaceutically acceptable salt thereof. r                         / H CF37—| NC In some embodiments, R of formula (VI) is selected from: / ,      / , △Qh , ? ? ? ? ? In some embodiments of the present disclosure, the compound of formula (IVa) is a compound of 15 In some embodiments, R1 of formula (VII) is selected from: 10 In some embodiments of the present disclosure, the compound of formula (IVa) is a compound of formula (VIII): 10 In some embodiments, the compound of formula (I) is Compound A as defined below. It is to be understood that the foregoing description of preferred embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited other than expressly set forth in the following claims. The present invention provides a Compound A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt, wherein, the Compound A is selected from any one of the following compounds in Table 1: Table 1. Certain Compounds of the Present invention Code Structure Code Structure Example 1 O 2 / —\ C- A । o Example 2 °T?T a -o r । nhA"A \     n^s W" Example 3 O 2 / —\   W H Example 4 / \_7 iz O )=o Example 5 °yOy O J, H JUL, -o C CB y 1 Example 6 v'vv0 o J "0 L-    1 H V _> A A QAj / ; nD N I Example 7 ■Ol iCi 1 \ O 0 °-< y-z    iz < ) r    zV Vl X—Z z o ^=° Example 8 wCj< rXx \— / IZ* O Vo Example 9 —o L_     1 h V OCpi / £ Qi NZ Example 10 °Y0r° 0 N-"\^ N~ / / Example 11 V^Y0 o r N= /    \        Is-. / Fxn / / N— / Example 12 O zx c. o ° * <  / \ 0 Example 13 °=< O ZI / —\ )-°, o o 1 iX / = / o'^x^k. 0 / Example 14 0 1 T^'V'O ?= /      P O  °“( j z IZ* O ^=° Example 15 O ZX / --\     CO y°. O O ' < F\ O'^X'^k ' 0 Example 16 oVO V° o -o X HAAV^ °\ A" 1 h Y n=< £     j£ / wCiPr £ Example 17 o=e o zx / --X Ws. €- A y°, । 0 O * < l\ £?T 0 0% Example 18 V^V0 o -0 r HAV °k Jr"      1 H Y N< C D * Q-CPr o^-x / C o''3^-7 Example 19 O zx / --X co o^LJ^W ? Cl Example 20 O zx / \ .CO. C- M. )-°, o ° * y / 1 XX Example 21 Example 22 N— /   \        1 .8 Q-zrC M-X-sS1 CFa Example 23 -o r° / — f \ O)          o J Q N-Z Example 24 Yrr''' Qyty^ N-X-5^ O^JnV     ' Example 25 Q-fXi N-X^ / ; Example 26 KXyO / ; Example 27 o^.-Q o ! ! / "tor N- /  \   _ L ys N-^S-ss*' o^Jn- / Example 28 0 1 tV° 0^°^° \ / iz* o \ )=° °=( Q Example 29 0 I OX O-VyV^    w N-\y o / yjN- / Example 30 ..... —z / O ZI / —\ x A2"      t v ZT    \ )-°, O ° ‘ r / \ 0 Example 31 °Y0Y° 0 -0 r° WV ~0 L_     1 H Y N< y o * N-X;^ n ? Z-A /    < tty x Example 32 °yQy° o -o r° . M           1 }n- V"J i 0= /          N-X^ h / ; “Yn- / Example 33 lPty^ r—* n-Xss^ / ; Example 34 °Y0Y0 0       V7 -o r° p~vO / ; Example 35 J fRa° ” N-X^ Example 36 Example 37 , Example 38 yyoaj cRcr°    ” N—X-s^ ZA /  < O\__\i~ /        CF3 Example 39 0 1Q i t’x-'0 / =( •££ P O ° / CO     \__ / iz* o \ Y° y r Example 40 °\z° 0 tl 1 VS-° / =( / V~\ p o-^ ^° H. IZ o \ )=o 8 O;sZ Example 41 f’’' N-'X-sssJ o r~\ w Example 42 0 11 1 ty-0 / =\      p o rA s Example 43 oYty^ Ox / —A   W      ( CF3 Example 44 O=OT=O 0 11 ' 7==( •< \ P z—<   zz / ) Q'"Y^ zz o \ g Example 45 -0 r° fQyV0 X’”' N-\afiJ < ^S-N \_ /       CF3 0 '—' Example 46 0 oY ^---1 O zr AA 0 Ozw-Q Example 47 - / yy / -ckgp a y? UHjy S? z-x /    < ~S-N N— /       CFs 0 '—' Example 48 °Y0r°o p,.. 7 -o r° > qaY ' o=^         nA> K / Example 49 Y* ('   <^0           0 x rCkyU o^n_ p-<JU cp_z 0 Example 50 O'V iQ ' )=( -^n p 0 o-( OA® zz O ___ g Example 51 or?Y$     Y -o r° A V^pY x AXpO 6 0 0 H / __^N_z         CF3 Example 52 7^0             0 %7n-ny° o । N- /  \        1 ,S 0-<ry^ Example 53 <>| 0 p / V0 0 I Y YVY N-Z \        I ,8 PYyA / °'' Example 54 °y0y° o 1 An'\& J, >g YY x pYrY nA7 0" / -A f     ” Example 55 YpY N-Z V       I ,8 OYrY nAZ o< / “A X oJs 'NV Example 56 °y Oy3 ° । An'P j, - ?H Ayr 0X^0 N'AP _y ” Example 57 °y0 / o , Yn-Y i -o r H A0yP a > a y'o a o 0. / —\ X *\ o'-Y- / - / Example 58 N—Z \          1 .S pYrY^ n-YY Example 59 PxQ A Example 60 vyyj । f~r X / kX N- / \       L ,S N-X^ Example 61 N-Z \        1 ,s Example 62 yQys । Example 63 " / YA xx / Example 64 vOy0 o -0 y W-x 0 Jr—      I H V n-Y 0 o i QxrV^ X N-Xjss* 0. / -^ / HC> Example 65 O ZI / —\ kx k? । O O I IX O'Xr---k 1 0 ■6 Example 66 °Y0y° 0 - r HnV N^S    I N=(   \      L r wxTt N-*X^ r / N—' / Example 67 Oy-Oy0 o - r w UXx N-^s-s^ A lA 0 Example 68 OY0Y° o -o Y Vn^V 0 Jr- 1 H V n / f d! * wxTY^ Example 69 0 n—\X o J ; 1    N— / Example 70 oy Qy° 0 -o r° nAk^ °' Jr* ? H Y / -A / k o^JnV Example 71 OyQyo 0 -0 r° HAV o L-     I H y Yx-u Ur N—\X / ; Example 72 °y 0y° 0 -o r hAv Jr- 1 H V N>0 A । wxPr IM-X^ / ; O n V Example 73 °=< o zi / —c Az- Vk v / ZI z \ r?. O o i ix y=Y ' ^x 0 1 Example 74 °=< O ZT / —\ tX AY F? . O o I IX Y=Z 0 1 Example 75 °=< o zi / -x ZX v / ZI z \ i O O ' T / \ 0 1 Example 76 o zi / —\ A. F? । O o \ Lz y=z o'^X-^X ’ X, 0 1 Example 77 °x O ZI / \ w OH. X , O O * V / A 1 ^x 0 Example 78 °x O ZI / \ ‘X o^LJ^W O'><iSX 1 44 0 Example 79 0 iQ ' T>^0 Q o-f ex1® in ) z IZ* O Example 80 O ZI / \ 4 1 0 0  * < l\ 1 0 Example 81 yCy o r\.^ 7 -o C "AOx H \    r^o <?    o X-' nXX id__\~y         cf3 Example 82 x%o ° <3__CF3 Example 83 nX^ r~\ f < —N^ ^N— /        CF3 Example 84 / =S^ 'N-Xsss^ Z-S /   < —N^ ^N— /        CF3 Example 85 Xcr° ° 'V —N n—(        CF3 Example 86 Xrr"° ° N-XX Z-A /   < —Jn— /        CF3 Example 87 Xh N— /   \        1  > 04x4^ NXX J nHS w Example 88 x / ==( zi \ 0 0 O'X v° H. ZZ O \ 8 OagZ Example 89 N— /   \ / Example 90 0 1 T^^^X"0 %= / zY“\ p O \— Z   -t4 / \ < X ^cn \__z IZ* O \ / ^° 8 °=hZ Example 91 ■s¥^AA rAAo ° °vJN^ Example 92 0 Example 93 o r-\.^ F c° "AV^Aa, AA'A3 ° Example 94 -, C° "AA^AJ, rpAO A " 7^  N—X-s?* Example 95 .      J N-AesssJ / ; Example 96 x"   r^o <7    0 Example 97 O A?. O ' y / A 1 0 1 Example 98 -.         J 7   < _ / Example 99 / -V /   < _V-Z       cf3 In another aspect, the present invention also provides a pharmaceutical composition comprising a compound, wherein a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt as defined above, and a pharmaceutically acceptable carrier, preferably, the 5 compound is the Compound A as defined above. In another aspect, the present invention also provides a use of a compound, wherein a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt, or the pharmaceutical composition as defined above in the preparation of a medicament used for the treatment of cancer, preferably, the compound is the Compound A as defined above. 10 In some embodiments of the present disclosure, wherein the cancer is a Ras-driven cancer. In some embodiments of the present disclosure, wherein the cancer comprises a Ras mutation. In some embodiments of the present disclosure, wherein the Ras mutation is a position 12, 13 or 61. In some embodiments of the present disclosure, wherein the Ras mutation is at position 12. In some embodiments of the present disclosure, wherein the Ras mutation is selected from the group 15 consisting ofG12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61Rand Q61L, or a combination thereof. In some embodiments of the present disclosure, wherein the Ras mutation is a position selected from the group consisting of G12D, G12V, and G12R, or a combination thereof. In some embodiments of the present disclosure, wherein the cancer is pancreatic cancer, appendiceal cancer, small bowel cancer, colorectal cancer, ampullary cancer, non-small cell lung cancer, cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma. In some embodiments of the present disclosure, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In some embodiments of the present disclosure, wherein the Ras protein is KRAS. In some embodiments, the compound can be used in combination with an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a S0S1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a P13K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORCl inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. In another aspect, the present invention also provides a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt as defined above, or the pharmaceutical composition as defined above, preferably the compound is the Compound A as defined above. In some embodiments of the present disclosure, wherein the cancer is a Ras-driven cancer. In some embodiments of the present disclosure, wherein the cancer comprises a Ras mutation. In some embodiments of the present disclosure, wherein the Ras mutation is a position 12, 13 or 61. In some embodiments of the present disclosure, wherein the Ras mutation is at position 12. In some embodiments of the present disclosure, wherein the Ras mutation is at a position selected from the group consisting of G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R and Q61L, or a combination thereof. In some embodiments of the present disclosure, wherein the Ras mutation is a position selected from the group consisting of G12D, G12V, and G12R, or a combination thereof. In some embodiments of the present disclosure, wherein the cancer is pancreatic cancer, appendiceal cancer, small bowel cancer, colorectal cancer, ampullary cancer, non-small cell lung cancer, cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumour, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma. In some embodiments of the present disclosure, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In some embodiments of the present disclosure, wherein the Ras protein is KRAS. In some embodiments, the method is provided of treating a Ras protein-related disorder in a subject in need thereof. In some embodiments, the method further comprises administering an additional anti-cancer therapy. In some embodiments, the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a S0S1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a P13K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORCl inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. It should be understood that each of the above technical features of the invention and each technical feature specifically described below (such as in Examples) can be combined with each other within the scope of the present invention so as to constitute new or preferred technical solutions. EXEMPLARY EMBODIMENTS Embodiment 1. The compound of any one of the preceding embodiments, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (i); (i) wherein n is 0, 1, 2, or 3; A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; B is selected from optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; G is optionally substituted Ci-6 alkylene; R8 and R9 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci-3 alkyl, or R8 and R9 combine with the atoms to which they are attached to form an optionally substituted C3.g cycloalkyl or a carbonyl; R10 and R11 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci_3 alkyl, or R10 and R11 combine with the atoms to which they are attached to form an optionally substituted C3_6 cycloalkyl or a carbonyl; R12 and R13 are each independently selected from hydrogen, deuterium, halogen, hydroxy, optionally substituted Ci_3 alkyl, -O(Ci_6 alkyl), -S(Ci_6 alkyl) or -N(Ci_6 alkyl)(Ci_6 alkyl); furthermore, the Ci_6 alkyl may be further optionally substituted; Ra is optionally substituted C3_g cycloalkyl, optionally substituted C3_g heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; Rb is selected from hydrogen, Ci_g alkyl, Ci_g alkoxyl, Ci_g haloalkyl, Ci_ghaloalkoxyl, optionally substituted C3_g cycloalkyl, or optionally substituted C3_g heterocycloalkyl (or 4 to 7- membered heterocycloalkyl); or provided that when n exceeds 1, any two of RB combine with the atoms to which they are attached to form a 3 to 6-membered ring, wherein the ring can be optionally substituted with halogen, hydroxy, and Ci_3 alkyl; X1 is N or C; X2 is N or -CRa-; X3 is N or -CRb-; X4 is N or -CRC-; X5 is N or C; X6 is S, O, N, or -CH-; Ra, Rb, and Rc are each independently hydrogen, halogen, cyano, Ci-3 alkyl, Ci-3 alkoxyl, Ci-3 haloalkyl, Ci-3 haloalkoxyl, C3.g cycloalkyl, or C3.g heterocycloalkyl (or 4 to 7-membered heterocycloalkyl); R3 is absent, or selected from hydrogen, Ci-g alkyl, or Ci-g haloalkyl, provided that when X6 is O or S, R3 is absent; E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-g alkyl, optionally substituted Ci-g alkoxyl, Ci-g aminoalkyl, Ci-g hydroxyalkyl, or -NReRf; wherein Re and Rf are independently selected from hydrogen, or optionally substituted Ci-g alkyl; R4 is hydrogen, optionally substituted Ci-g alkyl, optionally substituted Ci-g heteroalkyl, optionally substituted C3.io cycloalkyl, optionally substituted C3.io cycloalkenyl, optionally substituted C3.io heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally R6 Rl^N-y substituted 5 to 10-membered heteroaryl, or / ; R5 is hydrogen, Ci-g alkyl or C3.g cycloalkyl, furthermore, the Ci-g alkyl or C3.g cycloalkyl may be further optionally substituted; or R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl; wherein L is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rg is optionally substituted Ci_g alkyl; R6 is hydrogen, or optionally substituted Ci_g alkyl; R7 is optionally substituted Ci_g alkyl, optionally substituted Ci_g heteroalkyl, optionally substituted C3_io cycloalkyl, optionally substituted C3_i0 heterocycloalkyl (or 3 to 10-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6 and R7 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl. Embodiment 2. The compound of embodiment 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (1-1) (1-1) wherein X1, X2, X3, X4, X5, X6, A, B, E, G, RA, RB, R3, R4, R5 and n are as defined in embodiment 1. Embodiment 3. The compound of any one of embodiments 1 to 2, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of hydrogen, Ci^ alkyl, Ci-6 alkoxyl, Ci^ haloalkyl, Ci^ haloalkoxyl, Ci^ hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3.g cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -Ci-2 alkylene-C3.6 cycloalkyl, optionally substituted -Ci_2 alkylene-C3_g heterocycloalkyl, optionally substituted -Ci_2 alkylene-5 to 8-membered aryl, optionally substituted -Ci_2 alkylene-5 to 8-membered heteroaryl, optionally substituted -Ci_2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -Ci_2 alkylene-8 to 10-membered fused bicyclic heteroaryl; furthermore, the Ci_g alkyl, Ci_g alkoxyl, Ci_g haloalkyl, Ci_g haloalkoxyl, Ci_g hydroxyalkyl may be further optionally substituted; in R1, when the Ci_g alkyl, Ci_g alkoxyl, Ci_g haloalkyl, Ci_g haloalkoxyl, or Ci_g hydroxyalkyl is further substituted, the substituent is selected from the group consisting of Ci_g alkyl, Ci_g alkoxyl, Ci_g haloalkyl, Ci_g haloalkoxyl, Ci_ghydroxyalkyl, Ci_g aminoalkyl, optionally substituted C3_g cycloalkyl, optionally substituted C3_g heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; preferably, the substituent is selected from the group consisting of optionally substituted C3_g cycloalkyl, optionally substituted C3_g heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; more preferably, the substituent is optionally substituted C3.g heterocycloalkyl; Yis -CH- orN; R2 is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl; preferably, R2 is optionally substituted Ci^ alkyl; and Rm and Rn are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, Ci.g alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci^ haloalkoxyl, Ci^ hydroxyalkyl, Ci^ aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3.g heterocycloalkyl; furthermore, the Ci-g alkyl, Ci-g alkoxyl, Ci.g haloalkyl, Ci.g haloalkoxyl, Ci.ghydroxyalkyl may be further optionally substituted. In some embodiments, Rm and Rn are each independently selected from hydrogen, and Ci-g alkyl. Embodiment 4. The compound of embodiment 3, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted Ci-g alkyl; and, in R1, the Ci-g alkyl is further substituted, and the substituent is selected from optionally substituted C3.g cycloalkyl, optionally substituted C3.g heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl. Embodiment 5. The compound of any one of embodiments 3 to 4, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted Ci-g alkyl; in R1, the Ci-g alkyl is further substituted, and the substituent is optionally substituted C3.g heterocycloalkyl. Embodiment 6. The compound of any one of embodiments 3 to 4, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is Ci alkyl; and the Ci alkyl is further substituted with optionally substituted C3_g heterocycloalkyl, wherein the heterocycloalkyl is saturated and the heterocycloalkyl is attached to the rest of the molecule via the N atom on the ring. Embodiment 7. The compound of any one of embodiments 3 to 4, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is Ci alkyl; and the Ci alkyl is further substitut ed with optionally substituted C3_g heterocycloalkyl, wherein the heterocycloalkyl is saturated and the heterocycloalkyl is attached to the rest of the molecule via the N atom on the ring.and the C3_6 heterocycloalkyl is 5 to 7 menbered heterocycloalkyl and has 1 to 2 heteroatoms. Embodiment 8. The compound of any one of embodiments 3 to 7, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of HO         HO —N N N N— O=S-N N=S-N and Embodiment 9. The compound according to any one of embodiments 3 to 8, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is Ci alkyl substituted by Cg heterocycloalkyl, optionally wherein the Cg heterocycloalkyl is piperazine or morpholine. Embodiment 10. The compound of any one of embodiments 1 to 9, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl; preferably, is optionally substituted 3 to 6-membered cycloalkyl; more preferably, optionally substituted cyclopropyl. Embodiment 11. The compound of any one of embodiments 1 to 9, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein O R4 R5 O R4 is selected from the group consisting of: R5 is D D Embodiment 12. The compound of any one of embodiments 1 to 11, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 6-membered heteroarylene, the heteroatom is independently selected from one or two of N, O and S, and the number of the heteroatom is independently 1 to 3 preferably, A is optionally substituted 5-membered heteroarylene, the heteroatom is independently selected from N, O and S, and the number of the heteroatom is independently 1 to 2; preferably, one of the heteroatom is N, and the other, if present, is O or S; more preferably, A is selected from the group consisting of Embodiment 13. The compound of any one of embodiments 1 to 12, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein X1 is C, and / or X2 is -CRa-, and / or X3 is -CRb, and / or X4 is -CRC-, and / or X5 is -C-. Embodiment 14. The compound of any one of embodiments 1 to 13, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, wherein, the compound is selected from any one of the compounds in Table 1. Embodiment 15. The compound of any one of embodiments 1 to 14, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, wherein, the compound is selected from compounds of Examples 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 28, 29, 30, 31, 32, 33, 37,38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 84, 86, 87, 88, and 90 in Table 1. Embodiment 16. A pharmaceutical composition comprising: the compound of any one of embodiments 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Embodiment 17. A use of the compound of any one of embodiments 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 16, or the pharmaceutical composition comprising the same in the preparation of a medicament used for the treatment of cancer. Embodiment 18. The use of the compound of embodiment 17, wherein the cancer is selected from the group consisting of small cell lung cancer (SCLC), colorectal cancer (CRC), pancreatic cancer, and chol-angiocarcinoma, pancreatic cancer, appendiceal cancer, small bowel cancer, colorectal cancer, ampullary cancer, non-small cell lung cancer, cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, and squamous cell lung carcinoma, or combinations thereof. Embodiment 19. The use according to any one of embodiments 17 to 18, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, and cholangiocarcinoma. Embodiment 20. The compound according to any one of embodiments 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same for use in treating cancer. Embodiment 21. The compound for use according to embodiment 20, wherein the cancer is as defined in embodiment 18. Embodiment 22. The compound for use according to any one of embodiments 20 to 21, wherein the cancer is as defined in embodiment 19. Embodiment 23. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of any one of the preceding embodiments, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to embodiment 16, or the pharmaceutical composition comprising the same. Embodiment 24. The method according to embodiment 23, wherein the cancer is as defined in embodiment 18. Embodiment 25. The method according to any one of embodiments 23 to 24, wherein the cancer is as defined in embodiment 19. TERM DEFINITION Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term. As used herein, the term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceu tically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. As used herein, the term “solvate” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. As used herein, excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable, and includes carrier that is acceptable for veterinary use as well as human pharmaceutical use. A “pharmaceutically acceptable carrier” as used herein includes both one and more than one such carrier. The term “pharmaceutically acceptable carrier” also encompasses “pharmaceutically acceptable excipient” and “pharmaceutically acceptable diluent”. The particular carrier used in the pharmaceutical compositions of the present disclosure will depend upon the means and purpose for which the compounds of the present disclosure are being applied. As used herein, unless otherwise specified, the term “optionally substituted” refers to unsubtituted or being substituted with one or more (such as 1, 2, 3 or 4) substituents. Suitable substituents for each group can be found herein. Unless otherwise specified, exemplary substituents can be selected from the group consisting of D, halogen, -CN, -NO2, R1, -Cm alkylene-R1, -C2-4 alkenylene-R1, -C2-4 alkynylene-R1, -OR1, -OC(O)R'. -C(O)R\ -CO2R1, -CONR'R". -OC(O)NNR1R11, -NRT^R1, -NR1-C(O)NR11R111, ^“0(0)2^, -NH-C(NH2)=NH, -NR1C(NH2)=NH, -NH-C(NH2)=NR1, -S(O)R\ -S(O)2R'. -S(O)2NR1R11, 0 II . .. N=S— ...         ...     ... -S(O)(=N-R1)R11(e.g., / I ),-NR1S(O)2R11; wherein R1, R11 and R111 are each independently selected from the group consisting of H, Ci.6 alkyl, -C2-6 alkenyl, C2.6 alkynyl, C340 cycloalkyl, C340 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, C64o aryl, 5 to 10-membered heteroaryl, -Ci-4 alkylene-C34o cycloalkyl, -C1.4 alkylene-C34o cycloalkenyl, -C 1.4 alkylene-3 to 10-membered heterocycloalkyl, -Cm alkylene-3 to 10-membered heterocycloalkenyl, -Cm alkylene-C64o aryl, and -Cm alkylene-5 to 10-membered heteroaryl; or R1 and Ru, R11 and R111 together with the atom to which they are attached to form C340 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, Cg4o aryl, 5 to 10-membered heteroaryl; wherein the alkylene, alkenylene, alkynylene, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl can be unsubtituted or one or more (such as 1, 2, 3 or 4) or all of H atom in the group being substituted with substituents selected from the group consisting of D, halogen, -CN, -OH, Cm alkyl, Cm haloalkyl, Cm deuteroalkyl, Cm hydroxyalkyl, Cm aminoalkyl, amino, alkylamino, -C(0)Cm alkyl, -OCm alkyl, -0C(0)Cm alkyl, 0 II N=S— -S(0)Cm alkyl, -S(O)2Ci_6 alkyl, -COOCm alkyl, / I , oxo (=0), Cm alkylidene, Cm haloalkylidene, Cm deuteroalkylidene, Cm hydroxyalkylidene, Cm aminoalkylidene, C3.6 cycloalkyl optionally substituted with one or more of D, halogen, -CN, -OH, Cm alkyl, Cm haloalkyl, Cm deuteroalkyl, Cm hydroxyalkyl, and Cm aminoalkyl, 3 to 6-membered heterocycloalkyl optionally substituted with one or more of D, halogen, -CN, -OH, Cm alkyl, Cm haloalkyl, Cm deuteroalkyl, Cm hydroxyalkyl, and Cm aminoalkyl, 3 to 6-membered heterocycloalkenyl optionally substituted with one or more of D, halogen, -CN, -OH, Chalky!, Ci_6 haloalkyl, Ci_6 deuteroalkyl, Ci_6 hydroxyalkyl, and Ci_6 aminoalkyl, phenyl, 5 to 6-membered heteroaryl optionally substituted with one or more of D, halogen, -CN, -OH, Ci_6 alkyl, Ci_6 haloalkyl, Ci_6 deuteroalkyl, Ci_6 hydroxyalkyl, and Ci_6 aminoalkyl. In some embodiments, said “optionally substituted” means that the group is substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=0), thio (=S), C1-C4 alkyl, C1-C4 haloalkyl, C4-C4 hydroxyalkyl, C4-C4 alkoxy, C4-C4 haloalkoxy, C2-C4 alkenyl, C2-C4 alkyne, C3-C6 cycloalkyl, 3 to 6-membered heterocycloalkyl. In addition, if an optionally substituted group can be further substituted means in addition to being substituted by the above-mentioned substituents for “optionally substituted”, one or more hydrogen atoms in the group may also be substituted by other substituents specified (such as substituents for further substitution). As used herein, the term “alkyl” refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups having the number of carbon atoms designated (i.e., Ci.2o means 1 to 20 carbon atoms). Preferably an alkyl group is an alkyl having 1 to 12 i.e., Cn2 alkyl. Sometimes preferably 1 to 6 i.e., Ci-6 alkyl, sometimes more preferably 1 to 4, carbon atoms i.e., Ci-4 alkyl. Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4.4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methy 1-3-ethylpentyl, n-nonyl, 2-methyl -2-ethylhexyl, 2-methy 1-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the isomers of branched chain thereof. More preferably an alkyl group is a lower alkyl having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1.2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point, preferably the substituent group(s) is one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group. The term “alkylene” refers to a saturated linear or branched aliphatic hydrocarbon group, wherein having 2 residues derived by removing two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms. The straight or branched chain group containing 1 to 20 carbon atoms, preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylidene (-CH2CH2CH2CH2-) etc. The alkylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and het-erocylic alkylthio. As used herein, the term “alkenyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2- propenyl, 1-2-, or 3-butenyl, etc., preferably C2.2o alkenyl, more preferably C2.i2 alkenyl, and most preferably C2.g alkenyl. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group. The term “alkenylene” refers to an alkylene defined as above that has at least two carbon atomsand at least one carbon-carbon double bond, preferably C2.2o alkenylene, morepreferably C2.i2 alkenylene, and most preferably C2.g alkenylene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2, -CH=CHCH2CH2, -CH2CH=CHCH2- etc. The alkenylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio. As used herein, the term “alkynyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-2-, or 3-butynyl etc., preferably C2.2o alkynyl, more preferably C2.i2 alkynyl, and most preferably C2.g alkynyl. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio. As used herein, the term “aryl” refers to a 6 to 14-membered (or C6_i4) all-carbon monocyclic ring or a polycyclic fused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi-electron system. Preferably aryl is 6 to 10-membered (or Cg.i0), such as phenyl and naphthyl, most preferably phenyl. The aryl can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Representative examples include, but are not limited to, the following substituents: The aryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, hetero-cylicalkoxyl, cycloalkylthio and heterocylic alkylthio. The term “arylene” is a divalent group which is connected to the rest of the molecule through two single bonds, and the rest definitions are the same as the term “aryl”. As used herein, the term “heteroaryl” refers to an aryl system having 1 to 4 heteroatoms selected from the group consisting of O, S and N as ring atoms and having 5 to 14 ring atoms (referred as 5 to 14-membered). Preferably a heteroaryl is 5 to 10-membered, more preferably 5 or 6-membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, thiazolylfuryl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples include, but are not limited to, the following substituents: The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NReRf. The term “heteroarylene” is a divalent group which is connected to the rest of the molecule through two single bonds, and the rest definitions are the same as the term “heteroaryl”. The term "bicyclic" is intended to include spiro, fused-ring or bridged-ring. As used herein, the term “spiro” refers to two rings that shares one ring atom (e.g., carbon). As used herein, the term “fused” refers to two rings that share two adjacent ring atoms with one another. As used herein, the term “bridged” refers to two rings that share three adjacent ring atoms with one another. As used herein, the term “cycloalkyl” refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms (refered as C3_20 or 3 to 20 membered), preferably 3 to 12 carbon atoms (refered as C3_i2or 3 to 12 membered), more preferably 3 to 10 carbon atoms (refered as C3_i0or 3 to 10 membered), and most preferably 3 to 8 carbon atoms (refered as C3_8or 3 to 8 membered) or 3 to 6 carbon atoms (refered as C3_6or 3 to 6 membered). In some embodiments, cycloalkyl is monocyclic cycloalkyl. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. In some embodiments, cycloalkyl is polycyclic cycloalkyl (such as bicyclic cycloalkyl). In some embodiments, cycloalkyl is a spiro cycloalkyl, a fused cycloalkyl or a bridged cycloalkyl. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring. The cycloalkyl can be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl. Representative examples include, but are not limited to inda-nylacetic, tetrahydronaphthalene, benzocycloheptyl and so on. The cycloalkyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cyeloalkylthio, hetero-cylic alkylthio and oxo group. The term “cycloalkylene” is a divalent group which is connected to the rest of the molecule through two single bonds, and the rest definitions are the same as the term “cycloalkyl”. “Spiro Cycloalkyl” refers to a 5 to 20-membered polycyclic group with rings connected through one common carbon atom (called a spiro atom), wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a spiro cycloalkyl is 6 to 14-membered, and more preferably 7 to 10-membered. According to the number of common spiro atoms, a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered / 4-membered,           4-membered / 5 -membered,           4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiro cycloalkyl. Representative examples of spiro cycloalkyl include, but are not limited to the following substituents: “Fused Cycloalkyl” refers to a 5 to 20-membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably, a fused cycloalkyl group is 6 to 14-membered, more preferably 7 to 10-membered. According to the number of membered rings, fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following substituents: “Bridged Cycloalkyl” refers to a 5 to 20-membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds, but have no completely conjugated pi-electron system. Preferably, a bridged cycloalkyl is 6 to 14-membered, and more preferably 7 to 10-membered. According to the number of membered rings, bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents: As used herein, the term “heterocyclyl” or “heterocycloalkyl” refers to a 3 to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more, sometimes preferably one to five, sometimes more preferably one to three carbon ring atoms being replaced with heteroatoms selected from the group consisting of N, O, and S(O)m (wherein m is 0,1, or 2) as ring atoms, but excluding -O-O-, -O-S- or -S-S- in the ring, the remaining ring atoms being C. Preferably, heterocyclyl is a 3 to 12-membered ring having 1 to 4 heteroatoms (also referred as for example 3-12 membered heterocyclyl or heterocycloalkyl, or C2-n heterocyclyl or heterocycloalkyl); more preferably a 4 to 12-membered ring having 1 to 3 heteroatoms (also referred as for example 4-12 membered heterocyclyl or heterocycloalkyl, or C3_io heterocyclyl or heterocycloalkyl); more preferably a 3 to 10-membered ring having 1 to 3 heteroatoms (also referred as for example 3-10 membered heterocyclyl or heterocycloalkyl, or C2.9 heterocyclyl or heterocycloalkyl); more preferably a 4 to 8-membered ring having 1 to 3 heteroatoms (i.e., 4-8 membered heterocyclyl or heterocycloalkyl, or C2-7 heterocyclyl or heterocycloalkyl); most preferably a 5 to 7-membered ring having 1 to 2 heteroatoms (also referred as for example 5-7 membered heterocyclyl or heterocycloalkyl, or C3_6 heterocyclyl or heterocycloalkyl) or a 5 to 6-membered ring having 1 to 2 heteroatoms (also referred as for example 5-6 membered heterocyclyl or heterocycloalkyl, or C3_5 heterocyclyl or heterocycloalkyl). In some embodiments, heterocycloalkyl / heterocyclyl is monocyclic heterocycloalky 1 / heterocyclyl. Representative examples of monocyclic heterocyclyls or heterocycloalkyl include, but arenot limited to, oxetanyl, azabutyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl,sulfo-morpholinyl, homopiperazinyl, and so on. In some embodiments, heterocycloalkyl / heterocyclyl is polycyclic heterocycloalkyl / heterocyclyl (such as bicyclic heterocycloalkyl / heterocyclyl). In some embodiments, heterocycloalkyl / heterocyclyl is a spiro heterocycloalkyl / heterocyclyl, a fused heterocycloalkyl / heterocyclyl or a bridged heterocycloalkyl / heterocyclyl. Polycyclic heterocyclyl or heterocycloalkyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring. The “heterocyclyl” or “heterocycloalkyl” can be attached to the rest of the molecule via the N or C atom on the ring. In some embodiments, the “heterocyclyl” or “heterocycloalkyl” is attached to the rest of the molecule via the N atom on the ring. In some embodiments, specifically in the definition of R1, the “heterocyclyl” or “heterocycloalkyl” is attached to the rest of the molecule via the C atom on the ring. In some embodiments, the “heterocyclyl” or “heterocycloalkyl” I— / X has a structure of ! 5— / ; wherein is a heteroatom or a carbon atom. Examples of such heterocyclyl |-n^> I—O3        I—(  3 I—(  NH FN? NH groups are ’      , '       , ’        ,     '— / ,     \— / or ’ \— / . When the heter ocyclyl has substituents, the substituents may be attached to any atom in the ring, provided that a stable chemical structure results. The term “heterocycloalkylene” is a divalent group which is connected to the rest of the molecule by two single bonds, and the rest definitions are the same as the term “heterocycloalkyl”. “Spiro heterocyclyl” refers to a 5 to 20-membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably oneto three, heteroatoms selected from the group consisting of N, O, and S(O)m. (wherein m is 0,1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Preferably a spiro heterocyclyl is 6 to 14-membered, and more preferably 7 to 10-membered. According to the number of common spiroatoms, spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono-spiro heterocyclyl or di-spiro heterocyclyl, more preferably 4-membered / 4-membered, 4-membered / 5-membered,       4-membered / 6-membered,       5-membered / 5-membered,       or 5-membered / 6-membered mono-spiro heterocyclyl. Representative examples of spiro heterocyclyl include, but are not limited to the following substituents: “Fused Heterocyclyl" refers to a 5 to 20-membered polycyclic heterocyclyl group,wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S(O)P, (wherein p is 0,1,or 2) as ring atoms, the remaining ring atoms being C. Preferably a fused heterocyclyl is 6 to 14-membered, and more preferably 7 to 10-membered. According to the number of membered rings, fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 5 -membered / 5 -membered, or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to, the following substituents: As used herein, the ring of said heterocyclyl can be fused to the ring of an aryl, heteroaryl orcycloal-kyl,wherein the ringbound to the parent structure is heterocyclyl. Representative examples include, but are not limited to the following substituents: The heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogenthiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloal-koxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio. “Bridged Heterocyclyl” refers to a 5 to 14-membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, but have no completely conjugated pi-electron system, and the rings have one or more heteroatoms select ed from the group consisting of N, O, and S(O)m (wherein m is 0, 1, or 2) as ring atoms, the remaining ring atoms being C. Preferably a bridged heterocyclyl is 6 to 14-membered, and more preferably 7 to 10-membered. According to the number of membered rings, bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following substituents: As used herein, the term “Ci-ghaloalkoxyl” refers to an alkoxyl group in which one or more hydrogen atoms are replaced by a halogen, for example, -OCF3. As used herein, the term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, for example, -CF3. As used herein, the term “Ci_6 alkoxyCi_6 alkyl” refers to a Ci_6 alkyl group in which one or more hydrogen atoms are replaced by Ci_6 alkoxy or a Ci_6 alkoxy group in which one or more hydrogen atoms are replaced by Ci_6 alkyl. As used herein, the term “alkoxy” refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci_6 alkoxy means a straight or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of “alkoxy” as used herein include, but not limited to, methoxy, ethoxy, prop-1-oxy, pro-2-oxy, pentoxy, hexyloxy, and the like. As used herein, the term “aminoalkyl” refers to an alkyl moiety substituted by one or more amino moieties. Such as -CH2(NH2). As used herein, the term “alkylamino” refers to an amino group substituted by one or more alkyl such as -NH(Ci-6 alkyl) or -N(Ci^ alkyl)2. Examples of alkylamino include, but not limited to, -NH(CH3), -N(CH3)2. As used herein, the term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I). As used herein, the term "oxo" means that =0, oxygen atoms replace two hydrogens on the same carbon atom, that is, carbonyl groups replace methylene groups. As used herein, the term “Bond” refers to a covalent bond using a sign of “---”. In some embodiments, ---represents a double bond or single bond. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Methods of Synthesis The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes be low and in the examples. All substituents are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry. General synthetic procedure for preparing compounds as formula (II) are shown in Scheme 1: Scheme 1 Scheme 1 illustrates the preparation of compound of formula (II). At first the coupling of compounds of formula (1) can be obtained through standard Suzuki coupling conditions (for example Pd(dppf)C12 and K2CO3) to provide compound of formula (2). Compound of formula (2) was coupled with compound of formula (3) under Suzuki coupling conditions (for example Pd(dppf)C12 and K2CO3) to give compound of formula (4), which was converted to compound of formula (5) in the presence of iodization reagents, such I2 or NIS. Deprotection of compound of formula (5) to provide compound of formula (6), such as hydrolysis of the ester with LiOH-OH, or with TBAF deprotecting silicon protective group on hydroxyl group. Compound of formula (8) was attained by a routine coupling condition between compound of formula (6) and amine of formula (7) with coupling reagents, such as HATU, EDCI / HOBt or PyBOP etc, in the presence of an organic base, such as EtsN, DIPEA or pyridine, which was hydrolyzed to provide acid of formula (9) under a base, such as LiOH-OH. The intramolecular coupling of compound of formula (9) with coupling reagents, such as EDCI / HOBt and HATU, to give compound of formula (10). Then the coupling of compounds of formula (10) can be obtained through standard Suzuki coupling conditions (for example Pd(dppf)C12 and K2CO3) to provide compound of formula (11). Compound of formula (11) was coupled with compound of formula (12) under Suzuki coupling conditions (for example Pd(dppf)C12 and K2CO3) to give compound of formula (13), which was converted to compound of formula (14) with alkylate reagents, such iodomethane or iodoethane, in the presence of an inorganic base, such as Cs2CO3. Deprotection of compound (14) can afford compound of formula (15) in the presence of an acid, such as TFA. Compound of formula (II) can be obtained by a coupling reaction between acid of formula (16) and compound of formula (15) with coupling reagents, such as HATU, EDCI / HOBy, PyBOP or COMU, in the presence of a base, such as TEA, DIPEA, pyridine or 2,6-lutidine. Preparation of Intermediate Intermediate A: 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate Intermediate A Step 1. Preparation of (5-bromo-lH-indol-3-yl)methanol To a solution of 5-bromo-lH-indole-3-carbaldehyde (100.0 g, 0.45 mol) in premixed solvents THF / MeOH (1 L, V: V = 4:1) was stirred at 0°C for 5 mins, then NaBH4 (20.0g, 0.53 mol) was added into the above solution at room temperature. The resulting mixture was stirred at 0°C for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with H2O (300 mL) dropwise and diluted with EtOAc (100 mL), then the resulting mixture was extracted with EtOAc (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the crude product (5-bromo-lH-indol-3-yl)methanol (107.5g, 98%) as a white solid. The crude product was proceeded to the next reaction without purification. LCMS (ESI) calcd. for C9H8BrNO [M-H]+ m / z 224.07, found: 224.10 Step 2. Preparation of methyl 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropanoate To a solution of ((l-methoxy-2-methylprop-l-en-l-yl)oxy)trimethylsilane (157.3 g, 0.90 mol) in dry THF (150 mL) under N2 atmosphere, the reaction mixture was stirred at -40°C for 5 mins, then (5-bromo-lH-indol-3-yl)methanol (107.5 g, 0.48 mol) in dry THF (50 mL) was added under N2 atmosphere, After 10 mins, TMSOTf (90.0 g, 0.40 mol) in dry THF (50 mL) was added into the above solution by dropwise at nitrogen atmosphere. The reaction mixture was stirred at this temperature for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was warmed to room temperature and diluted with NaHCCL solution (100 mL), then the resulting mixture was extracted with EtOAc (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was further purified by silica gel chromatography eluting with petroleum ether / EtOAc (from 0% to 20%) to obtain methyl 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropanoate (98g, 70%) as a yellow solid. LCMS (ESI) calcd. for Ci4Hi6BrNO2 [M+H]+m / z 310.19, found: 310.20 Step 3. Preparation of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropan-l-ol To a solution of methyl 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropanoate (98g, 0.32 mol) and LiBH4 (40g, 1.82 mol) was added in dry THF (300 mL) at room temperature, the reaction mixture was stirred at 80°C for 12h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature, quenched with NH4C1 solution (150 mL) and diluted with EtOAc (100 mL), then the resulting mixture was extracted with EtOAc (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the crude product 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropan-l-ol (91.3g, 99%) as a light-yellow solid. The crude product was proceeded to the next reaction without purification. LCMS (ESI) calcd. for Ci3H16BrNO [M+H]+ m / z 282.18, found: 282.40 Step 4. Preparation of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate To a solution of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropan-l-ol (91.3g, 0.31 mol) in dry DCM (150 mL) at room temperature under N2 atmosphere, then DIPEA (62.7g, 0.49 mol), DMAP (4.0g, 0.03 mol) and AC2O (24.0 g, 0.31 mol) was added into the above solution under N2 atmosphere. The reaction mixture was stirred at room temperature for 3h. The reaction was monitored by LCMS. After completion, The reaction mixture was diluted with NaHCO3 solution (100 mL), then the resulting mixture was extracted with DCM (100 mL x 4), the combined organic phase was washed with saturated NaCl (50 mL), then died over with Na2SO4, following with concentration under reduced pressure to obtain crude one, which was purified by silica gel column eluting with petroleum ether / EtOAc (from 0% to 20%) to afford 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate (82.0 g, 79%) as a white solid. LCMS (ESI) calcd. for Ci5Hi8BrNO2 [M+H]+ m / z 324.22, found: 324.60 Intermediate B: methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxy carbonyl)amino)propanoate Br Intermediate B Step 1. Preparation of methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate To a solution of activated Zn dust (22 g, 334 mmol) and DMF (100 mL) was added to a 250 mL three-necked round-bottomed flask and purged with N2, then a solution of I2 (1.5 g, 6.08 mmol) in DMF (5 mL) was added to the above solution. The mixture was stirred for 10 min at rt, then a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (20 g, 60.79 mmol) in DMF (200 mL) was added dropwise over a period of 10 min. The mixture was heated at 35°C and stirred for 2 h, then the reaction was cooled to rt. Transfer the liquid to another 500 mL three-necked round-bottomed flask and purged with N2, and a solution of Pd(PPh3)Cl2 (2.1 g, 3.04 mmol) and 2,4-dibromothiazole 2 (17.7 g, 72.95 mmol) in DMF (100 mL) was added dropwise over a period of 10 min. The reaction was stirred at 50°C for 16 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 500 mL). The organic layers were combined, washed with saturated NaCl (2 x 500 mL), dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography purified by silica gel column eluting with EtOAc / PE from 0% to 25% to afford methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (10 g, 45.2 %) as a yellow solid. LCMS (ESI) calcd. for Ci2Hi7BrN2O4S [M+H]+ m / z 365.01, found: 367.3 Intermediate C: (S)-4-(methoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptan-2-ium 2,2,2-trifluoroacetate HOOC (COCI)2, DMF DCM step 1 TMSCHN2 THF / ACN step 2 CF3COOAg THF / H2O step 3 NaBH4 THF step 5 DMAP, TsCI, DIEA DCM step 6 CMPI, TEA, DMAP, DCM step 4 step 7 LiBr, NMP 1. LDA, DTBAD, DMPU 2. LiOH step 8 Boc ch3i, k2co3 DMF step 9 TFA DCM step 10 Intermediate C Step 1. Preparation of 3-oxocyclobutane-1-carbonyl chloride To a stirred solution of 3-oxocyclobutane-1-carboxylic acid (50 g, 438.60 mmol) in DCM (500 mL) and DMF (321 mg, 4.39 mmol) was added (COC1)2 (83.51 g, 657.89 mmol), the resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was used to next step without purification. LCMS (ESI) calcd. for C5H5C1O2 [M+H]+m / z 133.00, found: 133.4 Step 2. Preparation of 3-(2-diazoacetyl)cyclobutan-l-one To a stirred solution of crude 3-oxocyclobutane-l-carbonyl chloride in THF (250 mL) and CH3CN (250 mL) was added TMSCHN2 (2M in hexanes, 285 mL, 570.18 mmol) dropwisely at 0°C. The resulting mixture was stirred at rt for 18 h. After completion, the reaction solution was concentrated under reduced pressure to give the residual, the residual was purified by silica gel column (eluting with EtOAc / PE from 0% to 50%) to afford 3-(2-diazoacetyl)cyclobutan-l-one (60.2 g, 99.5 %) as a yellow oil. LCMS (ESI) calcd. for C6H6N2O2 [M+H]+ m / z 139.04, found: 139.4 Step 3. Preparation of 2-(3-oxocyclobutyl)acetic acid To a stirred solution of CF3COOAg (4.82 g, 21.81 mmol) in THF (300 mL), H2O (30 mL) and TEA (181.91 mL, 1.31 mol) was added a solution of 3-(2-diazoacetyl)cyclobutan-l-one (60.20 g, 436.23 mmol) in THF (300 mL) and H2O (30 mL) at 0°C, the reaction mixture was stirred at rt for 18 h. After completion, the reaction solution was concentrated under reduced pressure to give the residual, the residual was diluted with H2O and acidified with HC1 (2N) to pH = 2. The resuliting mixture was extracted with EtOAc (5*300 mL). The organic layers were combined and dried over Na2SO4, following with concentration under reduced pressure to afford crude 2-(3-oxocyclobutyl)acetic acid (55. 8g, 99.9 %) as a brown oil. LCMS (ESI) calcd. for C6H8O3 [M+H]+ m / z 129.13, found: 129.4 Step 4. Preparation of(S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one To a stirred solution of 2-(3-oxocyclobutyl)acetic acid (52.0 g, 406.3 mmol), (.S')-4-bcnzyloxazolidin-2-onc (71.9 g, 406.3 mmol), 4-Dimethylaminopyridine (5.0 g, 40.6 mmol) and triethylamine (141.2 mL, 1015.6 mmol) in DCM (1 L) was added 2-Chloro-l-methylpyridinium iodide (135.0 g, 528.1 mmol) in portions at 0°C . The reaction mixture was stirred at R.T. for 4 h. After completion, the reaction solution was diluted with H2O and extracted with DCM, the combined organic phase was washed with H2O dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give (^-d-benzyl-S-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (68 g 58.3 %) as a yellow oil. LCMS (ESI) calcd. for Ci6Hi7NO4 [M+H]+ m / z 288.1, found: 288.5 Step 5. Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one To a stirred solution of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (45.0 g, 156.8 mmol) in THF (500 mL) was added AcOH (17.9 mL, 313.6 mmol) and NaBH4 (6.5 g, 172.5 mmol) in portions at 0°C. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was diluted with H2O then concentrated under reduced pressure to remove THF. The residual was extracted with EtOAc, the combined organic phase was dried over Na2SO4, following with concentration under reduced pressure to obtain (>S')-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (45 g, 99.3 %) as a light yellow oil. LCMS (ESI) calcd. for Ci6Hi9NO4 [M+H]+ m / z 290.1, found: 290.5 Step 6. Preparation of (S)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate To a stirred solution of (>S')-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (48.0 g, 156.8 mmol) and DIEA (43.3 g, 249.1 mmol) in DCM (500 mL) was added 4-Dimethylaminopyridine (16.2 g, 132.9 mmol) and Tosyl chloride (34.8 g, 182.7 mmol) at 0°C. The reaction mixture was stirred at r.t. for 14 h. After completion, the reaction solution was diluted with H2O and extracted with DCM, the combined organic phase was washed with H2O dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 30%) to give (>S')-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, 84.3 %) as a yellow oil. LCMS (ESI) calcd. for C23H25NO6S [M+H]+ m / z 444.1, found: 444.6 Step 7. Preparation of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one To a stirred solution of (>S')-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, 139.8 mmol) in N-Methyl-2-pyrrolidone (650 mL) was added Lithium bromide (24.3 g, 279.6 mmol), the resulting mixture was stirred at 65°C for 13 h. The reaction was monitored by LCMS. After completion, the reaction solution was diluted with H2O and extracted with EtOAc, the combined organic phase was washed with NaCl (aq.) dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give (^-d-benzyl-S-(2-(3 -bromocyclobutyl)acetyl)oxazolidin-2-one (42 g, 85.3 %) as a light yellow oil. LCMS (ESI) calcd. for Ci6H18BrNO3 [M+H]+ m / z 352.0, found: 352.5 Step 8. Preparation of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid To a stirred solution of (5)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (30.0 g, 85.5 mmol) in THF (300 mL) was added LDA (2M in THF, 111.0 mmol) was added dropwise over a period of 15 minutes at -78°C under N2 condition. The reaction mixture was stirred at -78°C for 30 mins, then a solution of Di-tert-Butyl azodicarboxylate (23.6 g, 102.6 mmol) in DCM (50 mL) was added rapidly. The reaction mixture was stirred at -78°C for 30 mins, then l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (310 mL, 2565.0 mmol) was added dropwise at -78°C. The reaction mixture was stirred at r.t. for 14 h. After completion, the reaction solution was quenched with water (200 mL), then LiOH H2O (10.8 g, 256.5 mmol) was added and the reaction solution was stirred at r.t. for 2 h. After completion, the reaction solution was diluted with brine (200 mL) and washed with tert-Butyl methyl ether 2 times, the aqueous phase was acidified to pH = 3-4 with 2 N HC1. The resulting mixture was extracted with EtOAc, washed with water and brine, then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product (5)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.l.l]heptane-4-carboxylie acid, which was used directly for the next step. LCMS (ESI) calcd. for Ci6H26N2O6 [M+H]+ m / z 343.39, found: 343.5 Step           9.           Preparation           of          2,3-di-tert-butyl          4-methyl (S)-2,3-diazabicyclo[3.1.1 ]heptane-2,3,4-tricarboxylate To           a           stirred           solution           of          crude           product (5)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (27.0 g, 78.9 mmol) in DMF (300 mL) was added K2CO3 (27.3 g, 197.4 mmol) and lodomethane (10 mL, 157.8 mmol) at r.t.. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0%to 23%) to give 2,3-di-tert-butyl 4-methyl (5)-2,3-diazabicyclo[3.l.l]heptane-2,3,4-tricarboxylate (5.6 g, 18.45 % in two-steps) as a light yellow oil. LCMS (ESI) calcd. for Ci7H28N2O6 [M-H]' m / z 357.2, found: 357.6 Step 10. Preparation of    (S)-4-(methoxycarbonyl)-2,3-diazabicyclo [3.1.1 ]heptan-2-ium 2,2,2-trifluoroacetate To a stirred solution of 2,3-di-tert-butyl 4-methyl (5)-2,3-diazabicyclo [3. l.l]heptane-2,3,4-tricarboxylate (7.3 g, 0.18 mmol) in DCM (100 mL) was added TFA (40 mL), the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product (5)-4-(methoxycarbonyl)-2,3-diazabicyclo[3.1.1 ]heptan-2-ium 2,2,2-trifluoroacetate (7.2 g) as a yellow solid. LCMS (ESI) calcd. for Ci5H23BO4 [M+H]+m / z 157.09, found: 157.4 Intermediate D: tert-butyl ((63S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-61,62,63,64,6s,66-hexahy-dro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-4-yl)carbamate Br Intermediate D Step                          1.                          Preparation                          of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-lH-indol-3-yl)propyl acetate To a stirred solution of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate (20 g, 61.92 mmol) in 5 1,4-dioxane (400 mL) was added Pd(dppf)Cl2 (2.2 g, 3.10 mmol) and KOAc (18.4 g, 185.76 mmol). The reaction was stirred at 90°C for 16 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, the residual was diluted with H2O and extracted with EtOAc (500 mL x 3), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4, following with concentration under re-10 duced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from              0%              to              27%              to              afford 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-indol-3-yl)propyl acetate (18.7 g, 81.4 %) as a light yellow solid. LCMS (ESI) calcd. for C2iH30BNO4 [M+H]+ m / z 372.23, found: 372.5 15 Step                 2.                 Preparation                 of                 methyl (S )-3-( 4-( 3-( 3-acetoxy-2,2-dimethylpropyl)-lH-indol-5-yl)thiazol-2-yl)-2-( (tert-butoxycarbonyl)amino )pro panoate To                     a                    stirred                     solution                    of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)- lH-indol-3-yl)propyl acetate (18.7 g, 20   50.40 mmol), methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (27.5 g, 75.61 mmol) and K3PO4 (26.7 g, 126.01 mmol) in toluene / l,4-dioxane / H2O (300 mL, V:V:V = 4:1:1 ) was added Pd(dppf)Cl2 (1.6 g, 2.52 mmol) at rt. The reaction mixture was stirred at 70°C under N2 for 16 h. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane and toluene, the residual was diluted with H2O and extracted with EtOAc (500 mL x 3), the combined or-25 ganic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to        36% to afford methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)pro panoate (20.7 g, 77.6 %) as a light yellow solid. LCMS (ESI) calcd. for C27H35N3O6S [M+H]+ m / z 530.22, found: 530.6 Step                 3.                 Preparation                 of                 methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)ami no )propanoate To              a              stirred              solution              of              methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)pro panoate (12.3 g, 23.25 mmol) and NaHCO3 (2.3 g, 27.90 mmol) in THF (150 mL) under ice-water bath was added AgSO3CF3 (7.2 g, 27.90 mmol) in THF (50 mL) and I2 (5.0 g, 19.76 mmol) in THF (50 mL) by dropwise to the reaction mixture. The reaction was stirred at -20°C for 1 h, the reaction was monitored by LCMS. After completion, The reaction was quenched with saturated Na2S2O3 (200 mL) and was extracted with EtOAc (500 mL x 2), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to 40% to afford methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)am ino)propanoate (12.0 g, 78.8 %) as a light yellow solid. LCMS (ESI) calcd. for C27H34IN3O6S [M+H]+ m / z 656.12, found: 656.5 Step                          4.                          Preparation                          of (S )-2-( (tert-butoxycarbonyl )amino )-3-( 4-( 3-( 3-hydroxy-2,2-dimethylpropyl )-2-iodo-lPl-indol-5-yl )thiazol-2 -yl)propanoic acid To                  a                  solution                  of                  methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)am ino)propanoate (25 g, 38.17 mmol) in THF (500 mL) and H2O (100 mL) was added LiOHH2O (4.6 g, 190.84 mmol) at 0-10°C, the resulting mixture was stirred at 0-10°C for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 3-4 with 2 N HC1. The resulting mixture was extracted with EtOAc (300 mL x 2), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4 and concentrated to give the (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)propanoic acid (22.8 g, 100 %) as a light yellow solid. LCMS (ESI) calcd. for C24H30IN3O5S [M+H]+ m / z 599.10, found: 600.6 Step                          5.                          Preparation                          of (S)-2-((S)-2-( (tert-butoxycarbonyl )amino )-3-( 4-( 3-( 3-hydroxy-2,2-dimethylpropyl )-2-iodo-lH-indol-5-yl )th iazol-2-yl)propanoyl)-2,3-diazabicyclo[ 3.1.1 ]heptane-4-carboxylate To                            a                            solution                            of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)propanoic acid (1.10 g, 1.84 mmol) in DMF (15 mL) were added HATU (1.04 g, 2.75 mmol) and DIEA (1.30 mL, 7.35 mmol) at 0-10°C. The resulting mixture was stirred at 0-10°C for 10 min. Then me thyl (5)-2,3-diazabicyclo [3.1.1 ]heptane-4-carboxylate (472 mg, 1.84 mmol) was added into the reaction mixture, the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 400 mL), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to        60% to afford methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)t hiazol-2-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (1.23 g, 90.7 %) as a light yellow solid. LCMS (ESI) calcd. for C3iH40IN5O6S [M+H]+ m / z 738.2, found: 738.6 Step                          6.                          Preparation                          of (S)-2-((S)-2-( (tert-butoxycarbonyl )amino )-3-( 4-( 3-( 3-hydroxy-2,2-dimethylpropyl )-2-iodo-lH-indol-5-yl )th iazol-2-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid To                  a                  solution                  of                  methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)t hiazol-2-yl)propanoyl)-2,3-diazabicyclo[3.l.l]heptane-4-carboxylate (1.23 g, 24.53 mmol) in THF (1.23 g, 24.53 mmol) and H2O (6 mL) was added LiOHH2O (210 mg, 5.01 mmol) at 0-10°C, the resulting mixture was stirred at 0-10°C for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 3-4 with 2 N HC1. The resulting mixture was extracted with EtOAc (300 mL x 2), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4 and concentrated                           to                           give                           the (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)t hiazol-2-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (1.03 g, 85.3 %) as a light yellow solid. LCMS (ESI) calcd. for C30H38IN5O6S [M+H]+ m / z 724.1, found: 724.9 Step                  7.                  Preparation                  of                  tert-butyl ((64S,4S,Z)-l2-iodo-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2( 4,2)-thiazola-l(5,3)-indola-6( 2,4)-b icy do [3.1.1 ]heptanacycloundecaphane-4-yl (carbamate To a solution of TCFH (994 mg, 3.54 mmol) in ACN (80 mL) was added a solution of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)t hiazol-2-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid 22 (640 mg, 0.89 mmol) and NMI (582 mg, 7.08 mmol) in ACN (48 mL), the reaction was gradually improved temperature to room temperature and stirred for 2 h. The reaction was monitored by LCMS. After completion, the reaction was concentrated under reduced pressure to give crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 65% to afford tert-butyl ((64S,4S,Z)-12-iodo-10,10-dimethyl-5,7-dioxo-llH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4 )-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate 23 (199 mg, 31.7 %) as alight yellow solid. LCMS (ESI) calcd. for C30H36IN5O5S [M+H]+ m / z 706.2, found: 706.8 Step                 8.                 Preparation                 of                 tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-dia za-2( 4,2 )-thiazola-l(5,3 )-indola-6( 2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl )carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l2-iodo-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-b icyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (790 mg, 1.12 mmol), Pd2(dba)3 (154 mg, 0.17 mmol), SPhos (154 mg, 0.17 mmol) and AcOK(495 mg, 5.04 mmol) in toluene was added B2Pin2 (1.08 g, 8.40 mmol) at 0°C under N2 atmosphere. The reaction mixture was stirred at 60°C under N2 for 3h. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 60%) to give crude tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (810 mg) as a pale yellow solid. LCMS (ESI) calcd. for C36H48BN5O7S [M+H]+ m / z 706.3, found: 707.0 Intermediate E: (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine Intermediate E Step 1. Preparation of (S)-l-(3-bromopyridin-2-yl)ethan-l-ol To a stirred solution of TEA (151.76 g, 1.50 mol) was added FA (13.81 g, 299.96 mmol) at 0°C. Then (S,S)-N-(p-Toluenesulfonyl)-l,2-diphenylethanediamine(chloro)(p-cymene)ruthenium(II) (800 mg, 1.25 mmol) was added into the reaction mixture, the resulting mixture was stirred at 40°C under N2 for 0.5 h. l-(3-bromopyridin-2-yl)ethan-l-one (25.00 g, 124.98 mmol) was added into the reaction mixture, the re-sulitng mixture was stirred at 40°C under N2 for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (500 mL), washed with saturated NH4C1 (300 x 3 mL), then dried over Na2SO4. following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 25%) to give (S)-l-(3-bromopyridin-2-yl)ethan-l-ol (28.80 g, 95.0 %) as ayellow oil. LCMS (ESI) calcd. for C7H6BrNO [M+H]+ m / z 200.98, found: 202.1 Step 2. Preparation of (S)-3-bromo-2-(l-methoxyethyl)pyridine To a stirred solution of (S)-l-(3-bromopyridin-2-yl)ethan-l-ol (23.80 g, 117.82 mmol) in THF (240 mL) was added NaH (60% in oil, 7.07 g, 176.73 mmol) portion wisely at 0°C, the resulting mixture was stirred at 0°C for 1 h. CH3I (33.45 g, 235.64 mmol) was added into the reaction mixture at 0°C, the resulting mixture was stirred at rt for 15 h. The reaction mixture was quenched with H2O (50 mL) at 0°C and extracted with EtOAc (2*200 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 25%) to give (S)-3-bromo-2-(l-methoxyethyl)pyridine (23.39 g, 91.9 %) as a light yellow oil. LCMS (ESI) calcd. for C8H10BrNO [M+H]+ m / z 214.99, found: 216.3 Step                          3.                          Preparation                          of (S)-3-bromo-2-(l-methoxy ethy 1)-5-( 4,4,5,5-tetramethyl-l ff-dioxaborolan-2-yl)pyridine To a stirred solution of (S)-3-bromo-2-(l-methoxyethyl)pyridine (12.00 g, 55.56 mmol) B2Pin2 (15.53 g, 61.11 mmol) in THF (180 mL) was added [Ir(COD)(OMe)]2 (737 mg, 1.11 mmol) and dtbpy (895 mg, 3.33 mmol) at rt, the resulting mixture was stirred at 75°C under N2 for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give crude (S)-3-bromo-2-(l-methoxyethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (20.9 g) as an orange oil. LCMS (ESI) calcd. for Ci4H2iBBrNO3 [M+H]+ m / z 341.08, found: 342.4 Step 4. Preparation of (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid To              a              stirred              solution              of              crude (S)-3-bromo-2-(l-methoxyethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (16.20 g, 47.51 mmol) in THF (150 mL) and H2O (150 mL) were added NH4OAc (14.60 g, 190.03 mmol ) and NaIO4 (40.60 g, 190.03 mmol) at 0°C, the resulting mixture was stirred at rt for 3h. The reaction was monitored by LCMS. After completion, the reaction mixture was extracted with EtOAc (2*300 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid (10.98 g, 89.2%) as a yellow solid. LCMS (ESI) calcd. for C8HnBBrNO3 [M+H]+ m / z 259.00, found: 260.3 Step 5. Preparation of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine To a stirred solution of (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid (3.00 g, 11.58 mmol) in CH3CN (45 mL) was added NIS (3.13 g, 13.90 mmol) at rt, the resulting mixture was stirred at 75°C for 20h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with sat. aq. Na2SO3and concentrated to give the residue. The residue was extracted with EtOAc (2*30 mL). The organic layers were combined and washed with brine, then dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 20%) to give (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (2.65 g, 67.1%) as a brown solid. LCMS (ESI) calcd. for C8H9BrINO3 [M+H]+ m / z 340.89, found: 342.3 Preparation of compounds Unless otherwise defined, all technical and scientific terms in the present invention have the same meanings as generally understood by a person skilled in the art to which the invention belongs. In accordance with the general technical knowledge and customary means in the art, under the premise of not departing from the above-mentioned basic technical ideas of the present invention, other forms of modification, replacement or change can also be made. Unless otherwise stated, the raw materials and reagents used in the following embodiments are commercially available or may be prepared by known methods. Intermediate of Example 3: Synthesis of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol Step 1. Preparation of(S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol A mixture of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (200 mg, 0.59 mmol), 2-methylbut-3-yn-2-ol (99 mg, 1.17 mmol), K2CO3 (243 mg, 1.76 mmol), Pd(PPh3)2C12 (41 mg, 0.059 mmol) and Cui (11 mg, 0.059 mmol) in THF (4.5 mL) was stirred at 65°C under N2 for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 40%) to give (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol (160 mg, 91.3%) as a brown solid. LCMS (ESI) calcd. for Ci3Hi6BrNO2 [M+H]+ m / z 297.04, found: 298.4 Intermediate of Example 4: Synthesis of 3-bromo-2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridine Step 1: Synthesis of tert-butyl (S)-2-ethynylpyrrolidine-l-carboxylate To a stirred solution of tert-butyl (S)-2-formylpyrrolidine-l-carboxylate (2.0 g, 10.05 mmol) in MeOH (40 mL) was added K2CO3 (3.5 g, 25.13 mmol) and Dimethyl (1-Diazo-2-oxopropyl)phosphonate (2.3 g, 12.06 mmol) at r.t.. The reaction mixture was stirred at r.t. for overnight. After completion, the reaction solution was concentrated under reduced pressure to remove MeOH, the residual was diluted with H2O and extracted with EtOAc, the combined organic phase was dried over Na2SO4. following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give tert-butyl (S)-2-ethynylpyrrolidine-l-carboxylate (1.7 g, 86.7 %) as a colourless oil. LCMS (ESI) calcd. for CnH17NO2 [M+H]+ m / z 195.1, found: 196.3. Step                   2:                   Synthesis                   of                  tert-butyl (S)-2-( (5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate To a stirred solution of tert-butyl (S)-2-ethynylpyrrolidine-l-carboxylate (1.7 g, 8.72 mmol), (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (2.5 g, 7.26 mmol), Pd(PPh3)2C12 (509 mg, 0.73 mmol) and Cul(277 mg, 1.45 mmol) in 1,4-dioxane (40 mL) was added TEA (4 mL, 29.04 mmol) at r.t.. The reaction mixture was stirred at 35°C under N2 for 8 h. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, the residual was diluted with H2O and extracted with EtOAc, the combined organic phase was dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to                    30%)                    to                    give                    tert-butyl (S)-2-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate (2.8 g, 93.6 %) as a light yellow oil. LCMS (ESI) calcd. for Ci9H25BrN2O3 [M+H]+ m / z 409.1, found: 310.9. Step 3: Synthesis of 3-bromo-2-((S)-1-methoxy ethyl)-5-(((S)-pyrrolidin-2-yl)ethynyl)pyridine To              a              stirred              solution              of              tert-butyl (S)-2-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate (2.8 g, 6.84 mmol) in dichloromethane (30 mL) was added TFA (10 mL) slowly at r.t., the resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated to give the crude product 3-bromo-2-((S)-l-methoxyethyl)-5-(((S)-pyrrolidin-2-yl)ethynyl)pyridine (2.8 g, crude) as a yellow oil. LCMS (ESI) calcd. for Ci4Hi7BrN2O [M+H]+ m / z 309.2, found: 310.6. Step 4: Synthesis of 3-bromo-2-((S)-1-methoxy ethyl)-5-(((S)-1 -methylpyrrolidin-2-yl)ethynyl)pyridine To a stirred solution of (S)-4-(benzyloxy)-l-bromo-2-(l-methoxyethyl)benzene (2.12 g, 6.84 mmol) in DCM / MeOH (55 mL, V:V = 5:1 ) was added Formaldehyde (2.9 g, 37% in water , 35.9 mmol) and AcOH (0.5 mL) at r.t.. The reaction mixture was stirred at r.t. for 5 h, then NaBH3CN (734 mg, 11.7 mmol) was added. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was diluted with H2O and extracted with DCM, the combined organic phase was dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with DCM / MeOH from 0% to 10%) to give 3-bromo-2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridine (2.13 g, 96.1 %) as a light yellow oil. LCMS (ESI) calcd. for Ci5Hi9BrN2O [M+H]+ m / z 323.1, found: 323.4. Intermediate of Example 5: Synthesis of tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate „ / Boc Step 1. Preparation of tert-butyl (S)-3-ethynylpyrrolidine-l-carboxylate To a stirred solution of tert-butyl (R)-3-formylpyrrolidine-l-carboxylate (1 g, 5.0 mmol) and K2CO3 (1.4 g, 10.0 mmol) in MeOH (15 mL) was added dimethyl (l-diazo-2-oxopropyl)phosphonate (1.2 g, 6.0 mmol) at RT. The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (30 mL), then dried over Na2SO4, following with concen tration under reduced pressure to obtain crude product tert-butyl (S)-3-ethynylpyrrolidine-l-carboxylate (980 mg) as a yellow oil. LCMS (ESI) calcd. for CnH17NO2 [M+H-56]+ m / z 140.1, found: 140.4 Step                 2.                 Preparation                 of                 tert-butyl (5)-3-( (5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate A mixture of tert-butyl (S)-3-ethynylpyrrolidine-l-carboxylate (980 mg, 5.0 mmol), (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (1.7 g, 5.0 mmol), Cui (96 mg, 0.5 mmol) TEA (1.0 g, 10.0 mmol) and Pd(PPh3)2Cl2 (352 mg, 0.5 mmol) in THF (20 mL) was stirred at 50°C under N2 for 2 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 25%) to give tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate (1.8 g, 90 % in 2 steps) as a brown oil. LCMS (ESI) calcd. for Ci9H25BrN2O3 [M+H]+ m / z 409.1, found: 409.6 Intermediate of Example 6: Synthesis of (S)-3-bromo-2-(l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridine Step 1: Synthesis of 1 -methyl-4-((trimethylsilyl)ethynyl)-l H-pyrazole A mixture of 4-iodo-l-methyl-IH-pyrazole (1 g, 4.81 mmol), ethynyltrimethylsilane (708 mg, 7.21 mmol), TEA (1.46 g, 14.42 mmol), Pd(PPh3)2Cl2 (337 mg, 0.48 mmol) and Cui (92 mg, 0.48 mmol) in THF (15 mL) was stirred at 50°C under N2 for 1 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 50%) to give 1-methyl-4-((trimethylsilyl)ethynyl)-lH-pyrazole (500 mg, 58.4%) as a brown solid. LCMS (ESI) calcd. for C9Hi4N2Si [M+H]+ m / z 179.1, found: 179.4. Step 2: Synthesis of 4-ethynyl-l-methyl-lH-pyrazole To a stirred solution of 1-methyl-4-((trimethylsilyl)ethynyl)-lH-pyrazole (500 mg, 2.81 mmol)in THF (5mL) was added TBAF (IM in THF, 4.2 mL, 4.2 mmol) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. After completion, the reaction mixture was used to next step without purification. LCMS (ESI) calcd. for C6H6N2 [M+H]+m / z 106.1, found: 107.4. Step 3: Synthesis of (S)-3-bromo-2-(l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridine A mixture of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (735 mg, 2.16 mmol), 4-ethynyl-l-methyl-lH-pyrazole 3 (300 mg, 2.80 mmol), TEA (654 mg, 6.47 mmol), Pd(PPh3)2Cl2 (151 mg, 0.22 mmol) and Cui (41 mg, 0.22 mmol) in THF (6 mL) was stirred at 50°C under N2 for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 50%) to give (S)-3-bromo-2-(l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridine (379 mg, 55.0%) as a yellow solid. LCMS (ESI) calcd. for Ci3H16BrNO2 [M+H]+ m / z 320.0, found: 320.5. Intermediate of Example 8: Synthesis of (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)benzo[d]thiazole Synthesis of (3)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)benzo[d]thiazole To a stirred solution of 5-ethynylbenzo[d]thiazole (100 mg, 0.63 mmol), (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (178 mg, 0.52 mmol), Pd(PPh3)2C12 (37 mg, 0.05 mmol) and Cui (20 mg, 0.10 mmol) in 1,4-dioxane (3 mL) was added TEA (0.3 mL, 2.09 mmol) at r.t.. The reaction mixture was stirred at 50°C under N2 for 4 h. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, the residual was diluted with H2O and extracted with EtOAc , the combined organic phase was dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 95%) to give (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)benzo[d]thiazole (190 mg, 80.9%) as a light yellow solid. LCMS (ESI) calcd. for Ci7Hi3BrN2OS [M+H]+ m / z 373.0, found: 373.4. Intermediate of Example 9: Synthesis of (S)-3-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)imidazo[l,2-b]pyridazine Step 1: Synthesis of (S)-3-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)imidazo[l,2-b]pyridazine A mixture of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (200 mg, 0.59 mmol), 3-ethynylimidazo[l,2-b]pyridazine 2 (126 mg, 0.88 mmol), Cui (11 mg, 0.059 mmol), TEA (227 mg, 1.76 mmol) and Pd(PPh3)2C12 (41 mg, 0.059 mmol) in DMF (3 mL) was stirred at 65°C for 1 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with EtOAc / PE from              0%              to              100%)              to              obtain (S)-3-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)imidazo[l,2-b]pyridazine (200 mg, 95.2%) as a yellow oil. LCMS (ESI) calcd. for Ci6Hi3BrN4O [M+H]+ m / z 357.0, found 357.4. The following intermediates in Table 2 were prepared using the method described above in step for the preparation of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol or tert-butyl (S)-3 -((5 -bromo-6-((S)-1 -methoxyethyl)pyridin-3 -yl)ethynyl)pyrrolidine-1 -carboxylate and utilizing the appropriate starting materials and modifications. Table 2. Certain Intermediates containing alkynyl group of the Present invention Name Structure LCMS (S)-3-bromo-5-ethynyl-2-( 1-methoxy ethyl)pyridine \ / =N O Br [M+H]+ 240.1 / 242.1 (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol Br [M+H]+ 297.1 / 299.1 (S)-3-bromo-5-((l-fluorocyclopropyl)ethynyl)-2-(l-methoxyet hyl)pyridine F       / =N 'b Br [M+H]+ 298.2 / 300.2 3 -bromo-2-((S)-1 -methoxyethyl)-5 -(((S)-1 -methylpyrrolidin-2 -yl)ethynyl)pyridine \ r \ M—   / / \\__ / * \                Br [M+H]+ 323.2 / 325.2 (S)-2-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)-5-m ethyl-1,3,4-thiadiazole \ [  \...i=—( /  \\-- / \— / \ Br [M+H]+ 323.2 / 325.2 (S)-3 -bromo-2-( 1 -methoxyethyl)-5 -((1 -methyl- lH-pyrazol-4-yl)ethynyl)pyridine \ z-N   O = f VA \_ / \ Br [M+H]+ 320.2 / 322.2 (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)pyri midine \ N— / =N O N= /            V Br [M+H]+ 318.2 / 320.2 (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)benz o[d]thiazole r            z^n p s—e \ / \\__ / Br [M+H]+ 373.3 / 375.3 (S)-3-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)imid azo [ 1,2-b]pyrimidine O    \ K.N       / =N  0 O — Br [M+H]+ 357.2 / 359.2 Intermediate of Example 10: Synthesis of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-N,N-dimethylprop-2-yn-l-amine 5 Step 1: Synthesis of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-N,N-dimethylprop-2-yn-l-amine (2) To a solution of (R)-morpholin-3-ylmethanol (58 mg, 0.71 mmol) in DCM (2 mL) were added DIEA (244 mg, 1.89 mmol) and a solution of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (200 mg, 0.47 mmol) in DCM (2 mL) at rt, the resulting mixture was stirred at 10 rt for 15 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure to give the residual which was purified by silica gel column chromatography (eluting with MeOH / DCM       from       0% to       10%) to give (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-N,N-dimethylprop-2-yn-l-amine (73 mg, yield: 52.5%) as a brown oil. LCMS (ESI) calcd. for Ci3H17BrN2O [M+H]+ m / z 297.1, found 297.5. Intermediate of Example 11: Synthesis of 3-bromo-5-(3-((R)-3-fluoropyrrolidin-l-yl)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridine Step                           1:                           Synthesis                           of 3-bromo-5-(3-((R)-3-fluoropyrrolidin-l-yl)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridine To a stirred solution of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (350 mg, 0.83 mmol) in DCM (10 mL) was added (R)-3-fluoropyrrolidine (81 mg, 0.91 mmol) and DIEA (170 mg, 1.32 mmol) at r.t. , the resulting mixture was stirred at r.t. for 8 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with DCM / MeOH (30 mL, V:V = 10:1), washed with water (10 mL x 3) and saturated NaCl (10 x 2 mL), then dried over Na2SC>4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 5%) to give 3 -bromo-5 -(3-((R)-3 -fluoropyrrolidin-1 -yl)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridine (230 mg, 81.5 %) as a lihgt yellow oil. LCMS (ESI) calcd. for Ci5Hi8BrFN2O [M+H]+ m / z 341.1, found: 341.53. Intermediate of Example 12: Synthesis of (S)-3-bromo-2-(l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridine Step 1: Preparation of(S)-3-bromo-2-(l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridine A mixture of piperidine (66.2 mg, 0.78 mmol), (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (300 mg, 0.71 mmol) in DCM (5 mL) was added DIEA (182.7 mg, 1.4 mmol). The reaction mixture was stirred at rt for 3h. After completion, the mixture was was concentrated under reduced pressure. The residue was purified by FCC with EtOAc / PE =      0-30% to afford the (S)-3-bromo-2-(l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridine (206 mg, 86%) as a yellow oil. LCMS (ESI) calcd. for Ci6H21BrN2O [M+H]+ m / z 337.1, found 337.6 Intermediate of Example 13: Synthesis of (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)-4-methylpiperazine Step                         1:                         Preparation                         of (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)-4-methylpiperazine A mixture of 1-methylpiperazine (52 mg, 0.52 mmol), (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (200 mg, 0.47 mmol) in DCM (5 mL) was added DIEA (121.5 mg, 0.94 mmol). The reaction mixture was stirred at rt for 3h. After completion, the mixture was was concentrated under reduced pressure. The residue was purified by FCC with MeOH / DCM =      0-6% to afford the (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)-4-methylpiperazine (130 mg, 79%) as a yellow oil. LCMS (ESI) calcd. for Ci6H22BrN3O [M+H]+ m / z 352.1, found 352.6. Intermediate of Example 14: Synthesis of (S)-l-(4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazin-l-yl)ethan-l-one Step                           1:                           Synthesis                           of (S)-l-(4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazin-l-yl)ethan-l-one To a stirred solution of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (350 mg, 0.83 mmol) in DCM (10 mL) was added 1-(piperazin-l-yl)ethan-l-one (120 mg, 0.91 mmol) and DIEA (170 mg, 1.32 mmol) at r.t. , the resulting mixture was stirred at r.t. for 8 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with DCM / MeOH (30 mL, V:V = 10:1), washed with water (10 mL x 3) and saturated NaCl (10 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 5%) to give (S)-1 -(4-(3 -(5 -bromo-6-( 1 -methoxyethyl)pyridin-3 -yl)prop-2-yn-1 -yl)piperazin-1 -yl)ethan-1 -one (190 mg, 60.4 %) as a lihgt yellow oil. LCMS (ESI) calcd. for Ci7H22BrN3O2 [M+H]+ m / z 380.1, found: 380.5. Intermediate of Example 15: Synthesis of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine Step                          1.                          Preparation                          of 3-bromo-2-((S)-l-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-l-yn-l-yl)pyridine A mixture of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (10.00 g, 29.24 mmol), 2-(prop-2-yn-l-yloxy)tetrahydro-2H-pyran (4.92 g, 35.09 mmol), Cui (0.45 g, 2.34 mmol), TEA (8.88 g, 8.73 mmol) and Pd(PPh3)2C12 (1.64 g, 2.34 mmol) in THF (120.00 mL) was stirred at 50°C for 4h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 3% in 20 min) to obtain 3 -bromo-2-((>S')-1 -methoxyethyl)-5 -(3 -((tetrahydro-2H-pyran-2-yl)oxy)prop-1 -yn-1 -yl)pyridine (10.10 g, yield: 97.5%) as a yellow oil. LCMS (ESI) calcd. for Ci6H20BrNO3 [M+H]+ m / z 354.1, found 354.5. Step 2. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol To                            a                            solution                            of 3 -bromo-2-((>S')-1 -methoxyethyl)-5 -(3 -((tetrahydro-2H-pyran-2-yl)oxy)prop-1 -yn-1 -yl)pyridine (10.10 g, 28.51 mmol) in MeOH (100.00 mL) was added TsOH (19.64 g, 114.05 mmol) at 0°C, the mixture was stirred at room temperature for 5 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with DCM (50.00 mL) and H2O (150.00 mL) and extracted with DCM (50 mL x 3), the combined layers were washed with saturated NaCl (150.00 mL), dried over Na2SO4, concentrated to obtain (lS)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, yield: 92.2%) as a yellow oil. LCMS (ESI) calcd. for CnH12BrNO2 [M+H]+ m / z 270.0, found 270.3. Step 3. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate To a solution of (>S')-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, 26.28 mmol) in THF (100.00 mL) were added TsCl (10.02 g, 52.57 mmol) and KOH (2.95 g, 52.57 mmol) at 0°C, the mixture was stirred at 0°C for 2 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with EtOAc (50.00 mL) and water (100.00 mL), then extracted with EA (50.00 mL x 3). The combined organic phase was washed with brine (100.00 mL), dried over Na3SO4 and concentrated under reduced pressure. The residual was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 30% in 30 min) to obtain (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (10.50 g, yield: 94.2%) as a brown solid. LCMS (ESI) calcd. for Ci8H18BrNO4S [M+H]+ m / z 424.0, found 424.8. Step 4. Preparation of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine To a solution of morpholine (358 mg, 4.11 mmol) in DCM (10 mL) were added DIEA (1.21 g, 9.34 mmol) and a solution of (>S')-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (1.58 g, 3.74 mmol) in DCM (10 mL) at rt, the resulting mixture was stirred at rt for 16 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressureto give the residual which was purified by silica gel column chromatography (eluting with EtOAc / PE          from          0%          to          40%)          to          obtain (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine (980 mg, yield: 77.5%) as a brown oil. LCMS (ESI) calcd. for Ci5Hi9BrNO2 [M+H]+ m / z 339.1, found 339.6 Intermediate of Example 17: Synthesis of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)thiomorpholine 3-bromo-2-((S)-l-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-l-yn-l-yl)pyridine A mixture of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (10.00 g, 29.24 mmol), 2-(prop-2-yn-l-yloxy)tetrahydro-2H-pyran (4.92 g, 35.09 mmol), Cui (0.45 g, 2.34 mmol), TEA (8.88 g, 8.73 mmol) and Pd(PPh3)2Cl2 (1.64 g, 2.34 mmol) in THF (120.00 mL) was stirred at 50oC for 4h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 3% in 20 min) to obtain 3-bromo-2-((S)-l-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-l-yn-l-yl)pyridine 32 (10.10 g, yield: 97.5%) as a yellow oil. LCMS (ESI) calcd. for Ci6H20BrNO3 [M+H]+ m / z 354.1, found 354.5. Step 2. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol To                            a                            solution                            of 3 -bromo-2-((>S')-1 -methoxyethyl)-5 -(3 -((tetrahydro-2H-pyran-2-yl)oxy)prop-1 -yn-1 -yl)pyridine (10.10 g, 28.51 mmol) in MeOH (100.00 mL) was added TsOH (19.64 g, 114.05 mmol) at 0°C, the mixture was stirred at room temperature for 5 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with DCM (50.00 mL) and H2O (150.00 mL) and extracted with DCM (50 mL x 3), the combined layers were washed with saturated NaCl (150.00 mL), dried over Na2SO4, concentrated to obtain (>S')-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, yield: 92.2%) as a yellow oil. LCMS (ESI) calcd. for CnHi2BrNO2 [M+H]+ m / z 270.0, found 270.3. Step 3. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate To a solution of (>S')-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, 26.28 mmol) in THF (100.00 mL) were added TsCl (10.02 g, 52.57 mmol) and KOH (2.95 g, 52.57 mmol) at 0°C, the mixture was stirred at 0°C for 2 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with EtOAc (50.00 mL) and water (100.00 mL), then extracted with EA (50.00 mL x 3). The combined organic phase was washed with brine (100.00 mL), dried over Na2SO4 and concentrated under reduced pressure. The residual was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 30% in 30 min) to obtain (>S')-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (10.50 g, yield: 94.2%) as a brown solid. LCMS (ESI) calcd. for Ci8Hi8BrNO4S [M+H]+ m / z 424.0, found 424.8. Step                          4.                          Preparation                          of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)thiomorpholine 1,1-dioxide To a solution of thiomorpholine 1,1-dioxide (160 mg, 1.18 mmol) in DCM (2.5 mL) were added DIEA (229 mg, 1.77 mmol) and a solution of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (250 mg, 0.59 mmol) in DCM (2.5 mL) at rt, the resulting mixture was stirred at rt for 20 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure to give the residual which was purified by silica gel column chromatography (eluting with EtOAc / PE from 0% to 60%) to obtain (S)-4-(3-(5-bromo-6-( 1 -methoxyethyl)pyridin-3-yl)prop-2-yn-1 -yl)thiomorpholine 1,1 -dioxide (186 mg, yield: 81.7%) as a brown oil. LCMS (ESI) calcd. for CisHigBr^OjS [M+H]+ m / z 387.0, found 387.5. Intermediate of Example 19: Synthesis of ((R)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol Step                           1:                           Synthesis                           of ((R)-4-( 3-( 5-bromo-6-( (S )-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol To a solution of (R)-morpholin-3-ylmethanol (500 mg, 4.27 mmol) in DCM (10 mL) were added DIEA (1.10 g, 8.51 mmol) and a solution of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (1.80 g, 4.24 mmol) in DCM (15 mL) at rt, the resulting mixture was stirred at rt for 16 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure to give the residual which was purified by silica gel column chromatography (eluting with MeOH / DCM from 0% to 15% ) to give ((R)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol (1.1 g, yield: 70.0%) as a brown oil. LCMS (ESI) calcd. for Ci6H2iBrN2O3 [M+H]+ m / z 369.1, found 369.5. Intermediate of Example 20: Synthesis of ((S)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol Step                         1:                         Preparation                         of ((S)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol A mixture of (S)-morpholin-3-ylmethanol (61 mg, 0.52 mmol), (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (200 mg, 0.47 mmol) in DCM (5 mL) was added DIEA (121.5 mg, 0.94 mmol). The reaction mixture was stirred at rt for 3h. After completion, the mixture was was concentrated under reduced pressure. The residue was purified by FCC with EtOAc / PE =      0-30% to afford the ((S)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol (148 mg, 85%) as a yellow oil. LCMS (ESI) calcd. for CigH2iBrN2O3 [M+H]+ m / z 369.1, found 369.5 Intermediate of Example 31: Synthesis of (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)-4-(methylsulfonyl)piperazine step 3 Step                 1:                 Preparation                 of                 tert-butyl (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazine-l-carboxylate To a stirred solution of tert-butyl piperazine-1-carboxylate (145 mg, 0.778 mmol) in DCM (8 mL) was added (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (300 g, 0.707 mmol) and DIEA (183 mg, 1.414 mmol). The resulting mixture was stirred at rt for 4h. The reaction was concentrated under reduced pressure. The residue was purified by FCC with MeOH / DCM = 0-5% to                             afford                             the                             tert-butyl (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazine-l-carboxylate (200 mg, 65%) as yellow oil. LCMS (ESI) calcd. for C20H28BrN3O3 [M+H]+ m / z 438.1, found 438.5 Step 2: Preparation of (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazine To              a              stirred              solution              of              tert-butyl (S)-4-(3 -(5 -bromo-6-( 1 -methoxyethyl)pyridin-3 -yl)prop-2-yn-1 -yl)piperazine-1 -carboxylate (200 mg, 0.456 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for Ih. The reaction was concentrated under reduced pressure to afford the crude (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazine (220 mg) as yellow oil. LCMS (ESI) calcd. for Ci5H20BrN3O [M+H]+ m / z 338.1, found 338.5 Step                         3:                         Preparation                         of (5)-1-( 3-( 5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)-4-( methylsulfonyl)piperazine To a stirred solution of (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazine (152 mg, 0.45 mmol) in DCM (5 mL) was added TEA (136.5 mg, 1.35 mmol) and MsCl (51.5 mg, 0.45 mmol) at 0°C. The resulting mixture was stirred at 0°C for 0.5h. After completion, the reaction was quenched with H2O (10 mL) and extracted with EtOAc (10 mL*3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was was purified by FCC with         MeOH / DCM         =         0-5%         to         afford         the (S)-1 -(3 -(5 -bromo-6-( 1 -methoxyethyl)pyridin-3 -yl)prop-2-yn-1 -yl)-4-(methylsulfonyl)piperazine (170 mg, 90%) as a light yellow oil. LCMS (ESI) calcd. for CigH22BrN3O3S [M+H]+ m / z 416.1, found 416.5 The following intermediates in Table 3 were prepared using the method described above in step for the preparation of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine and utilizing the appropriate starting materials and modifications. Table 3. Certain Intermediates containing alkynyl group of t ie Present invention Name Structure LCMS (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-N,N-dimethylprop-2-yn-1 -amine / \ —N       / =N O Br [M+H]+ 297.2 / 299.2 3 -bromo-5 -(3 -((R)-3 -fluoropyrrolidin-1 -yl)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridine 6 / =N O Br [M+H]+341.2 / 343.2 (S)-3-bromo-2-(l-methoxyethyl)-5-(3-(piperidin-l -yl)prop-1 -yn-1 -yl)pyridine o N        / =N O Br [M+H]+ 337.3 / 339.3 (S)-l-(3-(5 -bromo-6-( 1 -methoxy ethyl)pyridin-3 -y l)prop-2-yn-1 -yl)-4-methylpiperazine \ N—X ( / \ x—N        / =N O Br [M+H]+352.1 / 354.1 (S)-1 -(4-(3 -(5 -bromo-6-( 1 -methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazin-l-yl)ethan-l-one _ ( / \ x—N        / =N O Br [M+H]+380.1 / 382.1 (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-y l)prop-2-yn-1 -yl)thiomorpholine 1,1 -dioxide P-y = Br [M+H]+338.1 / 340.1 ((R)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridi n-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol PH \ '--- / \ x—N        / =N O Br [M+H]+369.1 / 371.1 ((S)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin -3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol P^ OH x—N        / =N O Br [M+H]+369.1 / 371.1 (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-y l)prop-2-yn-1 -yl)thiomorpholine 1,1 -dioxide O    x x—N        / =N O Br [M+H]+ 387.3 / 389.3 (S)-l-(3-(5 -bromo-6-( 1 -methoxy ethyl)pyridin-3 -y l)prop-2-yn-1 -yl)-4-(methylsulfonyl)piperazine v N-\ Br [M+H]+ 416.1 / 418.1 Intermediate of Example 29: Synthesis of N-(dimethylcarbamoyl)-N-methyl-L-valine o 5 Step 1. Preparation of benzyl N-(dimethylcarbamoyl)-N-methyl-L-valinate A mixture of benzyl (2S)-3-methyl-2-(methylamino)butanoate (500 mg, 2.26 mmol) and dimethylcarbamyl chloride (1.215 g, 11.3 mmol) in THF (5 mL), was added TEA (2.286 g, 22.59 mmol and DMAP (276.02 mg, 2.26 mmol) in portions under nitrogen atmosphere. The reaction mixture was stirred at 65°C for 12 h under nitrogen atmosphere, then quenched with water (100 ml) and was extracted with EtOAc (50 10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, fdtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford benzyl N-(dimethylcarbamoyl)-N-methyl-L-valinate (400 mg, 58.3% yield) as a colorless oil. LCMS (ESI) calcd. for Ci6H25N2O3 [M+H]+ m / z 293.2, found: 293.4 Step 2. Preparation ofN-(dimethylcarbamoyl)-N-methyl-L-valine A mixture of benzyl N-(dimethylcarbamoyl)-N-methyl-L-valinate (400 mg, 1.37 mmol) and palladium hydroxide on carbon (400 mg, 2.85 mmol) in MeOH (10 mL) was stirred for 4 h under hydrogen atmosphere. The reaction mixture was fdtered and the fdter cake was washed with MeOH (100 mL x3). The filtrate was concentrated under reduced pressure to afford N-(dimethylcarbamoyl)-N-methyl-L-valine (200 5 mg, crude) as a colorless oil. LCMS (ESI) calcd. for C9H19N2O3 [M+H]+ m / z 203.1, found: 203.1 The following compounds in Table 4 were prepared according to the representative procedure described above for the synthesis ofN-methyl-N-((2R,3R)-3-phenyltetrahydrofuran-2-carbonyl)-L-valine and utilizing the appropriate starting materials and modifications. 10   ________________________Table 4. Certain Peptides of the Present invention________________________ Name Structure LCMS N-(dimethylcarbamoyl)-N-methyl-L-valine U ।            । HoArNYN-o [M+H]+ 203.3 N-methyl-N-(morpholine-4-carbonyl)-L-valine I o °=( Q [M+H]+ 245.3 N-((3 S,4R)-1 -(methoxy carbonyl)-4-methylpyrrolidine-3-carbony l)-N-methyl-L-valine o. o 1 [M+H]+ 301.4 N-methyl-N-((2R,3R)-3-phenyltetrahydrofuran-2-carbonyl)-L-va line o \ )=° '  Z— 0=1 [M+H]+ 306.4 (S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbon y 1) -2,7-diazaspiro [4.4]nonan-2-yl)-3 -methylbutanoic acid o [M+H]+ 350.5 (S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziri dine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)acetic acid [M+H]+ 376.5 N-( 1 -(4-(dimethylamino)-4-methylpent-2-ynoyl)-4-fluoropiperidi ne-4-carbonyl)-N-methyl-L-valine [M+H]+ 398.5 SPECIFIC EMBODIMENTS The present invention is described in detail below by embodiments, but does not imply any adverse restriction on the present invention. The compounds of the present invention can be prepared by a variety 15 of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the invention with other chemical synthesis methods, and the equivalent substitution methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, embodiments of the present invention. To those skilled in the art, various changes and improvements to the specific embodiments of the present invention without departing from the spirit and scope of the invention will be obvious and shall also be regarded as the scope of protection of the present invention. Each of the compounds set forth was prepared following one of the procedures set forth below. Unless 5 otherwise specified, intermediates that do not mention the synthesis method in the following synthesis routes are obtained by purchase or customization Example 1 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-di- 10 oxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphan e-4-yl) -2-methylcyclopropane-1 -carboxamide Method 1: Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol with 15 (S)-3-bromo-5-ethynyl-2-(l-methoxyethyl)pyridine in the Step 1 of Example 2 and Substituting (1 r,2R,3 S)-2,3 -dimethylcyclopropane-1 -carboxylic acid with (1 S,2S)-2-methylcyclopropane-1 -carboxylic acid in the Step 4 of Example 2, the title compound was prepared by the same procedures as described for Example 2. Method 2: atropisomer 1                                   atropisomer 2 Step 1: Synthesis of (S)-5-bromo-6-(l-methoxyethyl)pyridin-3-ol To              a              stirred              solution              of              crude (S)-3-bromo-2-(l-methoxyethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.00 g, 2.93 mmol) in THF (10 mL) and H2O (15 mL) were added NaOH (234 mg, 5.86 mmol ) and H2O2 (195 mg, 14.6 mmol) at rt. The resulting mixture was stirred at rt for 2 h. After completion, the reaction mixture was acified by IM HC1 aquous to pH = 4. The mixture was extracted with EtOAc (2*20 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give (S)-5-bromo-6-(l-methoxyethyl)pyridin-3-ol (600 mg, 88%) as a white solid. LCMS (ESI) calcd. for C8Hi0BrNO2 [M+H]+ m / z 231.0, found: 232.3 Step                   2:                   Synthesis                   of                  tert-butyl ((64S,4S,Z)-l2-( 5-hydroxy-2-( (S )-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1 H-8-oxa-62,63-d iaza-2(4,2 )-thiazola-l( 5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl )carbamate A mixture of (S)-5-bromo-6-(l-methoxyethyl)pyridin-3-ol (329 mg, 1.42 mmol), tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (500 mg, 0.709 mmol), K2CO2 (386 mg, 2.84 mmol) and Pd(dppf)Cl2 (58 mg, 0.071 mmol) in dioxane (16 mL) and H2O (4 mL) was stirred at 85°C under N2 for 19 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc 100%) to give tert-butyl ((64S,4S,Z)-12-(5-hydroxy-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-llH-8-oxa-62, 63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (500 mg, 96%) as a brown solid. LCMS (ESI) calcd. for C38H46N6O7S [M+H]+ m / z 730.3, found: 731.8 Step                           3:                           Synthesis                           of 5-((64 S,4S,Z)-4-((tert-butoxycarbonyl)amino)-K)J ()-dimethyl-5,7-dioxo-!! H-8-oxa-62,63-diaz.a-2(4,2)-thiaz. ola-l(5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 Jheptanacycloundecaphane-12-yl )-6-( (S )-1-methoxy ethyl )pyridin-3-y I trifluoromethanesulfonate To                    a                    solution                    of                   tert-butyl ((64S,4S,Z)-l2-(5-hydroxy-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63 -diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptanacycloundecaphane-4-yl)carbamate   (410 mg, 0.561 mmol) in DCM (6 mL) were added TEA (116 mg, 1.1 mmol) and N,N-Bis(trifluoromethanesulfonyl)aniline (228 g, 0.638 mmol) at 0°C, the mixture was stirred at 0°C for 2 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure. The residual was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 50% in 20 min) to obtain 5-((64S,4S,Z)-4-((tert-butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thia zola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 Jheptanacycloundecaphane-12-yl)-6-((S)-1 -methoxyethyl)pyridin-3 -yl trifluoromethanesulfonate (390 mg, yield: 80%) as a white solid. LCMS (ESI) calcd. for C39H45F3N6O9S2 [M+H]+ m / z 862.3, found 864.2. Step                   4:                   Synthesis                   of                  tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((trimethylsilyl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-lI H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6( 2,4 )-bicyclo[ 3.1.1 ]heptanacycloundecaphane-4-yl)car bamate A                                       mixture                                       of 5-((64S,4S,Z)-4-((tert-butoxycarbonyl)amino)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thia zola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 Jheptanacycloundecaphane-12-yl)-6-((S)-1 -methoxyethyl)pyridin-3 -yl trifluoromethane sulfonate (340 mg, 0.394 mmol), Cui (7 mg, 0.039 mmol), TEA (199 mg, 1.97 mmol) and Pd(PPh3)4 (45 mg, 0.039 mmol) in THF (10 mL) was stirred at 75°C for 4h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 50% in 10                     min)                     to                     obtain                    tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((trimethylsilyl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)ca rbamate (170 mg, yield: 53%) as a yellow oil. LCMS (ESI) calcd. for C43H54N6O6SSi [M+H]+ m / z 810.4, found 812.3. Step                   5:                   Synthesis                   of                  tert-butyl ((645,45,2)-11 -ethyl-12-(5-ethynyl-2-( (S )-1-methoxy ethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa -62,63-diaza-2(4,2 )-thiazola-l( 5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl )carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((trimethylsilyl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)ca rbamate (120 mg, 0.148 mmol) in DMF (2 mL) were added Cs2CO3 (145 mg, 0.444 mmol) and lodoethane (81 mg, 0.518 mmol) at 0°C, the resulting mixture was stirred at rt overnight. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL) and saturated NaCl (5 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 50% in 10 min) to obtain tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l ^-8-0 xa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)carbamate (100 mg, yield: 88%) as a yellow solid. LCMS (ESI) calcd. for C42H5oN606S [M+H]+ m / z 766.4, found: 768.4 Step                           6:                           Synthesis                           of (64S,4S,Z)-4-amino-lI-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-lIH-8-oxa-6 2,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6( 2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-5,7-dione To            a            stirred            solution            of            tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l 'H-8-o xa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)carbamate (120 mg, 0.156 mmol) in dichloromethane (2 mL) was added TFA (1 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated. The residue was dissolved in EtOAc (15 mL). The mixture was washed with sat.NaHCO3 aquous (10 mL) and brine (10 mL), then dried over Na2SO4. following with concentration under reduced pressure to obtain (64S,4S,Z)-4-amino-ll-ethyl-12-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-llH-8-o xa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5,7-dione (100 mg, yield: 96%) as a white solid. LCMS (ESI) calcd. for C37H42N6O4S [M+H]+ m / z 666.3, found: 667.7 Step 7: Synthesis of (1 S,2S)-N-((64S,4S,Z)-11 -ethyl-12-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-l 0,10-dimethyl-5,7-diox o-HH-8-oxa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide To                     a                    stirred                     solution                    of (64S,4S,Z)-4-amino-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-l1H-8-oxa -62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5,7-dione (100 mg, 0.150 mmol) and (lS,2S)-2-methylcyclopropane-l-carboxylic acid (18 mg, 0.18 mmol) and 1-methyl-IH-imidazole (37 mg, 0.45 mmol) in ACN (2 mL) was added TCFH (63 mg, 0.225 mmol) at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5 % NH4HCO3) from 20% to 95% in 30                            min)                            to                            give (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dio xo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-y l)-2-methylcyclopropane-l-carboxamide as atropisomer 1 (18 mg, 15%) as a white solid and (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dio xo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-y l)-2-methylcyclopropane-l-carboxamide as atropisomer 2 (i.e., compound of Example 1) (17 mg, 15%) as a white solid. LCMS (ESI) calcd. for C42H48N6O5S [M+H]+ m / z 748.3, found: 749.8. atropisomer 1: 4HNMR(400 MHz, DMSO-76) 5 8.84 (d, J= 1.8 Hz, 1H), 8.51 (d, J= 8.9 Hz, 1H), 8.41 (s, 1H), 8.06 (d, J= 2.0 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J= 8.9 Hz, 1H), 7.52 (d, J= 8.6 Hz, 1H), 5.89 (d,7 = 11.0 Hz, 1H), 5.30 (t, J =8.3 Hz, 1H), 4.71 (d, 7 = 11.1 Hz, 1H), 4.50 - 4.44 (m, 2H), 3.96-3.89 (m, 2H), 3.81-3.76 (m, 1H), 3.60-3.48 (m, 2H), 3.24 (d, J= 14.8 Hz, 1H), 3.16 - 2.97 (m, 6H), 2.65-2.63 (m, 1H), 2.35-2.28 (m, 2H), 2.13 (t, J= 9.8 Hz, 1H), 1.60 (t, J= 9.3 Hz, 1H), 1.49 (s, 1H), 1.18 (d, J= 6.2 Hz, 3H), 1.11-1.06 (m, 7H), 0.90 (s, 4H), 0.56-0.55 (m„ 1H), 0.45 (s, 3H). atropisomer 2 (i.e., compound of Example 1): ’H NMR (400 MHz, DMSO-7g) 5 8.83 (d, J= 2.0 Hz, 1H), 8.50 (d, J= 8.9 Hz, 1H), 8.40 (s, 1H), 7.91 (d, J= 2.0 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J= 9.9 Hz, 1H), 7.56 (d, J= 8.6 Hz, 1H),5.92 (d, 7= 11.1 Hz, 1H), 5.39-5.35 (m, 1H),4.65 (d, 7= 11.2 Hz, 1H), 4.52 (s, 1H), 4.49 - 4.44 (m, 1H), 4.34 - 4.23 (m, 2H), 4.07-4.01 (m, 1H), 3.57-3.49 (m, 2H), 3.27 - 3.08 (m, 6H), 2.91 (d, 7= 14.3 Hz, 1H), 2.62-2.60 (m, 1H), 2.47-2.42 (m, 1H), 2.32-2.29 (m, 1H), 2.13 (t, 7= 9.9 Hz, 1H), 1.54 (t, 7= 9.5 Hz, 1H), 1.49-1.47 (m, 1H), 1.34 (d, 7= 6.1 Hz, 3H), 1.05 (s, 4H), 0.91 - 0.81 (m, 7H), 0.55-0.54 (m, 2H), 0.30 (s, 3H). Example 2 (lS,2S)-N-((63S,4S,Z)-l1-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)p yridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,6s,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-ind ola-6(l,3)-pyridazinacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide atropisomer 1 atropisomer 2 Step                 1:                 Preparation                 of                 tert-butyl ((64S,4S,Z)-l2-( 5-( 3-hydroxy-3-methylbut-l-yn-l-yl )-2-( (S )-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1 H-8-oxa-62,63-diaza-2(4,2 )-thiazola-l(5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 Jheptanacycloundecapha ne-4-yl )carbamate A mixture of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol (106 mg, 0.37 mmol),                                                                                       tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (307 mg, 0.44 mmol), K2CO3 (127 mg, 0.92 mmol) and Pd(dppf)C12 (27 mg, 0.037 mmol) in toluene (6 mL), dioxane (2 mL) and H2O (2 mL) was stirred at 75°C under N2 for 22 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from           0%           to           100%)           to           give           tert-butyl ((64S,4S,Z)-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl -5,7^^0-1^-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaph ane-4-yl)carbamate (159 mg, 54.8 %) as a brown solid. LCMS (ESI) calcd. for C42H52N6O7S [M+H]+ m / z 784.36, found: 776.5 Step                 2:                 Preparation                 of                 tert-butyl ((64S,4S,Z)-11 -ethyl-12-(5-( 3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-di me-thyl-Sfl-dioxo-^HS-oxa-O2,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 Jheptanacyclounde caphane-4-yl )carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl -5,7^^0-1^-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaph ane-4-yl)carbamate (240 mg, 0.31 mmol) in DMF (3.5 mL) was added CS2CO3 (200 mg, 0.61 mmol) and lodoethane (96 mg, 0.61 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated NaCl (100 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 5%) to give tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dime- thyl-5,7-dioxo-l 1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacyclounde caphane-4-yl)carbamate as two atropisomers (190 mg, 75.5 %). Then the mixture was purified by prep-HPLC (Prep-HPLC method: column: Phenomenex Luna Cis75x30mmx3um; mobile phase: [wa-ter(FA)-ACN]; B%: l%-40%, 8min) to give the atropisomer 1 (84 mg, 34%) as a brown foam. LCMS (ESI) calcd. for C44H56N6O7S [M+H]+ m / z 812.39, found: 814.5 Step                         3:                         Preparation                         of (64S,4S,Z)-4-amino-!!-ethyl-12-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l O^O-dimethyl-^HS-oxa-O2^3-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 Jheptanacyclounde caphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-1 ^ethyl-l2-(5-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dime-thyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacyclounde caphane-4-yl)carbamate (atropisomer 1) (84 mg, 0.10 mmol) in dichloromethane (4 mL) was added TFA (1 mL) dropwise at rt, the resulting mixture was stirred at rt for Ih. The reaction mixture was concentrated to give the residue. The residue was purified with reverse phase chromatography (eluting with ACN / H2O (0.5       % NH4HCO3) from 0% to 60%) to give (64S,4S,Z)-4-amino-l1-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl )-10,10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloun decaphane-5,7-dione (62 mg, 93.6 %) as a yellow solid. LCMS (ESI) calcd. for C39H48N6O5S [M+H]+ m / z 712.34, found: 714.1 Step                         4:                         Preparation                         of (lr,2R,3S)-N-( (64S,4S,Z)-f -ethyl-12-(5-( 3-hydroxy-3-methylbut-l-yn-l-yl)-2-( (S)-l-methoxy ethyl)pyridin-3 -yl )-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2 )-thiazola-l( 5,3 )-indola-6( 2,4 )-bicyclo[3.1.1]he ptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To                     a                    stirred                     solution                    of (63S,4S,Z)-4-amino-l1-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl )-10,10-dimethyl-61,62,63,64,65,66-hexahydro-l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacyc loundecaphane-5,7-dione (62 mg, 0.10 mmol) and (lr,2R,3S)-2,3-dimethylcyclopropane-1 -carboxylic acid (11 mg, 0.11 mmol) and 2,6-lutidine (11 mg, 0.44 mmol) in ACN (8 mL) was added COMU (56 mg, 0.13 mmol) at rt, the resulting mixture was stirred at rt for 2h. The reaction mixture was concentrated to give the crude product. The crude product was purified by HPLC (ACN / H2O (0.5 % NH4HCO3) from 20% to 95% in                            30min)                            to                            give (lr,2R,3 S)-N-((64S,4S,Z)-11 -ethyl- l2-(5-(3-hydroxy-3-methylbut-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin -3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1] heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (40 mg, 64.5 %) as a white solid. LCMS (ESI) calcd. for C44H54N6O6S [M+H]+ m / z 794.38, found: 796.3. ‘H NMR (400 MHz, DMSO-<A) 5 8.75 (d, J= 2.1 Hz, IH), 8.55 - 8.48 (m, 2H), 7.81 (s, IH), 7.78 - 7.73 (m, 2H), 7.58 (d, J = 8.7 Hz, IH), 5.61-5.51 (m, 2H), 5.08 (d, J= 12.3 Hz, IH), 4.37-4.14 (m, 4H), 4.07 (dd, J= 14.7, 7.3 Hz, IH), 3.57 (s, 2H), 3.34 (s, IH), 3.30 (s, 2H), 3.25 (s, 3H), 3.14 (dd, J= 14.5, 9.1 Hz, IH), 2.98 (d, J= 14.5 Hz, IH), 2.81 - 2.70 (m, IH), 2.36 (d, J = 14.1 Hz, IH), 2.08 (d, J= 10.2 Hz, IH), 1.79 (s, 2H), 1.49 (s, 7H), 1.35 (d, J= 6.0 Hz, 3H), 1.05 (d, J= 10.9 Hz, 4H), 0.88 (dd, J= 17.3, 10.4 Hz, 6H), 0.54 (d, J= 5.4 Hz, IH), 0.33 (s, 3H). Example 3 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-((l-fluorocyclopropyl)ethynyl)-2-((S)-l-methoxyethyl)pyridin-3-y 1)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]he ptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol with (S)-3-bromo-5-((l-fluorocyclopropyl)ethynyl)-2-(l-methoxyethyl)pyridine in the Step 1 of Example 2 and Substituting           (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic           acid           with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Example 2, the title compound was prepared by the same procedures as described for Example 2. LCMS (ESI): 807.4 [M+l]+. ’H NMR (500 MHz, CDC13) 5 8.28 (d, J = 2.0 Hz, 2H), 8.08 (d, J = 12.6 Hz, 2H), 7.92 (d, J = 2.0 Hz, 2H), 7.77 (d, J = 2.4 Hz, 2H), 7.69 (dd, J = 7.7, 2.4 Hz, 2H), 7.59 (s, 2H), 7.48 (d, J = 7.7 Hz, 2H), 5.24 (q, J = 5.4 Hz, 2H), 4.90 (d, J = 8.4 Hz, 2H), 4.64 (q, J = 12.4 Hz, 2H), 4.15 (q, J = 4.4 Hz, 4H), 4.08 - 3.99 (m, 4H), 3.99 -3.89 (m, 4H), 3.33 (s, 6H), 3.31 - 3.23 (m, 3H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 4H), 2.72 (h, J = 7.9 Hz, 2H), 2.23 (q, J = 4.9 Hz, 8H), 2.13 - 1.97 (m, 8H), 1.94 (td, J = 10.2, 7.3 Hz, 2H), 1.69 - 1.60 (m, 8H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 2H), 1.37 (t, J = 4.4 Hz, 6H), 1.16 - 1.04 (m, 14H), 0.90 (d, J = 5.0 Hz, 6H). Example 4 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl) pyri-din-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[ 3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Method 1: Substituting 3-bromo-2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-3-yl)ethynyl)pyridine with 3-bromo-2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridine in the Step 3 of Example 5, the title compound was prepared by the same procedures as described for Example 5. Method 2: atropisomer 1 atropisomer 2 Step                   1:                   Synthesis                   of                  tert-butyl ((645,45,Z)-12-(2-((5)-1-methoxy ethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethy l-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 Jheptanacycloundecap hane-4-yl )carbamate A mixture of 3-bromo-2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridine (87                   mg,                   0.27                   mmol),                   tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (210 mg, 0.30 mmol), K2CO3(112 mg, 0.81 mmol) and Pd(dppf)Cl2 (30 mg, 0.041 mmol) in dioxane (3 mL) and H2O (0.7 mL) was stirred at 85°C under N2 for 16 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from           0%           to           10%)           to           give           tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimet hyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundec aphane-4-yl)carbamate (150 mg, 67.7 %) as a yellow solid. LCMS (ESI) calcd. for C45H55N7O6S [M+H]+ m / z 822.4, found: 823.6. Step                   2:                   Synthesis                   of                  tert-butyl ((645,45,2)-11 -ethyl-12-(2-((5)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10,10 -dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 Jheptanacycl oundecaphane-4-yl )carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimet hyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundec aphane-4-yl)carbamate (147 mg, 0.18 mmol) in DMF (2 mL) were added Cs2CO3 (105 mg, 0.32 mmol) and lodoethane (50 mg, 0.32 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (20 mL), washed with water (30 mL x 2) and saturated NaCl (50 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-TLC (eluting with DCM : MeOH          =           15           :           1)          to          give          tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)carbamate (26 mg, 16.9%) as atropisomer 1 and tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)carbamate (17 mg, 11.1%) as atropisomer 2 as pale yellow solid. LCMS (ESI) calcd. for C47H59N7O6S [M+H]+ m / z 850.4, found: 851.4. Step                           3:                           Synthesis                           of (64S, 4S,Z)-4-amino-l1 -ethyl-12-(2-( (S )-l-methoxyethyl)-5-( ((S )-I-methylpyrrolidin-2-yl)ethynyl)pyridin-3-y l)-I0,I0-dimethyl-I1H-8-oxa-62,63-diaza-2(4,2)-thiazola-I(5,3)-indola-6(2,4)-bicyclo[3.I.I]heptanacyclou ndecaphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)carbamate as atropisomer 2 (17 mg, 0.020 mmol) in dichloromethane (1 mL) was added TFA (0.25 mL) dropwisely at rt, the resulting mixture was stirred at rt for 2 h. The reaction mixture was                  concentrated                  to                  give                  crude (64S.4S.Z)-4-amino-l '-cthyl-l2-(2-((S)-l-mcthoxycthyl)-5-(((S)-l-mcthylpyrrolidin-2-yl)cthynyl)pyridin-3 -yl)-10,10-dimethyl-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptanacyclo undecaphane-5,7-dione which was used to next step without purification. LCMS (ESI) calcd. for C42H51N7O4S [M+H]+ m / z 750.4, found: 750.9. Step                           4:                           Synthesis                           of (lr,2R,3S)-N-((6tS,4S,Z)-lI-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridi n-3-yl)-10,10-dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To              a              stirred              solution              of              crude (64S,4S,Z)-4-amino-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3 -yl)-10,10-dimethyl-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptanacyclo undecaphane-5,7-dione (17 mg, 0.020 mmol) and (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid (2.2 mg, 0.020 mmol) and 2,6-lutidine (13 mg, 0.12 mmol) in ACN (1 mL) was added COMU (13 mg, 0.030 mmol) at rt, the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5 % NH4HCO3) from 20% to 95% in                     30                     min)                     to                     give (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyr id-in-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (5.6 mg) as a white solid. LCMS (ESI): 846.4 [M+l]+. ’H NMR (400 MHz, DMSO) 5 8.76 (d, J = 2.1 Hz, 1H), 8.42 - 8.34 (m, 2H), 7.83 - 7.77 (m, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.90 (d, J = 11.0 Hz, 1H), 5.36 (s, 1H), 4.64 (d, J = 10.7 Hz, 1H), 4.46 (d, J = 4.8 Hz, 1H), 4.33 - 4.20 (m, 2H), 4.04 (dd, J = 14.4, 7.3 Hz, 1H), 3.60 - 3.46 (m, 2H), 3.40 - 3.32 (m, 1H), 3.21 (s, 3H), 3.12 (dd, J = 14.9, 7.3 Hz, 1H), 2.91 (d, J = 13.7 Hz, 1H), 2.82 - 2.72 (m, 1H), 2.61 (d, J = 5.8 Hz, 1H), 2.40 (d, J = 16.0 Hz, 2H), 2.37 - 2.27 (m, 4H), 2.19 - 2.07 (m, 2H), 1.84 (ddd, J = 46.4, 30.9, 20.3 Hz, 4H), 1.56 (d, J = 9.6 Hz, 1H), 1.33 (t, J = 6.6 Hz, 3H), 1.20 (d, J = 10.7 Hz, 4H), 1.15 (d, J = 3.2 Hz, 2H), 1.10 - 1.00 (m, 4H), 0.92 - 0.77 (m, 5H), 0.31 (s, 3H). Example 5 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-3-yl)ethy nyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- (64 S, 4S,Z)-4-amino-10,10-dimethyl-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-lI H-8-oxa-62,63-diaz a-2(4,2)-thiazola-l(5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)carbamate (1.5 g, 2.1 mmol) in dichloromethane (30 mL) was added TFA (3 mL) dropwise at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was washed with sat. NaHCCL (30 mL), brine (30 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaz a-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5,7-dione (1.3 g) as a yellow solid. LCMS (ESI) calcd. for Cs^oBNjOjS [M+H]+ m / z 606.3, found: 607.4 Step                         2:                         Preparation                         of (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2 )-thiazola-l( 5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl )-2,3-di methylcyclopropane-1-carboxamide To                    a                    stirred                     solution                    of (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaz a-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5,7-dione (1.3 g, 2.1 mmol) and (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid (242 mg,2.1 mmol) and NMI (436 mg, 5.3 mmol) in ACN / DCM (15 mL / 15 mL) was added TCFH (896 mg, 3.2 mmol) at rt, the resulting mixture was stirred at rt for 30 min. The reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-di methylcyclopropane-1-carboxamide (1.5 g, 99% in 2 steps) as a yellow solid. LCMS (ESI) calcd. for G7H4xBNsO6S [M+H]+ m / z 702.3, found: 703.5 Step                 3:                 Preparation                 of                 tert-butyl (3S)-3-( (5-((64S,4S, Z)-4-( (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-10,10-dimethyl-5,7-dioxo-11 H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-l2-yl) -6-( (S)-1 -methoxy ethyl )pyridin-3-yl )ethynyl)pyrrolidine-l-carboxylate A                                       mixture                                       of (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-di methylcyclopropane-1-carboxamide (1 g,         1.4 mmol), tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate (583 mg, 1.4 mmol), K2CO2(491 mg, 3.6 mmol) and Pd(dppf)Cl2 (209 mg, 0.3 mmol) in dioxane (40 mL) and H2O (8 mL) was stirred at 90°C under N2 for 19 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 100%) to give tert-butyl (3S)-3-((5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-10,10-dimethyl-5,7-dioxo -11H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane- l2-yl) -6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate (900 mg, 70 %) as a yellow solid. LCMS (ESI) calcd. for C50H61N7O7S [M+H]+ m / z 904.4, found: 904.9 Step                 4:                 Preparation                 of                 tert-butyl (3S)-3-( (5-( (64S,4S,Z)-4-( (lr,2R,3S )-2,3-dimethylcyclopropane-l-carboxamido )-11 -ethyl-10,10-dimethyl-5, 7-dioxo-l1 H-8-oxa-62,63-diaza-2(4,2 )-thiazola-l(5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 Jheptanacycloundecapha ne-l2-yl)-6-((S )-1-methoxy ethyl )pyridin-3-yl )ethynyl )pyrrolidine-l-carboxylate To                     a                    stirred                     solution                    of (lr,2R,3S)-N-((64S,4S,Z)-l4-amino-10,10-dimethyl-5,7-dioxo-8-oxa-62,63-diaza-2(4,2)-thiazola-6(2,4)-bic yclo[3.1.1]heptana-l(l,3)-benzenacyclododecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (900 mg, 1.0 mmol) in DMF (9 mL) were added Cs2CO3 (649 mg, 2.0 mmol) and lodoethane (311 mg, 2.0 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 100%) to give                                                                                               tert-butyl (3S)-3-((5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-ll-ethyl-10,10-dimethyl-5.7-dioxo-1 ’H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaph ane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate as two atropisomers (927 mg, 99%) . Then the mixture was purified by prep-HPLC (Prep-HPLC method: column: Phenomenex Luna Cis75x30mmx3um; mobile phase: [water(FA)-ACN]; B%: l%-40%, 8min) to give the atropisomer 1 (412 mg, 44%) as yellow solids. LCMS (ESI) calcd. for C52H65N7O7S [M+H]+ m / z 932.5, found: 933.6 Step                         5:                         Preparation                         of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-pyrrolidin-3-yl)ethynyl)pyridin-3-yl) -10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptan acycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To              a              stirred              solution              of              tert-butyl (3S)-3-((5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-l1-ethyl-10,10-dimethyl-5.7-dioxo-1 ’H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaph ane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate (atropisomer 1) (412 mg, 1.0 mmol) in dichloromethane (10 mL) was added TFA (2.5 mL) dropwise at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was washed with sat. NaHCO3 (30 mL), brine (30 mL), then dried over Na2SO4. following with concentration under reduced pressure to obtain crude product (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-pyrrolidin-3-yl)ethynyl)pyridin-3-yl) -10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptan acycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (276 mg, 75%) as a yellow solid. LCMS (ESI) calcd. for C47H57N7O5S [M+H]+ m / z 832.4, found: 832.9 Step                         6:                         Preparation                         of (lr,2R,3S)-N-((64S,4S,Z)-1]-ethyl-12-(2-((S)-l-methoxyethyl)-5-(((S)-l-methylpyrrolidin-3-yl)ethynyl)pyridi n-3-yl)-10,10-dimethyl-5,7-dioxo-lIPI-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To                    a                    stirred                     solution                    of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-pyrrolidin-3-yl)ethynyl)pyridin-3-yl) -10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptan acycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (276 mg, 0.33 mmol) in MeOH (12 mL) were added formaldehyde (266 mg, 3.3 mmol, 37% in water) and NaBH3CN (62 mg, 0.97 mmol) at 0°C, the resulting mixture was stirred at rt for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 80%) to give (lr.2R.3S)-N-((64S.4S.Z)-l l-cthyl-l2-(2-((S)-l-mcthoxycthyl)-5-(((S)-l-mcthylpyrrolidin-3-yl)cthynyl)pyr id- in-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (156 mg, 25%) as a white solid. LCMS (ESI) calcd. for C48H59N7O5S [M+H]+ m / z 846.4, found: 846.9. ’H NMR (400 MHz, DMSO-dg) 5 8.72 (s, 1H), 8.40-8.37 (m, 2H), 7.80 (s, 1H), 7.76-7.72 (m, 2H), 7.55 (d, J= 8.4 Hz, 1H),5.9O (d, J= 11.2 Hz, lH),5.35(m, 1H),4.64 (d, J= 11.2 Hz, 1H), 4.47-4.46 (m, 1H), 4.30 - 4.22 (m, 2H), 4.07-4.03 (m, 1H), 3.57 - 3.50 (m, 2H), 3.22-3.20 (m, 5H), 3.14-3.09 (m, 1H), 2.93-2.89 (m, 1H), 2.81 (t, J= 8.4 Hz, 1H), 2.61-2.60 (m, 1H), 2.52 - 2.48 (m, 5H), 2.45-2.37 (m, 2H), 2.32-2.30 (m, 1H), 2.23-2.11 (m, 4H), 1.89-1.81 (m, 1H), 1.57 - 1.55 (m, 1H), 1.30 (d, J= 6.0 Hz, 1H), 1.21-1.14 (m, 1H), 1.08-1.04 (m, 5H), 0.86-0.83 (m, 5H), 0.30 (s, 3H). Example 6 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyrid in-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3. l.l]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol with (S)-3-bromo-2-(l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridine in the Step 1 of Example 2 and Substituting      (lr,2R, 3 S)-2,3 -dimethylcyclopropane-1 -carboxylic     acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Example 2, the title compound was prepared by the same procedures as described for Example 2. Method 2: Step atropisomer 1 atropisomer 2 1: Synthesis of (lS,2S)-N-( (64S,4S,Z)-l2-(2-( (S)-l-methoxyethyl)-5-( (l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-3-yl)-10,10 -dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycl oundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide A mixture of (S)-3-bromo-2-(l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridine (43 mg, 0.13                                                                                   mmol), (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaz a-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.l]heptanacycloundecaphane-5,7-dione (100 mg, 0.15 mmol), K2CO3(56 mg, 0.40 mmol) and Pd(dppf)Cl2 (15 mg, 0.020 mmol) in dioxane (2 mL) and H2O (0.5 mL) was stirred at 85°C under N2 for 5 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 10%)                                            to                                           give (lS,2S)-N-((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide (58 mg, 55.8 %) as a yellow solid. LCMS (ESI) calcd. for C44H48N8O5S [M+H]+ m / z 801.4, found: 801.8 Step                           2:                           Synthesis                           of (lS,2S)-N-( (64S,4S,Z)-1]-ethyl-12-(2-( (S)-l-methoxyethyl)-5-( (l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]hep tanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide To                     a                    stirred                     solution                    of (lS,2S)-N-((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide (58 mg, 0.073 mmol) in DMF (1.5 mL) were added Cs2CO3 (47 mg, 0.15 mmol) and lodoethane (23 mg, 0.15 mmol) at 0°C, the resulting mixture was stirred at rt for 22 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (20 mL), washed with water (20 mL x 2) and saturated NaCl (20 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 80%) to give (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]h eptanacycloundecaphane-4-yl)-2-methylcyclopropane-1 -carboxamide as atropisomer 1 (19 mg) and (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]h eptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide as atropisomer 2 (i.e., compound of Example 6) (16 mg) as white solids. LCMS (ESI) calcd. for C46H52N8O5S [M+H]+ m / z 829.4, found: 829.9 atropisomer 1: *HNMR (400 MHz, DMSO-76) 5 8.83 (d, J= 1.8 Hz, 1H), 8.52 (d, J= 9.0 Hz, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 8.01 (d, J= 1.7 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J= 4.5 Hz, 1H), 7.53 (d, J= 8.7 Hz, 1H), 5.89(d, J= 10.8Hz, 1H),5.31 (t,7=8.0Hz, 1H),4.72 (d, 7= 11.3 Hz, 1H), 4.48 (d, J= 5.1 Hz, 1H),3.93 (dt, J= 12.6, 6.8 Hz, 2H), 3.87- 3.74 (m, 3H), 3.58 (d, J= 10.8 Hz, 1H), 3.50 (d, J= 10.8 Hz, 1H), 3.24 (d, J = 14.9 Hz, 1H), 3.16 - 2.98 (m, 4H), 2.64 (d, J= 5.9 Hz, 1H), 2.34 (d, J= 13.9 Hz, 2H), 2.18 - 2.08 (m, 1H), 1.60 (t, J= 9.3 Hz, 1H), 1.49 (s, 1H), 1.19 (d, J= 6.2 Hz, 3H), 1.08 (dd, J= 14.2, 6.9 Hz, 5H), 0.90 (s, 3H), 0.56 (d, J= 5.3 Hz, 1H), 0.48 (s, 2H). atropisomer 2 (i.e., compound of Example 6): ’H NMR (400 MHz, DMSO-7g) 5 8.82 (d, J = 1.9 Hz, 1H), 8.51 (d, J= 8.7 Hz, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.87 (d, J= 2.0 Hz, 1H),7.8O (s, 1H), 7.73 (d, 7=9.9 Hz, 1H), 7.57 (d, 7= 8.6 Hz, 1H), 5.92 (d, 7= 11.1 Hz, 1H), 5.36 (s, 1H), 4.65 (d,7= 11.0 Hz, 1H), 4.47 (d, 7=5.1 Hz, 1H), 4.36-4.21 (m, 2H),4.07 (dd,7= 15.0, 7.4 Hz, 1H),3.84 (s, 2H),3.54 (dd, 7 = 20.2, 10.6 Hz, 2H), 3.28 (s, 2H), 3.22 (s, 3H), 3.11 (dd, 7= 14.7, 7.3 Hz, 1H), 2.93 (d, 7= 14.4 Hz, 1H), 2.61 (d, 7= 5.6 Hz, 1H), 2.43 (d, 7= 17.5 Hz, 2H), 2.35 - 2.25 (m, 1H), 2.14 (t, 7= 9.6 Hz, 1H), 1.57 (d, 7= 9.4 Hz, 1H), 1.48 (s, 1H), 1.35 (d, 7= 6.0 Hz, 2H), 1.21 (s, 1H), 1.05 (s, 3H), 0.89 (q, 7= 7.6 Hz, 5H), 0.55 (d, 7= 5.3 Hz, 1H), 0.31 (s, 3H). Example 7 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(pyrimidin-5-ylethynyl)pyridin-3-yl)-10,l 0-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana cycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol with (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)pyrimidine in the Step 1 of Example 2 and Substituting            (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic            acid            with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Example 2, the title compound was prepared by the same procedures as described for Example 2. LCMS (ESI): 827.4 [M+l]+. ’H NMR (500 MHz, CDC13) 5 9.15 (t, J = 1.7 Hz, 2H), 8.79 (d, J = 1.8 Hz, 4H), 8.31 (d, J = 2.0 Hz, 2H), 8.08 (d, J = 12.6 Hz, 2H), 8.04 (d, J = 2.0 Hz, 2H), 7.77 (d, J = 2.4 Hz, 2H), 7.69 (dd, J = 7.7, 2.4 Hz, 2H), 7.59 (s, 2H), 7.48 (d, J = 7.7 Hz, 2H), 5.24 (q, J = 5.4 Hz, 2H), 4.90 (d, J = 8.4 Hz, 2H), 4.64 (q, J = 12.4 Hz, 2H), 4.15 (q, J = 4.4 Hz, 4H), 4.08 - 3.99 (m, 4H), 3.99 - 3.89 (m, 4H), 3.33 (s, 6H), 3.31 - 3.23 (m, 3H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 4H), 2.72 (h, J = 7.9 Hz, 2H), 2.13 - 2.03 (m, 6H), 2.03 - 1.97 (m, 2H), 1.94 (td, J = 10.2, 7.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 6H), 1.65 - 1.60 (m, 1H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 2H), 1.37 (t, J = 4.4 Hz, 6H), 1.15 (s, 6H), 1.10 (s, 8H), 0.91 (d, J = 5.0 Hz, 6H). Example 8 (lS,2S)-N-((64S,4S,Z)-l2-(5-(benzo[d]thiazol-5-ylethynyl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethy l-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]he ptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol with (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)benzo[d]thiazole in the Step 1 of Example 2 and Substituting           (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic           acid           with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Example 2, the title compound was prepared by the same procedures as described for Example 2. LCMS (ESI): 882.3 [M+l]+. ’H NMR (500 MHz, CDC13) 5 9.01 (s, 2H), 8.39 (d, J = 2.0 Hz, 2H), 8.11 (d, J = 12.5 Hz, 2H), 7.97 (d, J = 2.0 Hz, 2H), 7.83 (d, J = 1.7 Hz, 2H), 7.77 (d, J = 2.2 Hz, 2H), 7.72 - 7.66 (m, 4H), 7.63 - 7.57 (m, 4H), 7.48 (d, J = 7.7 Hz, 2H), 5.24 (q, J = 5.4 Hz, 2H), 4.89 (d, J = 8.6 Hz, 2H), 4.64 (q, J = 12.4 Hz, 2H), 4.15 (q, J = 4.4 Hz, 4H), 4.08 - 3.99 (m, 4H), 3.99 - 3.89 (m, 4H), 3.33 (s, 6H), 3.31 - 3.23 (m, 3H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 4H), 2.72 (h, J = 7.9 Hz, 2H), 2.13 - 1.89 (m, 10H), 1.69 - 1.60 (m, 8H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 2H), 1.37 (t, J = 4.4 Hz, 6H), 1.12 (d, J = 24.9 Hz, 14H), 0.91 (d, J = 5.0 Hz, 6H). Example 9 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(imidazo[l,2-b]pyridazin-3-ylethynyl)-2-((S)-l-methoxyethyl)pyr id- in-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3. l.l]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide Method 1: Substituting      (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol      with (S)-3-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)imidazo[l,2-a]pyrimidine in the Step 1 of Example 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Example 2, the title compound was pre pared by the same procedures as described for Example 2. Method 2: TFA DCM, rt step 1 TCFH, NMI CH3CN / DCM, rt step 2 atropisomer 1                                                 atropisomer 2 Step                           1:                           Synthesis                           of (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,^4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza -2(4,2)-thiazola-l(5,3)-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)carbamate (1.0 g, 0.12 mmol) in dichloromethane (10 mL) was added TFA (1 mL) dropwisely at rt, the resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with DCM and basified to pH = 7 with saturated aq. NaHCO3 solution. The oaranic layer was separated, dried over anhydrous Na2SO4 and concentrated to give (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaz a-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5,7-dione (777 mg) as a grey solid. LCMS (ESI) calcd. for QiH^BNsOsS [M+H]+ m / z 606.3, found: 607.1. Step                           2:                           Synthesis                           of (lS,2S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-ox a-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2-methyl cyclopropane-1-carboxamide To                    a                    stirred                     solution                    of (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaz a-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5,7-dione 5 (777 mg, 1.28 mmol) and (lS,2S)-2-methylcyclopropane-l-carboxylic acid (129 mg, 1.28 mmol) andNMI (316 mg, 3.85 mmol) in ACN (7 mL) and DCM (7 mL) was added TCFH (540 mg, 1.93 mmol) at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluting with EtOAc / PE from 0% to 60% ) to give (lS,2S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-o xa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)-2-methyl cyclopropane-1-carboxamide (1.15 g) as a pale yellow solid. LCMS (ESI) calcd. for C36H46BN5O6S [M+H]+ m / z 688.3, found: 689.4. Step                           3:                           Synthesis                           of (lS,2S)-N-( (64S,4S,Z)-l2-(5-( imidazo[ l,2-b]pyridazin-3-ylethynyl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacy cloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide A mixture of (S)-3-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)imidazo[l,2-b]pyridazine (57 mg,                                        0.16                                        mmol), (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaz a-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptanacycloundecaphane-5,7-dione (120 mg, 0.17 mmol), K2CO3(66 mg, 0.48 mmol) and Pd(dppf)Cl2 (18 mg, 0.024 mmol) in dioxane (2 mL) and H2O (0.5 mL) was stirred at 85°C under N2 for 3 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 10%)                                            to                                           give (lS,2S)-N-((64S,4S,Z)-l2-(5-(imidazo[l,2-b]pyridazin-3-ylethynyl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l 0,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana cycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide (93 mg, 79.0 %) as a brown solid. LCMS (ESI) calcd. for C46H47N9O5S [M+H]+ m / z 838.3, found: 838.8. Step                           4:                           Synthesis                           of (lS,2S)-N-( (64S,4S,Z)-11 -ethyl-l2-(5-( imidazo[ 1,2-b]pyridazin-3-ylethynyl)-2-((S)-l-methoxyethyl)pyridin-3-yl )-10,10-dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2 )-thiazola-l(5,3)-indola-6( 2,4)-bicyclo[3.1.1]h eptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide To                     a                    stirred                     solution                    of (lS,2S)-N-((64S,4S,Z)-l2-(5-(imidazo[l,2-b]pyridazin-3-ylethynyl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l 0,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana cycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide (90 mg, 0.11 mmol) in DMF (2 mL) were added Cs2CO3 (70 mg, 0.22 mmol) and lodoethane (34 mg, 0.22 mmol) at 0°C, the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (20 mL), washed with water (50 mL x 2) and saturated NaCl (50 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 75%) to give (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(imidazo[l,2-b]pyridazin-3-ylethynyl)-2-((S)-l-methoxyethyl)pyridi n-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide as atropisomer 1 (33.5 mg) and (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(imidazo[l,2-b]pyridazin-3-ylethynyl)-2-((S)-l-methoxyethyl)pyridi n-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide as atropisomer 2 (i.e., compound of Example 9) (23.0 mg) as white solids. LCMS (ESI) calcd. for C48H5iN9O5S [M+H]+ m / z 866.4, found: 866.8. atropisomer 1: 4H NMR (400 MHz, DMSO-76) 5 8.96 (d, 7 = 2.0 Hz, 1H), 8.73 - 8.66 (m, 1H), 8.51 (d, J= 8.9 Hz, 1H), 8.42 (s, 1H), 8.26 - 8.22 (m, 1H), 8.17 (d, J= 2.0 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J= 8.6 Hz, 1H), 7.54 (d, J= 8.7 Hz, 1H), 7.38 (dd, J= 9.2, 4.5 Hz, 1H), 5.88 (d, J= 11.1 Hz, 1H),5.31 (t, 7= 8.0 Hz, 1H), 4.72 (d,7= 11.2 Hz, 1H), 4.48 (d, 7= 5.0 Hz, 1H), 4.03-3.77 (m, 3H), 3.59 (d,7= 10.8 Hz, 1H), 3.51 (d, 7 = 10.9 Hz, 1H), 3.24 (d,7= 14.7 Hz, 1H), 3.19 - 2.98 (m, 4H), 2.70 - 2.61 (m, 1H), 2.34 (dd,7= 16.0, 10.2 Hz, 2H), 2.18-2.07 (m, 1H), 1.60 (t, 7= 9.3 Hz, 1H), 1.49 (s, 1H), 1.21 (d, 7 =6.2 Hz, 3H), 1.11 (t, 7= 7.1 Hz, 2H), 1.06 (s, 3H), 0.91 (s, 3H), 0.58 - 0.44 (m, 3H). atropisomer 2 (i.e., compound of Example 9): ’H NMR (400 MHz, DMSO-7g) 5 8.95 (d, 7 = 1.9 Hz, 1H), 8.68 (d, 7 = 3.8 Hz, 1H), 8.50 (d, 7= 8.9 Hz, 1H), 8.42 (s, 1H), 8.24 (d, 7= 6.6 Hz, 2H), 8.01 (d, 7= 1.7 Hz, 1H), 7.79 (s, 1H), 7.74 (d, 7= 8.3 Hz, 1H), 7.57 (d, 7= 8.7 Hz, 1H), 7.37 (dd, 7= 9.2, 4.4 Hz, 1H), 5.91 (d, 7= 11.2 Hz, 1H), 5.37 (s, 1H), 4.65 (d, 7= 11.2 Hz, 1H), 4.47 (d, 7 = 4.7 Hz, 1H), 4.37 - 4.21 (m, 2H), 4.08 (dd, 7= 14.5, 7.2 Hz, 1H), 3.55 (dd, 7= 21.5, 10.6 Hz, 2H), 3.24 (s, 3H), 3.12 (dd, 7= 14.9, 7.6 Hz, 1H), 2.95 (d,7= 14.7 Hz, 1H), 2.61 (d, 7= 5.3 Hz, 1H), 2.44 (d, 7 =3.9 Hz, 1H), 2.35 - 2.24 (m, 1H), 2.14 (t, 7 = 9.6 Hz, 1H), 1.55 (t, 7= 9.3 Hz, 1H), 1.48 (s, 1H), 1.37 (d, 7= 6.0 Hz, 3H), 1.20 (s, 1H), 1.03 (d,7= 19.4 Hz, 4H), 0.89 (d, 7= 9.7 Hz, 6H), 0.54 (d, 7 = 4.9 Hz, 1H), 0.34 (s, 3H). Example 10 (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-(dimethylamino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl )-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[ 3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-N,N-dimethylprop-2-yn-l-amine in the Step 1 of Exam ple 16, the title compound was prepared by the same procedures as described for Example 16. Step                           1: Synthesis of (lr,2R,3S )-N-( (64S,4S,Z)-l2-( 5-( 3-( dimethylamino )prop-l-yn-l-yl)-2-( (S )-l-methoxyethyl)pyridin-3-yl)-10,1 0-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2 )-thiazola-1(5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 Jheptanacyc loundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide A mixture of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-N,N-dimethylprop-2-yn-l-amine (70                         mg,                          0.24                         mmol), (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-di methylcyclopropane-1-carboxamide (191 mg, 0.27 mmol), K2CO3(98 mg, 0.71 mmol) and Pd(dppf)Cl2 (26 mg, 0.035 mmol) in dioxane (3 mL) and H2O (0.7 mL) was stirred at 85°C under N2 for 3 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 10%) to give (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-(dimethylamino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l 0,10-dimethyl-5,7-dioxo-l 4H-8-oxa-62,63 -diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana cycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (150 mg, 79.0 %) as a brown solid. LCMS (ESI) calcd. for C44H53N7O5S [M+H]+ m / z 792.4, found: 792.9. Step                           2:                           Synthesis                           of (1 r,2R, 3S)-N-((64S,4S,Z)-12-((R)-5 -(3-(dimethy lamino)prop-l -yn-1 -yl)-2-((S)-l-methoxyethyl)-3,4-dihy drop yridin-3-yl)-!1 -ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2( 4,2)-thiazola-l(5,3)-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1 -carboxamide To                     a                    stirred                     solution                    of (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-(dimethylamino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l 0,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana cycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (150 mg, 0.19 mmol) in DMF (4 mL) were added Cs2CO3 (99 mg, 0.30 mmol) and lodoethane (48 mg, 0.30 mmol) at 0°C, the resulting mixture was stirred at rt for 4 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (20 mL), washed with water (100 mL x 2) and saturated NaCl (60 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 85%) to give (lr,2R,3S)-N-((64S,4S,Z)-l2-((R)-5-(3-(dimethylamino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)-3,4-dihydr opyridin-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide as atropisomer 1                            (25.5                            mg)                            and (lr,2R,3S)-N-((64S,4S,Z)-l2-((R)-5-(3-(dimethylamino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)-3,4-dihydr opyridin-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.l]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide as atropisomer 2 (i.e., compound of Example 10) (18.3 mg) as white solids. LCMS (ESI) calcd. for C46H59N7O5S [M+H]+ m / z 822.4, found: 822.0. atropisomer 1: ‘H NMR (400 MHz, DMSO-76) 5 8.80 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 10.0 Hz, 2H), 7.98 (d, 7 = 2.0 Hz, 1H), 7.80 (s, 1H), 7.72 (d,7=8.7Hz, 1H), 7.52 (d, J= 8.7 Hz, 1H), 5.86 (d, J= 11.1Hz, 1H), 5.29 (t, J= 8.5 Hz, 1H), 4.71 (d, J= 11.2 Hz, 1H), 4.47 (d, J= 5.1 Hz, 1H), 4.01 - 3.85 (m, 2H), 3.79 (dd, J= 14.6, 7.4 Hz, 1H), 3.63 - 3.45 (m, 3H), 3.23 (d, J= 14.7 Hz, 2H), 3.16- 2.96 (m, 4H), 2.71 - 2.57 (m, 1H), 2.37-2.20 (m, 6H), 2.19 - 2.07 (m, 1H), 1.60 (t, J= 9.3 Hz, 1H), 1.30-1.11 (m, 5H), 1.14-0.99 (m, 6H), 0.86 (d, J= 26.9 Hz, 2H), 0.46 (s, 2H). atropisomer 2 (i.e., compound of Example 10): *HNMR (400 MHz, DMSO-cL) 5 8.79 (d, J= 2.0 Hz, 1H), 8.44 - 8.34 (m, 2H), 7.85 (d, J= 1.9 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J= 8.6 Hz, 1H), 7.56 (d, J= 8.8 Hz, 1H), 5.91 (d, J= 10.9 Hz, 1H), 5.36 (s, 1H), 4.63 (d, J= 11.3 Hz, 1H), 4.46 (d, J= 5.0 Hz, 1H), 4.27 (dt, J= 12.2, 6.8 Hz, 2H), 4.05 (dd, J= 14.6, 7.5 Hz, 1H), 3.60 - 3.47 (m, 3H), 3.27 - 3.05 (m, 5H), 2.91 (d, J= 13.6 Hz, 1H), 2.60 (d, 7= 5.5 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.29 (d,7= 11.6 Hz, 5H), 2.17 - 2.09 (m, 1H), 1.601.48 (m, 1H), 1.34 (d, 7= 6.0 Hz, 2H), 1.28- 1.10 (m, 4H), 1.06 (dd,7= 10.2, 5.8 Hz, 4H), 0.93 - 0.77 (m, 4H), 0.31 (s, 2H). Example 11 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-((R)-3-fluoropyrrolidin-l-yl)prop-l-yn-l-yl)-2-((S)-l-metho xyeth-yI)pyridin-3-yI)-10,10-dimethyI-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazoIa-l(5,3)-indoIa-6(2,4)-b icyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with 3-bromo-5-(3-((R)-3-fluoropyrrolidin-l-yl)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridine in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16. LCMS (ESI): 864.4 [M+l]+. ’H NMR (500 MHz, CDC13) 5 8.39 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 13.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.87 - 4.80 (m, 1H), 4.63 (dt, J = 13.0, 12.3 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.63 - 3.57 (m, 1H), 3.55 (s, 1H), 3.52 - 3.45 (m, 1H), 3.33 (s, 3H), 3.31 - 3.18 (m, 3H), 3.06 (d, J = 2.6 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.72 (h, J = 7.9 Hz, 1H), 2.47 (t, J = 8.6 Hz, 1H), 2.29 (q, J = 5.6 Hz, 1H), 2.14 - 1.97 (m, 5H), 1.74 (dq, J = 8.6, 5.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.95 (d, J = 5.1 Hz, 6H). Example 12 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyri din-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[ 3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxy ethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with (S)-3-bromo-2-(l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridine in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16. Method 2: atropisomer 1                                          atropisomer 2 Step                         1:                         Preparation                         of (lr,2R,3S)-N-( (64S,4S,Z)-l2-( 2-( (S)-l-methoxyethyl)-5-( 3-(piperidin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,1 0-dimethyl-5,7-dioxo-l1 H-8-oxa-62,63-diaza-2(4,2 fthiazola- l(5,3)-indola-6( 2,4 )-bicyclo[3.1.1 Jheptanacyc loundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide A mixture of (S)-3-bromo-2-(l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridine (48 mg, 0.14                                                                                   mmol), (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-di methylcyclopropane-1-carboxamide (100 mg, 0.14 mmol), K2CO3 (58 mg, 0.42 mmol) and Pd(dppf)C12 (22 mg, 0.03 mmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 85°C under N2 for 16h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC with         MeOH / DCM         =         0-6%         to         afford         the (lr,2R,3S)-N-((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-l 1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (98 mg, 84%) as a yellow solid. LCMS (ESI) calcd. for C47H57N7O5S [M+H]+ m / z 832.4, found: 832.9 Step                         2:                         Preparation                         of (lr,2R,3S)-N-((645,45^)-11-ethyl-12-(2-((5)-1-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1 H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]hep tanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To                    a                    stirred                     solution                    of (lr,2R,3S)-N-((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10, 10-dimethyl-5,7-dioxo-l 1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (98 mg, 0.117 mmol) in DMF (5 mL) were added CS2CO3 (115.1 mg, 0.353 mmol) and lodoethane (55.2 mg, 0.353 mmol). The resulting mixture was stirred at rt for 0.5h. After completion, the reaction mixture was diluted with EtOAc (20 mL) and H2O (20 mL). The mixture was extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (20 mL*2), dried over anhydrous Na2SO4 and concentration under reduced pressure. The residue was purified              by              pre-HPLC              to              give              the (lr.2R.3S)-N-((64S.4S.Z)-l '-cthyl-l2-(2-((S)-l-mcthoxycthyl)-5-(3-(pipcridin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]h eptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide as atropisomer 1 (38 mg) and (lr.2R.3S)-N-((64S.4S.Z)-l '-cthyl-l2-(2-((S)-l-mcthoxycthyl)-5-(3-(pipcridin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]h eptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide as atropisomer 2 (i.e., compound of Example 12 ) (28 mg) as white solids. LCMS (ESI) calcd. for C49H6iN7O5S [M+H]+ m / z 860.4, found: 860.5. atropisomer 1: 4H NMR (400 MHz, DMSO-14) 5 8.81 (d, J = 1.8 Hz, 1H), 8.42 (d, J = 8.8 Hz, 2H), 7.99 (d, J = 1.9 Hz, 1H), 7.82 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 5.89 (d, J = 10.9 Hz, 1H), 5.31 (t, J = 8.3 Hz, 1H), 4.73 (d, J = 11.1 Hz, 1H), 4.49 (d, J = 5.0 Hz, 1H), 3.99 - 3.89 (m, 2H), 3.81 (dd, J = 14.8, 7.4 Hz, 1H), 3.60 (d, J = 10.8 Hz, 1H), 3.52 (d, J = 7.2 Hz, 3H), 3.30 - 2.98 (m, 7H), 2.66 (dd, J = 11.4, 5.6 Hz, 1H), 2.44 (s, 3H), 2.39 - 2.29 (m, 2H), 2.15 (t, J = 9.8 Hz, 1H), 1.67 - 1.46 (m, 5H), 1.43 - 1.01 (m, 18H), 0.92 (s, 3H), 0.48 (s, 3H). atropisomer 2 (i.e., compound of Example 12 ): 4H NMR (400 MHz, DMSO) 5 8.78 (d, J = 1.8 Hz, 1H), 8.40 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 10.9 Hz, 1H), 5.29 (t, J = 8.3 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 5.0 Hz, 1H), 3.99 - 3.86 (m, 2H), 3.79 (dd, J = 14.8, 7.4 Hz, 1H), 3.63 - 3.42 (m, 4H), 3.26 - 2.98 (m, 6H), 2.64 (d, J = 5.7 Hz, 1H), 2.36 - 2.27 (m, 2H), 2.13 (t, J = 9.8 Hz, 1H), 1.60 (t, J = 9.4 Hz, 1H), 1.54 - 1.47 (m, 3H), 1.35 (s, 2H), 1.29 - 1.00 (m, 14H), 0.90 (s, 3H), 0.46 (s, 3H). Example 13 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-mdola-6(2,4) -bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)-4-methylpiperazine in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16. Method 2: atropisomer 1                                                 atropisomer 2 Step                 1:                 Preparation                 of                 tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-di me-thyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 Jheptanacyclounde caphane-4-yl )carbamate A mixture of (S)-l-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)-4-methylpiperazine (100                  mg,                   0.28                  mmol),                  tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (200 mg, 0.28 mmol), K2CO3 (117.5 mg, 0.85 mmol) and Pd(dppf)C12 (41.5 mg, 0.06 mmol) in dioxane (6 mL) and H2O (1.5 mL) was stirred at 85°C under N2 for 16h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC with MeOH / DCM = 0-10% to afford the tert-butyl ((64S,4S,Z)-12-(2-((S)-1 -methoxyethyl)-5 -(3 -(4-methylpiperazin-1 -yl)prop-1 -yn-1 -yl)pyridin-3 -y 1) -10,10-d ime- thyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacyclounde caphane-4-yl)carbamate (180 mg, 76%) as a yellow solid. LCMS (ESI) calcd. for C46H58N80gS [M+H]+ m / z 851.4, found: 852.1 Step                 2:                 Preparation                 of                 tert-butyl ((648,48^)-11-ethyl-12-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-l 0,10-dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 Jheptana cycloundecaphane-4-yl )carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-12-(2-((S)-1 -methoxyethyl)-5 -(3 -(4-methylpiperazin-1 -yl)prop-1 -yn-1 -yl)pyridin-3 -y 1) -10,10-d ime-thyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacyclounde caphane-4-yl)carbamate (180 mg, 0.21 mmol) in DMF (6 mL) were added Cs2CO3 (206.4 mg, 0.64 mmol) and lodoethane (99 mg, 0.64 mmol). The resulting mixture was stirred at rt for 0.5h. After completion, the reaction mixture was diluted with EtOAc (20 mL) and H2O (20 mL). The mixture was extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (20 mL*2), dried over anhydrous Na2SO4 and concentration under reduced pressure. The residue was purified by FCC with MeOH / DCM = 0-7%                   to                   afford                   the                   tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl) -10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptan acycloundecaphane-4-yl)carbamate (115 mg, 62%) as yellow solid. LCMS (ESI) calcd. for C48H62N8O6S [M+H]+ m / z 879.5, found: 880.0 Step                         3:                         Preparation                         of (64S,4S,Z)-4-amino-lI-ethyl-l2-(2-( (S)-l-methoxyethyl)-5-( 3-( 4-methylpiperazin-l -yl)prop-l -yn-1 -yl)pyridi n-3-yl)-10,10-dimethyl-l1 H-8-oxa-62,63-diaza-2( 4,2 )-thiazola-l(5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanac ycloundecaphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl) -10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]heptan acycloundecaphane-4-yl)carbamate (115 mg, 0.13 mmol) in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to give (64S,4S,Z)-4-amino-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyri din-3-yl)-10,10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana cycloundecaphane-5,7-dione 7 (186 mg) of its TFA salt as a yellow solid. LCMS (ESI) calcd. for C43H54N8O4S [M+H]+ m / z 779.4, found: 779.9 Step                         4:                         Preparation                         of (lr,2R,3S)-N-((645,45,2)-11-ethyl-12-(2-((5)-1-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)p y ridin-3-yl)-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[ 3. l.l]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To                    a                    stirred                     solution                    of (64S,4S,Z)-4-amino-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyri din-3-yl)-10,10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana cycloundecaphane-5,7-dione (101.3 mg, 0.13 mmol) in MeCN (2.5 mL) and DCM (2.5 mL) was added (lr,2R,3S)-2,3-dimethyIcyclopropane-1 -carboxylic acid (16.3 mg, 0.14 mmol), TCFH (109.3 mg, 0.39 mmol) and NMI (106.7 mg, 1.3 mmol). The resulting mixture was stirred at rt for 0.5h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC to give the (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-y l)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicycl o[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide as atropisomer 1 (38 mg)                                                                               and (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-y l)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicycl o[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide as atropisomer 2 (i.e., compound of Example 13 ) (22 mg) as white solids. LCMS (ESI) calcd. for C49H62N8O5S [M+H]+ m / z 875.5, found: 875.6 atropisomer 1: ’H NMR (400 MHz, DMSO-< / 6) 5 8.78 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 11.7 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 5.86 (d, J = 11.1 Hz, 1H), 5.29 (t, J = 7.9 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 3.99 - 3.72 (m, 4H), 3.60 - 3.47 (m, 4H), 3.27 - 2.98 (m, 8H), 2.64 (dd, J = 11.6, 5.9 Hz, 1H), 2.52 (s, 2H), 2.41 - 2.22 (m, 6H), 2.17 - 2.09 (m, 4H), 1.59 (t, J = 9.2 Hz, 1H), 1.27-1.13 (m, 7H), 1.11 - 1.03 (m, 8H), 0.89 (s, 3H), 0.45 (s, 3H). atropisomer 2 (i.e., compound of Example 13 ): ’H NMR (400 MHz, DMSO) 5 8.78 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 11.7 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 5.86 (d, J = 11.1 Hz, 1H), 5.29 (t, J = 7.9 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 3.99 - 3.72 (m, 4H), 3.60 - 3.47 (m, 4H), 3.27 - 2.98 (m, 8H), 2.60 (dd, J = 27.9, 22.1 Hz, 5H), 2.41 - 2.22 (m, 6H), 2.17 - 2.09 (m, 4H), 1.59 (t, J = 9.2 Hz, 1H), 1.29 - 1.02 (m, 16H), 0.89 (s, 3H), 0.45 (s, 3H). Example 14 (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-(4-acetylpiperazin-l-yl)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyrid in-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-b icyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with (S)-1 -(4-(3-(5 -bromo-6-( 1 -methoxyethyl)pyridin-3 -yl)prop-2-yn-1 -yl)piperazin-1 -yl)ethan-1 -one in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16. LCMS (ESI): 903.5 [M+l]+. ’H NMR (500 MHz, CDC13) 5 8.39 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 13.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.63 (dt, J = 13.0, 12.3 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.60 - 3.52 (m, 3H), 3.52 - 3.45 (m, 4H), 3.33 (s, 3H), 3.31 - 3.23 (m, 2H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 2H), 2.72 (h, J = 7.9 Hz, 1H), 2.55 - 2.50 (m, 4H), 2.50 - 2.43 (m, 2H), 2.13 - 1.97 (m, 7H), 1.74 (dq, J = 8.6, 5.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.95 (d, J = 5.1 Hz, 6H). Example 15 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-y 1)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]he ptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide Substituting          (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic         acid         with (lS,2S)-2-methylcyclopropane-l -carboxylic acid in the Step 4 of Example 16, the title compound was prepared by the same procedures as described for Example 16. LCMS (ESI): 848.4 [M+l]+. ’H NMR (500 MHz, CDC13) 5 8.39 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 12.5 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.64 (q, J = 12.4 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 -3.89 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.58 (d, J = 2.6 Hz, 2H), 3.33 (s, 3H), 3.31 - 3.23 (m, 2H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 2H), 2.78 - 2.66 (m, 5H), 2.13 -2.03 (m, 3H), 2.03 - 1.97 (m, 1H), 1.94 (td, J = 10.2, 7.2 Hz, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.65 - 1.60 (m, 1H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 1H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 4H), 0.91 (d, J = 5.0 Hz, 3H). Example 16 Synthesis of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide atropisomer 1 atropisomer 2 Step                 1:                 Preparation                 of                 tert-butyl ((64S,4S,Z)-12-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7 -di oxo-11H-8-oxa-62,63-diaza-2( 4,2)-thiazola-l(5,3)-indola-6( 2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4 -yl)carbamate A mixture of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine (253 mg, 0.74                                         mmol),                                         tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (525 mg, 0.74 mmol), K2CO3 (309 mg, 2.24 mmol) and Pd(dppf)Cl2 (55 mg, 0.075 mmol) in dioxane (8 mL) and H2O (2 mL) was stirred at 85°C under N2 for 19 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 100%)                           to                           give                           tert-butyl ((64S,4S,Z)-12-(2-((S)-1 -methoxyethyl)-5 -(3 -morpholinoprop-1 -yn-1 -yl)pyridin-3 -yl)-10,10-dimethyl-5,7-di-oxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (323 mg, 52.1 %) as a yellow solid. LCMS (ESI) calcd. for C45H55N7O7S [M+H]+ m / z 838.4, found: 839.5 Step                 2:                 Preparation                 of                 tert-butyl ((648,48,2)-11 -ethyl-12-(2-((8)-1-methoxyethyl)-5-(3-morpholinoprop- 1-yn-l -yl)pyridin-3-yl)-10,10-dimeth yl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2 )-thiazola-l(5,3)-indola-6( 2,4 )-bicyclo[3.1.1 Jheptanacycloundeca phane-4-yl )carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-12-(2-((S)-1 -methoxyethyl)-5 -(3 -morpholinoprop-1 -yn-1 -yl)pyridin-3 -yl)-10,10-dimethyl-5,7-di-oxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (323 mg, 0.39 mmol) in DMF (4.5 mL) were added Cs2CO3 (251 mg, 0.77 mmol) and lo-doethane (120 mg, 0.77 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 80%) to give tert-butyl ((64S,4S,Z)-11-ethyl- l2-(2-((S)-1 -methoxyethyl)-5 -(3-morpholinoprop-1 -yn-1 -yl)pyridin-3 -yl)-10,10-dimet hyl-5,7-dioxo-l 1H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundec aphane-4-yl)carbamate as atropisomer 1 (100 mg) and atropisomer 2 (140 mg) as white solids. LCMS (ESI) calcd. for C47H59N7O7S [M+H]+ m / z 866.4, found: 866.8. Step 3: Preparation of (64 S,4S,2)-4-amino-11-ethyl-12-(2-((8)-l-methoxyethyl)-5-(3-morpholinoprop-1-yn-l-yl)pyridin-3-yl)-10,10 -dimethyl-11 H-8-oxa-62,63-diaza-2( 4,2)-thiazola-l(5,3)-indola-6( 2,4 )-bicyclo[ 3.1.1 Jheptanacycloundecaph ane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-11-ethyl- l2-(2-((S)-1 -methoxyethyl)-5 -(3-morpholinoprop-1 -yn-1 -yl)pyridin-3 -yl)-10,10-dimet hyl-5,7-dioxo-l 1H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundec aphane-4-yl)carbamate as atropisomer 1 (100 mg, 0.12 mmol) in dichloromethane (4 mL) was added TFA (1 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concen- trated                   and                   lyophilized                   to                   give (64S,4S,Z)-4-amino-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10, 10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundeca phane-5,7-dione (110 mg) of its TFA salt as a yellow solid. LCMS (ESI) calcd. for C42H51N7O5S [M+H]+ m / z 766.4, found: 766.9 Step                         4:                         Preparation                         of (lr,2R,3S)-N-((64S,4S,Z)-1]-ethyl-12-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2 )-thiazola-l(5,3)-indola-6( 2,4)-bicyclo[3.1.1 Jheptan acycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To                    a                    stirred                     solution                    of (64S,4S,Z)-4-amino-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10, 10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundeca phane-5,7-dione (125 mg, 0.16 mmol) and (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid (19 mg, 0.16 mmol) and 2,6-lutidine (88 mg, 0.82 mmol) in ACN (5 mL) was added COMU (105 mg, 0.24 mmol) at rt, the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5 % NH4HCO3) from 20% to 95% in 30 min)                                            to                                            give (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl )-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hepta nacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (85 mg, 61.7%) as a white solid. LCMS (ESI) calcd. for C48H59N7O6S [M+H]+ m / z 862.4, found: 862.9. 1HNMR(400MHz, DMSO-i / 6) 5 8.82 (s, 1H), 8.40 (d, J= 13.3 Hz, 2H), 7.90 (s, 1H),7.81 (s, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.57 (d, J= 8.8 Hz, 1H), 5.92 (d, J= 10.8 Hz, 1H), 5.34 (d, J= 22.7 Hz, 2H), 4.64 (d, J= 11.2 Hz, 1H), 4.48 (d, J= 4.9 Hz, 1H), 4.37 - 4.21 (m, 2H), 4.06 (d, J= 7.6 Hz, 5H), 3.75 - 3.48 (m, 6H), 3.22 (s, 3H), 3.16 (s, 10H), 3.00 - 2.85 (m, 2H), 2.62 (d, J= 5.7 Hz, 3H), 2.41 (d, J= 15.0 Hz, 1H), 2.32 (s, 1H), 2.21-2.09 (m, 1H), 1.99 (d, J= 8.0 Hz, 1H), 1.55 (s, 1H), 1.35 (d, J= 6.1 Hz, 2H), 1.22 (s, 4H), 1.16 (s, 2H), 1.07 (dd, J= 10.3, 5.8 Hz, 4H), 0.87 (t, J= 9.6 Hz, 4H), 0.32 (s, 3H). Example 17 (lS,2S)-N-((64S,4S,Z)-l2-(5-(3-(l,l-dioxidothiomorpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyr id-in-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-b icyclo[3.1.1]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)thiomorpholine 1,1-dioxide in the Step 1 of Example 16 and Substituting (lr,2R,3 S)-2,3 -dimethylcyclopropane-1 -carboxylie acid with (lS,2S)-2-methylcyclopropane-l -carboxylic acid in the Step 4 of Example 16, the title compound was prepared by the same procedures as described for Example 16. Method 2: atropisomer 1 atropisomer 2 Step                 1:                 Preparation                 of                 tert-butyl ((64S,4S,Z)-l2-(5-(3-(l,l-dioxidothiomorpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10 -dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycl oundecaphane-4-yl )carbamate A mixture of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)thiomorpholine 1,1-dioxide             (209            mg,             0.54            mmol),            tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (383 mg, 0.54 mmol), K2CO3 (225 mg, 1.62 mmol) and Pd(dppf)C12 (78 mg, 0.11 mmol) in dioxane (10 mL) and H2O (2.5 mL) was stirred at 85°C under N2 for 5 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to                    10%)                    to                    give                    tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)carbamate (312 mg, 65.1%) as ayellow solid. LCMS (ESI) ealed. for C45H55N7O8S2 [M+H]+ m / z 886.3, found: 886.9 Step                                              2:                                               tert-butyl ((64S,4S,Z)-12-(5-(3-(1, l-dioxidothiomorpholino)prop-l-yn-l-yl)-2-((S)-l-methoxy ethyl)pyridin-3-yl)-11 -et hyl- 10,10-dimethyl-5,7-dioxo-11 H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]he ptanacycloundecaphane-4-yl)carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)carbamate (310 mg, 0.35 mmol) in DMF (5 mL) were added Cs2CO3 (183 mg, 0.56 mmol) and lodoethane (88 mg, 0.56 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (20 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by column chromatography (eluting with EtOAc / PE from 0% to 100%) to give tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-11 -c thyl-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ] he ptanacycloundecaphane-4-yl)carbamate as atropisomer 1 (160 mg) and atropisomer 2 (156 mg) (Yield: 98.8%) as a yellow foam. LCMS (ESI) calcd. for C47H59N7O8S2 [M+H]+ m / z 914.4, found: 914.9 Step                                                                                            3: (64S,4S,Z)-4-amino-l2-( 5-( 3-( 1,1-dioxidothiomorpholino )prop-l-yn-l-yl)-2-( (S )-l-methoxyethyl)pyridin-3-yl)-!1 -ethyl-10,10-dimethyl-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hepta nacycloundecaphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-11 -c thyl-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ] he ptanacycloundecaphane-4-yl)carbamate as atropisomer 1 (160 mg, 0.18 mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwise at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was             concentrated             and             lyophilized             to             give (64S,4S,Z)-4-amino-12-(5-(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxy ethyl)pyridin-3 -yl)-l1-ethyl-10,10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hept anacycloundecaphane-5,7-dione (190 mg) of its TFA salt as a yellow solid. LCMS (ESI) calcd. for C42H5iN7O6S2 [M+H]+ m / z 814.3, found: 814.8 Step                                                                                            4: (IS, 2S)-N-((64S,4S,Z)-12-(5-(3-(1, l-dioxidothiomorpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-!1 -ethyl-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo [ 3. l.l]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide To                    a                    stirred                     solution                    of (64S,4S,Z)-4-amino-12-(5-(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxy ethyl)pyridin-3 -yl)-l1-ethyl-10,10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hept anacycloundecaphane-5,7-dione (190 mg, 0.16 mmol) and (lS,2S)-2-methylcyclopropane-1 -carboxylic acid (18 mg, 0.16 mmol) and NMI (128 mg, 1.56 mmol) in ACN (2 mL) and DCM (2 mL) was added TCFH (131 mg, 0.47 mmol) at rt, the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-TLC (with EA) to give (1 S,2S)-N-((64S,4S,Z)-12-(5-(3-(1,1 -dioxidothiomorpholino)prop- 1-yn-1 -yl)-2-((S) -1 -methoxyethyl)pyridi n-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy clo [3. l.l]heptanacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamide (23 mg, 16.1%) as a white solid. LCMS (ESI) calcd. for C47H57N7O7S2 [M+H]+ m / z 896.3, found: 896.4. ’H NMR (400 MHz, DMSO-r / 6) 5 8.78 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.40 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 5.91 (d, J = 11.1 Hz, 1H), 5.37 (s, 1H), 4.64 (d, J = 10.8 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 4.37 - 4.20 (m, 2H), 4.04 (dd, J = 15.2, 7.3 Hz, 1H), 3.73 (s, 2H), 3.54 (dd, J = 20.9, 11.1 Hz, 2H), 3.21 (s, 4H), 3.11 (t, J = 10.5 Hz, 4H), 3.03 (s, 3H), 2.91 (d, J = 14.3 Hz, 1H), 2.61 (d, J = 5.7 Hz, 1H), 2.40 (d, J = 14.1 Hz, 1H), 2.31 (s, 1H), 2.18 - 2.08 (m, 1H), 1.55 (s, 1H), 1.47 (s, 1H), 1.34 (d, J = 6.0 Hz, 2H), 1.21 (s, 1H), 1.05 (s, 3H), 0.86 (t, J = 6.9 Hz, 5H), 0.54 (d, J = 5.4 Hz, 1H), 0.31 (s, 3H). Example 18 (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-(l,l-dioxidothiomorpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl) pyri- din-3-yI)-l1-ethyI-10,10-dimethyI-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazoIa-l(5,3)-indoIa-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)thiomorpholine 1,1-dioxide in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16. Method 2: N t 1 H L ,Boc --O C f H XO          / x N^S fl J            PinB—J J ^^^Br ____ I"                        Pd(dppf)CI2, K2CO3, dioxane / H2O, 85°C y "'° 1 H --O TFA, DCM, rt                       ~°\ .,          t step 3                         J—rZ’^Z V V' JL J N T                                                       N J 1 H L ,Boc                                                       1 H L ,Boc --O    Z^N                                 --0    Z>N' —0 Jr" Jx                                —0 Jr" zk z\                      Etl, CS2CO3                                      s / N=\                           DMF, rt                   / X=\ V. / / —X JI J                                   V / / —X JL J step 2                  \J / J H                 < / N                           O;W r° [ h Y TFA     TCFH.NMI                ~°\ , ZC   N^s CH3CN / DCM, rt                       7 step 4 J oA_ / N Step                   1:                   Synthesis                   of                  tert-butyl ((64S,4S,Z)-l2-(5-(3-(l,l-dioxidothiomorpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10 -dimethyl-5,7-dioxo-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycl oundecaphane-4-yl )carbamate A mixture of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)thiomorpholine 1,1-dioxide             (186            mg,             0.48            mmol),            tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (341 mg, 0.48 mmol), K2CO3 (200 mg, 1.45 mmol) and Pd(dppf)C12 (71 mg, 0.097 mmol) in dioxane (7.6 mL) and H2O (1.9 mL) was stirred at 85°C under N2 for 15 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from           0%           to           10%)           to           give           tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)carbamate (312 mg, 73.5 %) as a brown solid. LCMS (ESI) calcd. for C45H55N7O8S2 [M+H]+ m / z 886.4, found: 886.9 Step                   2:                   Synthesis                   of                  tert-butyl ((64S,4S,Z)-12-(5-(3-(1, l-dioxidothiomorpholino)prop-l-yn-l-yl)-2-((S)-l-methoxy ethyl)pyridin-3-yl)-11 -et hyl- 10,10-dimethyl-5,7-dioxo-11 H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]he ptanacycloundecaphane-4-yl)carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-10, 10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cloundecaphane-4-yl)carbamate (310 mg, 0.35 mmol) in DMF (5 mL) were added CS2CO3 (183 mg, 0.56 mmol) and lodoethane (88 mg, 0.56 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (20 mL), washed with water (50 mL x 2) and saturated NaCl (50 mL), then dried over Na2SO4. following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 100%) to give tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-11 -c thyl-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ] he ptanacycloundecaphane-4-yl)carbamate (316 mg, 97.8%) as brown solid. LCMS (ESI) calcd. for C47H59N7O8S2 [M+H]+ m / z 914.4, found: 914.9. Step                           3:                           Synthesis                           of (64S,4S,Z)-4-amino-l2-( 5-( 3-( 1,1-dioxidothiomorpholino )prop-l-yn-l-yl)-2-( (S )-l-methoxyethyl)pyridin-3-yl)-!1 -ethyl-10,10-dimethyl-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hepta nacycloundecaphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-12-(5 -(3 -(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl)pyridin-3 -yl)-11- ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]h eptanacycloundecaphane-4-yl)carbamate (316mg, 0.35mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated                            to                             give                             crude (64S,4S,Z)-4-amino-12-(5-(3-(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxy ethyl)pyridin-3 -yl)-l1-ethyl-10,10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hept anacycloundecaphane-5,7-dione which was used to next step without purification. LCMS (ESI) calcd. for C42H51N7O6S2 [M+H]+ m / z 814.3, found: 814.8 Step                           4:                           Synthesis                           of (lr,2R,3S)-N-((64S,4S,Z)-12-((R)-5-(3-( 1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-l-methoxyethyl)-S^-dihydropyridin-S-yl)-!1 -ethyl-10,10-dimethyl-5, V-dioxo-^HS-oxa^rf-diaza^ld^fthiazola-1( 5,3)-1 ndola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide To              a              stirred              solution              of              crude (64S,4S,Z)-4-amino-l1-ethyl-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methox yeth-yl)pyridin-3 -yl)-10,10-dimethyl-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]h eptanacycloundecaphane-5,7-dione        (220        mg,        0.27        mmol) and (lr,2R,3S)-2,3-dimethylcyclopropane-1 -carboxylic acid (24 mg, 0.21 mmol) and NMI (132 mg, 1.61 mmol) in ACN (3 mL) and DCM (3 mL) was added TCFH (136 mg, 0.49 mmol) at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-TLC (eluting with 100% EtOAc) to give (1 r,2R,3 S)-N-((64S,4S,Z)-12-((R)-5 -(3-(1,1 -dioxidothiomorpholino)prop-1 -yn-1 -yl)-2-((S)-1 -methoxyethyl )-3,4-dihydropyridin-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3) -indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (34.3 mg) as a white solid. LCMS (ESI) calcd. for C48H6iN7O7S2 [M+H]+ m / z 912.4, found: 911.2. 1HNMR(400MHz, DMSO-76) 5 8.79 (s, 1H), 8.39 (d,7= 11.6Hz, 2H),7.86(s, lH),7.80(s, 1H), 7.73 (d, J= 8.1 Hz, 1H), 7.56 (d, J= 8.8 Hz, 1H), 5.91 (d, 7= 11.0 Hz, lH),5.36(s, 1H),4.64 (d, 7= 11.0 Hz, 1H), 4.46 (d, 7 = 4.6 Hz, 1H), 4.35 - 4.21 (m, 2H), 4.05 (dd, 7= 14.8, 6.9 Hz, 2H), 3.73 (s, 2H), 3.53 (dd, 7 = 20.6, 10.7 Hz, 2H), 3.21 (s, 3H), 3.13 (d, 7= 4.9 Hz, 4H), 3.03 (s, 3H), 2.61 (d, 7= 6.0 Hz, 1H), 2.42 (s, 1H), 2.30 (s, 1H), 2.17-2.09 (m, 1H), 1.56 (d, 7= 8.9 Hz, 1H), 1.40- 1.28 (m, 3H), 1.25- 1.10 (m, 5H), 1.11-0.99 (m, 5H), 0.94 - 0.80 (m, 5H), 0.31 (s, 3H). Example 19 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-i ndola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with ((R)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16 Method 2: Step                   1:                   Synthesis                   of                  tert-butyl ((64S,4S,Z)-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl )-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]hepta nacycloundecaphane-4-yl)carbamate A mixture of ((R)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol (71 mg, 0.19                                         mmol),                                         tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (150 mg, 0.21 mmol), K2CO3 (80 mg, 0.58 mmol) and Pd(dppf)C12 (21 mg, 0.029 mmol) in dioxane (3 mL) and H2O (0.7 mL) was stirred at 85°C under N2 for 16 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from           0%           to           10%)           to           give           tert-butyl ((64S,4S,Z)-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hep tanacycloundecaphane-4-yl)carbamate (146 mg, 88.5 %) as a pale yellow solid. LCMS (ESI) calcd. for C46H57N7O8S [M+H]+ m / z 868.4, found: 868.9 Step                   2:                   Synthesis                   of                  tert-butyl ((648,48^)-11-ethyl-12-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyr id-in-S-ylflOJO-dimethyl-S^-dioxo-^HS-oxa^2^3-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)carbamate To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]hep tanacycloundecaphane-4-yl)carbamate (915 mg, 1.05 mmol) in DMF (10 mL) were added CS2CO3 (628 mg, 1.93 mmol) and lodoethane (301 mg, 1.93 mmol) at 0°C, the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (20 mL), washed with water (100 mL x 2) and saturated NaCl (60 mL), then dried over Na2SO4. following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 85%) to give tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)p yridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[ 3.1.1]heptanacycloundecaphane-4-yl)carbamate (190 mg, 20.0%) as white solid. LCMS (ESI) calcd. for C47H59N7O6S [M+H]+ m / z 896.4, found: 896.9 Step                           3:                           Synthesis                           of (64S,4S,Z)-4-amino-l1 -ethyl-12-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxye thyl )pyridin-3-yl flOJO-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-1( 5,3)-indola-6( 2,4 )-bicyclo[3.1.1 ]heptanacycloundecaphane-5,7-dione To              a              stirred              solution              of              tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)p yridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[ 3.1.1]heptanacycloundecaphane-4-yl)carbamate (190 mg, 0.21 mmol) in dichloromethane (3 mL) was added TFA (0.75 mL) dropwisely at rt, the resulting mixture was stirred at rt for 2 h. The reaction mixture was                  concentrated                  to                  give                  crude (64S,4S,Z)-4-amino-l1-ethyl-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methox yeth-yl)pyridin-3 -yl)-10,10-dimethyl-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]h eptanacycloundecaphane-5,7-dione which was used to next step without purification. LCMS (ESI) calcd. for C43H53N7O6S [M+H]+ m / z 796.4, found: 796.9. Step                           4:                           Synthesis                           of (lr,2R,3S)-N-((648,48^)-11-ethyl-12-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-met hoxyeth-yl)py ridin-3-yl)-! 0,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyc lo[3.1.1 ]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To              a              stirred              solution              of              crude (64S,4S,Z)-4-amino-l1-ethyl-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methox yeth-yl)pyridin-3 -yl)-10,10-dimethyl-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1 (5,3)-indola-6(2,4)-bicyclo [3.1.1 ]h eptanacycloundecaphane-5,7-dione        (256        mg,        0.29        mmol) and (lr,2R,3S)-2,3-dimethyIcyclopropane-1 -carboxylic acid (32 mg, 0.29 mmol) and 2,6-lutidine (181 mg, 1.68 mmol) in ACN (10 mL) was added COMU (181 mg, 0.42 mmol) at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (eluting with ACN / H2O (0.5 % NH4HCO3) from 20% to 95% in 30 min) to give (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-((R)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-m ethoxyeth-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy clo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (98 mg) as a white solid. LCMS (ESI) calcd. for C49H6iN7O7S [M+H]+ m / z 892.4, found: 892.9. 4H NMR (400 MHz, DMSO-<A) 5 8.78 (d, J = 1.8 Hz, 1H), 8.43 - 8.35 (m, 2H), 7.87 - 7.76 (m, 2H), 7.73 (d, J= 8.6 Hz, 1H), 7.56 (d, J= 8.7 Hz, 1H), 5.91 (d, J= 11.2 Hz, 1H), 5.36 (s, 1H), 4.68 - 4.41 (m, 3H), 4.35 - 4.18 (m, 2H), 4.05 (dd, J= 14.8, 7.2 Hz, 1H), 3.86-3.61 (m, 4H), 3.62 - 3.39 (m, 4H), 3.33 (s, 1H), 3.27- 3.16 (m, 4H), 3.17 - 3.03 (m, 2H), 2.92 (d, J= 14.1 Hz, 1H), 2.68 (d, J= 11.4 Hz, 1H), 2.63-2.56 (m, 2H), 2.53 (d, J= 10.6 Hz, 1H), 2.45 - 2.35 (m, 2H), 2.34 - 2.25 (m, 1H), 2.13 (t, J= 9.9 Hz, 1H), 1.60 - 1.49 (m, 1H), 1.34 (d, J= 6.0 Hz, 3H), 1.18 (d, J= 24.3 Hz, 4H), 1.06 (dd, J= 10.2, 5.7 Hz, 5H),0.87 (d, J= 10.1 Hz, 5H), 0.32 (s, 3H). LCMS (ESI): 892.4 [M+l]+. ‘H NMR (400 MHz, DMSO) 5 8.78 (d, J = 1.8 Hz, 1H), 8.43 - 8.35 (m, 2H), 7.87 - 7.76 (m, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 5.91 (d, J = 11.2 Hz, 1H), 5.36 (s, 1H), 4.68 - 4.41 (m, 3H), 4.35 - 4.18 (m, 2H), 4.05 (dd, J = 14.8, 7.2 Hz, 1H), 3.86 - 3.61 (m, 4H), 3.62 - 3.39 (m, 4H), 3.33 (s, 1H), 3.27 - 3.16 (m, 4H), 3.17 - 3.03 (m, 2H), 2.92 (d, J = 14.1 Hz, 1H), 2.68 (d, J = 11.4 Hz, 1H), 2.63 - 2.56 (m, 2H), 2.53 (d, J = 10.6 Hz, 1H), 2.45 - 2.35 (m, 2H), 2.34 - 2.25 (m, 1H), 2.13 (t, J = 9.9 Hz, 1H), 1.60 - 1.49 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.18 (d, J = 24.3 Hz, 4H), 1.06 (dd, J = 10.2, 5.7 Hz, 5H), 0.87 (d, J = 10.1 Hz, 5H), 0.32 (s, 3H). Example 20 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-((S)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l -methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-in dola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with ((S)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16 Method 2: Step                         1:                         Preparation                         of (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-((S)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethy fpyridin-S-yf-IOJO-dimethyl-Sy-dioxo-l1 H-8-oxa-(f,(f -diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicycl o[3.1.1 ]heptanacycloundecaphane-4-yl )-2,3-dimethylcyclopropane-l-carboxamide A                                       mixture                                       of ((S)-4-(3-(5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholin-3-yl)methanol (70.2 mg, 0.19                                                                                   mmol), (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-di methylcyclopropane-1-carboxamide (160 mg, 0.23 mmol), K2CO3 (79 mg, 0.57 mmol) and Pd(dppf)C12 (27.8 mg, 0.04 mmol) in dioxane (8 mL) and H2O (1.6 mL) was stirred at 85°C under N2 for 16h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC with MeOH / DCM =       0-7% to afford the (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-((S)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyet hyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bic yclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (145 mg, 88%) as a yellow solid. LCMS (ESI) calcd. for C47H57N7O7S [M+H]+ m / z 864.4, found: 865.1 Step                         2:                         Preparation                         of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-((S)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-met hoxyeth- y l)py ridin-3-yl)- / 0 J 0-dimethyl-5y-dioxo H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyc lo[3.1.1 ]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide To                    a                    stirred                     solution                    of (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-((S)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyet hyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bic yclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (115 mg, 0.133 mmol) in DMF (5 mL) were added CS2CO3 (129.8 mg, 0.4 mmol) and lodoethane (62.3 mg, 0.4 mmol). The resulting mixture was stirred at rt for 0.5h. After completion, the reaction mixture was diluted with EtOAc (20 mL) and H2O (20 mL). The mixture was extracted with EtOAc (10 mL*3). The combined organic layer was washed with brine (20 mL*2), dried over anhydrous Na2SO4 and concentration under reduced pressure. The residue was purified by pre-HPLC to give the (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-((S)-3-(hydroxymethyl)morpholino)prop-l-yn-l-yl)-2-((S)-l-m ethoxyeth-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy clo[3.l.l]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1 -carboxamide (38 mg) as white solid. LCMS (ESI) calcd. for C49H6iN7O7S [M+H]+ m / z 892.4, found: 892.9. 4H NMR (500 MHz, CDC13) 5 8.39 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 13.0 Hz, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.63 (dt, J = 13.0, 12.3 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 -3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.84 - 3.78 (m, 1H), 3.78 - 3.73 (m, 3H), 3.73 - 3.64 (m, 4H), 3.59 (d, J = 8.2 Hz, 1H), 3.33 (s, 3H), 3.31 - 3.23 (m, 1H), 3.22 (d, J = 3.5 Hz, 1H), 3.11 - 3.01 (m, 3H), 3.01 -2.93 (m, 2H), 2.72 (h, J = 7.9 Hz, 1H), 2.47 (t, J = 8.6 Hz, 1H), 2.13 - 2.03 (m, 3H), 2.03 - 1.97 (m, 1H), 1.74 (dq, J = 8.6, 5.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.95 (d, J = 5.1 Hz, 6H). Example 21 (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-N -((64S,4S,Z)-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1-(2,2,2-trifl uoro-ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaph ane-4-yl)-3-methylbutanamide Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol with (S)-3-bromo-5-ethynyl-2-(l-methoxyethyl)pyridine in the Step 1 of Example 2, Substituting iodoethane with l,l,l-trifluoro-2-iodoethane in the Step 2 of Example 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic                       acid                       with (S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-3-meth ylbutanoic acid in the Step 4 of Example 2, the title compound was prepared by the same procedures as described for Example 2. LCMS (ESI): 1052.5 [M+l]+. *HNMR (500 MHz, CDC13) 5 8.49 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 12.5 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.72 (d, J = 2.7 Hz, 2H), 4.57 (q, J = 12.4 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.85 (d, J = 6.2 Hz, 1H), 3.64 - 3.54 (m, 3H), 3.46 (s, 1H), 3.37 (d, J = 1.3 Hz, 2H), 3.33 (s, 3H), 3.31 - 3.18 (m, 2H), 3.01 (d, J = 2.0 Hz, 2H), 2.99 - 2.92 (m, 1H), 2.88 - 2.80 (m, 3H), 2.79 - 2.72 (m, 1H), 2.70 (d, J = 8.0 Hz, 1H), 2.41 (t, J = 1.5 Hz, 3H), 2.21 (dp, J = 6.5, 5.7 Hz, 1H), 2.13 - 2.08 (m, 1H), 2.08 - 2.04 (m, 2H), 2.04 - 1.98 (m, 2H), 1.94 (t, J = 6.7 Hz, 1H), 1.89-1.81 (m, 3H), 1.67 (d, J = 5.3 Hz, 3H), 1.21 (dd, J = 7.9, 4.9 Hz, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (dd, J = 7.6, 5.0 Hz, 2H), 0.95 (d, J = 5.7 Hz, 3H), 0.90 (d, J = 5.5 Hz, 3H). Example 22 (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-N -((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3. l.l]heptanacycloundecaphane-4-yl)-3-methylbutanamide Substituting iodoethane with l,l,l-trifluoro-2-iodoethane in the Step 2 of Example 16 and Substituting              (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic              acid              with (S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-3-meth ylbutanoic acid in the Step 4 of Example 16, the title compound was prepared by the same procedures as described for Example 16. LCMS (ESI): 1151.6 [M+l]+. 1HNMR(500 MHz, CDC13) 5 8.39 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 12.5 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.72 (d, J = 2.7 Hz, 2H), 4.57 (q, J = 12.4 Hz, 1H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.85 (d, J = 6.2 Hz, 1H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.63 - 3.54 (m, 5H), 3.37 (d, J = 1.3 Hz, 2H), 3.33 (s, 3H), 3.31 - 3.18 (m, 2H), 3.01 (d, J = 2.0 Hz, 2H), 3.00 - 2.92 (m, 1H), 2.88 - 2.80 (m, 3H), 2.79 - 2.66 (m, 6H), 2.41 (t, J = 1.5 Hz, 3H), 2.21 (dp, J = 6.5, 5.7 Hz, 1H), 2.13 - 2.08 (m, 1H), 2.08 - 2.04 (m, 2H), 2.04 - 1.97 (m, 2H), 1.94 (t, J = 6.7 Hz, 1H), 1.89-1.81 (m, 3H), 1.67 (d, J = 5.3 Hz, 3H), 1.21 (dd, J = 7.9, 4.9 Hz, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (dd, J = 7.6, 5.0 Hz, 2H), 0.95 (d, J = 5.7 Hz, 3H), 0.90 (d, J = 5.5 Hz, 3H). Example 23 (2S)-2-cydopentyl-2-((S)-7-((2R,3R)-3-cydopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4] mman-2-yl)-N-((22S,64S,4S)-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-morpholina-l(5,3)-ind ola-6(2,4)-bicydo[3.1.1]heptanacydoundecaphane-4-yl)acetamide Substituting                                                                                  tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-di aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate with tert-butyl ((22S,64S,4S)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-morpholina- l(5,3)-indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)carbamate   in the Step 1 of Example 16, Substituting iodoethane with l,l,l-trifluoro-2-iodoethane in the Step 2 of Example 16 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nona n-2-yl)acetic acid in the Step 4 of Example 16, the title compound was prepared by the same procedures as described for Example 16. LCMS (ESI): 1179.7 [M+l]+. *HNMR (500 MHz, CDC13) 5 8.54 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J = 1.3 Hz, 1H), 7.56 (s, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 4.76 (s, 1H), 4.57 - 4.51 (m, 2H), 4.46 (d, J = 12.5 Hz, 1H), 4.32 (s, 1H), 4.24 (s, 1H), 4.15 (s, 1H), 4.01 (d, J = 13.7 Hz, 2H), 3.89 (d, J = 12.8 Hz, 2H), 3.84 - 3.78 (m, 3H), 3.77 (s, 1H), 3.73 (d, J = 17.2 Hz, 3H), 3.68 (s, 2H), 3.63 (s, 2H), 3.50 (d, J = 16.8 Hz, 2H), 3.38 - 3.24 (m, 7H), 2.85 - 2.75 (m, 3H), 2.67 (s, 1H), 2.62 - 2.55 (m, 6H), 2.52 (s, 1H), 2.47 (d, J = 10.1 Hz, 4H), 2.25 (s, 1H), 2.20 (d, J = 10.3 Hz, 2H), 1.98 (s, 1H), 1.92 (d, J = 11.5 Hz, 2H), 1.88 (s, 1H), 1.85 - 1.77 (m, 4H), 1.75 (d, J = 12.3 Hz, 1H), 1.72 - 1.65 (m, 7H), 1.59 (d, J = 13.0 Hz, 2H), 1.44 (d, J = 13.0 Hz, 2H), 1.37 (d, J = 4.9 Hz, 2H), 1.23 (d, J = 4.9 Hz, 2H), 1.16 (s, 3H), 1.11 (s, 3H). Example 24 l-(4-(dimethylamino)-4-methylpent-2-ynoyl)-N-((2S)-l-(((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethy l)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2 )-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)amino)-3-methyl-l-oxobu tan-2-yl)-4-fluoro-N-methylpiperidine-4-carboxamide Substituting          (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic         acid         with N-( 1 -(4-(dimethylamino)-4-methylpent-2-ynoyl)-4-fluoropiperidine-4-carbonyl)-N-methyl-L-valine in the Step 4 of Example 16, the title compound was prepared by the same procedures as described for Example 16. LCMS (ESI): 1145.6 [M+l]+. ’H NMR (500 MHz, CDC13) 5 8.39 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 12.6 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.75 (d, J = 7.3 Hz, 1H), 4.65 (q, J = 12.4 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.76 - 3.68 (m, 4H), 3.68 - 3.54 (m, 6H), 3.33 (s, 3H), 3.32 - 3.18 (m, 2H), 3.06 (d, J = 2.6 Hz, 2H), 2.96 (s, 3H), 2.78 - 2.66 (m, 5H), 2.47 (dt, J = 9.3, 6.5 Hz, 4H), 2.35 (s, 6H), 2.21 (dhept, J = 7.3, 5.1 Hz, 1H), 2.13 - 1.97 (m, 4H), 1.67 (d, J = 5.3 Hz, 3H), 1.43 - 1.35 (m, 9H), 1.15 (s, 3H), 1.10 (s, 3H), 0.79 (d, J = 5.1 Hz, 3H), 0.75 (d, J = 5.0 Hz, 3H). Example 25 l-(4-(dimethylamino)-4-methylpent-2-ynoyl)-N-((2S)-l-(((64S,4S,Z)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-m ethoxyeth- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-b icy- clo[3.1.1]heptanacycloundecaphane-4-yl)amino)-3-methyl-l-oxobutan-2-yl)-4-fluoro-N-methylpiperi dine-4-carboxamide Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol with (S)-3-bromo-5-ethynyl-2-(l-methoxyethyl)pyridine in the Step 1 of Example 2 and Substituting (lr,2R, 3 S)-2,3-dimethy Icy clopropane-1 -carboxylic                       acid                       with N-( 1 -(4-(dimethylamino)-4-methylpent-2-ynoyl)-4-fluoropiperidine-4-carbonyl)-N-methyl-L-valine in the Step 4 of Example 2, the title compound was prepared by the same procedures as described for Example 2. LCMS (ESI): 1046.5 [M+l]+. *HNMR (500 MHz, CDC13) 5 8.49 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 12.6 Hz, 1H), 8.08 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.75 (d, J = 7.3 Hz, 1H), 4.65 (q, J = 12.4 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.71 (dd, J = 9.3, 6.8 Hz, 2H), 3.62 (dd, J = 9.4, 6.7 Hz, 2H), 3.46 (s, 1H), 3.33 (s, 3H), 3.32 - 3.18 (m, 2H), 3.06 (d, J = 2.6 Hz, 2H), 2.96 (s, 3H), 2.72 (h, J = 7.9 Hz, 1H), 2.47 (dt, J = 9.3, 6.5 Hz, 4H), 2.35 (s, 6H), 2.21 (dhept, J = 7.3, 5.1 Hz, 1H), 2.13 - 1.97 (m, 4H), 1.67 (d, J = 5.3 Hz, 3H), 1.43 - 1.35 (m, 9H), 1.15 (s, 3H), 1.10 (s, 3H), 0.79 (d, J = 5.1 Hz, 3H), 0.75 (d, J = 5.0 Hz, 3H). Example 26 l-(4-(dimethylamino)-4-methylpent-2-ynoyl)-N-((2S)-l-(((22S,64S,4S)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyeth- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-morpholina-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)amino)-3-methyl-l-oxobutan-2-yl)-4-fluoro-N-methy lpiperidine-4-carboxamide Method 1: Substituting (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine with (S)-3-bromo-5-ethynyl-2-(l-methoxyethyl)pyridine in the Step 1 of Example 23 and Substituting (S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nona n-2-yl)acetic                                           acid                                           with N-( 1 -(4-(dimethylamino)-4-methylpent-2-ynoyl)-4-fluoropiperidine-4-carbonyl)-N-methyl-L-valine in the Step 4 of Example 23, the title compound was prepared by the same procedures as described for Example 23. Method 2: Step              1:              Synthesis              of             methyl              tert-butyl ((22 S, 648,48)-11 -ethyl-12-(2-((8)-1 -methoxy ethyl)-5-((triethylsilyl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-di-oxo-11H-8-oxa-62,63-diaza-2( 4,2)-morpholina-l( 5,3)-indola-6( 2,4)-bicyclo[3.1.1 Jheptanacycloundecaphan e-4-yl )carbamate A                                       mixture                                       of 5-((22S,64S,4S)-4-((tert-butoxycarbonyl)amino)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-morpholina-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-l2-yl)-6-((S)-l-methoxyet hyl)pyridin-3-yl trifluoromethane sulfonate (190 mg, 0.21 mmol), (triethylsilyl)acetylene (149 mg, 1.06 mmol), Cui (8 mg, 0.04 mmol) and Pd(PPh3)4 (49 mg, 0.04 mmol) in TEA / DMF (2 mL / 10 mL) was stirred at 100°C for 1 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column eluting with EtOAc / PE from 0% to 100% to afford tert-butyl ((22S.64S.4S)-I '-cthyl-l2-(2-((S)-l-mcthoxycthyl)-5-((tricthylsilyl)cthynyl)pyridin-3-yl)-IO. IO-dimcthyl-5. 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-morpholina-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecap hane-4-yl)carbamate (170 mg, 90 %) as a light yellow solid. LCMS (ESI) calcd. for C49H7oN607Si [M+H]+ m / z 883.5, found: 884.4. Step                           2:                           Synthesis                           of (22S, 648,48 )-4-amino-l1 -ethyl-12-(2-((S)-l-methoxyethyl)-5-( (triethylsilyl )ethynyl )pyridin-3-yl)-10,10-dimet hyl-^HS-oxa-O2,63-diaza-2(4,2 )-morpholina-l(5,3 )-indola-6( 2,4 )-bicyclo[3.1.1 Jheptanacycloundecaphan e-5,7-dione To              a              stirred              solution              of              tert-butyl ((22S,64S,4S)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-((triethylsilyl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-morpholina-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecap hane-4-yl)carbamate (170 mg, 0.2 mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwise at rt, the resulting mixture was stirred at rt for ...

Claims

1. A compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (I);(I)whereinn is 0, 1, 2, or 3;A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;B is selected from optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene;G is optionally substituted Ci-g alkylene;R8 and R9 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci-3 alkyl, or R8 and R9 combine with the atoms to which they are attached to form an optionally substituted C3.g cycloalkyl or a carbonyl;R10 and R11 are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted Ci_3 alkyl, or R10 and R11 combine with the atoms to which they are attached to form an optionally substituted C3_g cycloalkyl or a carbonyl;R12 and R13 are each independently selected from hydrogen, deuterium, halogen, hydroxy, optionally substituted Ci_3 alkyl, -O(Ci_g alkyl), -S(Ci_g alkyl) or -N(Ci_g alkyl)(Ci_g alkyl); furthermore, the Ci_g alkyl may be further optionally substituted;Ra is optionally substituted C3_g cycloalkyl, optionally substituted C3_g heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl;Rb is selected from hydrogen, C1-6 alkyl, Ci^alkoxyl, C1-6 haloalkyl, Ci.ghaloalkoxyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3.g heterocycloalkyl (or 4 to 7- membered heterocycloalkyl); or provided that when n exceeds 1, any two of RB combine with the atoms to which they are attached to form a 3 to 6-membered ring, wherein the ring can be optionally substituted with halogen, hydroxy, andCi-3 alkyl;X1 is N or C;X2 is N or -CRa-;X3 is N or -CRb-;X4 is N or -CRC-;X5 is N or C;X6 is S, O, N, or -CH-;Ra, Rb, and Rc are each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloal-kyl, C1-3 haloalkoxyl, C3.6 cycloalkyl, or C3.6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl);R3 is absent, or selected from hydrogen, C1-6 alkyl, or Ci^ haloalkyl, provided that when X6 is O or S, R3 is absent;E is a bond, or selected from N, or -CRd-, wherein Rd is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-6 alkyl, optionally substituted Ci^ alkoxyl, C1-6 aminoalkyl, Ci^ hydroxyalkyl, or -NReRf; wherein Re and Rf are independently selected from hydrogen, or optionally substituted C1-6 alkyl;R4 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C340 cycloalkyl, optionally substituted C340 cycloalkenyl, optionally substituted C340 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionallyR6Rl^N^y substituted 5 to 10-membered heteroaryl, or        ' ;R5 is hydrogen, Ci^ alkyl or C3.6 cycloalkyl, furthermore, the Ci^ alkyl or C3.6 cycloalkyl may be further optionally substituted;or R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl;whereinL is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rg is optionally substituted Ci-6 alkyl;R6 is hydrogen, or optionally substituted C1-6 alkyl;R7 is optionally substituted Ci^ alkyl, optionally substituted C4.6 heteroalkyl, optionally substituted C340 cycloalkyl, optionally substituted C340 heterocycloalkyl (or 3 to 10-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl;or L, R6 and R7 combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11-membered bicyclic heterocycloalkyl.

2. The compound according to claim 1, or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (1-1)(1-1)wherein X1, X2, X3, X4, X5, X6, A, B, E, G, RA, RB, R3, R4, R5 and n are as defined in claim 1.

3. The compound according to claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinB is optionally substituted R2RAis R1whereinR1 is selected from the group consisting of hydrogen, Ci_6 alkyl, Ci_6 alkoxyl, Ci_6 haloalkyl, Ci_6 haloalkoxyl, Ci_6 hydroxyalkyl, Ci_6 aminoalkyl, optionally substituted C3_6 cycloalkyl, optionally substituted C3.6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2 alkylcnc-Cvg cycloalkyl, optionally substituted -C1-2 alkylcnc-Cvg heterocycloalkyl, optionally substituted -C 1.2 alkylene-5 to 8-membered aryl, optionally substituted -C1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic heteroaryl; furthermore, the Ci^ alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci^ haloalkoxyl, Ci.g hydroxyalkyl may be further optionally substituted;in R1, when the Ci-6 alkyl, Ci^ alkoxyl, Ci^ haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl is further substituted, the substituent is selected from the group consisting of Ci-6 alkyl, Ci^ alkoxyl, Ci-6 haloalkyl, Ci.g haloalkoxyl, Ci.ghydroxyalkyl, Ci.g aminoalkyl, optionally substituted C3.g cycloalkyl, optionally substituted C3.6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; preferably, the substituent is selected from the group consisting of optionally substituted C3_g cycloalkyl, optionally substituted C3_g heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; more preferably, the substituent is optionally substituted C3_g heterocycloalkyl;Yis -CH- orN;R2 is optionally substituted Ci_g alkoxy, or optionally substituted Ci_g alkyl; preferably, R2 is optionally substituted Ci_g alkyl; andRm and Rn are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, Ci^ alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci^ haloalkoxyl, Ci^ hydroxyalkyl, Ci^ aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3.g heterocycloalkyl; furthermore, the Ci^ alkyl, Ci-6 alkoxyl, Ci.g haloalkyl, Ci-6 haloalkoxyl, Ci.ghydroxyalkyl may be further optionally substituted. In some embodiments, Rm and Rn are each independently selected from hydrogen, and Ci-g alkyl.

4. The compound according to claim 3, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinR1 is optionally substituted Ci-g alkyl;and, in R1, the Ci-g alkyl is further substituted, and the substituent is selected from optionally substituted C3.g cycloalkyl, optionally substituted C3.g heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl.

5. The compound according to claim 3, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinR1 is optionally substituted Ci-g alkyl;in R1, the Ci-g alkyl is further substituted, and the substituent is optionally substituted C3.g heterocycloalkyl.

6. The compound of claim 3, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is Ci alkyl; and the Ci alkyl is further substituted with optionally substituted C3_g heterocycloalkyl, wherein the heterocycloalkyl is saturated and the heterocycloalkyl is attached to the rest of the molecule via the N atom on the ring.

7. The compound of claim 3, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is Ci alkyl; and the Ci alkyl is further substituted with optionally substituted C3.g heterocycloalkyl, wherein the heterocycloalkyl is saturated and the heterocycloalkyl is attached to the rest of the molecule via the N atom on the ring.and the C3.g heterocycloalkyl is 5 to 7 menbered heterocycloalkyl and has 1 to 2 heteroatoms.

8. The compound according to claim 3, or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein9. The compound according to claim 3, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R1 is Ci alkyl substituted by C6 heterocycloalkyl, optionally wherein the C6 heterocycloalkyl is piperazine or morpholine.

10. The compound of claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R4 and R5 combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl; preferably, is optionally substituted 3 to 6-membered cycloalkyl; more preferably, optionally substituted cyclopropyl.

11. The compound according to claim 1, or a stereoisomer thereof, a pharmaceutically acceptable saltthereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinis selected from the group consisting of:

12. The compound according to claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinA is optionally substituted 5 to 6-membered heteroarylene, the heteroatom is independently selected from one or two of N, O and S, and the number of the heteroatom is independently 1 to 3preferably, A is optionally substituted 5-membered heteroarylene, the heteroatom is independently selected from N, O and S, and the number of the heteroatom is independently 1 to 2; preferably, one of the heteroatom is N, and the other, if present, is O or S;more preferably, A is selected from the group consisting of13. The compound according to claim 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinX1 is C, and / or X2 is -CRa-, and / or X3 is -CRb, and / or X4 is -CRC-, and / or X5 is -C-.

14. The compound according to claim 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, wherein, the compound is selected from any one of the compounds in Table 1.

15. The compound according to claim 14, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, wherein, the compound is selected from compounds of Examples 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 28, 29, 30, 31, 32, 33, 37,38, 39, 40,41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 84, 86, 87, 88, and 90 in Table 1.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. A use of the compound according to any one of claims 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 16 in the preparation of a medicament used for the treatment of cancer.

18. The use according to claim 17, wherein the cancer is selected from the group consisting of small cell lung cancer (SCLC), colorectal cancer (CRC), pancreatic cancer, and cholangiocarcinoma, pancreatic cancer, appendiceal cancer, small bowel cancer, colorectal cancer, ampullary cancer, non-small cell lung cancer, cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, and squamous cell lung carcinoma, or combinations thereof.

19. The use according to claim 17, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, and cholangiocarcinoma.

20. The compound according to any one of claims 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same for use in treating cancer.

21. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same.

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