WO2025214350A1

WO2025214350A1 - Macrocyclic compounds as ras inhibitors for the treatment of cancer

Info

Publication number: WO2025214350A1
Application number: PCT/CN2025/087799
Authority: WO
Inventors: Xiaotian TONG; Wenbo ZHOU; Huang Chen; Jian Lu; Shihong Peng; Mingyao Liu
Original assignee: Sunrise Oncology Hong Kong Ltd
Current assignee: Sunrise Oncology Hong Kong Ltd
Priority date: 2024-04-08
Filing date: 2025-04-08
Publication date: 2025-10-16
Anticipated expiration: 2026-10-08

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

Macrocyclic compounds as RAS inhibitors for the treatment of cancer

TECHNICAL FIELD

The present invention belongs to the field of medicine, and specifically, relates to macrocyclic com-pounds 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 SOS1, 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 dif-ferentiation through multiple cascading reactions, including the PI3K-AKT-mTOR, RAF-MEK-ERK, and RALGDS-RAL pathways. Mutations in RAS are often driving forces for carcinogenesis and tumor devel-opment, as they disrupt the guanine exchange cycle and lock RAS in the activated state, continuously acti-vating 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 occur-rence 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 mel-anoma, 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 can-cer 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 ap-proved for marketing in United States, which was the second marketed oral inhibitor in the world that spe-cifically optimizes the KRAS G12C mutant. The approval of these two drugs marked a successful break-through 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 SOS1 and RAF1, keeping RAS protein in a locked state alone, unable to activate down-stream 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 for-mation of a high affinity three-component complex between a synthetic ligand and two intracellular pro-teins 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, cyclo-philin 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 occlu-sion 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 pharma-ceutically 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 C_1-6 alkylene;

R⁸ and R⁹ are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, op-tionally substituted C_1-3 alkyl, or R⁸ and R⁹ combine with the atoms to which they are attached to form an optionally substituted C_3-6 cycloalkyl or a carbonyl;

R¹⁰ and R¹¹ are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, op-tionally substituted C_1-3 alkyl, or R¹⁰ and R¹¹ combine with the atoms to which they are attached to form an optionally substituted C_3-6 cycloalkyl or a carbonyl;

R¹² and R¹³ are each independently selected from hydrogen, deuterium, halogen, hydroxy, optionally substituted C_1-3 alkyl, -O (C_1-6 alkyl) , -S (C_1-6 alkyl) or -N (C_1-6 alkyl) (C_1-6 alkyl) ; furthermore, the C_1-6 alkyl may be further optionally substituted;

R^A is optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 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 substi-tuted 8 to 10-membered fused bicyclic heteroaryl;

R^B is selected from hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, optionally sub-stituted C_3-6 cycloalkyl, or optionally substituted C_3-6 heterocycloalkyl (or 4 to 7-membered heterocycloal-kyl) ; or provided that when n exceeds 1, any two of R^B 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 C_1-3 alkyl;

X¹ is N or C;

X² is N or -CR^a-;

X³ is N or -CR^b-;

X⁴ is N or -CR^c-;

X⁵ is N or C;

X⁶ is S, O, N, or -CH-;

R^a, R^b, and R^c are each independently hydrogen, halogen, cyano, C_1-3 alkyl, C_1-3 alkoxyl, C_1-3 haloal-kyl, C_1-3 haloalkoxyl, C_3-6 cycloalkyl, or C_3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl) ;

R³ is absent, or selected from hydrogen, C_1-6 alkyl, or C_1-6 haloalkyl, provided that when X⁶ is O or S, R³ is absent;

E is a bond, or selected from N, or -CR^d-, wherein R^d is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 alkoxyl, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, or -NR^eR^f; wherein R^e and R^f are independently selected from hydrogen, or optionally sub-stituted C_1-6 alkyl;

R⁴ is hydrogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 cycloalkenyl, optionally substituted C_3-10 heterocy-cloalkyl (or 4 to 12-membered heterocycloalkyl) , optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, or

R⁵ is hydrogen, C_1-6 alkyl or C_3-6 cycloalkyl, furthermore, the C_1-6 alkyl or C_3-6 cycloalkyl may be fur-ther optionally substituted;

or R⁴ and R⁵ combine with the atoms to which they are attached to form a ring, wherein the ring is se-lected 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) -, -CHR^g-or -C (R^g) ₂-, wherein R^g is optionally substituted C_1-6 alkyl;

R⁶ is hydrogen, or optionally substituted C_1-6 alkyl;

R⁷ is optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heterocycloalkyl (or 3 to 10-membered heterocycloalkyl) , op-tionally 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 pharmaceuti-cally 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. 1 The reference compound and the representative Compound A significantly inhibited the interac-tion of RAF1 with active RAS^Mutant protein or RAS^WT 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 adminis-trating 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 RAF1 with active RAS^Mutant protein or RAS^WT protein and proliferation of KRAS-related tumor cells. In addition, some compounds of the present inven-tion 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 ac-tivities to in the positive control compounds in vitro studies. The present invention is completed on this basis.

In one aspect, the present invention provides a compound of formula (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 H.

In some embodiments, the compound of formula (I) is a compound of formula (I-1)

wherein X¹, X², X³, X⁴, X⁵, X⁶, A, B, E, G, R^A, R^B, R³, R⁴, R⁵ and n are as defined in formula I.

In some embodiments, B is optionally substituted

In some embodiments, or deuteratedpreferably,

In some embodiments, R^A isIn some embodiments, R¹ is selected from the group con-sisting of hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 amino-alkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl, optionally substi-tuted 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, op-tionally substituted -C_1-2 alkylene-C_3-6 cycloalkyl, optionally substituted -C_1-2 alkylene-C_3-6 heterocycloalkyl, optionally substituted -C_1-2 alkylene-5 to 8-membered aryl, optionally substituted -C_1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicyclic heteroaryl (preferably, R¹ is selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hy-droxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocyclo-alkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, op-tionally substituted 8 to 10-membered fused bicyclic aryl, and optionally substituted 8 to 10-membered fused bicyclic heteroaryl) ; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hy-droxyalkyl (preferably the C_1-6 alkyl) may be further optionally substituted.

In some embodiments, R¹ is optionally substituted -C_1-2 alkylene-C_3-6 cycloalkyl, optionally substitut-ed -C_1-2 alkylene-C_3-6 heterocycloalkyl, optionally substituted -C_1-2 alkylene-5 to 8-membered aryl, option-ally substituted -C_1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicy-clic heteroaryl; preferably, is optionally substituted -C_1-2 alkylene-C_3-6 cycloalkyl, optionally substituted -C_1-2 alkylene-C_3-6 heterocycloalkyl; more preferably, optionally substituted -methylene-C_3-6 heterocycloal-kyl.

In some embodiments, “C_3-6 heterocycloalkyl” is selected from heterocycloalkyl for R^1’ as defined in formula VI, VII or VIII.

In some embodiments, in R¹, when the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, or C_1-6 hydroxyalkyl (preferably, the C_1-6 alkyl) is further substituted, the substituent is selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 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; pref-erably, the substituent is selected from the group consisting of optionally substituted C_3-6 cycloalkyl, op-tionally substituted C_3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substi-tuted 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 C_3-6 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, C_1-6 alkyl, C_1-6 hydroxyalkyl, C_1-6 deuteroalkyl, C_3-6 cycloalkyl, C_3-6 heterocycloalkyl, -CONRⁱRⁱⁱ (e.g., -CON (C_1-6 al-kyl) ₂) , -S (O) ₂Rⁱ (e.g., -S (O) ₂ (C_1-6 alkyl) ) , and -S (O) (=N-Rⁱ) Rⁱⁱ (e.g., ) .

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, C_1-6 alkyl, C_1-6 hydroxyalkyl, and C_1-6 deuteroalkyl.

In some embodiments, R¹ is - (CH₂) -R^1’ , and R^1’ is as defined in formula VI, VII, or VIII.

In some embodiments, R^M and R^N are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl may be further optionally substituted. In some embodiments, R^M and R^N are each independently selected from hydrogen, and C_1-6 alkyl.

In some embodiments, Y is -CH-or N; preferably, Y is N.

In some embodiments, R² is optionally substituted C_1-6 alkoxy, or optionally substituted C_1-6 alkyl; preferably, R² is optionally substituted C_1-6 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, C_1-6 alkoxy, C_1-6 deu-teroalkoxy, and C_1-6 haloalkoxy.

In some embodiments of the present disclosure, B isR^A is optionally substituted phenyl or optionally substituted 6-membered heteroaryl; in some embodiments, the compound of formula (I) is a compound of formula (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

G is optionally substituted C_1-6 alkylene;

Y is -CH-or N;

R¹² and R¹³ are each independently selected from hydrogen, deuterium, halogen, hydroxy, optionally substituted C_1-3 alkyl, -O (C_1-6 alkyl) , -S (C_1-6 alkyl) or -N (C_1-6 alkyl) (C_1-6 alkyl) ; furthermore, the C_1-6 alkyl may be further optionally substituted; Y is -CH-or N;

X¹ is N or C;

X² is N or -CR^a-;

X³ is N or -CR^b-;

X⁴ is N or -CR^c-;

X⁵ is N or C;

X⁶ is S, O, N, or -CH-;

R^a, R^b, and R^c are each independently hydrogen, halogen, cyano, C_1-3 alkyl, C_1-3 alkoxyl, C_1-3 haloal-kyl, C_1-3 haloalkoxyl, C_3-6 cycloalkyl, or C_3-6 heterocycloalkyl (or 3 to 6-membered heterocycloalkyl) ;

R¹ is selected from hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxy-alkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted 3 to 6-membered het-erocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered het-eroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, and C_1-6 hydroxyalkyl may be further optionally substituted;

R² is optionally substituted C_1-6 alkoxy, or optionally substituted C_1-6 alkyl;

R^M and R^N are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substi-tuted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl) ; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, and C_1-6 hydroxyalkyl may be fur-ther optionally substituted;

E is a bond, or selected from N, or -CR^d-, wherein R^d is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 alkoxyl, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, or -NR^eR^f; wherein R^e and R^f are each independently selected from hydrogen, or optionally substituted C_1-6 alkyl;

or R⁴ and R⁵ combine with the atoms to which they are attached to form a ring, wherein the ring is se-lected 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

R⁶ is hydrogen, or optionally substituted C_1-6 alkyl;

R⁷ is optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl) , op-tionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl;

In some embodiments, X¹ is C, and/or X² is -CR^a- (preferably -CH-) , and/or X³ is -CR^b- (preferably -CH-) , and/or X⁴ is -CR^c- (preferably -CH-) , and/or X⁵ is -C-.

In some embodiments, R^a, R^b, and R^c are each independently selected from the group consisting of hydrogen, halogen, cyano, C_1-3 alkyl, C_1-3 alkoxyl, C_1-3 haloalkyl, and C_1-3 haloalkoxyl; preferably, R^a, R^b, and R^c are each independently hydrogen, or C_1-3 alkyl.

In some embodiments of the present disclosure, X¹, X², X³, X⁴ and X⁵ are -CH-, R^M and R^N are hy-drogen.

In some embodiments of the present disclosure, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted C_1-3 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)

wherein X¹, X², X³, X⁴, X⁵, X⁶, A, B, E, G, Y, R^M, R^N, R¹, R³, R⁴, R⁵ and n are as defined in formula II.

In some embodiments, the compound of formula (II) is a compound of formula (III) :

wherein

G is optionally substituted C_1-6 alkylene;

Y is -CH-or N;

X⁶ is S, O, N, or -CH-;

R^a and R^b are each independently hydrogen, halogen, cyano, C_1-3 alkyl, C_1-3 alkoxyl, C_1-3 haloalkyl, C_1-3 haloalkoxyl, C_3-6 cycloalkyl, or C_3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl) ;

R¹ is selected from hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxy-alkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 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 sub-stituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, and C_1-6 hydroxyalkyl may be further optionally substituted;

wherein

R⁶ is hydrogen, or optionally substituted C_1-6 alkyl;

Furthermore, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, C_3-5 het-erocycloalkyl (or 4 to 6-membered heterocycloalkyl) , C_3-6 heterocycloalkyl (or 4 to 7-membered heterocy-cloalkyl) , 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, C_1-6 heteroalkyl, C_3-10 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 for-mula (IVa) or formula (IVb) :

wherein

G is optionally substituted C_1-6 alkylene;

Y is -CH-or N;

X⁶ is S, O, N, or -CH-;

R^a and R^b are each independently hydrogen, halogen, cyano, C_1-3 alkyl, C_1-3 alkoxyl, C_1-3 haloalkyl, C_1-3 haloalkoxyl, C_3-6 cycloalkyl, C_3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl) ;

R¹ is selected from hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxy-alkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 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 sub-stituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl may be further optionally substituted;

In some embodiments, R¹ is optionally substituted C_1-6 alkyl;

preferably, in R¹, the C_1-6 alkyl is further substituted, the substituent is selected from optionally sub-stituted C_3-6 cycloalkyl, optionally substituted C_3-6 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 C_3-6 heterocycloalkyl;

In some embodiments, R¹ is

preferably, R¹ is

more preferably, R¹ is

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;

In some embodiments of the present disclosure, is

preferably, is

more preferably, is

wherein

R⁶ is hydrogen, or optionally substituted C_1-6 alkyl;

R⁷ is optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl;

Furthermore, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, C_3-5 het-erocycloalkyl, C_3-6 heterocycloalkyl (or 3 to 6-membered heterocycloalkyl) , 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, C_1-6 heteroalkyl, C_3-10 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 substi-tuted 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 heterocy-cloalkylene, the heteroatom is independently selected from one or two of N, O and S, and the number of the heteroatom is independently 1 to 2. In some embodiments, A is

In some embodiments of the present disclosure, A is optionally substituted 5 to 6-membered arylene;

In some embodiments, A is

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 het-eroarylene, 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.

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 inde-pendently 1 to 2; preferably, one of the heteroatom is N, and the other, if present, is O or S.

In some embodiments, A is

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 heterocycloal-kenylene, optionally substituted 4 to 11-membered bicyclic alkylene, and optionally substituted 4 to 11-membered bicyclic heteroalkylene.

In some embodiments, B is

In some embodiments of the present disclosure, G is optionally substituted C_1-6 alkylene; preferabaly, G is optionally substituted -C (C_1-3alkyl) 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 C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, or optionally substi-tuted C_3-6 heterocycloalkyl (or 3 to 6-membered heterocycloalkyl) .

In some embodiments, R¹ is

In some embodiments of the present disclosure, R¹ is C_1-6 alkyl and the C_1-6 alkyl is further substituted with optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl.

In some embodiments of the present disclosure, R¹ is C₁ alkyl; and the C₁ alkyl is further substituted with optionally substituted C_3-6 heterocycloalkyl, wherein the heterocycloalkyl is saturated and the hetero-cycloalkyl is attached to the rest of the molecule via the N atom on the ring.

In some embodiments of the present disclosure, R¹ is C₁ alkyl; and the C₁ alkyl is further substituted with optionally substituted C_3-6 heterocycloalkyl, wherein the heterocycloalkyl is saturated and the hetero-cycloalkyl is attached to the rest of the molecule via the N atom on the ring. and the C_3-6 heterocycloalkyl is 5 to 7 menbered heterocycloalkyl and has l to 2 heteroatoms.

In some embodiments, R¹ is

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, R¹ is

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 selected from one or two of N, O and S, and the number of the heteroatom is independently 1 to 4.

In some embodiments, R¹ is

In some embodiments of the present disclosure, R² is optionally substituted C_1-6 alkyl or optionally substituted C_1-6 alkoxy.

In some embodiments, R² ispreferably,

In some embodiments of the present disclosure, R³ is C_1-6 alkyl. In some embodiments, R³ is C_1-6 deu-terated alkyl. In some embodiments, R³ is

In some embodiments of the present disclosure, R³ is C_1-6 haloalky.

In some embodiments, R³ is

In some embodiments of the present disclosure, E is a bond, or selected from N, or -CR^d-, wherein R^d is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 alkoxyl, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, or -NR^eR^f; wherein R^e and R^f are independent-ly selected from hydrogen, or optionally substituted C_1-6 alkyl; preferably, E is a bond, or selected from N, or -CR^d-, wherein R^d is selected from hydrogen, halogen, hydroxy or C_1-6 alkyl.

In some embodiments of the present disclosure, R^d is halogen; In some embodiments, R^d is -F, -Cl, -Br or -I; preferably, -F.

In some embodiments of the present disclosure, R^d is C_1-6 alkyl;

In some embodiments, R^d is

In some embodiments of the present disclosure, R^d is C_1-6 haloalkyl; In some embodiments, R^d is -CF₃.

In some embodiments of the present disclosure, R^d is C_1-6 alkoxyl;

In some embodiments, R^d is

In some embodiments of the present disclosure, R^d is C_1-6 aminoalkyl; In some embodiments, R^d is

In some embodiments of the present disclosure, R^e or R^f is C_1-6 alkyl; In some embodiments, R^e or R^f is independently selected fromand preferably the other is hydrogen.

In some embodiments, L is selected from -CH₂-, -C (O) -, -CHR^g-or -C (R^g) ₂-, wherein R^g is optionally substituted C_1-6 alkyl.

In some embodiments, R⁴ is hydrogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl) , optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, or

preferably, R⁴ is hydrogen, optionally substituted C_1-6 alkyl, or

In some embodiments, R⁶ is hydrogen, or optionally substituted C_1-6 alkyl; preferably, hydrogen, or C_1-6 alkyl.

In some embodiments, R⁷ is optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; preferably, R⁷ is C_1-6 alkyl, op-tionally substituted C_3-10 cycloalkyl.

In some embodiments of the present disclosure, R⁴ is hydrogen, optionally substituted C_1-6 alkyl, op-tionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 het-erocycloalkyl (or 4 to 12-membered heterocycloalkyl) , optionally substituted 6 to 10-membered aryl, op-tionally substituted 5 to 10-membered heteroaryl, orwherein R⁶ is hydrogen, or optionally sub-stituted C_1-6 alkyl; R⁷ is optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 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 C_1-6 alkyl. In some embodiments of the present disclosure, R⁴ is hydrogen, C_1-6 alkyl, 3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 6 to 10-membered aryl, 5 to 10-membered heteroaryl, orwherein R⁶ is hydrogen, or C_1-6 alkyl; R⁷ is C_1-6 alkyl, 3-to 10-membered heterocycloalkyl; wherein the 3 to 10-membered heterocycloalkyl is optionally substituted by C_1-6 alkyl, 6 to 10-membered aryl, -CO-O-C_3-6 cycloalkyl or -CO-O-C_1-6 alkyl; the 3 to 6-membered cycloalkyl is optionally substituted by hydroxyl, cy-ano, halogen, or C_1-6 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-bly, R⁴ is hydrogen, C_1-6 alkyl, orwherein R⁶ is hydrogen, or C_1-6 alkyl; R⁷ is C_1-6 alkyl, 3 to 10-membered heterocycloalkyl.

In some embodiments, in R⁴, C_3-10 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 C_1-6 alkyl, optionally sub-stituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heterocycloalkyl, the heteroatom is N, O or S, and the number of the heteroatom is independently 1 to 2. In some embodi-ments, R⁴ is

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

In some embodiments of the present disclosure, R⁵ is optionally substituted C_1-6 alkyl. In some em-bodiments, R⁵ is

In some embodiments of the present disclosure, R⁵ is optionally substituted C_3-6 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 of N, 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 cyclo-alkyl, 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

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 sub-stituents selected from the group consisting of C_1-4 alkyl, C_1-4 deuteroalkyl, cyano, C_1-4 hydroxyalkyl, and C_1-4 haloalkyl.

In some embodiments of the present disclosure, R⁶ is optionally substituted C_1-6 alkyl; In some em-bodiments, R⁶ is

In some embodiments, R⁷ is optionally substituted C_3-10 cycloalkyl, or optionally substituted C_3-10 het-erocycloalkyl.

In some embodiments, in R⁷, substituents for C_3-10 heterocycloalkyl are selected from the group con-sisting of halogen, C_1-6 alkyl, 6 to 10-membered aryl, -CO-O-C_3-6 cycloalkyl, -CO-O-C_1-6 alkyl, -CO-C_3-6 cycloalkyl, -CO-C_1-6 alkyl, -CO-C_1-6 alkenyl, and -CO-C_1-6 alkynyl, and/or substituents for C_3-10 cycloalkyl are selected from the group consisting of hydroxyl, cyano, halogen, or C_1-6 alkyl.

In some embodiments, in R⁷, substituents for C_3-10 heterocycloalkyl are selected from the group con-sisting of C_1-6 alkyl, 6 to 10-membered aryl, -CO-O-C_3-6 cycloalkyl and -CO-O-C_1-6 alkyl, and/or substitu-ents for C_3-10 cycloalkyl are selected from the group consisting of hydroxyl, cyano, halogen, or C_1-6 alkyl.

In some embodiments, in R⁷, C_3-10 heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of N, O and S.

In some embodiments, R⁷ is optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heter-ocycloalkyl; preferably, the C_3-10 heterocycloalkyl optionally substituted by C_1-6 alkyl, C_6-10 aryl , -CO-O-C_3-6 cycloalkyl or -CO-O-C_1-6 alkyl; the C_3-10 cycloalkyl optionally substituted by hydroxyl, cyano, halogen, or C_1-6 alkyl; in C_3-10 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 C_1-6 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-ments, R⁷ is

In some embodiments, R⁷ is optionally substituted C_3-6 cycloalkyl. In some embodiments, in R⁷, the C_3-6 cycloalkyl is

In some embodiments of the present disclosure, R⁷ is C_3-6 cycloalkyl;

In some embodiments, R⁷ is

In some embodiments, R⁷ is optionally substituted C_6-10 aryl. In some embodiments, in R⁷, the C_6-10 aryl is

In some embodiments of the present disclosure, R⁷ is C_6-10 aryl.

In some embodiments, R⁷ is

In some embodiments, R⁷ is optionally substituted C_1-6 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) Rⁱ or -NHC (O) Rⁱ; wherein Rⁱ is selected from the group consisting of C_1-6 alkyl, -C_2-6alkenyl, C_2-6 al-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, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 deuteroalkyl, C_1-6 hydroxyalkyl, C_1-6 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-C_1-6 alkyl.

In some embodiments, in R⁷, the 3-to 6-membered heterocycloalkyl contains 1 or 2 heteroatoms se-lected from N and O.

In some embodiments of the present disclosure, R⁷ is C_1-6 alkyl or 3 to 6-membered heterocycloalkyl; the 3 to 6-membered heterocycloalkyl optionally substituted by 6 to 10-membered aryl or -CO-O-C_1-6 alkyl; in 3 to 6-membered heterocycloalkyl, the heteroatom is independently selected from one or two of N and O, and the number of the heteroatom is independently 1 to 2.

In some embodiments, R⁷ is

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 cy-cloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substi-tuted 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 (O) Rⁱ; wherein Rⁱ is selected from the group consisting of C_1-6 alkyl, -C_2-6alkenyl, C_2-6 alkynyl, C_3-10 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, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 deuteroalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, alkylamino, and C_3-6 cycloalkyl.

In some embodiments, is

In some embodiments of the present disclosure, is

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 formula (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, R^a, R^b, R^c, R^A, R^B, R^M, R^N, R¹, R², R³, 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, and stereoisomers thereof or their pharmacologically acceptable salts:

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-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) . Pro-tium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may pro-vide 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 for-mula (VI) :

or a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof.

In some embodiments, R^1’ of formula (VI) is selected from:

In some embodiments of the present disclosure, the compound of formula (IVa) is a compound of formula (VII) :

In some embodiments, R^1’ of formula (VII) is selected from:

In some embodiments of the present disclosure, the compound of formula (IVa) is a compound of formula (VIII) :

In some embodiments, R^1’ of formula (VIII) is selected from:

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 varia-tions 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

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 phar-maceutically acceptable salt as defined above, and a pharmaceutically acceptable carrier, preferably, the compound is the Compound A as defined above.

In another aspect, the present invention also provides a use of a compound, wherein a pharmaceuti-cally 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.

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 consisting of G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R and Q61L, or a com-bination 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 ther-apy.

In some embodiments, the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a Pl3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 in-hibitor, 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 com-pound 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 com-pound is the Compound A as defined above.

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 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 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.

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) ;

wherein

n is 0, 1, 2, or 3;

G is optionally substituted C_1-6 alkylene;

X¹ is N or C;

X² is N or -CR^a-;

X³ is N or -CR^b-;

X⁴ is N or -CR^c-;

X⁵ is N or C;

X⁶ is S, O, N, or -CH-;

wherein

R⁶ is hydrogen, or optionally substituted C_1-6 alkyl;

Embodiment 2. The compound of embodiment 1, or a stereoisomer thereof, a pharmaceutically ac-ceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharma-ceutically acceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-1)

wherein X¹, X², X³, X⁴, X⁵, X⁶, A, B, E, G, R^A, R^B, 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 phar-maceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein

B is optionally substitutedand

R^A is

wherein

R¹ is selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substi-tuted C_3-6 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 -C_1-2 alkylene-C_3-6 cycloalkyl, optionally substituted -C_1-2 alkylene-C_3-6 heterocycloalkyl, optionally substituted -C_1-2 alkylene-5 to 8-membered aryl, optionally substituted -C_1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicy-clic heteroaryl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl may be further optionally substituted;

in R¹, when the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, or C_1-6 hydroxyalkyl is further substituted, the substituent is selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally sub-stituted C_3-6 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 consist-ing of optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl, optionally substi-tuted 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 C_3-6 heterocycloalkyl;

Y is -CH-or N;

R² is optionally substituted C_1-6 alkoxy, or optionally substituted C_1-6 alkyl; preferably, R² is optionally substituted C_1-6 alkyl; and

R^M and R^N are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substi-tuted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl may be further optionally substituted. In some embodi-ments, R^M and R^N are each independently selected from hydrogen, and C_1-6 alkyl.

Embodiment 4. The compound of embodiment 3, or a stereoisomer thereof, a pharmaceutically ac-ceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharma-ceutically acceptable salt thereof, wherein

R¹ is optionally substituted C_1-6 alkyl;

and, in R¹, the C_1-6 alkyl is further substituted, and the substituent is selected from optionally substi-tuted C_3-6 cycloalkyl, optionally substituted C_3-6 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.

Embodiment 5. The compound of any one of embodiments 3 to 4, or a stereoisomer thereof, a phar-maceutically 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 C_1-6 alkyl;

in R¹, the C_1-6 alkyl is further substituted, and the substituent is optionally substituted C_3-6 heterocy-cloalkyl.

Embodiment 6. The compound of any one of embodiments 3 to 4, or a stereoisomer thereof, a phar-maceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R¹ is C₁ alkyl; and the C₁ alkyl is further substitut-ed with optionally substituted C_3-6 heterocycloalkyl, wherein the heterocycloalkyl is saturated and the het-erocycloalkyl 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 phar-maceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein R¹ is C₁ alkyl; and the C₁ alkyl is further substitut-ed with optionally substituted C_3-6 heterocycloalkyl, wherein the heterocycloalkyl is saturated and the het-erocycloalkyl is attached to the rest of the molecule via the N atom on the ring. and the C_3-6 heterocycloal-kyl is 5 to 7 menbered heterocycloalkyl and has l to 2 heteroatoms.

Embodiment 8. The compound of any one of embodiments 3 to 7, or a stereoisomer thereof, a phar-maceutically 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

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 C₁ alkyl substituted by C₆ heterocy-cloalkyl, optionally wherein the C₆ heterocycloalkyl is piperazine or morpholine.

Embodiment 10. The compound of any one of embodiments 1 to 9, or a stereoisomer thereof, a phar-maceutically 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; pref-erably, is optionally substituted 3 to 6-membered cycloalkyl; more preferably, optionally substituted cyclo-propyl.

Embodiment 11. The compound of any one of embodiments 1 to 9, or a stereoisomer thereof, a phar-maceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, wherein

is selected from the group consisting of:

is

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 se-lected 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 -CR^a-, and/or X³ is -CR^b, and/or X⁴ is -CR^c-, 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 com-pounds 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 embodi-ments 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 solv-ate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composi-tion according to embodiment 16, or the pharmaceutical composition comprising the same in the prepara-tion 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 leuke-mia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodys-plastic 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 se-lected 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 solv-ate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composi-tion 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 preced-ing 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 composi-tion comprising the same.

Embodiment 24. The method according to embodiment 23, wherein the cancer is as defined in em-bodiment 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 cor-responding 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 car-rier. The term “pharmaceutically acceptable carrier” also encompasses “pharmaceutically acceptable ex-cipient” 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, Rⁱ, -C_1-4 alkylene-Rⁱ, -C_2-4 alkenylene-Rⁱ, -C_2-4 alkynylene-Rⁱ, -ORⁱ, -OC (O) Rⁱ, -C (O) Rⁱ, -CO₂Rⁱ, -CONRⁱRⁱⁱ, -OC (O) NNRⁱRⁱⁱ, -NRⁱⁱC (O) Rⁱ, -NRⁱ-C (O) NRⁱⁱRⁱⁱⁱ, -NRⁱⁱC (O) ₂Rⁱ, -NH-C (NH₂) =NH, -NRⁱC (NH₂) =NH, -NH-C (NH₂) =NRⁱ, -S (O) Rⁱ, -S (O) ₂Rⁱ, -S (O) ₂NRⁱRⁱⁱ, -S (O) (=N-Rⁱ) Rⁱⁱ (e.g., ) , -NRⁱS (O) ₂Rⁱⁱ; wherein Rⁱ, Rⁱⁱ and Rⁱⁱⁱ are each independently selected from the group consisting of H, C_1-6 alkyl, -C_2-6 alkenyl, C_2-6 alkynyl, C_3-10 cycloalkyl, C_3-10 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, C_6-10 aryl, 5 to 10-membered het-eroaryl, -C_1-4 alkylene-C_3-10 cycloalkyl, -C_1-4 alkylene-C_3-10 cycloalkenyl, -C_1-4 alkylene-3 to 10-membered heterocycloalkyl, -C_1-4 alkylene-3 to 10-membered heterocycloalkenyl, -C_1-4 alkylene-C_6-10 aryl, and -C_1-4 alkylene-5 to 10-membered heteroaryl; or Rⁱ and Rⁱⁱ, Rⁱⁱ and Rⁱⁱⁱ together with the atom to which they are attached to form C_3-10 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloal-kenyl, C_6-10 aryl, 5 to 10-membered heteroaryl; wherein the alkylene, alkenylene, alkynylene, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl can be unsub-tituted 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, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 deuteroalkyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, amino, alkylamino, -C (O) C_1-6 alkyl, -OC_1-6 alkyl, -OC (O) C_1-6 alkyl, -S (O) C_1-6 alkyl, -S (O) ₂C_1-6 alkyl, -COOC_1-6 alkyl, oxo (=O) , C_1-6 alkylidene, C_1-6 haloalkylidene, C_1-6 deuteroalkylidene, C_1-6 hydroxyalkylidene, C_1-6 aminoalkylidene, C_3-6 cycloalkyl optionally substituted with one or more of D, halogen, -CN, -OH, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 deuteroalkyl, C_1-6 hydroxyalkyl, and C_1-6 aminoalkyl, 3 to 6-membered heterocycloalkyl optionally substituted with one or more of D, hal-ogen, -CN, -OH, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 deuteroalkyl, C_1-6 hydroxyalkyl, and C_1-6 aminoalkyl, 3 to 6-membered heterocycloalkenyl optionally substituted with one or more of D, halogen, -CN, -OH, C_1-6 al-kyl, C_1-6 haloalkyl, C_1-6 deuteroalkyl, C_1-6 hydroxyalkyl, and C_1-6 aminoalkyl, phenyl, 5 to 6-membered het-eroaryl optionally substituted with one or more of D, halogen, -CN, -OH, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 deuteroalkyl, C_1-6 hydroxyalkyl, and C_1-6 aminoalkyl. In some embodiments, said “optionally substituted” means that the group is substituted by one or more substituents selected from the group consisting of deu-terium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O) , thio (=S) , C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ hydroxyalkyl, C₁-C₄ alkoxy, C₁-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 substi-tution) .

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., C_1-20 means 1 to 20 carbon atoms) . Preferably an alkyl group is an alkyl having 1 to 12 i.e., C_1-12 alkyl. Sometimes preferably 1 to 6 i.e., C_1-6 alkyl, sometimes more preferably 1 to 4, carbon atoms i.e., C_1-4 alkyl. Representative exam-ples 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-methy1-3-ethylpentyl, n-nonyl, 2-methy1-2-ethylhexyl, 2-methy1-3-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 lim-ited 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 substit-uent 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 al-kane 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 al-kylene 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 unsub-stituted. 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 at-oms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2-propenyl, 1-2-, or 3-butenyl, etc., preferably C_2-20 alkenyl, more preferably C_2-12 alkenyl, and most preferably C_2-6 alkenyl. The alkenyl group can be substituted or unsubstituted. When substituted, the substituent group (s) is pref-erably 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, cycloal-koxyl, 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 C_2-20 alkenylene, morepreferably C_2-12 alkenylene, and most preferably C_2-6 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 sub-stituted 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 at-oms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-2-, or 3-butynyl etc., preferably C_2-20 alkynyl, more preferably C_2-12 alkynyl, and most preferably C_2-6 alkynyl. The alkynyl group can be substituted or unsubstituted. When substituted, the substituent group (s) is pref-erably 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, hetero-cylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

As used herein, the term “aryl” refers to a 6 to 14-membered (or C_6-14) 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 C_6-10) , 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 pref-erably 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 sin-gle 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 exam-ple, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, thiazolylfuryl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The het-eroaryl 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, sub-stituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloal-koxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NR^eR^f.

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 an-other.

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 C_3-20 or 3 to 20 membered) , prefera-bly 3 to 12 carbon atoms (refered as C_3-12 or 3 to 12 membered) , more preferably 3 to 10 carbon atoms (refered as C_3-10 or 3 to 10 membered) , and most preferably 3 to 8 carbon atoms (refered as C_3-8 or 3 to 8 membered) or 3 to 6 carbon atoms (refered as C_3-6 or 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, cy-cloheptyl, 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 cycloal-kyl, 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 con-tain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Pref-erably, 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 exam-ples 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 pref-erably 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 fol-lowing 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 het-eroatoms selected from the group consisting of N, O, and S (O) _m (wherein m is 0, l, 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 heterocy-clyl or heterocycloalkyl, or C_2-11 heterocyclyl or heterocycloalkyl) ; more preferably a 4 to 12-membered ring having l to 3 heteroatoms (also referred as for example 4-12 membered heterocyclyl or heterocycloal-kyl, or C_3-10 heterocyclyl or heterocycloalkyl) ; more preferably a 3 to 10-membered ring having 1 to 3 het-eroatoms (also referred as for example 3-10 membered heterocyclyl or heterocycloalkyl, or C_2-9 heterocy-clyl or heterocycloalkyl) ; more preferably a 4 to 8-membered ring having l to 3 heteroatoms (i.e., 4-8 membered heterocyclyl or heterocycloalkyl, or C_2-7 heterocyclyl or heterocycloalkyl) ; most preferably a 5 to 7-membered ring having l to 2 heteroatoms (also referred as for example 5-7 membered heterocyclyl or heterocycloalkyl, or C_3-6 heterocyclyl or heterocycloalkyl) or a 5 to 6-membered ring having l to 2 het-eroatoms (also referred as for example 5-6 membered heterocyclyl or heterocycloalkyl, or C_3-5 heterocyclyl or heterocycloalkyl) . In some embodiments, heterocycloalkyl/heterocyclyl is monocyclic heterocycloal-kyl/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 heterocy-cloalkyl/heterocyclyl (such as bicyclic heterocycloalkyl/heterocyclyl) . In some embodiments, heterocyclo-alkyl/heterocyclyl is a spiro heterocycloalkyl/heterocyclyl, a fused heterocycloalkyl/heterocyclyl or a bridged heterocycloalkyl/heterocyclyl. Polycyclic heterocyclyl or heterocycloalkyl includes the heterocy-clyl having a spiro ring, fused ring or bridged ring. The “heterocyclyl” or “heterocycloalkyl” can be at-tached 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 embodi-ments, 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” has a structure ofwherein is a heteroatom or a carbon atom. Examples of such heterocyclyl groups areWhen 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 con-sisting 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 di-vided 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 bicy-clic 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 l4-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 tetra-cyclic bridged heterocyclyl, more preferably bicyclic or tricyclic bridged heterocyclyl. Representative ex-amples of bridged heterocyclyl include, but are not limited to, the following substituents:

As used herein, the term “C_1-6 haloalkoxyl” 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 “C_1-6 alkoxyC_1-6 alkyl” refers to a C_1-6 alkyl group in which one or more hy-drogen atoms are replaced by C_1-6 alkoxy or a C_1-6 alkoxy group in which one or more hydrogen atoms are replaced by C_1-6 alkyl.

As used herein, the term “alkoxy” refers to a straight or branched alkoxy group containing the speci-fied number of carbon atoms. For example, C_1-6 alkoxy means a straight or branched alkoxy group con-taining at least 1, and at most 6, carbon atoms. Examples of “alkoxy” as used herein include, but not lim-ited 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 (C_1-6 alkyl) or -N (C_1-6 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 io-dine (I) .

As used herein, the term "oxo" means that =O, 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 embodi-ments, 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 pro-cesses 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) Cl₂ 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) Cl₂ 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 hydroly-sis 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 pres-ence of an organic base, such as Et₃N, DIPEA or pyridine, which was hydrolyzed to provide acid of for-mula (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) Cl₂ 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) Cl₂ 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 for-mula (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-1H-indol-3-yl) -2, 2-dimethylpropyl acetate

Step 1. Preparation of (5-bromo-1H-indol-3-yl) methanol

To a solution of 5-bromo-1H-indole-3-carbaldehyde (100.0 g, 0.45 mol) in premixed solvents THF/MeOH (1 L, V: V = 4: 1) was stirred at 0℃ 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℃ 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-1H-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-1H-indol-3-yl) -2, 2-dimethylpropanoate

To a solution of ( (1-methoxy-2-methylprop-1-en-1-yl) oxy) trimethylsilane (157.3 g, 0.90 mol) in dry THF (150 mL) under N₂ atmosphere, the reaction mixture was stirred at -40℃ for 5 mins, then (5-bromo-1H-indol-3-yl) methanol (107.5 g, 0.48 mol) in dry THF (50 mL) was added under N₂ atmos-phere, 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 reac-tion was monitored by LCMS. After completion, the reaction mixture was warmed to room temperature and diluted with NaHCO₃ 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-1H-indol-3-yl) -2, 2-dimethylpropanoate (98g, 70%) as a yellow solid.

LCMS (ESI) calcd. for C₁₄H₁₆BrNO₂ [M+H] ⁺ m/z 310.19, found: 310.20

Step 3. Preparation of 3- (5-bromo-1H-indol-3-yl) -2, 2-dimethylpropan-1-ol

To a solution of methyl 3- (5-bromo-1H-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℃ for 12h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature, quenched with NH₄Cl 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-1H-indol-3-yl) -2, 2-dimethylpropan-1-ol (91.3g, 99%) as a light-yellow solid. The crude prod-uct was proceeded to the next reaction without purification.

LCMS (ESI) calcd. for C₁₃H₁₆BrNO [M+H] ⁺ m/z 282.18, found: 282.40

Step 4. Preparation of 3- (5-bromo-1H-indol-3-yl) -2, 2-dimethylpropyl acetate

To a solution of 3- (5-bromo-1H-indol-3-yl) -2, 2-dimethylpropan-1-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 extract-ed 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-1H-indol-3-yl) -2, 2-dimethylpropyl acetate (82.0 g, 79%) as a white solid.

LCMS (ESI) calcd. for C₁₅H₁₈BrNO₂ [M+H] ⁺ m/z 324.22, found: 324.60

Intermediate B: methyl (S) -3- (4-bromothiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate

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℃ 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℃ 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 C₁₂H₁₇BrN₂O₄S [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

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 (COCl) 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 prod-uct. The crude product was used to next step without purification.

LCMS (ESI) calcd. for C₅H₅ClO₂ [M+H] ⁺ m/z 133.00, found: 133.4

Step 2. Preparation of 3- (2-diazoacetyl) cyclobutan-1-one

To a stirred solution of crude 3-oxocyclobutane-1-carbonyl chloride in THF (250 mL) and CH₃CN (250 mL) was added TMSCHN₂ (2M in hexanes, 285 mL, 570.18 mmol) dropwisely at 0℃. 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-1-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-1-one (60.20 g, 436.23 mmol) in THF (300 mL) and H₂O (30 mL) at 0℃, 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 HCl (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 re-duced 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-benzyloxazolidin-2-one (71.9 g, 406.3 mmol) , 4-Dimethylaminopyridine (5.0 g, 40.6 mmol) and tri-ethylamine (141.2 mL, 1015.6 mmol) in DCM (1 L) was added 2-Chloro-1-methylpyridinium iodide (135.0 g, 528.1 mmol) in portions at 0℃ . The reaction mixture was stirred at R. T. for 4 h. After comple-tion, 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 (S) -4-benzyl-3- (2- (3-oxocyclobutyl) acetyl) oxazolidin-2-one (68 g 58.3 %) as a yellow oil.

LCMS (ESI) calcd. for C₁₆H₁₇NO₄ [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 por-tions at 0℃. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was di-luted 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 C₁₆H₁₉NO₄ [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℃. 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 re-duced 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℃ for 13 h. The reaction was moni-tored 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 (S) -4-benzyl-3- (2- (3-bromocyclobutyl) acetyl) oxazolidin-2-one (42 g, 85.3 %) as a light yellow oil.

LCMS (ESI) calcd. for C₁₆H₁₈BrNO₃ [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 (S) -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℃ under N₂ condition. The reaction mixture was stirred at -78℃ for 30 mins, then a solu-tion of Di-tert-Butyl azodicarboxylate (23.6 g, 102.6 mmol) in DCM (50 mL) was added rapidly. The reac-tion mixture was stirred at -78℃ for 30 mins, then 1, 3-Dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (310 mL, 2565.0 mmol) was added dropwise at -78℃. The reaction mixture was stirred at r.t. for 14 h. Af-ter 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 HCl. 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 (S) -2, 3-bis (tert-butoxycarbonyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylic acid, which was used directly for the next step.

LCMS (ESI) calcd. for C₁₆H₂₆N₂O₆ [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 (S) -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 Iodomethane (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 (S) -2, 3-diazabicyclo [3.1.1] heptane-2, 3, 4-tricarboxylate (5.6 g, 18.45 %in two-steps) as a light yellow oil.

LCMS (ESI) calcd. for C₁₇H₂₈N₂O₆ [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 (S) -2, 3-diazabicyclo [3.1.1] 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 (S) -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 C₁₅H₂₃BO₄ [M+H] ⁺ m/z 157.09, found: 157.4

Intermediate D: tert-butyl

( (6³S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahy-

dro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate

Step 1. Preparation of 2, 2-dimethyl-3- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-3-yl) propyl acetate

To a stirred solution of 3- (5-bromo-1H-indol-3-yl) -2, 2-dimethylpropyl acetate (20 g, 61.92 mmol) in 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℃ 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 re-sidual 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-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-1, 3, 2-dioxaborolan-2-yl) -1H-indol-3-yl) propyl acetate (18.7 g, 81.4 %) as a light yellow solid.

LCMS (ESI) calcd. for C₂₁H₃₀BNO₄ [M+H] ⁺ m/z 372.23, found: 372.5

Step 2. Preparation of methyl (S) -3- (4- (3- (3-acetoxy-2, 2-dimethylpropyl) -1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate

To a stirred solution of 2, 2-dimethyl-3- (5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-3-yl) propyl acetate (18.7 g, 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/1, 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℃ 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-ganic phase was washed with saturated NaCl (500 mL) , then dried over Na₂SO₄, following with concentra-tion 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) -1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate (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-1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate

To a stirred solution of methyl (S) -3- (4- (3- (3-acetoxy-2, 2-dimethylpropyl) -1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate (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℃ 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-1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) 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-1H-indol-5-yl) thiazol-2-yl) propanoic acid

To a solution of methyl (S) -3- (4- (3- (3-acetoxy-2, 2-dimethylpropyl) -2-iodo-1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate (25 g, 38.17 mmol) in THF (500 mL) and H₂O (100 mL) was added LiOH·H₂O (4.6 g, 190.84 mmol) at 0-10℃, the resulting mixture was stirred at 0-10℃ for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 3-4 with 2 N HCl. 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-1H-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-1H-indol-5-yl) thiazol-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-1H-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℃. The resulting mixture was stirred at 0-10℃ for 10 min. Then me-thyl (S) -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 com-pletion, 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 concen-tration 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-1H-indol-5-yl) thiazol-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 C₃₁H₄₀IN₅O₆S [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-1H-indol-5-yl) thiazol-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-1H-indol-5-yl) thiazol-2-yl) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylate (1.23 g, 24.53 mmol) in THF (1.23 g, 24.53 mmol) and H₂O (6 mL) was added LiOH·H₂O (210 mg, 5.01 mmol) at 0-10℃, the resulting mixture was stirred at 0-10℃ for 2 h. The reaction was monitored by LCMS. After completion, the reaction mix-ture was acidified to pH = 3-4 with 2 N HCl. 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-1H-indol-5-yl) thiazol-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) -1²-iodo-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] 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-1H-indol-5-yl) thiazol-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-11H-8-oxa-62, 63-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate 23 (199 mg, 31.7 %) as a light 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-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²-iodo-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] 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℃ under N₂ atmosphere. The reaction mixture was stirred at 60℃ 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-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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- (1-methoxyethyl) pyridine

Step 1. Preparation of (S) -1- (3-bromopyridin-2-yl) ethan-1-ol

To a stirred solution of TEA (151.76 g, 1.50 mol) was added FA (13.81 g, 299.96 mmol) at 0℃. Then (S,S) -N- (p-Toluenesulfonyl) -1, 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℃ under N₂ for 0.5 h. 1- (3-bromopyridin-2-yl) ethan-1-one (25.00 g, 124.98 mmol) was added into the reaction mixture, the re-sulitng mixture was stirred at 40℃ under N₂ for 1 h. The reaction was monitored by LCMS. After comple-tion, the reaction mixture was diluted with EtOAc (500 mL) , washed with saturated NH₄Cl (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) -1- (3-bromopyridin-2-yl) ethan-1-ol (28.80 g, 95.0 %) as a yellow oil.

LCMS (ESI) calcd. for C₇H₆BrNO [M+H] ⁺ m/z 200.98, found: 202.1

Step 2. Preparation of (S) -3-bromo-2- (1-methoxyethyl) pyridine

To a stirred solution of (S) -1- (3-bromopyridin-2-yl) ethan-1-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℃, the resulting mixture was stirred at 0℃ for 1 h. CH₃I (33.45 g, 235.64 mmol) was added into the reaction mixture at 0℃, the result-ing mixture was stirred at rt for 15 h. The reaction mixture was quenched with H₂O (50 mL) at 0℃ 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- (1-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- (1-methoxyethyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

To a stirred solution of (S) -3-bromo-2- (1-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℃ 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- (1-methoxyethyl) -5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (20.9 g) as an orange oil.

LCMS (ESI) calcd. for C₁₄H₂₁BBrNO₃ [M+H] ⁺ m/z 341.08, found: 342.4

Step 4. Preparation of (S) - (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) boronic acid

To a stirred solution of crude (S) -3-bromo-2- (1-methoxyethyl) -5- (4, 4, 5, 5-tetramethyl-1, 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℃, 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 lay-ers 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- (1-methoxyethyl) pyridin-3-yl) boronic acid (10.98 g, 89.2%) as a yellow solid.

LCMS (ESI) calcd. for C₈H₁₁BBrNO₃ [M+H] ⁺ m/z 259.00, found: 260.3

Step 5. Preparation of (S) -3-bromo-5-iodo-2- (1-methoxyethyl) pyridine

To a stirred solution of (S) - (5-bromo-6- (1-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℃ for 20h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with sat. aq. Na₂SO₃ and 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- (1-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 accord-ance with the general technical knowledge and customary means in the art, under the premise of not de-parting from the above-mentioned basic technical ideas of the present invention, other forms of modifica-tion, replacement or change can also be made.

Unless otherwise stated, the raw materials and reagents used in the following embodiments are com-mercially available or may be prepared by known methods.

Intermediate of Example 3:

Synthesis of (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol

Step 1. Preparation of (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol

A mixture of (S) -3-bromo-5-iodo-2- (1-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) ₂Cl₂ (41 mg, 0.059 mmol) and CuI (11 mg, 0.059 mmol) in THF (4.5 mL) was stirred at 65℃ under N₂ for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude prod-uct which was purified by silica gel column (eluting with EtOAc/PE from 0%to 40%) to give (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol (160 mg, 91.3%) as a brown solid.

LCMS (ESI) calcd. for C₁₃H₁₆BrNO₂ [M+H] ⁺ m/z 297.04, found: 298.4

Intermediate of Example 4:

Synthesis of 3-bromo-2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyridine

Step 1: Synthesis of tert-butyl (S) -2-ethynylpyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (S) -2-formylpyrrolidine-1-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-1-carboxylate (1.7 g, 86.7 %) as a colourless oil.

LCMS (ESI) calcd. for C₁₁H₁₇NO₂ [M+H] ⁺ m/z 195.1, found: 196.3.

Step 2: Synthesis of tert-butyl (S) -2- ( (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (S) -2-ethynylpyrrolidine-1-carboxylate (1.7 g, 8.72 mmol) , (S) -3-bromo-5-iodo-2- (1-methoxyethyl) pyridine (2.5 g, 7.26 mmol) , Pd (PPh₃) ₂Cl₂ (509 mg, 0.73 mmol) and CuI (277 mg, 1.45 mmol) in 1, 4-dioxane (40 mL) was added TEA (4 mL, 29.04 mmol) at r.t.. The re-action mixture was stirred at 35℃ under N₂ for 8 h. After completion, the reaction solution was concen-trated 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) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate (2.8 g, 93.6 %) as a light yellow oil.

LCMS (ESI) calcd. for C₁₉H₂₅BrN₂O₃ [M+H] ⁺ m/z 409.1, found: 310.9.

Step 3: Synthesis of 3-bromo-2- ( (S) -1-methoxyethyl) -5- ( ( (S) -pyrrolidin-2-yl) ethynyl) pyridine

To a stirred solution of tert-butyl (S) -2- ( (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-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) -1-methoxyethyl) -5- ( ( (S) -pyrrolidin-2-yl) ethynyl) pyridine (2.8 g, crude) as a yellow oil.

LCMS (ESI) calcd. for C₁₄H₁₇BrN₂O [M+H] ⁺ m/z 309.2, found: 310.6.

Step 4: Synthesis of 3-bromo-2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyridine

To a stirred solution of (S) -4- (benzyloxy) -1-bromo-2- (1-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 di-luted 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 col-umn (eluting with DCM/MeOH from 0%to 10%) to give 3-bromo-2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyridine (2.13 g, 96.1 %) as a light yellow oil.

LCMS (ESI) calcd. for C₁₅H₁₉BrN₂O [M+H] ⁺ m/z 323.1, found: 323.4.

Intermediate of Example 5:

Synthesis of tert-butyl

(S) -3- ( (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate

Step 1. Preparation of tert-butyl (S) -3-ethynylpyrrolidine-1-carboxylate

To a stirred solution of tert-butyl (R) -3-formylpyrrolidine-1-carboxylate (1 g, 5.0 mmol) and K₂CO₃ (1.4 g, 10.0 mmol) in MeOH (15 mL) was added dimethyl (1-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-1-carboxylate (980 mg) as a yellow oil.

LCMS (ESI) calcd. for C₁₁H₁₇NO₂ [M+H-56] ⁺ m/z 140.1, found: 140.4

Step 2. Preparation of tert-butyl (S) -3- ( (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate

A mixture of tert-butyl (S) -3-ethynylpyrrolidine-1-carboxylate (980 mg, 5.0 mmol) , (S) -3-bromo-5-iodo-2- (1-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℃ 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) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate (1.8 g, 90 %in 2 steps) as a brown oil.

LCMS (ESI) calcd. for C₁₉H₂₅BrN₂O₃ [M+H] ⁺ m/z 409.1, found: 409.6

Intermediate of Example 6:

Synthesis of (S) -3-bromo-2- (1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-yl) ethynyl) pyridine

Step 1: Synthesis of 1-methyl-4- ( (trimethylsilyl) ethynyl) -1H-pyrazole

A mixture of 4-iodo-1-methyl-1H-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℃ under N₂ for 1 h. After completion, the reaction mixture was concen-trated 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) -1H-pyrazole (500 mg, 58.4%) as a brown solid.

LCMS (ESI) calcd. for C₉H₁₄N₂Si [M+H] + m/z 179.1, found: 179.4.

Step 2: Synthesis of 4-ethynyl-1-methyl-1H-pyrazole

To a stirred solution of 1-methyl-4- ( (trimethylsilyl) ethynyl) -1H-pyrazole (500 mg, 2.81 mmol) in THF (5mL) was added TBAF (1M 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- (1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-yl) ethynyl) pyridine

A mixture of (S) -3-bromo-5-iodo-2- (1-methoxyethyl) pyridine (735 mg, 2.16 mmol) , 4-ethynyl-1-methyl-1H-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℃ under N₂ for 2 h. The re-action 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- (1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-yl) ethynyl) pyridine (379 mg, 55.0%) as a yellow solid.

LCMS (ESI) calcd. for C₁₃H₁₆BrNO₂ [M+H] + m/z 320.0, found: 320.5.

Intermediate of Example 8:

Synthesis of (S) -5- ( (5-bromo-6- (1-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- (1-methoxyethyl) pyridine (178 mg, 0.52 mmol) , Pd (PPh₃) ₂Cl₂ (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 re-action mixture was stirred at 50℃ under N₂ for 4 h. After completion, the reaction solution was concen-trated 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- (1-methoxyethyl) pyridin-3-yl) ethynyl) benzo [d] thiazole (190 mg, 80.9%) as a light yellow solid.

LCMS (ESI) calcd. for C₁₇H₁₃BrN₂OS [M+H] ⁺ m/z 373.0, found: 373.4.

Intermediate of Example 9:

Synthesis of (S) -3- ( (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) ethynyl) imidazo [1, 2-b] pyridazine

Step 1: Synthesis of (S) -3- ( (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) ethynyl) imidazo [1, 2-b] pyridazine

A mixture of (S) -3-bromo-5-iodo-2- (1-methoxyethyl) pyridine (200 mg, 0.59 mmol) , 3-ethynylimidazo [1, 2-b] pyridazine 2 (126 mg, 0.88 mmol) , CuI (11 mg, 0.059 mmol) , TEA (227 mg, 1.76 mmol) and Pd (PPh₃) ₂Cl₂ (41 mg, 0.059 mmol) in DMF (3 mL) was stirred at 65℃ for 1 h under N₂ at-mosphere, 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- (1-methoxyethyl) pyridin-3-yl) ethynyl) imidazo [1, 2-b] pyridazine (200 mg, 95.2%) as a yellow oil.

LCMS (ESI) calcd. for C₁₆H₁₃BrN₄O [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- (1-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

Intermediate of Example 10:

Synthesis of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -N, N-dimethylprop-2-yn-1-amine

Step 1: Synthesis of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -N, N-dimethylprop-2-yn-1-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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate (200 mg, 0.47 mmol) in DCM (2 mL) at rt, the resulting mixture was stirred at 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- (1-methoxyethyl) pyridin-3-yl) -N, N-dimethylprop-2-yn-1-amine (73 mg, yield: 52.5%) as a brown oil.

LCMS (ESI) calcd. for C₁₃H₁₇BrN₂O [M+H] + m/z 297.1, found 297.5.

Intermediate of Example 11:

Synthesis of

3-bromo-5- (3- ( (R) -3-fluoropyrrolidin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridine

Step 1: Synthesis of 3-bromo-5- (3- ( (R) -3-fluoropyrrolidin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridine

To a stirred solution of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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 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 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 C₁₅H₁₈BrFN₂O [M+H] ⁺ m/z 341.1, found: 341.53.

Intermediate of Example 12:

Synthesis of (S) -3-bromo-2- (1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-yl) pyridine

Step 1: Preparation of (S) -3-bromo-2- (1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-yl) pyridine

A mixture of piperidine (66.2 mg, 0.78 mmol) , (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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- (1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-yl) pyridine (206 mg, 86%) as a yellow oil.

LCMS (ESI) calcd. for C₁₆H₂₁BrN₂O [M+H] ⁺ m/z 337.1, found 337.6

Intermediate of Example 13:

Synthesis of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4-methylpiperazine

Step 1: Preparation of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4-methylpiperazine

A mixture of 1-methylpiperazine (52 mg, 0.52 mmol) , (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4-methylpiperazine (130 mg, 79%) as a yellow oil.

LCMS (ESI) calcd. for C₁₆H₂₂BrN₃O [M+H] ⁺ m/z 352.1, found 352.6.

Intermediate of Example 14:

Synthesis of

(S) -1- (4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) piperazin-1-yl) ethan-1-one

Step 1: Synthesis of (S) -1- (4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) piperazin-1-yl) ethan-1-one

To a stirred solution of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate (350 mg, 0.83 mmol) in DCM (10 mL) was added 1- (piperazin-1-yl) ethan-1-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 C₁₇H₂₂BrN₃O₂ [M+H] ⁺ m/z 380.1, found: 380.5.

Intermediate of Example 15:

Synthesis of (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine

Step 1. Preparation of 3-bromo-2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridine

A mixture of (S) -3-bromo-5-iodo-2- (1-methoxyethyl) pyridine (10.00 g, 29.24 mmol) , 2- (prop-2-yn-1-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 50℃ for 4h under N₂ atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the fil-trate 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 C₁₆H₂₀BrNO₃ [M+H] ⁺ m/z 354.1, found 354.5.

Step 2. Preparation of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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℃, 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, con-centrated to obtain (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-ol (7.10 g, yield: 92.2%) as a yellow oil.

LCMS (ESI) calcd. for C₁₁H₁₂BrNO₂ [M+H] ⁺ m/z 270.0, found 270.3.

Step 3. Preparation of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate

To a solution of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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℃, the mixture was stirred at 0℃ for 2 h under N₂ atmosphere, the reaction was monitored by LCMS. After com-pletion, 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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate (10.50 g, yield: 94.2%) as a brown solid.

LCMS (ESI) calcd. for C₁₈H₁₈BrNO₄S [M+H] ⁺ m/z 424.0, found 424.8.

Step 4. Preparation of (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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 re-duced 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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine (980 mg, yield: 77.5%) as a brown oil.

LCMS (ESI) calcd. for C₁₅H₁₉BrNO₂ [M+H] ⁺ m/z 339.1, found 339.6

Intermediate of Example 17:

Synthesis of (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide

A mixture of (S) -3-bromo-5-iodo-2- (1-methoxyethyl) pyridine (10.00 g, 29.24 mmol) , 2- (prop-2-yn-1-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 50℃ for 4h under N₂ atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the fil-trate 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 32 (10.10 g, yield: 97.5%) as a yellow oil.

LCMS (ESI) calcd. for C₁₆H₂₀BrNO₃ [M+H] + m/z 354.1, found 354.5.

LCMS (ESI) calcd. for C₁₁H₁₂BrNO₂ [M+H] ⁺ m/z 270.0, found 270.3.

LCMS (ESI) calcd. for C₁₈H₁₈BrNO₄S [M+H] ⁺ m/z 424.0, found 424.8.

Step 4. Preparation of (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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 ob-tain (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 C₁₅H₁₉BrN₂O₃S [M+H] + m/z 387.0, found 387.5.

Intermediate of Example 19:

Synthesis of

( (R) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholin-3-yl) methanol

Step 1: Synthesis of ( (R) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholin-3-yl) methanol (1.1 g, yield: 70.0%) as a brown oil.

LCMS (ESI) calcd. for C₁₆H₂₁BrN₂O₃ [M+H] + m/z 369.1, found 369.5.

Intermediate of Example 20:

Synthesis of

( (S) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholin-3-yl) methanol

Step 1: Preparation of ( (S) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholin-3-yl) methanol

A mixture of (S) -morpholin-3-ylmethanol (61 mg, 0.52 mmol) , (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholin-3-yl) methanol (148 mg, 85%) as a yellow oil. LCMS (ESI) calcd. for C₁₆H₂₁BrN₂O₃ [M+H] ⁺ m/z 369.1, found 369.5

Intermediate of Example 31:

Synthesis of

(S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4- (methylsulfonyl) piperazine

Step 1: Preparation of tert-butyl (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) piperazine-1-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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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 reac-tion 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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) piperazine-1-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) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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 1h. The reaction was concentrated under reduced pressure to afford the crude (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) piperazine (220 mg) as yellow oil. LCMS (ESI) calcd. for C₁₅H₂₀BrN₃O [M+H] ⁺ m/z 338.1, found 338.5

Step 3: Preparation of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4- (methylsulfonyl) piperazine

To a stirred solution of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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℃. The resulting mixture was stirred at 0℃ 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 C₁₆H₂₂BrN₃O₃S [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- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine and uti-lizing the appropriate starting materials and modifications.

Table 3. Certain Intermediates containing alkynyl group of the Present invention

Intermediate of Example 29:

Synthesis of N- (dimethylcarbamoyl) -N-methyl-L-valine

Step 1. Preparation of benzyl N- (dimethylcarbamoyl) -N-methyl-L-valinate

A mixture of benzyl (2S) -3-methy1-2- (methylamino) butanoate (500 mg, 2.26 mmol) and dimethyl-carbamyl 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℃ for 12 h under nitrogen atmosphere, then quenched with water (100 ml) and was extracted with EtOAc (50 mL x 3) . The combined organic phase was dried over anhydrous sodium sulfate, filtered 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 C₁₆H₂₅N₂O₃ [M+H] ⁺ m/z 293.2, found: 293.4

Step 2. Preparation of N- (dimethylcarbamoyl) -N-methyl-L-valine

A mixture of benzyl N- (dimethylcarbamoyl) -N-methyl-L-valinate (400 mg, 1.37 mmol) and palladi-um hydroxide on carbon (400 mg, 2.85 mmol) in MeOH (10 mL) was stirred for 4 h under hydrogen at-mosphere. The reaction mixture was filtered and the filter cake was washed with MeOH (100 mL x3) . The filtrate was concentrated under reduced pressure to afford N- (dimethylcarbamoyl) -N-methyl-L-valine (200 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 de-scribed above for the synthesis of N-methyl-N- ( (2R, 3R) -3-phenyltetrahydrofuran-2-carbonyl) -L-valine and utilizing the appropriate starting materials and modifications.

Table 4. Certain Peptides of the Present invention

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 of synthesis methods well known to those skilled in the art, including the specific embodiments listed be-low, 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 in-clude, 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 otherwise specified, intermediates that do not mention the synthesis method in the following synthesis routes are obtained by purchase or customization

Example 1

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-di-oxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -3-bromo-5-ethynyl-2- (1-methoxyethyl) pyridine in the Step 1 of Example 2 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 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:

Step 1: Synthesis of (S) -5-bromo-6- (1-methoxyethyl) pyridin-3-ol

To a stirred solution of crude (S) -3-bromo-2- (1-methoxyethyl) -5- (4, 4, 5, 5-tetramethyl-1, 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 1M HCl aquous to pH = 4. The mixture was extracted with EtOAc (2*20 mL) . The organic lay-ers 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- (1-methoxyethyl) pyridin-3-ol (600 mg, 88%) as a white solid.

LCMS (ESI) calcd. for C₈H₁₀BrNO₂ [M+H] ⁺ m/z 231.0, found: 232.3

Step 2: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate

A mixture of (S) -5-bromo-6- (1-methoxyethyl) pyridin-3-ol (329 mg, 1.42 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (500 mg, 0.709 mmol) , K₂CO₃ (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℃ 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) -1-methoxyethyl) 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] 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- ( (6⁴S, 4S, Z) -4- ( (tert-butoxycarbonyl) amino) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiaz ola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate

To a solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) 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] 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℃, the mixture was stirred at 0℃ for 2 h under N₂ atmosphere, the reaction was monitored by LCMS. After completion, the mixture was concen-trated 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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazo-la-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (trimethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹ H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

A mixture of 5- ( (6⁴S, 4S, Z) -4- ( (tert-butoxycarbonyl) amino) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazo-la-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (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℃ for 4h under N₂ atmosphere, the reac-tion 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) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (trimethylsilyl) 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] heptanacycloundecaphane-4-yl) carbamate (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 ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (trimethylsilyl) 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] heptanacycloundecaphane-4-yl) carbamate (120 mg, 0.148 mmol) in DMF (2 mL) were added Cs₂CO₃ (145 mg, 0.444 mmol) and Iodoethane (81 mg, 0.518 mmol) at 0℃, 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) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate (100 mg, yield: 88%) as a yellow solid.

LCMS (ESI) calcd. for C₄₂H₅₀N₆O₆S [M+H] ⁺ m/z 766.4, found: 768.4

Step 6: Synthesis of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-5, 7-dione To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] 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-11-ethyl-12- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-5, 7-dione (100 mg, yield: 96%) as a white solid.

LCMS (ESI) calcd. for C₃₇H₄₂N₆O4_S [M+H] ⁺ m/z 666.3, found: 667.7

Step 7: Synthesis of (1S, 2S) -N- ( (64S, 4S, Z) -11-ethyl-12- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

To a stirred solution of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-5, 7-dione (100 mg, 0.150 mmol) and (1S, 2S) -2-methylcyclopropane-1-carboxylic acid (18 mg, 0.18 mmol) and 1-methyl-1H-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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide as atropisomer 1 (18 mg, 15%) as a white solid and (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-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: ¹H NMR (400 MHz, DMSO-d₆) δ 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, J =11.0 Hz, 1H) , 5.30 (t, J = 8.3 Hz, 1H) , 4.71 (d, J = 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) : ¹H NMR (400 MHz, DMSO-d₆) δ 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, J = 11.1 Hz, 1H) , 5.39-5.35 (m, 1H) , 4.65 (d, J = 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, J = 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, J = 9.9 Hz, 1H) , 1.54 (t, J = 9.5 Hz, 1H) , 1.49-1.47 (m, 1H) , 1.34 (d, J = 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

(1S, 2S) -N- ( (6³S, 4S, Z) -1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Step 1: Preparation of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate

A mixture of (S) -4- (5-bromo-6- (1-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-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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) Cl₂ (27 mg, 0.037 mmol) in toluene (6 mL) , dioxane (2 mL) and H₂O (2 mL) was stirred at 75℃ 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) -1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-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-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate (240 mg, 0.31 mmol) in DMF (3.5 mL) was added Cs₂CO₃ (200 mg, 0.61 mmol) and Iodoethane (96 mg, 0.61 mmol) at 0℃, 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 con-centration 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) -1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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%: 1%-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-1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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 1h. 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-1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (6³S, 4S, Z) -4-amino-1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacyc loundecaphane-5, 7-dione (62 mg, 0.10 mmol) and (1r, 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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3-hydroxy-3-methylbut-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] 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. ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (d, J = 2.1 Hz, 1H) , 8.55 -8.48 (m, 2H) , 7.81 (s, 1H) , 7.78 -7.73 (m, 2H) , 7.58 (d, J =8.7 Hz, 1H) , 5.61 -5.51 (m, 2H) , 5.08 (d, J = 12.3 Hz, 1H) , 4.37 -4.14 (m, 4H) , 4.07 (dd, J = 14.7, 7.3 Hz, 1H) , 3.57 (s, 2H) , 3.34 (s, 1H) , 3.30 (s, 2H) , 3.25 (s, 3H) , 3.14 (dd, J = 14.5, 9.1 Hz, 1H) , 2.98 (d, J = 14.5 Hz, 1H) , 2.81 -2.70 (m, 1H) , 2.36 (d, J = 14.1 Hz, 1H) , 2.08 (d, J = 10.2 Hz, 1H) , 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, 1H) , 0.33 (s, 3H) .

Example 3

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- ( (1-fluorocyclopropyl) ethynyl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -3-bromo-5- ( (1-fluorocyclopropyl) ethynyl) -2- (1-methoxyethyl) pyridine in the Step 1 of Example 2 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-carboxylic acid in the Step 4 of Example 2, the title compound was pre-pared by the same procedures as described for Example 2. LCMS (ESI) : 807.4 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyri-din-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Method 1:

Substituting 3-bromo-2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-3-yl) ethynyl) pyridine with 3-bromo-2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyridine in the Step 3 of Exam-ple 5, the title compound was prepared by the same procedures as described for Example 5.

Method 2:

Step 1: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-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] heptanacycloundecaphane-4-yl) carbamate

A mixture of 3-bromo-2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyridine (87 mg, 0.27 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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℃ under N₂ for 16 h. After completion, the reaction mixture was concen-trated 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- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyridin-3-yl) -10, 10-dimet hyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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 ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-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] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyridin-3-yl) -10, 10-dimet hyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (147 mg, 0.18 mmol) in DMF (2 mL) were added Cs₂CO₃ (105 mg, 0.32 mmol) and Iodoethane (50 mg, 0.32 mmol) at 0℃, 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) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-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] heptanacy cloundecaphane-4-yl) carbamate (26 mg, 16.9%) as atropisomer 1 and tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-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] 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-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-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] heptanacyclou ndecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-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] 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-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-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 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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of crude (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-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 (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-2-yl) ethynyl) pyrid-in-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (5.6 mg) as a white solid.

LCMS (ESI) : 846.4 [M+1] ⁺. ¹H NMR (400 MHz, DMSO) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Step 1: Preparation of (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-12- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-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) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] 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. NaHCO₃ (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-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (1.3 g) as a yel-low solid.

LCMS (ESI) calcd. for C₃₁H₄₀BN₅O₅S [M+H] + m/z 606.3, found: 607.4

Step 2: Preparation of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (1.3 g, 2.1 mmol) and (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (1.5 g, 99%in 2 steps) as a yellow solid.

LCMS (ESI) calcd. for C₃₇H₄₈BN₅O₆S [M+H] + m/z 702.3, found: 703.5

Step 3: Preparation of tert-butyl (3S) -3- ( (5- ( (6⁴S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate

A mixture of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (1 g, 1.4 mmol) , tert-butyl (S) -3- ( (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate (583 mg, 1.4 mmol) , K₂CO₃ (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℃ 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- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-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- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-carboxylate

To a stirred solution of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1⁴-amino-10, 10-dimethyl-5, 7-dioxo-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-6 (2, 4) -bicyclo [3.1.1] heptana-1 (1, 3) -benzenacyclododecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (900 mg, 1.0 mmol) in DMF (9 mL) were added Cs₂CO₃ (649 mg, 2.0 mmol) and Iodoethane (311 mg, 2.0 mmol) at 0℃, 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- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -11-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-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%: 1%-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-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-1-carboxamide

To a stirred solution of tert-butyl (3S) -3- ( (5- ( (64S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) ethynyl) pyrrolidine-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-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-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-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 ] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-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-1-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℃, 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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (S) -1-methylpyrrolidin-3-yl) ethynyl) pyrid-in-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (156 mg, 25%) as a white solid.

LCMS (ESI) calcd. for C₄₈H₅₉N₇O₅S [M+H] ⁺ m/z 846.4, found: 846.9.

¹H NMR (400 MHz, DMSO-d₆) δ 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) , 5.90 (d, J = 11.2 Hz, 1H) , 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

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -3-bromo-2- (1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-yl) ethynyl) pyridine in the Step 1 of Example 2 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-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:

Step 1: Synthesis of (1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

A mixture of (S) -3-bromo-2- (1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-yl) ethynyl) pyridine (43 mg, 0.13 mmol) , (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-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, 0.15 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℃ 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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-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] heptanacy cloundecaphane-4-yl) -2-methylcyclopropane-1-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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

To a stirred solution of (1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-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] heptanacy cloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide (58 mg, 0.073 mmol) in DMF (1.5 mL) were added Cs₂CO₃ (47 mg, 0.15 mmol) and Iodoethane (23 mg, 0.15 mmol) at 0℃, 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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide as atropisomer 1 (19 mg) and (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (1-methyl-1H-pyrazol-4-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-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: ¹H NMR (400 MHz, DMSO-d₆) δ 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 = 10.8 Hz, 1H) , 5.31 (t, J = 8.0 Hz, 1H) , 4.72 (d, J = 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) : ¹H NMR (400 MHz, DMSO-d₆) δ 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) , 7.80 (s, 1H) , 7.73 (d, J = 9.9 Hz, 1H) , 7.57 (d, J = 8.6 Hz, 1H) , 5.92 (d, J = 11.1 Hz, 1H) , 5.36 (s, 1H) , 4.65 (d, J = 11.0 Hz, 1H) , 4.47 (d, J = 5.1 Hz, 1H) , 4.36 -4.21 (m, 2H) , 4.07 (dd, J = 15.0, 7.4 Hz, 1H) , 3.84 (s, 2H) , 3.54 (dd, J = 20.2, 10.6 Hz, 2H) , 3.28 (s, 2H) , 3.22 (s, 3H) , 3.11 (dd, J = 14.7, 7.3 Hz, 1H) , 2.93 (d, J = 14.4 Hz, 1H) , 2.61 (d, J = 5.6 Hz, 1H) , 2.43 (d, J = 17.5 Hz, 2H) , 2.35 -2.25 (m, 1H) , 2.14 (t, J = 9.6 Hz, 1H) , 1.57 (d, J = 9.4 Hz, 1H) , 1.48 (s, 1H) , 1.35 (d, J = 6.0 Hz, 2H) , 1.21 (s, 1H) , 1.05 (s, 3H) , 0.89 (q, J = 7.6 Hz, 5H) , 0.55 (d, J = 5.3 Hz, 1H) , 0.31 (s, 3H) .

Example 7

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -5- ( (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) ethynyl) pyrimidine in the Step 1 of Example 2 and Sub-stituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-carboxylic acid in the Step 4 of Example 2, the title compound was pre-pared by the same procedures as described for Example 2. LCMS (ESI) : 827.4 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (5- (benzo [d] thiazol-5-ylethynyl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -5- ( (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) ethynyl) benzo [d] thiazole in the Step 1 of Example 2 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-carboxylic acid in the Step 4 of Example 2, the title compound was pre-pared by the same procedures as described for Example 2. LCMS (ESI) : 882.3 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (imidazo [1, 2-b] pyridazin-3-ylethynyl) -2- ( (S) -1-methoxyethyl) pyrid-in-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -3- ( (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) ethynyl) imidazo [1, 2-a] pyrimidine in the Step 1 of Ex-ample 2 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-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:

Step 1: Synthesis of (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-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) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] 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-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (777 mg) as a grey solid.

LCMS (ESI) calcd. for C₃₁H₄₀BN₅O₅S [M+H] ⁺ m/z 606.3, found: 607.1.

Step 2: Synthesis of (1S, 2S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione 5 (777 mg, 1.28 mmol) and (1S, 2S) -2-methylcyclopropane-1-carboxylic acid (129 mg, 1.28 mmol) and NMI (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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] 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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (5- (imidazo [1, 2-b] pyridazin-3-ylethynyl) -2- ( (S) -1-methoxyethyl) 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] heptanacy cloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

A mixture of (S) -3- ( (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) ethynyl) imidazo [1, 2-b] pyridazine (57 mg, 0.16 mmol) , (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-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℃ 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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (5- (imidazo [1, 2-b] pyridazin-3-ylethynyl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (imidazo [1, 2-b] pyridazin-3-ylethynyl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

To a stirred solution of (1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (5- (imidazo [1, 2-b] pyridazin-3-ylethynyl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1 0, 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide (90 mg, 0.11 mmol) in DMF (2 mL) were added Cs₂CO₃ (70 mg, 0.22 mmol) and Iodoethane (34 mg, 0.22 mmol) at 0℃, the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was di-luted 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 (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (imidazo [1, 2-b] pyridazin-3-ylethynyl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide as atropisomer 1 (33.5 mg) and (1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (imidazo [1, 2-b] pyridazin-3-ylethynyl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide as atropisomer 2 (i.e., compound of Example 9) (23.0 mg) as white solids.

LCMS (ESI) calcd. for C₄₈H₅₁N₉O₅S [M+H] ⁺ m/z 866.4, found: 866.8.

atropisomer 1: ¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (d, J = 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, J = 8.0 Hz, 1H) , 4.72 (d, J = 11.2 Hz, 1H) , 4.48 (d, J = 5.0 Hz, 1H) , 4.03 -3.77 (m, 3H) , 3.59 (d, J = 10.8 Hz, 1H) , 3.51 (d, J = 10.9 Hz, 1H) , 3.24 (d, J = 14.7 Hz, 1H) , 3.19 -2.98 (m, 4H) , 2.70 -2.61 (m, 1H) , 2.34 (dd, J = 16.0, 10.2 Hz, 2H) , 2.18 -2.07 (m, 1H) , 1.60 (t, J = 9.3 Hz, 1H) , 1.49 (s, 1H) , 1.21 (d, J = 6.2 Hz, 3H) , 1.11 (t, J = 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) : ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J = 1.9 Hz, 1H) , 8.68 (d, J = 3.8 Hz, 1H) , 8.50 (d, J = 8.9 Hz, 1H) , 8.42 (s, 1H) , 8.24 (d, J = 6.6 Hz, 2H) , 8.01 (d, J = 1.7 Hz, 1H) , 7.79 (s, 1H) , 7.74 (d, J = 8.3 Hz, 1H) , 7.57 (d, J = 8.7 Hz, 1H) , 7.37 (dd, J = 9.2, 4.4 Hz, 1H) , 5.91 (d, J = 11.2 Hz, 1H) , 5.37 (s, 1H) , 4.65 (d, J = 11.2 Hz, 1H) , 4.47 (d, J = 4.7 Hz, 1H) , 4.37 -4.21 (m, 2H) , 4.08 (dd, J = 14.5, 7.2 Hz, 1H) , 3.55 (dd, J = 21.5, 10.6 Hz, 2H) , 3.24 (s, 3H) , 3.12 (dd, J = 14.9, 7.6 Hz, 1H) , 2.95 (d, J = 14.7 Hz, 1H) , 2.61 (d, J = 5.3 Hz, 1H) , 2.44 (d, J = 3.9 Hz, 1H) , 2.35 -2.24 (m, 1H) , 2.14 (t, J =9.6 Hz, 1H) , 1.55 (t, J = 9.3 Hz, 1H) , 1.48 (s, 1H) , 1.37 (d, J = 6.0 Hz, 3H) , 1.20 (s, 1H) , 1.03 (d, J = 19.4 Hz, 4H) , 0.89 (d, J = 9.7 Hz, 6H) , 0.54 (d, J = 4.9 Hz, 1H) , 0.34 (s, 3H) .

Example 10

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (dimethylamino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -N, N-dimethylprop-2-yn-1-amine in the Step 1 of Exam-ple 16, the title compound was prepared by the same procedures as described for Example 16.

Method 2:

Step 1: Synthesis of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (dimethylamino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 1 0-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

A mixture of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -N, N-dimethylprop-2-yn-1-amine (70 mg, 0.24 mmol) , (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-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℃ under N₂ for 3 h. After com-pletion, 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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (dimethylamino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- ( (R) -5- (3- (dimethylamino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) -3, 4-dihydropyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (dimethylamino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (150 mg, 0.19 mmol) in DMF (4 mL) were added Cs₂CO₃ (99 mg, 0.30 mmol) and Iodoethane (48 mg, 0.30 mmol) at 0℃, 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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- ( (R) -5- (3- (dimethylamino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) -3, 4-dihydropyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 1 (25.5 mg) and (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- ( (R) -5- (3- (dimethylamino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) -3, 4-dihydropyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-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: ¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J = 2.0 Hz, 1H) , 8.39 (d, J = 10.0 Hz, 2H) , 7.98 (d, J = 2.0 Hz, 1H) , 7.80 (s, 1H) , 7.72 (d, J = 8.7 Hz, 1H) , 7.52 (d, J = 8.7 Hz, 1H) , 5.86 (d, J = 11.1 Hz, 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) : ¹H NMR (400 MHz, DMSO-d₆) δ 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, J = 5.5 Hz, 1H) , 2.45 -2.38 (m, 1H) , 2.29 (d, J = 11.6 Hz, 5H) , 2.17 -2.09 (m, 1H) , 1.60 -1.48 (m, 1H) , 1.34 (d, J = 6.0 Hz, 2H) , 1.28 -1.10 (m, 4H) , 1.06 (dd, J = 10.2, 5.8 Hz, 4H) , 0.93 -0.77 (m, 4H) , 0.31 (s, 2H) .

Example 11

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (R) -3-fluoropyrrolidin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with 3-bromo-5- (3- ( (R) -3-fluoropyrrolidin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-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+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with (S) -3-bromo-2- (1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-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:

Step 1: Preparation of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-yl) pyridin-3-yl) -10, 1 0-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

A mixture of (S) -3-bromo-2- (1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-yl) pyridine (48 mg, 0.14 mmol) , (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (100 mg, 0.14 mmol) , K₂CO₃ (58 mg, 0.42 mmol) and Pd (dppf) Cl₂ (22 mg, 0.03 mmol) in dioxane (5 mL) and H₂O (1 mL) was stirred at 85℃ under N₂ for 16h. After com-pletion, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC with MeOH/DCM = 0-6%to afford the (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-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] heptanacy cloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-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] heptanacy cloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (98 mg, 0.117 mmol) in DMF (5 mL) were added Cs₂CO₃ (115.1 mg, 0.353 mmol) and Iodoethane (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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-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] h eptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 1 (38 mg) and (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (piperidin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 2 (i.e., compound of Example 12 ) (28 mg) as white solids.

LCMS (ESI) calcd. for C₄₉H₆₁N₇O₅S [M+H] ⁺ m/z 860.4, found: 860.5.

atropisomer 1: ¹H NMR (400 MHz, DMSO-d₆) δ 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 ) : ¹H NMR (400 MHz, DMSO) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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:

Step 1: Preparation of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

A mixture of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4-methylpiperazine (100 mg, 0.28 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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) Cl₂ (41.5 mg, 0.06 mmol) in dioxane (6 mL) and H₂O (1.5 mL) was stirred at 85℃ under N₂ for 16h. After completion, the reaction mixture was concen-trated 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-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (180 mg, 76%) as a yellow solid. LCMS (ESI) calcd. for C₄₆H₅₈N₈O₆S [M+H] ⁺m/z 851.4, found: 852.1

Step 2: Preparation of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-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-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (180 mg, 0.21 mmol) in DMF (6 mL) were added Cs₂CO₃ (206.4 mg, 0.64 mmol) and Iodoethane (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) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-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-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-yl) pyri din-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] heptanacycloundecaphane-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-yl) pyri din-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] heptanacycloundecaphane-5, 7-dione (101.3 mg, 0.13 mmol) in MeCN (2.5 mL) and DCM (2.5 mL) was added (1r, 2R, 3S) -2, 3-dimethylcyclopropane-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 mix-ture was concentrated under reduced pressure. The residue was purified by pre-HPLC to give the (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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) -bicycl o[3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 1 (38 mg) and (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4-methylpiperazin-1-yl) prop-1-yn-1-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) -bicycl o[3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-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: ¹H NMR (400 MHz, DMSO-d₆) δ 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 ) : ¹H NMR (400 MHz, DMSO) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (4-acetylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-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+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Step 1: Preparation 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-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

A mixture of (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine (253 mg, 0.74 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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℃ 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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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 ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimeth yl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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 Io-doethane (120 mg, 0.77 mmol) at 0℃, 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 concen-tration 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-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimet hyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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 (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimet hyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] 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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundeca phane-5, 7-dione (125 mg, 0.16 mmol) and (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (85 mg, 61.7%) as a white solid.

LCMS (ESI) calcd. for C₄₈H₅₉N₇O₆S [M+H] ⁺ m/z 862.4, found: 862.9.

¹H NMR (400 MHz, DMSO-d₆) δ 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

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyrid-in-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide in the Step 1 of Example 16 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-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:

Step 1: Preparation 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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

A mixture of (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide (209 mg, 0.54 mmol) , tert-butyl ( (64S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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) Cl₂ (78 mg, 0.11 mmol) in dioxane (10 mL) and H₂O (2.5 mL) was stirred at 85℃ under N₂ for 5 h. After completion, the reaction mixture was concentrat-ed 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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacy cloundecaphane-4-yl) carbamate (312 mg, 65.1%) as a yellow solid.

LCMS (ESI) calcd. for C₄₅H₅₅N₇O₈S₂ [M+H] ⁺ m/z 886.3, found: 886.9

Step 2: 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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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 Iodoethane (88 mg, 0.56 mmol) at 0℃, the resulting mixture was stirred at rt for 3 h. The reac-tion 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 chromatog-raphy (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-e 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] heptanacycloundecaphane-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-1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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-methoxyethyl) pyridin-3 -yl) -1¹-ethyl-10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (190 mg) of its TFA salt as a yellow solid.

LCMS (ESI) calcd. for C₄₂H₅₁N₇O₆S₂ [M+H] ⁺ m/z 814.3, found: 814.8

Step 4: (1S, 2S) -N- ( (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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-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-methoxyethyl) pyridin-3 -yl) -1¹-ethyl-10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] hept anacycloundecaphane-5, 7-dione (190 mg, 0.16 mmol) and (1S, 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 (1S, 2S) -N- ( (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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide (23 mg, 16.1%) as a white solid.

LCMS (ESI) calcd. for C₄₇H₅₇N₇O₇S₂ [M+H] ⁺ m/z 896.3, found: 896.4.

¹H NMR (400 MHz, DMSO-d₆) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyri-din-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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:

Step 1: Synthesis 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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

A mixture of (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide (186 mg, 0.48 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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) Cl₂ (71 mg, 0.097 mmol) in dioxane (7.6 mL) and H₂O (1.9 mL) was stirred at 85℃ under N₂ for 15 h. After completion, the reaction mixture was concen-trated 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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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 Iodoethane (88 mg, 0.56 mmol) at 0℃, the resulting mixture was stirred at rt for 3 h. The reac-tion 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 con-centration under reduced pressure to obtain crude product which was purified by silica gel column (elut-ing 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-ethyl-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] heptanacycloundecaphane-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-1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-1¹H-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) -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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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 concen-trated to give crude (6⁴S, 4S, Z) -4-amino-1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione which was used to next step without purification.

Step 4: Synthesis of (1r, 2R, 3S) -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) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of crude (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-5, 7-dione (220 mg, 0.27 mmol) and (1r, 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 (1r, 2R, 3S) -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) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (34.3 mg) as a white solid.

LCMS (ESI) calcd. for C₄₈H₆₁N₇O₇S₂ [M+H] ⁺ m/z 912.4, found: 911.2.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H) , 8.39 (d, J = 11.6 Hz, 2H) , 7.86 (s, 1H) , 7.80 (s, 1H) , 7.73 (d, J = 8.1 Hz, 1H) , 7.56 (d, J = 8.8 Hz, 1H) , 5.91 (d, J = 11.0 Hz, 1H) , 5.36 (s, 1H) , 4.64 (d, J = 11.0 Hz, 1H) , 4.46 (d, J = 4.6 Hz, 1H) , 4.35 -4.21 (m, 2H) , 4.05 (dd, J = 14.8, 6.9 Hz, 2H) , 3.73 (s, 2H) , 3.53 (dd, J = 20.6, 10.7 Hz, 2H) , 3.21 (s, 3H) , 3.13 (d, J = 4.9 Hz, 4H) , 3.03 (s, 3H) , 2.61 (d, J = 6.0 Hz, 1H) , 2.42 (s, 1H) , 2.30 (s, 1H) , 2.17 -2.09 (m, 1H) , 1.56 (d, J = 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with ( (R) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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) -1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate

A mixture of ( (R) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholin-3-yl) methanol (71 mg, 0.19 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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) Cl₂ (21 mg, 0.029 mmol) in dioxane (3 mL) and H₂O (0.7 mL) was stirred at 85℃ under N₂ for 16 h. After completion, the reaction mixture was concen-trated 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- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-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 ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyrid-in-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 ] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate (915 mg, 1.05 mmol) in DMF (10 mL) were added Cs₂CO₃ (628 mg, 1.93 mmol) and Iodoethane (301 mg, 1.93 mmol) at 0℃, 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) -1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] 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-1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] 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-1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of crude (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-5, 7-dione (256 mg, 0.29 mmol) and (1r, 2R, 3S) -2, 3-dimethylcyclopropane-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (R) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (98 mg) as a white solid.

LCMS (ESI) calcd. for C₄₉H₆₁N₇O₇S [M+H] ⁺ m/z 892.4, found: 892.9.

¹H NMR (400 MHz, DMSO-d₆) δ 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+1] ⁺. ¹H NMR (400 MHz, DMSO) δ 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

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (S) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -in dola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with ( (S) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- ( (S) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

A mixture of ( (S) -4- (3- (5-bromo-6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholin-3-yl) methanol (70.2 mg, 0.19 mmol) , (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (160 mg, 0.23 mmol) , K₂CO₃ (79 mg, 0.57 mmol) and Pd (dppf) Cl₂ (27.8 mg, 0.04 mmol) in dioxane (8 mL) and H₂O (1.6 mL) was stirred at 85℃ 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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- ( (S) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyet hyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-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 (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (S) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- ( (S) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyet hyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (115 mg, 0.133 mmol) in DMF (5 mL) were added Cs₂CO₃ (129.8 mg, 0.4 mmol) and Iodoethane (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 or-ganic layer was washed with brine (20 mL*2) , dried over anhydrous Na₂SO₄ and concentration under re-duced pressure. The residue was purified by pre-HPLC to give the (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3- ( (S) -3- (hydroxymethyl) morpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (38 mg) as white sol-id.

¹H NMR (500 MHz, CDCl₃) δ 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-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoro-ethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -3-bromo-5-ethynyl-2- (1-methoxyethyl) pyridine in the Step 1 of Example 2, Substituting iodoethane with 1, 1, 1-trifluoro-2-iodoethane in the Step 2 of Example 2 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-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+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting iodoethane with 1, 1, 1-trifluoro-2-iodoethane in the Step 2 of Example 16 and Substitut-ing (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-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+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate in the Step 1 of Example 16, Substituting iodoethane with 1, 1, 1-trifluoro-2-iodoethane in the Step 2 of Ex-ample 16 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-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+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-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 16, the title compound was prepared by the same procedures as described for Example 16.LCMS (ESI) : 1145.6 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyeth-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) -bicy-clo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting (S) -4- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) -2-methylbut-3-yn-2-ol with (S) -3-bromo-5-ethynyl-2- (1-methoxyethyl) pyridine in the Step 1 of Example 2 and Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-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+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyeth-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Method 1:

Substituting (S) -4- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) morpholine with (S) -3-bromo-5-ethynyl-2- (1-methoxyethyl) pyridine in the Step 1 of Example 23 and Substituting (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-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 ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-di-oxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

A mixture of 5- ( (2²S, 6⁴S, 4S) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyet hyl) pyridin-3-yl trifluoromethanesulfonate (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℃ 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) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (170 mg, 90 %) as a light yellow solid.

LCMS (ESI) calcd. for C₄₉H₇₀N₆O₇Si [M+H] ⁺ m/z 883.5, found: 884.4.

Step 2: Synthesis of (2²S, 6⁴S, 4S) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-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 1 h. The reaction mixture was washed with sat. NaHCO₃ (3 mL) , brine (3 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product (2²S, 6⁴S, 4S) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dime-thyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (150 mg, crude) as a yellow solid.

LCMS (ESI) calcd. for C₄₄H₆₂N₆O₅Si [M+H] + m/z 783.5, found: 784.5.

Step 3: Synthesis of tert-butyl 4- ( ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacyclou ndecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate

To a solution of N- (1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carbonyl) -N-methyl-L-valine (83 mg, 0.23 mmol) in DMF (3 mL) were added HATU (109 mg, 0.29 mmol) and DIEA (123 mg, 0.96 mmol) at 0-10℃. The resulting mixture was stirred at 0-10℃ for 10 min. Then (2²S, 6⁴S, 4S) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dime-thyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (150 mg, 0.20 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 30 mL) , the combined organic phase was washed with saturated NaCl (100 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 afford tert-butyl 4- ( ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacyclou ndecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (40 mg, 19 %) as a light yellow solid.

LCMS (ESI) calcd. for C₆₁H₈₉FN₈O₉Si [M+H] ⁺ m/z 1125.7, found: 1126.7.

Step 4: Synthesis of tert-butyl 4- ( ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate

To a solution of tert-butyl 4- ( ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (triethylsilyl) ethynyl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (40 mg, 0.036 mmol) in THF (3 mL) was added TBAF (0.07 mL, 1M in THF, 0.07 mmol) at 0-10℃. The resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the re-action mixture was diluted with brine and extracted with EtOAc (2 x 30 mL) , the combined organic phase was washed with saturated NaCl (100 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude tert-butyl 4- ( ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (36 mg, crude) as a light yellow solid.

LCMS (ESI) calcd. for C₅₅H₇₅FN₈O₉ [M+H] ⁺ m/z 1011.6, found: 1012.7.

Step 5: Synthesis of N- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

To a stirred solution of tert-butyl 4- ( ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (36 mg, 0.036 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 washed with sat. NaHCO₃ (3 mL) , brine (3 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product N- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide (32 mg, crude) as a yellow solid.

LCMS (ESI) calcd. for C₃₇H₄₇F₃N₆O₈S [M+H] + m/z 911.5, found: 912.1.

Step 6: Synthesis of 1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-meth oxyeth-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicy-clo[3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

To a solution of 4- (dimethylamino) -4-methylpent-2-ynoic acid (9.2 mg, 0.06 mmol) in DMF (2 mL) were added HATU (23 mg, 0.06 mmol) and DIEA (25 mg, 0.20 mmol) at 0-10℃. The resulting mixture was stirred at 0-10℃ for 10 min. Then N- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide (36 mg, 0.04 mmol) was added into the reaction mixture, the resulting mixture was stirred at rt for 2 h. The reaction was moni-tored by LCMS. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 30 mL) , the combined organic phase was washed with saturated NaCl (100 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (ACN/H₂O (0.5 %NH₄HCO₃) from 20%to 95%in 30 min) to give 1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-met hoxyeth-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicy-clo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide (5 mg, 12%) as a white solid.

LCMS (ESI) calcd. for C₆₁H₇₉N₁₁O₇ [M+H] ⁺ m/z 1048.6, found: 1049.5.

¹H NMR (500 MHz, CDCl₃) δ 8.49 (d, J = 2.0 Hz, 1H) , 8.24 (d, J = 12.1 Hz, 1H) , 8.06 (d, J = 2.0 Hz, 1H) , 7.36 (d, J = 7.9 Hz, 1H) , 7.21 (d, J = 2.2 Hz, 1H) , 7.01 (dd, J = 7.9, 2.2 Hz, 1H) , 5.24 (q, J = 5.4 Hz, 1H) , 4.90 (d, J = 8.6 Hz, 1H) , 4.75 (d, J = 7.3 Hz, 1H) , 4.47 (q, J = 11.9 Hz, 1H) , 4.15 (q, J = 4.4 Hz, 2H) , 4.12 -4.06 (m, 1H) , 4.06 -3.99 (m, 2H) , 3.99 -3.89 (m, 2H) , 3.86 (dd, J = 7.5, 4.8 Hz, 1H) , 3.81 (dd, J =7.5, 4.8 Hz, 1H) , 3.74 -3.65 (m, 3H) , 3.65 -3.58 (m, 3H) , 3.55 (d, J = 8.6 Hz, 1H) , 3.48 -3.42 (m, 2H) , 3.33 (s, 3H) , 3.09 (s, 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) , 2.25 -1.97 (m, 7H) , 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 27

(2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -3-methyl-2- (1, 3, 3-trimethylureido) butanamide

Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with N- (dimethylcarbamoyl) -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) : 950.5 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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 = 2.3 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) , 4.70 -4.59 (m, 2H) , 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) , 3.32 -3.18 (m, 2H) , 3.06 (d, J = 2.6 Hz, 2H) , 2.93 (d, J = 1.6 Hz, 9H) , 2.78 -2.66 (m, 5H) , 2.21 (dhept, J = 8.1, 5.1 Hz, 1H) , 2.13 -1.97 (m, 4H) , 1.67 (d, J = 5.3 Hz, 3H) , 1.37 (t, J = 4.4 Hz, 3H) , 1.15 (s, 3H) , 1.10 (s, 3H) , 0.79 (d, J = 5.1 Hz, 3H) , 0.75 (d, J = 5.1 Hz, 3H) .

Example 28

N- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundeca-phane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -N-methylmorpholine-4-carboxamide

Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with N-methyl-N- (morpholine-4-carbonyl) -L-valine in the Step 4 of Example 16, the title compound was pre-pared by the same procedures as described for Example 16. LCMS (ESI) : 992.5 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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 =2.3 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) , 4.70 -4.59 (m, 2H) , 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) , 3.64 -3.58 (m, 2H) , 3.58 -3.51 (m, 8H) , 3.33 (s, 3H) , 3.31 -3.18 (m, 2H) , 3.06 (d, J = 2.6 Hz, 2H) , 2.93 (s, 3H) , 2.78 -2.66 (m, 5H) , 2.22 (dhept, J = 8.1, 5.1 Hz, 1H) , 2.13 -1.97 (m, 4H) , 1.67 (d, J = 5.3 Hz, 3H) , 1.37 (t, J = 4.4 Hz, 3H) , 1.15 (s, 3H) , 1.10 (s, 3H) , 0.79 (d, J = 5.1 Hz, 3H) , 0.75 (d, J = 5.0 Hz, 3H) .

Example 29

(2R, 3R) -N- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -N-methyl-3-phenyltetrahydrofuran-2-carboxamide

Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with N-methyl-N- ( (2R, 3R) -3-phenyltetrahydrofuran-2-carbonyl) -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) : 1053.5 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 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) , 7.33 -7.22 (m, 5H) , 5.24 (q, J = 5.4 Hz, 1H) , 4.90 (d, J = 8.4 Hz, 1H) , 4.79 (d, J = 8.1 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 -3.94 (m, 2H) , 3.94 -3.89 (m, 1H) , 3.89 -3.84 (m, 1H) , 3.79 -3.70 (m, 3H) , 3.66 (dd, J = 6.5, 3.8 Hz, 2H) , 3.58 (d, J = 2.6 Hz, 2H) , 3.33 (s, 3H) , 3.31 -3.18 (m, 2H) , 3.06 (d, J = 2.6 Hz, 2H) , 2.97 (s, 3H) , 2.78 -2.66 (m, 5H) , 2.30 (ddd, J = 7.5, 5.5, 4.8 Hz, 1H) , 2.26 -2.15 (m, 2H) , 2.13 -1.97 (m, 4H) , 1.67 (d, J = 5.3 Hz, 3H) , 1.37 (t, J = 4.4 Hz, 3H) , 1.15 (s, 3H) , 1.10 (s, 3H) , 0.79 (d, J = 5.1 Hz, 3H) , 0.74 (d, J = 5.0 Hz, 3H) .

Example 30

methyl (3S, 4R) -3- ( ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-methylpyrrolidine-1-carboxylate

Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with N- ( (3S, 4R) -1- (methoxycarbonyl) -4-methylpyrrolidine-3-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) : 1048.5 [M+1] ⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.39 (d, J = 2.0 Hz, 1H) , 8.30 (d, J = 12.6 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) , 4.90 (d, J = 8.4 Hz, 1H) , 4.77 (d, J = 8.1 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) , 3.79 -3.70 (m, 3H) , 3.69 -3.61 (m, 6H) , 3.61 -3.54 (m, 2H) , 3.54 -3.48 (m, 1H) , 3.40 (dd, J = 9.5, 6.4 Hz, 1H) , 3.33 (s, 3H) , 3.31 -3.21 (m, 2H) , 3.21 -3.12 (m, 1H) , 3.06 (d, J = 2.6 Hz, 2H) , 2.99 (s, 3H) , 2.78 -2.66 (m, 5H) , 2.54 (dt, J = 12.4, 6.3 Hz, 1H) , 2.20 (dhept, J = 8.1, 5.1 Hz, 1H) , 2.13 -1.97 (m, 4H) , 1.67 (d, J = 5.3 Hz, 3H) , 1.37 (t, J = 4.4 Hz, 3H) , 1.15 (s, 3H) , 1.10 (s, 3H) , 1.01 (d, J = 6.2 Hz, 3H) , 0.79 (d, J = 5.1 Hz, 3H) , 0.74 (d, J =5.0 Hz, 3H) .

Example 31

Step 1: Preparation of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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

A mixture of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4- (methylsulfonyl) piperazine (118.1 mg, 0.28 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (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) Cl₂ (41.5 mg, 0.06 mmol) in dioxane (6 mL) and H₂O (1.5 mL) was stirred at 85℃ under N₂ for 4h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC with MeOH/DCM = 0-5%to afford the tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] hept anacycloundecaphane-4-yl) carbamate 7 (176 mg, 69%) as a yellow solid.

LCMS (ESI) calcd. for C₄₆H₅₈N₈O₈S₂ [M+H] ⁺ m/z 915.4, found: 915.9

Step 2: Preparation of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] hept anacycloundecaphane-4-yl) carbamate (176 mg, 0.192 mmol) in DMF (5 mL) were added Cs₂CO₃ (187.7 mg, 0.577 mmol) and Iodoethane (90 mg, 0.577 mmol) . The resulting mixture was stirred at rt for 2h. After completion, the reaction mixture was diluted with EtOAc (5 mL) and H₂O (10 mL) . The mixture was ex-tracted with EtOAc (10 mL*3) . The combined organic layer was washed with brine (10 mL*2) , dried over anhydrous Na₂SO₄ and concentration under reduced pressure. The residue was purified by FCC with MeOH/DCM = 0-5%to afford the tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) carbamate (131 mg, 72%) as white solid.

LCMS (ESI) calcd. for C₄₈H₆₂N₈O₈S₂ [M+H] ⁺ m/z 943.4, found: 943.9

Step 3: Preparation of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) carbamate (131 mg, 0.138 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-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-5, 7-dione (162 mg) of its TFA salt as a yellow oil.

LCMS (ESI) calcd. for C₄₃H₅₄N₈O₆S₂ [M+H] ⁺ m/z 843.4, found: 843.8

Step 4: Preparation of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-5, 7-dione (116 mg, 0.138 mmol) in ACN (3 mL) and DCM (3 mL) was added (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid (17.4 mg, 0.152 mmol) , TCFH (116 mg, 0.414 mmol) and NMI (113 mg, 1.38 mmol) . The resulting mixture was stirred at rt for 0.5h. The reaction mix-ture was concentrated under reduced pressure. The residue was purified by pre-TLC with EtOAc to give the (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop -1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropiso-mer 1 (11 mg) and (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropiso-mer 2 (i.e., compound of Example 31) (15 mg) as white solids.

LCMS (ESI) calcd. for C₄₉H₆₂N₈O₇S₂ [M+H] ⁺ m/z 939.4, found: 939.9

atropisomer 1: ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 -8.76 (m, 1H) , 8.40 (t, J = 10.7 Hz, 2H) , 7.87 (d, J = 2.1 Hz, 1H) , 7.80 (s, 1H) , 7.73 (d, J = 7.3 Hz, 1H) , 7.56 (d, J = 8.6 Hz, 1H) , 5.91 (d, J = 11.3 Hz, 1H) , 5.35 (s, 1H) , 4.64 (d, J = 10.9 Hz, 1H) , 4.46 (dd, J = 9.6, 4.2 Hz, 1H) , 4.37 -4.21 (m, 2H) , 4.05 (dd, J = 15.4, 7.9 Hz, 1H) , 3.67 -3.48 (m, 4H) , 3.27 -3.19 (m, 3H) , 3.17 -3.08 (m, 4H) , 2.86 (s, 2H) , 2.70 -2.56 (m, 4H) , 2.32 (ddd, J = 15.5, 12.2, 10.3 Hz, 2H) , 2.17 -2.10 (m, 1H) , 1.55 (s, 1H) , 1.37 -0.99 (m, 18H) , 0.94 -0.73 (m, 7H) , 0.31 (s, 2H) .

atropisomer 2: ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J = 1.8 Hz, 1H) , 8.42 (d, J = 8.6 Hz, 2H) , 8.03 (d, J = 1.9 Hz, 1H) , 7.82 (s, 1H) , 7.74 (d, J = 7.9 Hz, 1H) , 7.54 (d, J = 8.7 Hz, 1H) , 5.89 (d, J = 11.1 Hz, 1H) , 5.31 (t, J = 8.1 Hz, 1H) , 4.73 (d, J = 11.0 Hz, 1H) , 4.49 (d, J = 5.0 Hz, 1H) , 3.99 -3.90 (m, 2H) , 3.82 (dd, J = 14.6, 7.2 Hz, 1H) , 3.70 -3.57 (m, 3H) , 3.51 (d, J = 10.6 Hz, 1H) , 3.25 (d, J = 14.6 Hz, 1H) , 3.19 -2.99 (m, 8H) , 2.88 (s, 2H) , 2.64 (s, 4H) , 2.40 -2.28 (m, 2H) , 2.15 (t, J = 9.6 Hz, 1H) , 1.62 (t, J = 9.4 Hz, 1H) , 1.31 -1.04 (m, 18H) , 0.94 -0.77 (m, 4H) , 0.48 (s, 3H) .

Example 32

(2S) -4- (3- (5- ( (6⁴S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -1¹-ethyl-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] heptanacycloundeca-phane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -N, N-dimethylmorpholine-2-carboxamide

Step 1: tert-butyl (S) -2- (dimethylcarbamoyl) morpholine-4-carboxylate

To a stirred solution of (S) -4- (tert-butoxycarbonyl) morpholine-2-carboxylic acid (833 mg, 3.60 mmol) , dimethylamine hydrochloride (352 mg, 4.32 mmol) in DMF (10 mL) were added DIEA (1.4 g, 10.81 mmol) and HATU (2.1 g, 5.40 mmol) at rt , the resulting mixture was stirred at rt for 22 h. The reac-tion was monitored by LCMS. After completion, The reaction was diluted with H₂O (100 mL) and ex-tracted with EtOAc (20 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 CH₃OH/DCM from 0%to 10%) to afford tert-butyl (S) -2- (dimethylcarbamoyl) morpholine-4-carboxylate (405 mg, 43.6 %) as a brown oil.

LCMS (ESI) calcd. for C₁₂H₂₂N₂O₄ [M+H] ⁺ m/z 259.2, found: 259.5.

Step 2: (S) -N, N-dimethylmorpholine-2-carboxamide

To a stirred solution of tert-butyl (S) -2- (dimethylcarbamoyl) morpholine-4-carboxylate (405 mg, 1.57 mmol) in DCM (6 mL) was TFA (2 mL) at rt , the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude (S) -N, N-dimethylmorpholine-2-carboxamide (880 mg) as a brown oil of its TFA salt.

LCMS (ESI) calcd. for C₇H₁₄N₂O₂ [M+H] ⁺ m/z 159.1, found: 159.3.

Step 3: (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-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) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (4.3 g, 6.10 mmol) in DCM (40 mL) was added TFA (5 mL) at rt, the resulting mixture was stirred at rt for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with DCM (50 mL) , washed with saturated NaHCO₃ (100 x 2 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (3.4 g, 91.9 %) as a brown foam.

LCMS (ESI) calcd. for C₃₁H₄₀BN₅O₅S [M+H] ⁺ m/z 606.3, found: 607.0.

Step 4: (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (6⁴S, 4S, Z) -4-amino-10, 10-dimethyl-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (2.1 g, 3.42 mmol) and (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid (390 mg, 3.42 mmol) and NMI (702 mg, 8.55 mmol) in ACN (20 mL) and DCM (20 mL) was added TCFH (1.4 g, 5.13 mmol) at rt, the resulting mix-ture was stirred at rt for 1 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by column chromatography (eluting with EtOAc/PE from 0%to 65%) to give (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (2.2 g, 93.4%) as a pale yellow foam.

LCMS (ESI) calcd. for C₃₇H₄₈BN₅O₆S [M+H] ⁺ m/z 702.3, found: 701.7.

Step 5: (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

A mixture of 3-bromo-2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyridine (1.0 g, 2.83 mmol) , (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (2.1 g, 2.97 mmol) , K₂CO₃ (1.2 g, 8.50 mmol) and Pd (dppf) Cl₂ (311 mg, 0.42 mmol) in dioxane (30 mL) and H₂O (7.5 mL) was stirred at 85℃ under N₂ for 6 h. After comple-tion, the reaction mixture was concentrated to give the crude product which was purified by silica gel col-umn (eluting with MeOH/DCM from 0%to 10%) to give (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyri-din-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (1.1 g, 46.7 %) as a yellow foam.

LCMS (ESI) calcd. for C₄₇H₅₆N₆O₇S [M+H] ⁺ m/z 849.4, found: 849.9.

Step 6: (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-yl) pyri-din-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (1.1 g, 1.30 mmol) in DMF (11 mL) were added Cs₂CO₃ (844 mg, 2.59 mmol) and Iodoethane (405 mg, 2.59 mmol) at 0℃, the result-ing mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (25 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 10%to 95%) to give (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 1 (171 mg) and atropisomer 2 (168 mg) (Yield: 29.8%) as a white solid.

LCMS (ESI) calcd. for C₄₉H₆₀N₆O₇S [M+H] ⁺ m/z 877.4, found: 877.9

Step 7: (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3-hydroxyprop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- ( (tetrahydro-2H-pyran-2-yl) oxy) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 1 (171 mg, 0.20 mmol) in MeOH (9 mL) was added TsOH (329 mg) at rt, the resulting mixture was stirred at rt for 16 h. The reaction mixture was concentrated and purified by silica gel column (eluting with EtOAc/PE from 0%to 100%) to give crude (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3-hydroxyprop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (183 mg) as a yellow foam.

LCMS (ESI) calcd. for C₄₄H₅₂N₆O₆S [M+H] + m/z 793.4, found: 793.9

Step 8: 3- (5- ( (6⁴S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -1¹-ethyl-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] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl methanesulfonate

To a stirred solution of crude (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5- (3-hydroxyprop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1 0, 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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (183 mg, 0.23 mmol) in DCM (7.5 mL) were added DIEA (298 mg, 2.30 mmol) and Ms₂O (241 mg, 1.38 mmol) at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with DCM (15 mL) and washed with H₂O (20 mL) and brine (20 mL) . The organic layer was separated and concentrated to give crude 3- (5- ( (6⁴S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl methanesulfonate (132 mg, Yield: 65.7%) as a pale yellow foam.

LCMS (ESI) calcd. for C₄₅H₅₄N₆O₈S₂ [M+H] ⁺ m/z 871.3, found: 871.9

Step 9: (2S) -4- (3- (5- ( (64S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -11-ethyl-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] heptanacycloundeca phane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -N, N-dimethylmorpholine-2-carboxamide

To a stirred solution of (S) -N, N-dimethylmorpholine-2-carboxamide (132 mg, 0.23 mmol) in DCM (10 mL) were added DIEA (391 mg, 3.02 mmol) and the crude 3- (5- ( (6⁴S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl methanesulfonate (263 mg, 0.30 mmol) at rt, the resulting mixture was stirred at 40℃ for 16 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (eluting with CH₃CN/H₂O (0.1%NH₄HCO₃) from 10%to 80%) to give (2S) -4- (3- (5- ( (6⁴S, 4S, Z) -4- ( (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -N, N-dimethylmorpholine-2-carboxamide (18 mg, Yield: 64.3%) as a white solid.

LCMS (ESI) calcd. for C₅₁H₆₄N₈O₇S [M+H] ⁺ m/z 933.5, found: 934.0.

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J = 1.9 Hz, 1H) , 8.41 (d, J = 9.0 Hz, 2H) , 7.90 -7.80 (m, 2H) , 7.75 (d, J = 8.5 Hz, 1H) , 7.58 (d, J = 8.6 Hz, 1H) , 5.94 (d, J = 11.1 Hz, 1H) , 5.38 (s, 1H) , 4.66 (d, J =10.9 Hz, 1H) , 4.48 (d, J = 5.0 Hz, 1H) , 4.36 -4.22 (m, 3H) , 4.07 (dd, J = 15.0, 7.5 Hz, 1H) , 3.87 (d, J =10.1 Hz, 1H) , 3.67 -3.49 (m, 4H) , 3.23 (s, 3H) , 3.19 -3.07 (m, 1H) , 3.01 (s, 3H) , 2.94 (d, J = 14.3 Hz, 1H) , 2.86 -2.71 (m, 4H) , 2.63 (d, J = 5.8 Hz, 1H) , 2.43 (dd, J = 20.4, 9.5 Hz, 3H) , 2.34 (dd, J = 11.2, 8.0 Hz, 2H) , 2.20 -2.10 (m, 1H) , 1.57 (s, 1H) , 1.36 (d, J = 6.0 Hz, 3H) , 1.28 -1.20 (m, 1H) , 1.17 (d, J = 4.1 Hz, 2H) , 1.08 (dd, J = 10.4, 5.7 Hz, 5H) , 0.87 (d, J = 7.1 Hz, 5H) , 0.33 (s, 3H) .

Example 33

(2S) -2- (7- ( (R) -aziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Step 1: Synthesis of methyl trityl-D-serinate

To a mixture of methyl D-serinate hydrochloride (5.00 g, 32.14 mmol) and TEA (8.13 g, 80.34 mmol) in DCE (70 mL) was added TrtCl (8.96 g, 32.14 mmol) at room temperature, the mixture was stirred at 50℃under N₂ atmosphere overnight. The reaction was monitored by LCMS, after completion, the mixture was concentrated and the residue was purified by silica gel column chromatography (eluting with EtOAc/PE, from 0%to 6%in 20 min) to obtain methyl trityl-D-serinate (11.20 g, 30.99 mmol, yield: 96.4 %) as a light yellow solid.

LCMS (ESI) calcd. for C₂₃H₂₃NO₃ [M+Na] ⁺ m/z 384.2, found 384.5.

Step 2: Synthesis of methyl (R) -1-tritylaziridine-2-carboxylate

To a mixture of (1.00 g, 2.77 mmol) and TEA (0.84 g, 8.30 mmol) in DCE (10 mL) was added MsCl (0.38 g, 3.32 mmol) at 0℃, the mixture was stirred at r.t. for 4h and at 80℃ for 16 h under N₂ atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with water (40 mL) and extracted with DCM (20 mL x 3) , the combined organic layer was washed with brine (40 mL) , dried over Na₂SO₄, concentrated and purified by flash chromatography column (eluting with EtOAc/PE from 0%to 2%in 10 min) to obtain methyl (R) -1-tritylaziridine-2-carboxylate (760 mg, 2.21 mmol, yield: 79.8 %) as a white solid.

LCMS (ESI) calcd. for C₂₃H₂₁NO₂ [M+H] ⁺ m/z 344.2, found 344.6.

Step 3: Synthesis of (R) -1-tritylaziridine-2-carboxylic acid

Methyl (R) -1-tritylaziridine-2-carboxylate (500 mg, 1.46 mmol) was dissolved in a mixture of THF (15 mL) and H₂O (2 mL) at 0℃, 1M NaOH (20 mL) was added, followed by 1M LiOH (10 mL) , the mix-ture was stirred for 2h at 0℃. The reaction was monitored by LCMS, after completion, the mixture was diluted with DCM (50 mL) and 15%aqueous citric acid (40 mL) , the organic phase was further washed with 15%citric acid solution (3 x 20 mL) and the combined aqueous phases were extracted with DCM (3 x 20 mL) , the combined organic phase was concentrated and the residue was purified by reverse phase col-umn (eluting with MeCN/H₂O, from 5%to 34%in 35 min) to give (R) -1-tritylaziridine-2-carboxylic acid (380 mg, 1.15 mmol, yield: 78.8%) as a white solid.

LCMS (ESI) calcd. for C₂₂H₁₉NO₂ [M-H] ^-m/z 328.1, found: 328.5.

Step 4: Synthesis of benzyl (R) -2-hydroxy-3-methylbutanoate

To a mixture of BnOH (3.84 g, 35.55 mmol) in toluene (50 mL) was added TsOH (0.58g, 3.39 mmol) at r.t., the mixture was stirred at 80℃ for 1h and then (R) -2-hydroxy-3-methylbutanoic acid (4.00 g, 33.86 mmol) was added, the reaction was stirred at 80℃ for 1 h under N₂ atmosphere, the mixture was monitored by LCMS. After completion, the mixture was diluted with water (100 mL) and extracted with EA (50 mL x 3) .The combined organic phase was concentrated under reduced pressure and the the residue was purified by silica gel column chromatography (eluting with EtOAc/PE, from 0%to 5%in 20 min) to afford benzyl (R) -2-hydroxy-3-methylbutanoate (5.21 g, 25.02 mmol, yield: 73.9%) as a colorless oil.

LCMS (ESI) calcd. for C₁₂H₁₆O₃ [M+H] ⁺ m/z 209.1, found: 209.3.

Step 5: Synthesis of benzyl (R) -3-methyl-2- ( ( (trifluoromethyl) sulfonyl) oxy) butanoate

To a mixture of benzyl (R) -2-hydroxy-3-methylbutanoate (5.21 g, 25.02 mmol) and 2, 6-lutidine (2.95g, 27.52 mmol) in DCM (100 mL) was added Tf₂O (7.41 g, 26.27 mmol) slowly at 0℃, the mixture was stirred at 0℃ for 2 h under N₂ atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 3) , the combined organic layer was washed with brine (100 mL) , dried over Na₂SO₄ and concentrated, the residue was purified by flash chromatography column (eluting with EtOAc/PE, from 0%to 2%in 10 min) to obtain benzyl (R) -3-methyl-2- ( ( (trifluoromethyl) sulfonyl) oxy) butanoate (6.70 g, 19.69 mmol, yield: 78.7 %) as a color-less oil.

LCMS (ESI) calcd. for C₁₃H₁₅F₃O₅S [M+NH₄] ⁺ m/z 358.1, found: 358.4.

Step 6: Synthesis of tert-butyl 7- ( (S) -1- (benzyloxy) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate

A mixture of benzyl (R) -3-methyl-2- ( ( (trifluoromethyl) sulfonyl) oxy) butanoate (376 mg, 1.10 mmol) and tert-butyl 2, 7-diazaspiro [4.4] nonane-2-carboxylate (250 mg, 1.10 mmol) in THF (10 mL) was stirred at r.t. for 2h, the reaction was monitored by LCMS. After completion, the mixture was diluted with EtOAc (20) and water (40 mL) , then extracted with EtOAc (20 mL x 3) , the combined organic layer was washed with brine (40 mL) , dried over Na₂SO₄ and concentrated , the residual was purified by silica gel column chro-matography (eluting with EtOAc/PE, from 0%to 10%in 15 min) to obtain tert-butyl 7- ( (S) -1- (benzyloxy) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (200 mg, 0.48 mmol, yield: 43.6%) as a colorless oil.

LCMS (ESI) calcd. for C₂₄H₃₆N₂O₄ [M+H] ⁺ m/z 417.3, found: 418.2.

Step 7: Synthesis of benzyl (2S) -3-methyl-2- (2, 7-diazaspiro [4.4] nonan-2-yl) butanoate hydrochloride

A mixture of tert-butyl 7- ( (S) -1- (benzyloxy) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (200 mg, 0.48 mmol) in 4M HCl in dioxane (3 mL) was stirred at r.t. for 1h under N₂ atmosphere, the reaction was moni-tored by LCMS. After completion, the mixture was concentrated to afford benzyl (2S) -3-methyl-2- (2, 7-diazaspiro [4.4] nonan-2-yl) butanoate hydrochloride (169 mg, 0.48 mmol, yield: 100.0%) as a white solid.

LCMS (ESI) calcd. for C₁₉H₂₈N₂O₂ [M+H] ⁺ m/z 317.2, found: 317.6.

Step 8: Synthesis of benzyl (2S) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanoate

To a mixture of benzyl (2S) -3-methyl-2- (2, 7-diazaspiro [4.4] nonan-2-yl) butanoate hydrochloride (169 mg, 0.48 mmol) , DIEA (619 mg, 4.79 mmol) and (R) -1-tritylaziridine-2-carboxylic acid (175 mg, 0.48 mmol) in ACN (5 mL) was added HATU (273 mg, 0.72mmol) , the mixture was stirred at r.t. for 3 h under N₂ atmosphere, the reaction was monitored by LCMS. After completion, the mixture was purified by reverse phase column (eluting with MeCN/H₂O, from 5%to 88%in 35 min) to afford benzyl (2S) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanoate (210 mg, 0.33 mmol, yield: 69.6%) as a light yellow solid.

LCMS (ESI) calcd. for C₄₁H₄₅N₃O₃ [M+H] ⁺ m/z 628.4, found: 629.6.

Step 9: Synthesis of (2S) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanoic acid

A mixture of benzyl (2S) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanoate (210 mg, 0.33 mmol) and 10%Pd/C (40 mg) in MeOH (5 mL) was stirred at room temperature for 16 h under H₂ atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the fil-trate was concentrated to afford (2S) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanoic acid (120 mg, 0.22 mmol, yield: 66.7 %) as a white solid.

LCMS (ESI) calcd. for C₃₄H₃₉N₃O₃ [M+H] ⁺ m/z 538.3, found: 538.7.

Step 10: Synthesis of (2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanamide

To a solution of (2S) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanoic acid (16 mg, 0.03 mmol) in DMF (1 mL) were added HATU (16 mg, 0.04 mmol) and DIEA (19 mg, 0.14 mmol) at 0-10℃. The resulting mixture was stirred at RT for 10 min. Then (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundeca phane-5, 7-dione (22 mg, 0.03 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 30 mL) , the combined organic phase was washed with 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 af-ford (2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 1 0-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] heptanacycloundeca-phane-4-yl) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanamide (27 mg, 73 %) as a yellow solid.

LCMS (ESI) calcd. for C₇₆H₈₈N₁₀O₇S [M+H] ⁺ m/z 1285.7.

Step 11: Synthesis of (2S) -2- (7- ( (R) -aziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyeth-yl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -3-methylbutanamide

To a stirred solution of (2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundeca-phane-4-yl) -3-methyl-2- (7- ( (R) -1-tritylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) butanamide (27 mg, 0.02 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was washed with sat. NaHCO₃ (10 mL) , brine (10 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure, the residue was puri-fied by pre-HPLC (eluting with CH₃CN/H₂O (0.1%NH₄HCO₃) from 20%to 70%) to give (2S) -2- (7- ( (R) -aziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyeth-yl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -3-methylbutanamide (1.4 mg, 6.4 %) as a white solid.

LCMS (ESI) calcd. for C₅₇H₇₄N₁₀O₇S [M+H] ⁺ m/z 1043.6, found: 1045.2.

¹H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 1.9 Hz, 1H) , 8.40 (s, 1H) , 8.22 (m, 1H) , 7.83 (d, J =9.8 Hz, 2H) , 7.74 (d, J = 8.4 Hz, 1H) , 7.57 (d, J = 8.7 Hz, 1H) , 5.98 -5.88 (m, 1H) , 5.33 (s, 1H) , 4.73 (d, J = 10.4 Hz, 1H) , 4.49 (s, 1H) , 4.37 -4.21 (m, 2H) , 4.07 (m, 1H) , 3.75 (m, 1H) , 3.67 -3.45 (m, 7H) , 3.42 -3.30 (m, 8H) , 3.27 -3.15 (m, 4H) , 2.96 (d, J = 14.2 Hz, 1H) , 2.78 (m, 3H) , 2.61 (m, 3H) , 2.54 -2.50 (m, 3H) , 2.47 -2.43 (m, 2H) , 2.34 (dd, J = 20.4, 9.5 Hz, 2H) , 2.18 -2.09 (m, 1H) , 2.03 -1.54 (m, 7H) , 1.34 (d, J = 6.0 Hz, 3H) , 1.24 -1.12 (m, 2H) , 1.04 -0.74 (m, 9H) , 0.28 (s, 3H) .

Example 34

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting N- (1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carbonyl) -N-methyl-L-valine with (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid in the Step 3 of Example 26, the title compound was prepared by the same procedures as described for Example 26.

Example 35

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoro-ethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting bromoethane with 2-bromo-1, 1, 1-trifluoroethane in the Step of Example 34, the title compound was prepared by the same procedures as described for Example 34.

Example 36

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid with (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetic acid in the Step 3 of Example 34, the title compound was prepared by the same procedures as described for Example 34.

Example 37

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting triethyl (ethynyl) silane with 4- (prop-2-yn-1-yl) morpholine in the Step 1 and substituting N- (1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carbonyl) -N-methyl-L-valine with (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid in the Step 3 of Example 26, the title compound was prepared by the same procedures as described for Example 26.

Example 38

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting bromoethane with 2-bromo-1, 1, 1-trifluoroethane in the Step of Example 37, the title com-pound was prepared by the same procedures as described for Example 37. Example 39

1-acryloyl-N- ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyri-din-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Step 1: Synthesis of benzyl N- (tert-butoxycarbonyl) -N-methyl-L-valinate

To a stirred solution of (S) -2, 3-bis (tert-butoxycarbonyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylic acid (2.31 g, 10.0 mmol) in DMF (20 mL) was added K₂CO₃ (2.72 g, 20.0 mmol) and (bromome-thyl) benzene (2.05 g, 12.0 mmol) at r.t.. The reaction mixture was stirred at r.t. for 3 h. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 50 mL) . The organic layers were combined, washed with saturated NaCl (2 x 50 mL) , dried over anhydrous Na₂SO₄ and concentrated to give the crude product which was purified by silica gel column (eluting with EA/PE from 0%to 10%) to give benzyl N- (tert-butoxycarbonyl) -N-methyl-L-valinate (2) (2.9 g, 90%) as a colorless oil.

LCMS (ESI) calcd. for C₁₈H₂₇NO₄ [M-H] ⁺ m/z 321.2, found: 322.6.

Step 2: Synthesis of benzyl methyl-L-valinate HCl salt

To a stirred solution of benzyl N- (tert-butoxycarbonyl) -N-methyl-L-valinate (2.90 g, 9.03 mmol) in DCM (10 mL) was added HCl/dioxane (15 mL, 4M) , the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product benzyl methyl-L-valinate HCl salt (2.3 g, 99%) as a white solid.

LCMS (ESI) calcd. for C₁₃H₁₉NO₂ [M+H] ⁺ m/z 221.1, found: 222.9.

Step 3: Synthesis of tert-butyl (S) -4- ( (1- (benzyloxy) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate

To a solution of benzyl methyl-L-valinate HCl salt (362 mg, 1.41 mmol) in DMF (3 mL) was added 1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carboxylic acid (347 mg, 1.41 mmol) , HATU (770 mg, 2.03 mmol) and DIEA (404 mg, 4.00 mmol) at rt. The resulting mixture was stirred atrt overnight. After com-pletion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 10 mL) , the combined organic phase was washed with saturated NaCl (10 mL) , then dried over Na₂SO₄, following with concen-tration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc/PE from 0%to 35%to afford tert-butyl (S) -4- ( (1- (benzyloxy) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (300 mg, 47 %) as a colorless oil.

LCMS (ESI) calcd. for C₂₄H₃₅FN₂O₅ [M+H] ⁺ m/z 450.3, found: 396.1.

Step 4: Synthesis of N- (1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carbonyl) -N-methyl-L-valine

To a solution of tert-butyl (S) -4- ( (1- (benzyloxy) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (300 mg, 0.667 mmol) in CH₃OH (10 mL) was added Pd/C (60 mg, 10%) , the resulting mixture was stirred at rt for 3 hours under H₂ atmosphere (1 atm) . The reaction was monitored by LCMS. After completion, the mixture was filtered and concentrated to give the N- (1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carbonyl) -N-methyl-L-valine (230 mg, 96%) as a color-less oil.

LCMS (ESI) calcd. for C₁₇H₂₉FN₂O₅ [M+H] ⁺ m/z 360.2, found: 361.6.

Step 5: Synthesis of tert-butyl 4- ( ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundeca-phane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate

To a stirred solution of (6³S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloun decaphane-5, 7-dione (45 mg, 0.06 mmol) and N- (1- (tert-butoxycarbonyl) -4-fluoropiperidine-4-carbonyl) -N-methyl-L-valine (18 mg, 0.072 mmol) and 1-methyl-1H-imidazole (9 mg, 0.12 mmol) in ACN (2 mL) was added TCFH (21 mg, 0.078 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 tert-butyl 4- ( ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundeca-phane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (20 mg, 30%) as a white solid.

LCMS (ESI) calcd. for C₅₈H₇₈FN₉O₉S [M+H] ⁺ m/z 1095.6, found: 1097.1.

Step 6: Synthesis of N- ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10 , 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide TFA salt

To a stirred solution of tert-butyl 4- ( ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundeca-phane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) (methyl) carbamoyl) -4-fluoropiperidine-1-carboxylate (20 mg, 0.018 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 and lyophilized to give N- ( (2S) -1- ( ( (63S, 4S, Z) -11-ethyl-12- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-61, 62, 63, 64, 65, 66-hexahydro-11H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundeca-phane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide (21 mg, 100%) of its TFA salt as a yellow solid.

LCMS (ESI) calcd. for C₅₃H₇₀FN₉O₇S [M+H] ⁺ m/z 995.5, found: 997.1.

Step 7: Synthesis of 1-acryloyl-N- ( (2S) -1- ( ( (63S, 4S, Z) -11-ethyl-12- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyri din-3-yl) -10, 10-dimethyl-5, 7-dioxo-61, 62, 63, 64, 65, 66-hexahydro-11H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6(1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4 -carboxamide

To a stirred solution of N- ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundeca-phane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide TFA salt (21 mg, 0.019 mmol) in DCM (2 mL) was added DIEA (10 mg, 0.076 mmol) and acryloyl chloride (4 mg, 0.038 mmol) at rt, the resulting mixture was stirred at rt overnight. 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 1-acryloyl-N- ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyrid-in-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide (6 mg, 30%) as a white solid.

LCMS (ESI) calcd. for C₅₆H₇₂FN₉O₈S [M+H] ⁺ m/z 1049.5, found: 1051.1.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (d, J = 1.5 Hz, 1H) , 8.48 -8.42 (m, 2H) , 7.85 -7.78 (m, 2H) , 7.74 (d, J = 7.7 Hz, 1H) , 7.56 (d, J = 8.6 Hz, 1H) , 6.89-6.80 (m, 1H) , 6.15-6.10 (m, 1H) , 5.69 (d, J = 11.2 Hz, 1H) , 5.46-5.41 (m, 1H) , 5.09 -5.02 (m, 1H) , 4.70 (d, J = 11.5 Hz, 1H) , 4.38 -4.15 (m, 6H) , 4.12-3.94 (m, 3H) , 3.60-3.54 (m, 8H) , 3.24 (s, 3H) , 3.07 (d, J = 5.3 Hz, 4H) , 2.99 -2.92 (m, 2H) , 2.89-2.86 (m, 1H) , 2.79-2.70 (m, 1H) , 2.42-2.33 (m, 3H) , 2.23-1.92 (m, 6H) , 1.82-1.73 (m, 2H) , 1.56-1.43 (m, 2H) , 1.33 (d, J =6.0 Hz, 3H) , 1.01-1.98 (m, 1H) , 0.94 -0.81 (m, 9H) , 0.76 (d, J = 6.4 Hz, 3H) , 0.31 (s, 3H) .

Example 40

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide in the Step 1 of Example 37, the title compound was prepared by the same procedures as described for Example 37.

Example 41

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide in the Step 1 of Example 38, the title compound was prepared by the same procedures as described for Example 38.

Example 42

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth yl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid with (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetic acid in the Step 3 of Example 41, the title compound was prepared by the same procedures as described for Example 41.

Example 43

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting bromoethane with 2-bromo-1, 1, 1-trifluoroethane in the Step of Example 42, the title compound was prepared by the same procedures as described for Example 42.

Example 44

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N - ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 1- (methylsulfonyl) -4- (prop-2-yn-1-yl) piperazine in the Step 1 of Example 37, the title compound was prepared by the same procedures as described for Ex-ample 37.

Example 45

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting bromoethane with 2-bromo-1, 1, 1-trifluoroethane in the Step of Example 44, the title compound was prepared by the same procedures as described for Example 44.

Example 46

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (methylsulfonyl) piperazin-1-yl) prop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid with (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetic acid in the Step 3 of Example 44, the title compound was prepared by the same procedures as described for Example 44.

Example 47

Substituting bromoethane with 2-bromo-1, 1, 1-trifluoroethane in the Step of Example 46, the title compound was prepared by the same procedures as described for Example 46.

Example 48

(2S) -4- (3- (5- ( (2²S, 6⁴S, 4S) -4- ( (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspi-ro [4.4] nonan-2-yl) -3-methylbutanamido) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -N, N-dimethylmorpholine-2-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with (S) -N, N-dimethyl-4- (prop-2-yn-1-yl) morpholine-2-carboxamide in the Step 1 of Example 37, the title compound was prepared by the same procedures as described for Example 37.

Example 49

Substituting bromoethane with 2-bromo-1, 1, 1-trifluoroethane in the Step of Example 48, the title compound was prepared by the same procedures as described for Example 48.

Example 50

(2S) -4- (3- (5- ( (2²S, 6⁴S, 4S) -4- ( (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbon-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetamido) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza -2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -N, N-dimethylmorpholine-2-carboxamide

Substituting (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid with (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetic acid in the Step 3 of Example 48, the title compound was prepared by the same procedures as described for Example 48.

Example 51

(2S) -4- (3- (5- ( (2²S, 6⁴S, 4S) -4- ( (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbon-yl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetamido) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8 -oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -N, N-dimethylmorpholine-2-carboxamide

Substituting bromoethane with 2-bromo-1, 1, 1-trifluoroethane in the Step of Example 50, the title compound was prepared by the same procedures as described for Example 50.

Example 52

1-acryloyl-N- ( (2S) -1- ( ( (6³S, 4S, Z) -1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-yl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide in the Step of Example 39, the title compound was prepared by the same procedures as described for Example 39.

Example 53

1-acryloyl-N- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1²- (5- (3- (1, 1-dioxidothiomorpholino) prop-1-yn-1-yl) -2- ( (S) -1-methoxyeth-yl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting hexahydropyridazine-3-carboxylic acid with 2, 3-diazabicyclo [3.1.1] heptane-4-carboxylic acid in the Step of Example 52, the title compound was prepared by the same procedures as described for Example 52.

Example 54

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (6³S, 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-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide in the Step and substituting acrylic acid with 4- (dimethylamino) -4-methylpent-2-ynoic acid in the Step 7 of Ex-ample 39, the title compound was prepared by the same procedures as described for Example 39.

Example 55

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (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-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (prop-2-yn-1-yl) thiomorpholine 1, 1-dioxide in the Step 7 of Example 53, the title compound was prepared by the same procedures as described for Example 53.

Example 56

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (2²S, 6³S, 4S) -1²- (5- (3- (1, 1-dioxidothiomorpholi-no) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting tert-butyl ( (6³S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6³S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) c arbamate in the Step 1 of Example 54, the title compound was prepared by the same procedures as de-scribed for Example 54.

Example 57

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate in the Step 1 of Example 55, the title compound was prepared by the same procedures as described for Example 55.

Example 58

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyeth-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indo-la-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (6³S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate in the Step 1 of Example 25, the title compound was prepared by the same procedures as described for Example 25.

Example 59

1- (4- (dimethylamino) -4-methylpent-2-ynoyl) -N- ( (2S) -1- ( ( (2²S, 6³S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyeth-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6³S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate in the Step 1 of Example 25, the title compound was prepared by the same procedures as de-scribed for Example 25.

Example 60

1-acryloyl-N- ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacy cloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (6³S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate in the Step 1 and substituting acrylic acid with 4- (dimethylamino) -4-methylpent-2-ynoic acid in the Step 7 of Example 25, the title compound was prepared by the same procedures as described for Example 25.

Example 61

1-acryloyl-N- ( (2S) -1- ( ( (6³S, 4S, Z) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-di

me-thyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacy cloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting tert-butyl ( (6³S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate with tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate in the Step 1 of Example 60, the title compound was prepared by the same procedures as described for Example 60.

Example 62

1-acryloyl-N- ( (2S) -1- ( ( (6³S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dime thyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundeca-phane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting tert-butyl ( (6³S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6³S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) c arbamate in the Step 1 of Example 60, the title compound was prepared by the same procedures as de-scribed for Example 60.

Example 63

1-acryloyl-N- ( (2S) -1- ( ( (6⁴S, 4S) -1¹-ethyl-1²- (5-ethynyl-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dime thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -4-fluoro-N-methylpiperidine-4-carboxamide

Substituting tert-butyl ( (6³S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate in the Step 1 of Example 60, the title compound was prepared by the same procedures as described for Example 60.

Example 64

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (1, 1-dioxidothiomorpholino) -4-hydroxybut-1-yn-1-yl) -2- ( (S) -1-methoxyeth-yl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (1-hydroxybut-3-yn-2-yl) thiomorpholine 1, 1-dioxide in the Step 1 of Example 16, the title compound was prepared by the same procedures as de-scribed for Example 16.

Example 65

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Step 1: Synthesis of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4- (oxetan-3-yl) piperazine

To a stirred solution of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate (300 mg, 0.71 mmol) in DCM (10 mL) was added 1- (oxetan-3-yl) piperazine (121 mg, 0.85 mmol) and DIEA (227 mg, 1.77 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 7%) to give (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4- (oxetan-3-yl) piperazine (227 mg, 81.6 %) as a yellow oil.

LCMS (ESI) calcd. for C₁₈H₂₄BrN₃O₂ [M+H] ⁺ m/z 394.1, found: 394.5.

Step 2: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] heptanacy cloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (200 mg, 0.28 mmol) , (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4- (oxetan-3-yl) piperazine (111 mg, 0.28 mmol) and K₂CO₃ (117 mg, 0.85 mmol) in 1, 4-dioxane/H₂O (7 mL, V: V= 6: 1 ) was added Pd (dppf) Cl₂ (20 mg, 0.03 mmol) at r.t.. The reaction mixture was stirred at 85℃ under N₂ for 8 h. After completion under reduced pressure to obtain crude product which was purified by rsilica gel column (elut-ing with MeOH/DCM from 0%to 5%) to give tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) carbamate (240 mg, 95.1 %) as a brown solid.

LCMS (ESI) calcd. for C₄₈H₆₀N₈O₇S [M+H] ⁺ m/z 893.4, found: 893.9.

Step 3: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] h eptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) carbamate (220 mg, 0.25 mmol) in DMF (5 mL) was added Cs₂CO₃ (241 mg, 0.74 mmol) and EtI (115 mg, 0.74 mmol) at 0℃., the resulting mixture was stirred at r.t. for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with DCM/MeOH (11 mL, V:V = 10: 1) , washed with water (10 mL x 3) and saturated NaCl (10 x 2 mL) , then dried over Na₂SO₄, fol-lowing with concentration under reduced pressure to obtain crude product which was purified by rsilica gel column (eluting with MeOH/DCM from 0%to 5%) to give tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) carbamate (60 mg, 26.4 %) as a white solid.

LCMS (ESI) calcd. for C₅₀H₆₄N₈O₇S [M+H] ⁺ m/z 921.5, found: 922.0.

Step 4: Synthesis of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-yl) pyri-din-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] heptanacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) carbamate (60 mg, 0.065 mmol) in dichloromethane (5 mL) was added TFA (1 mL) slowly at r.t., the resulting mixture was stirred at rt for 2 h. The reaction mixture was concen-trated to give the crude product (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) 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] heptanacycloundecaphane-5, 7-dione (60 mg, crude ) as a light yellow solid.

LCMS (ESI) calcd. for C₅₀H₆₄N₈O₇S [M+H] ⁺ m/z 821.5, found: 822.0.

Step 5: Synthesis of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn -1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) 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] heptanacycloundecaphane-5, 7-dione (60 mg, 0.065 mmol) and (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid (10 mg, 0.085 mmol) and NMI (21 mg, 0.260 mmol) in ACN/DMF (3.5 mL, V: V= 6: 1) was added TCFH (27 mg, 0.098 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 HPLC (ACN/H₂O (0.5 %NH₄HCO₃) from 40%to 95%in 30 min) to give (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3- (4- (oxetan-3-yl) piperazin-1-yl) prop-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (19 mg, 31.9 %) as a white solid.

LCMS (ESI) calcd. for C₅₁H₆₄N₈O₆S [M+H] ⁺ m/z 917.5, found: 918.0.

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J = 1.9 Hz, 1H) , 8.41 (d, J = 10.7 Hz, 2H) , 7.87 (d, J = 1.9 Hz, 1H) , 7.82 (s, 1H) , 7.75 (d, J = 8.5 Hz, 1H) , 7.58 (d, J = 8.7 Hz, 1H) , 5.93 (d, J = 11.2 Hz, 1H) , 5.38 (s, 1H) , 4.66 (d, J = 11.2 Hz, 1H) , 4.50 (dd, J = 13.0, 6.4 Hz, 3H) , 4.40 (t, J = 6.0 Hz, 2H) , 4.35 -4.24 (m, 2H) , 4.07 (dd, J = 14.7, 7.4 Hz, 1H) , 3.61 -3.51 (m, 4H) , 3.39 (dd, J = 12.6, 6.1 Hz, 1H) , 3.23 (s, 3H) , 3.14 (dd, J = 14.7, 7.2 Hz, 1H) , 2.94 (d, J = 14.3 Hz, 1H) , 2.67 -2.55 (m, 4H) , 2.42 (d, J = 14.9 Hz, 2H) , 2.36 -2.12 (m, 6H) , 1.57 (t, J = 9.1 Hz, 1H) , 1.36 (d, J = 6.0 Hz, 3H) , 1.24 (dt, J = 11.3, 5.8 Hz, 2H) , 1.20 -1.14 (m, 2H) , 1.13 -1.04 (m, 5H) , 0.92 -0.82 (m, 5H) , 0.33 (s, 3H) .

Example 66

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (1'-methyl- [1, 4'-bipiperidin] -4-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4-ethynyl-1'-methyl-1, 4'-bipiperidine in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16.

Example 67

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (1- (tetrahydro-2H-pyran-4-yl) azetidi n-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) -in dola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 3-ethynyl-1- (tetrahydro-2H-pyran-4-yl) azetidine in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Ex-ample 16.

Example 68

(1r, 2R, 3S) -N- ( (64S, 4S, Z) -12- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -11-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Step 1: Synthesis of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4-cyclopropylpiperazine

To a solution of 1-cyclopropylpiperazine (126 mg, 1.00 mmol) in DCM (5 mL) were added DIEA (129 g, 1.00 mmol) and a solution of (S) -3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl 4-methylbenzenesulfonate (212 mg, 0.500 mmol) in DCM (5 mL) at rt, the resulting mixture was stirred at rt for 2 h. After completion, the mixture was concentrated under reduced pressureto give a reside which was purified by silica gel column chromatography (eluting with EtOAc/PE from 0%to 40%) to obtain (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4-cyclopropylpiperazine (180 mg, yield: 95%) as a yellow oil.

LCMS (ESI) calcd. for C₁₈H₂₄BrN₃O [M+H] + m/z 377.1, found 378.5.

Step 2: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 1 0-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] heptanacycloundecaphane-4-yl) carbamate

A mixture of (S) -1- (3- (5-bromo-6- (1-methoxyethyl) pyridin-3-yl) prop-2-yn-1-yl) -4-cyclopropylpiperazine (100 mg, 0.26 mmol) , tert-butyl ( (6⁴S, 4S, Z) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (200 mg, 0.286 mmol) , K₂CO₃ (106 mg, 0.78 mmol) and Pd (dppf) Cl₂ (20 mg, 0.026 mmol) in dioxane (4 mL) and H₂O (1 mL) was stirred at 85℃ under N₂ for 8 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 15%) to give tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanac ycloundecaphane-4-yl) carbamate (120 mg, 53 %) as a yellow solid.

LCMS (ESI) calcd. for C₄₈H₆₀N₈O₆S [M+H] ⁺ m/z 876.4, found: 877.9.

Step 3: Synthesis of tert-butyl ( (64S, 4S, Z) -12- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -11-ethyl-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] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) 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] heptanac ycloundecaphane-4-yl) carbamate (120 mg, 0.138 mmol) in DMF (3 mL) were added Cs₂CO₃ (90 mg, 0.276 mmol) and Iodoethane (42 mg, 0.276 mmol) at 0℃, the resulting mixture was stirred at rt overnight. After completion, the reaction mixture was diluted with EtOAc (20 mL) , washed with water (10 mL x 2) and saturated NaCl (10 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 100%) to give tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) carbamate (50 mg, 40%) as a yellow solid.

LCMS (ESI) calcd. for C₅₀H₆₄N₈O₆S [M+H] ⁺ m/z 904.5, found: 906.0.

Step 4: Synthesis of (6⁴S, 4S, Z) -4-amino-1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3 -yl) -1¹-ethyl-10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] hept anacycloundecaphane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) carbamate (60 mg, 0.066 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 concen-trated. 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-1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (50 mg, yield: 94%) as a yellow solid.

LCMS (ESI) calcd. for C₄₅H₅₆N₈O₄S [M+H] ⁺ m/z 804.4, found: 805.9.

Step 5: Synthesis of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of ( (6⁴S, 4S, Z) -4-amino-1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin -3-yl) -1¹-ethyl-10, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione (50 mg, 0.062 mmol) and (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid (8 mg, 0.074 mmol) and 1-methyl-1H-imidazole (15 mg, 0.093 mmol) in ACN (2 mL) was added TCFH (26 mg, 0.093 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 prod-uct was purified by pre-HPLC (ACN/H₂O (0.5 %NH₄HCO₃) from 20%to 95%in 30 min) to give (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) py ridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 1 (16 mg, 29%) as a white solid and (1r, 2R, 3S) -N- ( (64S, 4S, Z) -12- (5- (3- (4-cyclopropylpiperazin-1-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -11-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide as atropisomer 2 (i.e., compound of Example 68) (10 mg, 18%) as a white solid.

LCMS (ESI) calcd. for C₅₁H₆₄N₈O₅S [M+H] ⁺ m/z 900.5, found: 901.9.

atropisomer 1: ¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (d, J = 1.8 Hz, 1H) , 8.41-8.39 (m, 2H) , 7.97 (d, J = 1.9 Hz, 1H) , 7.80 (s, 1H) , 7.72 (d, J = 8.6 Hz, 1H) , 7.52 (d, J = 8.7 Hz, 1H) , 5.87 (d, J = 11.1 Hz, 1H) , 5.29 (t, J = 7.7 Hz, 1H) , 4.71 (d, J = 10.9 Hz, 1H) , 4.47 (dd, J = 9.9, 4.8 Hz, 1H) , 3.95 -3.87 (m, 2H) , 3.84 -3.77 (m, 1H) , 3.59 -3.47 (m, 4H) , 3.23 (d, J = 14.8 Hz, 1H) , 3.14 -2.99 (m, 5H) , 2.64-2.63 (m, 1H) , 2.53 (s, 8H) , 2.33-2.31 (m, 2H) , 2.13-2.11 (m, 1H) , 1.62-1.57 (m, 2H) , 1.25 -1.03 (m, 15H) , 0.89 (s, 3H) , 0.45 (s, 3H) , 0.39-0.35 (m, 2H) , 0.27 -0.21 (m, 2H) .

atropisomer 2 (i.e., compound of Example 68) : ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (d, J = 2.1 Hz, 1H) , 8.40-8.37 (m, 2H) , 7.83 (d, J = 1.9 Hz, 1H) , 7.80 (s, 1H) , 7.73 (d, J = 8.7 Hz, 1H) , 7.56 (d, J = 8.7 Hz, 1H) , 5.91 (d, J = 11.2 Hz, 1H) , 5.36 (t, J = 8.4 Hz, 1H) , 4.64 (d, J = 10.9 Hz, 1H) , 4.46 (dd, J = 8.8, 3.6 Hz, 1H) , 4.32 -4.22 (m, 2H) , 4.07-4.01 (m, 1H) , 3.59 -3.47 (m, 4H) , 3.21 (s, 3H) , 3.11 (dd, J = 14.7, 7.2 Hz, 2H) , 2.91 (d, J = 14.4 Hz, 2H) , 2.65-2.54 (m, 4H) , 2.45-2.38 (m, 6H) , 2.31-2.27 (m, 1H) , 2.16 -2.09 (m, 1H) , 1.61-1.52 (m, 2H) , 1.33 (d, J = 6.1 Hz, 3H) , 1.25 -0.98 (m, 10H) , 0.87-0.86 (m, 6H) , 0.37-0.24 (m, 7H) .

Example 69

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1²- (5- (3- (1, 4-oxazepan-4-yl) prop-1-yn-1-yl) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (prop-2-yn-1-yl) -1, 4-oxazepane in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16.

Example 70

(1r, 2R, 3S) -N- ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16.

Example 71

(1r, 2R, 3S) -N- ( (2²R, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²R, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate in the Step 1 of Example 16, the title compound was prepared by the same procedures as described for Example 16.

Example 72

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinobut-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with 4- (but-3-yn-2-yl) morpholine in the Step 1 of Exam-ple 16, the title compound was prepared by the same procedures as described for Example 16.

Example 73

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with (R) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 1 and substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-carboxylic acid in the Step 4 of Example 7, the title compound was pre-pared by the same procedures as described for Example 7.

Example 74

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting 4- (prop-2-yn-1-yl) morpholine with (R) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 1 of Example 7, the title compound was prepared by the same procedures as described for Example 7.

Example 75

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (S) -3- (4-methylpiperazin-1-yl) but-1-yn-1-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting (R) -1- (but-3-yn-2-yl) -4-methylpiperazine with (S) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 1 of Example 73, the title compound was prepared by the same procedures as described for Example 73.

Example 76

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (S) -3- (4-methylpiperazin-1-yl) but-1-yn-1 -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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting (R) -1- (but-3-yn-2-yl) -4-methylpiperazine with (S) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 1 of Example 74, the title compound was prepared by the same procedures as described for Example 74.

Example 77

Substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-carboxylic acid in the Step 19 of Example 78, the title compound was prepared by the same procedures as described for Example 78.

Example 78

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Step 1: Synthesis of (S) -but-3-yn-2-yl methanesulfonate

To a stirred solution of (S) -but-3-yn-2-ol 3 (300 mg, 4.28 mmol) in DCM (5mL) and DIEA (1.38g, 10.70 mmol) was added MsCl (736 mg, 6.42 mmol) , the resulting mixture was stirred at rt for 5 h. The re-action 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 10%) to give (S) -but-3-yn-2-yl methanesulfonate (470 mg, 74.2%) as a brown oil.

Step 2: Synthesis of (R) -4- (but-3-yn-2-yl) morpholine

To a stirred solution of (S) -but-3-yn-2-yl methanesulfonate (230 mg, 1.55 mmol) in THF (4 mL) was addedmorpholine (677 mg, 7.77 mmol) dropwisely at rt, the resulting mixture was stirred at 75℃ for 5 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 80%) to afford (R) -4- (but-3-yn-2-yl) morpholine (69 mg, 32.0 %) as a yellow oil.

LCMS (ESI) calcd. for C₈H₁₃NO [M+H] ⁺ m/z 140.1, found: 140.3.

Step 3: Synthesis of (S) -2- (1-methoxyethyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine

To a stirred solution of (S) -3-bromo-2- (1-methoxyethyl) pyridine (80.1 g, 370.83 mmol) and B₂Pin₂ (113.1 g, 445.00 mmol) in 1, 4-dioxane (1000 mL) were added Pd (dppf) Cl₂ (23.1 g, 31.52 mmol ) and KOAc (109.2 g, 1.11 mol) . The reaction was stirred at 100℃ for 18 h under N₂ atmosphere. The reaction was monitored by LCMS. After completion, the reaction solution was concentrated under reduced pressure to give the residual which was purified by neutral Al₂O₃ column (eluting with EtOAc/PE from 0%to 100%) to afford (S) -2- (1-methoxyethyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (130.8 g) as a brown oil.

LCMS (ESI) calcd. for C₁₄H₂₂BNO₃ [M+H] ⁺ m/z 264.2, found: 264.5.

Step 4: Synthesis of (S) -3- (5-bromo-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate

To a stirred solution of 3- (5-bromo-2-iodo-1H-indol-3-yl) -2, 2-dimethylpropyl acetate (12.2 g, 27.17 mmol) , (S) -2- (1-methoxyethyl) -3- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (11.4 g, 43.47 mmol) and K₂CO₃ (11.3 g, 81.51 mmol) in 1, 4-dioxane (180 mL) and H₂O (45 mL) was added Pd (dppf) Cl₂ (2.0 g, 2.72 mmol) at rt. The reaction mixture was stirred at 90℃ under N₂ for 18 h. After completion, the reaction solution was concentrated under reduced pressure to remove 1, 4-dioxane to give the residual which was purified by silica gel column (eluting with EtOAc/PE from 0%to 80%) to afford (S) -3- (5-bromo-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (10.5 g, 84.1 %) as a yellow solid.

LCMS (ESI) calcd. for C₂₃H₂₇BrN₂O₃ [M+H] ⁺ m/z 459.1, found: 459.5.

Step 5: Synthesis of (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate

To a stirred solution of (S) -3- (5-bromo-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (12.4 g, 27.10 mmol) in DMF (120 mL) were added Cs₂CO₃ (17.6 g, 54.19 mmol) and Iodoethane (6.3 g, 40.64 mmol) at 0℃, the resulting mixture was stirred at rt for 18 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (200 mL) , washed with water (1000 mL x 2) and saturated NaCl (1000 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 (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (10.4 g, 79.0 %) as a brown solid.

LCMS (ESI) calcd. for C₂₅H₃₁BrN₂O₃ [M+H] ⁺ m/z 487.2, found: 487.6.

Step 6: Synthesis of (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropan-1-ol

To a solution of (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (10.4 g, 21.42 mmol) in THF (100 mL) , MeOH (50 mL) and H₂O (50 mL) was added LiOH (2.7 g, 64.26 mmol) at 0-10℃, the resulting mixture was stirred at 0-10℃ for 20 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the residue. The residue was di-luted with H₂O and acidified to pH = 4-5 with 2 N HCl. The resulting mixture was extracted with EtOAc (100 mL x 2) , the combined organic phase was washed with saturated NaCl (100 mL) , 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 80%) to afford (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropan-1-ol (5.0 g, 52.0 %) as a yellow solid.

LCMS (ESI) calcd. for C₂₃H₂₉BrN₂O₂ [M+H] ⁺ m/z 445.2, found: 445.6.

Step 7: Synthesis of (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate

To a stirred solution of (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropan-1-ol (5.0 g, 11.15 mmol) in DCM (50 mL) were added DIEA (2.9 g, 22.30 mmol) , DMAP (136 mg, 1.11 mmol) and Ac₂O (1.20 g, 11.71 mmol) at rt , t he resulting mixture was stirred at rt for 18 h. The reaction was moni-tored by LCMS. After completion, the reaction mixture was concetrated to give the crude product which was purified by silica gel column (eluting with EA/PE from 0%to 50%) to give (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (5.1 g, 94.3 %) as a pale yellow solid.

Step 8: Synthesis of (S) - (5- (3- (3-acetoxy-2, 2-dimethylpropyl) -5-bromo-1-ethyl-1H-indol-2-yl) -6- (1-methoxyethyl) pyridin-3-yl) boronic acid

To a stirred solution of (S) -3- (5-bromo-1-ethyl-2- (2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (5.1 g, 10.51 mmol) , B₂Pin₂ (4.0 g, 15.77 mmol) in THF (100 mL) was added [Ir (COD) Cl] ₂ (353 mg, 0.53 mmol) and dtbpy (423 mg, 1.58 mmol) at rt , the resulting mixture was stirred at 85℃ under N₂ for 24 h. The re-action was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was used to next step without purification.

Step 9: Synthesis of (S) -3- (5-bromo-1-ethyl-2- (5-hydroxy-2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate

To a stirred solution of crude (S) - (5- (3- (3-acetoxy-2, 2-dimethylpropyl) -5-bromo-1-ethyl-1H-indol-2-yl) -6- (1-methoxyethyl) pyridin-3-yl )boronic acid (4.5 g, 8.40 mmol) in THF (300 mL) was added H₂O₂ (4.8 g, 41.98 mmol) at r.t. The reaction mixture was stirred at r.t. for 2 h. After completion, reaction mixture was diluted with EtOAc (60 mL) , washed with water (50 mL x 2) and saturated NaCl (50 mL) , then dried over Na₂SO₄, following with con-centration under reduced pressure to obtain the crude (S) -3- (5-bromo-1-ethyl-2- (5-hydroxy-2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (3.4 g, 80.9 %) as a yellow solid.

LCMS (ESI) calcd. for C₂₅H₃₁BrN₂O₄ [M+H] ⁺ m/z 503.2, found: 503.7.

Step 10: Synthesis of (S) -3- (2- (5- (benzyloxy) -2- (1-methoxyethyl) pyridin-3-yl) -5-bromo-1-ethyl-1H-indol-3-yl) -2, 2-dimethylpropy l acetate

To a stirred solution of crude (S) -3- (5-bromo-1-ethyl-2- (5-hydroxy-2- (1-methoxyethyl) pyridin-3-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (3.4 g, 6.79 mmol) in CH₃CN (68 mL) were added K₂CO₃ (2.8 g, 20.38 mmol) and BnBr (1.7 g, 10.19 mmol) , the resulting mixture was stirred at 85℃ for 16 h. The reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA/PE from 0%to 30%) to give (S) -3- (2- (5- (benzyloxy) -2- (1-methoxyethyl) pyridin-3-yl) -5-bromo-1-ethyl-1H-indol-3-yl) -2, 2-dimethylpropyl acetate (3.2 g, 79.4 %) as a yellow foam.

LCMS (ESI) calcd. for C₃₂H₃₇BrN₂O₄ [M+H] ⁺ m/z 593.2, found: 593.6.

Step 11: Synthesis of (S) -3- (2- (5- (benzyloxy) -2- (1-methoxyethyl) pyridin-3-yl) -1-ethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate

To a stirred solution of (S) -3- (2- (5- (benzyloxy) -2- (1-methoxyethyl) pyridin-3-yl) -5-bromo-1-ethyl-1H-indol-3-yl) -2, 2-dimethylpropyl acetate (3.2 g, 5.39 mmol) and B₂Pin₂ (2.1 g, 8.08 mmol) in 1, 4-dioxane (45 mL) were added Pd (dppf) Cl₂ (395 mg, 0.54 mmol ) and KOAc (1.6 g, 16.17 mol ) . The reaction mixture was stirred at 90℃ for 5 h under N₂ atmosphere. The reaction was monitored by LCMS. After completion, the reaction solu-tion was concentrated under reduced pressure to give the residual which was purified by silica gel col-umn (eluting with EtOAc/PE from 0%to 30%) to afford (S) -3- (2- (5- (benzyloxy) -2- (1-methoxyethyl) pyridin-3-yl) -1-ethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborola n-2-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetate (3.7 g) as a yellow oil.

LCMS (ESI) calcd. for C₃₈H₄₉BrN₂O₆ [M+H] ⁺ m/z 641.4, found: 641.9.

Step 12: Synthesis of methyl (S) -2- ( (S) -3- (4- (3- (3-acetoxy-2, 2-dimethylpropyl) -2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylate

To a stirred solution of methyl (S) -2- ( (S) -3- (4-bromothiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] hepta ne-4-carboxylate (11.9 g, 24.31 mmol) , (S) -3- (2- (5- (benzyloxy) -2- (1-methoxyethyl) pyridin-3-yl) -1-ethyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborola n-2-yl) -1H-indol-3-yl) -2, 2-dimethylpropyl acetat (15.6 g, 24.31 mmol) and K₂CO₃ (10.1 g, 73.19 mmol) in toluene/1, 4-dioxane/H₂O (350 mL, V: V: V = 3: 1: 1 ) was added Pd (dppf) Cl₂ (1.8 g, 2.46 mmol) at rt. The reaction mixture was stirred at 90℃ under N₂ for 22 h. After completion, the reaction solution was concen-trated under reduced pressure to remove 1, 4-dioxane and toluene, the residual was diluted with H₂O and extracted with EtOAc (100 mL x 2) , the combined organic phase was washed with saturated NaCl (200 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 80%) to afford methyl (S) -2- ( (S) -3- (4- (3- (3-acetoxy-2, 2-dimethylpropyl) -2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1 -ethyl-1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylate (17.2 g, 76.8 %) as a brown foam.

LCMS (ESI) calcd. for C₅₀H₆₂N₆O₉S [M+H] ⁺ m/z 923.4, found: 924.7.

Step 13: Synthesis of (S) -2- ( (S) -3- (4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethylpropyl) -1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylic acid

To a solution of methyl (S) -2- ( (S) -3- (4- (3- (3-acetoxy-2, 2-dimethylpropyl) -2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1 -ethyl-1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylate (17.4 g, 18.66 mmol) in THF (170 mL) , MeOH (45 mL) and H₂O (85 mL) was added LiOH (3.9 g, 93.28 mmol) at 0-10℃, the resulting mixture was stirred at rt for 17 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the residue. The residue was diluted with H₂O and acidified to pH = 4-5 with 2 N HCl. The resulting mixture was extracted with EtOAc (200 mL x 2) , the combined organic phase was washed with saturated NaCl (200 mL) , then dried over Na₂SO₄ and concentrated to give crude (S) -2- ( (S) -3- (4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethyl pro-pyl) -1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane -4-carboxylic acid (17.4 g) as a brown foam.

LCMS (ESI) calcd. for C₄₇H₅₈N₆O₈S [M+H] ⁺ m/z 867.4, found: 868.6.

Step 14: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) carba mate

To a solution of crude (S) -2- ( (S) -3- (4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethyl pro-pyl) -1H-indol-5-yl) thiazol-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane -4-carboxylic acid (13.0 g, 15.01 mmol) , HOBt (10.1 g, 75.06 mmol) and DIEA (64.0 g, 495.38 mmol) in DCM (1300 mL) under ice-water bath was added EDCI (80.6 g, 420.32 mmol) in batches. The reaction was gradually improved temperature to room temperature and stirred for 22 h, the reaction was monitored by LCMS. After completion, the reaction was washed with H₂O (700 mL x 3) and NH₄Cl (aq) (700 mL x 3) , 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 65%) to afford tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) carba mate (6.4 g, 50.3 %) as a yellow foam.

LCMS (ESI) calcd. for C₄₇H₅₆N₅O₆S [M+H] ⁺ m/z 849.4, found: 850.2.

Step 15: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1²- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-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] heptanacycloundecaphane-4-yl) carba mate (6.2 g, 7.28 mmol) in IPA (180 mL) was added Pd (OH) ₂/C (10%, 1.2 g) at rt , the resulting mixture was stirred at 85℃ for 60 h. The reaction was monitored by LCMS. After completion, the reaction mixture was filtered and the filtrate was concentrated to give crude tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbamate (6.6 g) as a white solid.

LCMS (ESI) calcd. for C₄₀H₅₀IN₆O₇S [M+H] ⁺ m/z 759.4, found: 760.2.

Step 16: Synthesis of 5- ( (6⁴S, 4S, Z) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-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] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate

To a solution of crude tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) 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] heptanacycloundecaphane-4-yl) carbama te (6.60 g, 8.71 mmol) in DCM (130 mL) were added DIEA (2.2 g, 17.41 mmol) and PhN (Tf) ₂ (3.1 g, 8.71 mmol) at 0-10℃. The resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure to obtain crude product which was purified by silica gel column eluting with (EtOAc/PE from 0%to 60%) to afford 5- ( (6⁴S, 4S, Z) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-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] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (4.8 g, 61.9 %) as a white foam.

LCMS (ESI) calcd. for C₄₁H₄₉F₃N₆O₉S₂ [M+H] ⁺ m/z 891.3, found: 892.2.

Step 17: Synthesis of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-yl) pyridin-3-yl) -10, 10-dime thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate

A mixture of 5- ( (6⁴S, 4S, Z) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-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] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (256 mg, 0.29 mmol) , (R) -4- (but-3-yn-2-yl) morpholine (60 mg, 0.43 mmol) , CuI (9 mg, 0.043 mmol) , TEA (87 mg, 0.86 mmol) and Pd (PPh₃) ₂Cl₂ (50 mg, 0.043 mmol) in DMF (4 mL) was stirred at 100℃ 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 MeOH/DCM from 0%to 10%) to obtain tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (120 mg, 47.1%) as a brown foam.

LCMS (ESI) calcd. for C₄₈H₆₁N₇O₇S [M+H] ⁺ m/z 880.4, found: 881.4.

Step 18: Synthesis of (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-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] heptanacycloundeca phane-5, 7-dione

To a stirred solution of tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (120 mg, 0.14 mmol) in dichloromethane (2 mL) was added TFA (0.6 mL) drop-wisely 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-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-yl) pyridin-3-yl) -1 0, 10-dimethyl-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-5, 7-dione which was used to next step without purification.

LCMS (ESI) calcd. for C₄₃H₅₃N₇O₅S [M+H] ⁺ m/z 780.4, found: 781.4.

Step 19: Synthesis of (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-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] hept anacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

To a stirred solution of crude (6⁴S, 4S, Z) -4-amino-1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-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] heptanacycloundecaphane-5, 7-dione (106 mg, 0.14 mmol) and (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid (16 mg, 0.14 mmol) and NMI (112 mg, 1.37 mmol) in ACN (1.5 mL) and DCM (1.5 mL) was added TCFH (58 mg, 0.20 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 CH₃CN/H₂O (0.1%NH₄HCO₃) from 20%to 80%) to give (1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3-morpholinobut-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide (26.8 mg) as a white solid.

LCMS (ESI) calcd. for C₄₉H₆₁N₇O₆S [M+H] ⁺ m/z 876.4, found: 876.5.

¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H) , 8.40 (d, J = 6.5 Hz, 2H) , 7.89 (s, 1H) , 7.81 (s, 1H) , 7.74 (d, J = 8.5 Hz, 1H) , 7.57 (d, J = 8.7 Hz, 1H) , 5.92 (d, J = 11.1 Hz, 1H) , 5.35 (s, 1H) , 4.65 (d, J = 10.9 Hz, 1H) , 4.46 (d, J = 4.7 Hz, 1H) , 4.37 -4.20 (m, 2H) , 4.05 (dd, J = 14.7, 7.6 Hz, 1H) , 3.89 (s, 2H) , 3.64 -3.46 (m, 6H) , 3.24 (d, J = 16.8 Hz, 3H) , 3.12 (dd, J = 15.1, 7.1 Hz, 1H) , 2.92 (d, J = 13.9 Hz, 1H) , 2.61 (d, J = 5.7 Hz, 1H) , 2.45 -2.36 (m, 2H) , 2.30 (d, J = 5.5 Hz, 1H) , 2.13 (t, J = 9.7 Hz, 1H) , 1.56 (s, 1H) , 1.48 (s, 5H) , 1.34 (d, J = 5.9 Hz, 3H) , 1.22 (s, 2H) , 1.16 (s, 2H) , 1.06 (dd, J = 10.5, 5.8 Hz, 5H) , 0.85 (d, J = 8.2 Hz, 5H) , 0.30 (s, 3H) .

Example 79

(1S, 2S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (S) -3-morpholinobut-1-yn-1-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] heptanacycloundecaphane-4-yl) -2-methylcyclopropane-1-carboxamide

Substituting (R) -4- (but-3-yn-2-yl) morpholine with (S) -4- (but-3-yn-2-yl) morpholine in the Step 17 and substituting (1r, 2R, 3S) -2, 3-dimethylcyclopropane-1-carboxylic acid with (1S, 2S) -2-methylcyclopropane-1-carboxylic acid in the Step 19 of Example 78, the title compound was prepared by the same procedures as described for Example 78.

Example 80

(1r, 2R, 3S) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (S) -3-morpholinobut-1-yn-1-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] heptanacycloundecaphane-4-yl) -2, 3-dimethylcyclopropane-1-carboxamide

Substituting (R) -4- (but-3-yn-2-yl) morpholine with (S) -4- (but-3-yn-2-yl) morpholine in the Step 17 of Example 78, the title compound was prepared by the same procedures as described for Example 78.

Example 81

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6³S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) acetamide

Substituting tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate with tert-butyl ( (2²S, 6³S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) c arbamate in the Step 1 of Example 23, the title compound was prepared by the same procedures as de-scribed for Example 23.

Example 82

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N - ( (2²S, 6³S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -in dola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) -3-methylbutanamide

Substituting (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetic acid with (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid in the Step 4 of Example 81, the title compound was prepared by the same procedures as described for Example 81.

Example 83

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6³S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) acetamide

Substituting 4- (prop-2-yn-1-yl) morpholine with (R) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 1 of Example 81, the title compound was prepared by the same procedures as described for Example 81.

Example 84

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting tert-butyl ( (2²S, 6³S, 4S) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹- (2, 2, 2-trifluor oethyl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacyclound ecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6⁴S, 4S) -10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹- (2, 2, 2-trifluor oethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate in the Step 1 of Example 83, the title compound was prepared by the same proce-dures as described for Example 83.

Example 85

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6³S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morp holina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) -3-methylbutanamide

Substituting 4- (prop-2-yn-1-yl) morpholine with (R) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 4 of Example 82, the title compound was prepared by the same procedures as described for Example 82.

Example 86

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N - ( (2²S, 6⁴S, 4S) -1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹- (2, 2, 2-trifluoroethyl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -in dola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetic acid with (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid in the Step 4 of Example 84, the title compound was prepared by the same procedures as described for Example 84.

Example 87

(2S) -2- (7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) pyridin-3-yl) -10, 10-dimet hyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Step 1: Synthesis of 5- ( (6⁴S, 4S, Z) -4-amino-1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoro-methanesulfonate

To a stirred solution of 5- ( (6⁴S, 4S, Z) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (330 mg, 0.37 mmol) in dichloromethane (10 mL) was added TFA (3 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was washed with sat. NaHCO₃ (10 mL) , brine (10 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product 5- ( (6⁴S, 4S, Z) -4-amino-1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoro-methanesulfonate (293 mg) as a yellow solid.

LCMS (ESI) calcd. for C₃₆H₄₁F₃N₆O₇S₂ [M+H] ⁺ m/z 791.2, found: 792.5.

Step 2: Synthesis of tert-butyl 7- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) -1 0, 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] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate

To a solution of (2S) -2- (7- (tert-butoxycarbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-methylbutanoic ac-id (121 mg, 0.37 mmol) in DMF (6 mL) were added HATU (183 mg, 0.37 mmol) and DIEA (239 mg, 1.85 mmol) at 0-10℃. The resulting mixture was stirred at RT for 30 min. Then 5- ( (6⁴S, 4S, Z) -4-amino-1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoro-methanesulfonate (293 mg, 0.37 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 di-luted with brine and extracted with EtOAc (2 x 30 mL) , the combined organic phase was washed with sat-urated NaCl (50 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to ob-tain crude product which was purified by silica gel column eluting with EtOAc/PE from 0%to 100%to afford tert-butyl 7- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (trifluoromethyl) sulfonyl) oxy) 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) amino) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (280 mg, 69 %) as a yellow solid.

LCMS (ESI) calcd. for C₅₃H₆₉F₃N₈O₁₀S₂ [M+H] ⁺ m/z 1099.5, found: 1101.0.

Step 3: Synthesis of 5- ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-4- ( (2S) -3-methyl-2- (2, 7-diazaspiro [4.4] nonan-2-yl) butanamido) -5, 7 -dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate

To a stirred solution of tert-butyl 7- ( (2S) -1- ( ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (trifluoromethyl) sulfonyl) oxy) 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) amino) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxylate (280 mg, 0.25 mmol) in dichloromethane (2 mL) was added TFA (0.5 mL) dropwisely at rt, the resulting mix-ture was stirred at rt for 1 h. The reaction mixture was washed with sat. NaHCO₃ (10 mL) , brine (10 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product 5- ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-4- ( (2S) -3-methyl-2- (2, 7-diazaspiro [4.4] nonan-2-yl) butanamido) -5, 7 -dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (255 mg) as a yellow solid.

LCMS (ESI) calcd. for C₄₈H₆₁F₃N₈O₈S₂ [M+H] ⁺ m/z 999.4, found: 1000.1.

Step 4: Synthesis of 5- ( (6⁴S, 4S, Z) -4- ( (2S) -2- (7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-methylbutanamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl tri-fluoromethanesulfonate

To a solution of lithium (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carboxylate (75 mg, 0.51 mmol) in DMF (3 mL) were added HATU (116 mg, 0.31 mmol) and DIEA (329 mg, 2.5 mmol) at 0-10℃. The resulting mixture was stirred at RT for 30 min. Then 5- ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-4- ( (2S) -3-methyl-2- (2, 7-diazaspiro [4.4] nonan-2-yl) butanamido) -5, 7 -dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane -1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (255 mg, 0.25 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 30 mL) , the combined organic phase was washed with 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 MeOH/DCM from 0%to 7%to afford 5- ( (6⁴S, 4S, Z) -4- ( (2S) -2- (7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-methylbutanamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl tri-fluoromethanesulfonate (160 mg, 56 %) as an orange oil.

LCMS (ESI) calcd. for C₅₃H₆₉F₃N₈O₁₀S₂ [M+H] ⁺ m/z 1122.5, found: 1123.2.

Step 5: Synthesis of (2S) -2- (7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1 ¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3 -methylbutanamide

To a stirred solution of 5- ( (6⁴S, 4S, Z) -4- ( (2S) -2- (7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-methylbutanamido) -1¹-ethyl-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] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl tri-fluoromethanesulfonate (80 mg, 0.071 mmol) and 5-ethynylpyrimidine (15 mg, 0.14 mmol) , CuI (2 mg, 0.011 mmol) , TEA (0.5 mL) and Pd (PPh₃) ₄ (12 mg, 0.011 mmol) in DMF (2 mL) was stirred at 90℃ 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 pre-HPLC (eluting with CH₃CN/H₂O (0.1%NH₄HCO₃) from 20%to 70%) to give (2S) -2- (7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) 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] heptanacycloundecaphane-4-yl) -3-methylbutanamide (28 mg, 36 %) as a white solid.

LCMS (ESI) calcd. for C₆₀H₇₃N₁₁O₆S [M+H] ⁺ m/z 1076.6, found: 1077.5.

¹H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H) , 9.08 (s, 1H) , 8.99 (s, 1H) , 8.43 (s, 1H) , 8.37 -8.14 (m, 2H) , 8.09 (s, 1H) , 7.88 (d, J = 9.7 Hz, 1H) , 7.76 (t, J = 12.4 Hz, 1H) , 7.64 -7.55 (m, 1H) , 6.01 -5.89 (m, 1H) , 5.34 (dd, J = 13.5, 8.1 Hz, 1H) , 4.76 (d, J = 11.3 Hz, 1H) , 4.50 (s, 1H) , 4.41-4.35 (m, 2H) , 4.04 (dt, J = 63.0, 19.2 Hz, 2H) , 3.76 -3.36 (m, 5H) , 3.29 (s, 4H) , 3.13 -2.55 (m, 8H) , 2.53 (s, 5H) , 2.46 -2.06 (m, 6H) , 2.04 -1.54 (m, 6H) , 1.49 -1.18 (m, 5H) , 1.07 -0.71 (m, 9H) , 0.62-0.55 (m, 2H) , 0.39 -0.21 (m, 4H) , 0.19-0.15 (m, 1H) .

Example 88

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N - ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) pyridin-3-yl) -10, 10-dimet hyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Step 1: Synthesis of methyl (S) -3- ( (S) -4- (3- (3-acetoxy-2, 2-dimethylpropyl) -2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate

To a stirred solution of (S) -3- (2- (5- (benzyloxy) -2- (1-methoxyethyl) pyridin-3-yl) -5-bromo-1-ethyl-1H-indol-3-yl) -2, 2-dimethylpropyl acetate (2.6 g, 4.4 mmol) , methyl (S) -2- ( (tert-butoxycarbonyl) amino) -3- ( (S) -morpholin-2-yl) propanoate (1.3 g, 4.4 mmol) and Cs₂CO₃ (3.6 g, 11 mmol) in 1, 4-dioxane (50 mL) were added RuphosG₃Pd (367 mg, 0.4 mmol) and Ruphos (410 mg, 0.9 mmol at rt. The reaction mixture was stirred at 100 ℃ under N₂ for 18 h. After completion, the reaction solution was concentrated under reduced pressure to remove 1, 4-dioxane to give the residual which was purified by silica gel column (eluting with EtOAc/PE from 0%to 80%) to afford methyl (S) -3- ( (S) -4- (3- (3-acetoxy-2, 2-dimethylpropyl) -2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-et hyl-1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate (2 g, 57 %) as a yellow oil.

LCMS (ESI) calcd. for C₄₅H₆₀N₄O₉ [M+H] ⁺ m/z 801.4, found: 802.6.

Step 2: Synthesis of (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethylpropy l) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoic acid

To a solution of methyl (S) -3- ( (S) -4- (3- (3-acetoxy-2, 2-dimethylpropyl) -2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-et hyl-1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoate (1.7 g, 2.1 mmol) in THF (18 mL) and H₂O (6 mL) was added LiOHH₂O (267 mg, 6.4 mmol) at 0-10℃ , the resulting mixture was stirred at RT for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 3-4 with 2 N HCl. 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 concen-trated to give (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethylpropyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoic acid (1.58 g, 100 %) as a light yellow solid.

LCMS (ESI) calcd. for C₄₂H₅₆N₄O₈ [M+H] ⁺ m/z 745.4, found: 746.3.

Step 3: Synthesis of methyl (S) -2- ( (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethylpro-pyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylate

To a solution of (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethylpropyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoic acid (1.58 g, 2.1 mmol) in DMF (20 mL) were added HATU (1.05 g, 2.8 mmol) and DIEA (1.37 g, 10.6 mmol) at 0-10℃. The re-sulting mixture was stirred at 0-10℃ for 10 min. Then methyl (S) -2, 3-diazabicyclo [3.1.1] heptane-4-carboxylate hydrochloride (531 mg, 2.8 mmol) was added into the reaction mixture, the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. Af-ter completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 30 mL) , the combined organic phase was washed with saturated NaCl (100 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product which was purified by silica gel col-umn eluting with EtOAc/PE from 0%to 100%to afford methyl (S) -2- ( (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimet hylpro-pyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] hept ane-4-carboxylate (750 mg, 40 %) as a light yellow solid.

LCMS (ESI) calcd. for C₄₉H₆₆N₆O₉ [M+H] ⁺ m/z 883.5, found: 884.2.

Step 4: Synthesis of (S) -2- ( (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimethylpro-pyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] hept ane-4-carboxylic acid

To a solution of (S) -2- ( (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimet hylpro-pyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] hept ane-4-carboxylate (750 mg, 0.85 mmol) in THF (6 mL) and H₂O (2 mL) was added LiOH·H₂O (107 mg, 2.55 mmol) at 0-10℃ , the resulting mixture was stirred at RT for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 3-4 with 2 N HCl. The resulting mix-ture was extracted with EtOAc (30 mL x 2) , the combined organic phase was washed with saturated NaCl (50 mL) , then dried over Na₂SO₄ and concentrated to give (S) -2- ( (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimet hylpro-pyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] hept ane-4-carboxylic acid (700 mg, 95 %) as a light yellow solid.

LCMS (ESI) calcd. for C₄₈H₆₄N₆O₉ [M+H] ⁺ m/z 869.5, found: 870.6.

Step 5: Synthesis of tert-butyl ( (2²S, 6⁴S, 4S) -1²- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H -8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) c arbamate

To a solution of TCFH (905 mg, 3.2 mmol) and NMI (528 mg, 6.4 mmol) in ACN (100 mL) was added a solution of (S) -2- ( (S) -3- ( (S) -4- (2- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1-ethyl-3- (3-hydroxy-2, 2-dimet hylpro-pyl) -1H-indol-5-yl) morpholin-2-yl) -2- ( (tert-butoxycarbonyl) amino) propanoyl) -2, 3-diazabicyclo [3.1.1] hept ane-4-carboxylic acid (700 mg, 0.8 mmol) in ACN (40 mL) at 0-10℃, the reaction was gradually im-proved 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 puri-fied by silica gel column (eluting with EtOAc/PE from 0%to 100%to afford tert-butyl ( (2²S, 6⁴S, 4S) -1²- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹ H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (310 mg, 45 %) as a white solid.

LCMS (ESI) calcd. for C₄₈H₆₂N₆O₈ [M+H] ⁺ m/z 851.5, found: 852.4.

Step 6: Synthesis of tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate

To a stirred solution of tert-butyl ( (2²S, 6⁴S, 4S) -1²- (5- (benzyloxy) -2- ( (S) -1-methoxyethyl) pyridin-3-yl) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹ H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate (310 mg, 0.36 mmol) in MeOH (10 mL) was added Pd/C (10%, 31 mg) at rt , the resulting mix-ture was stirred at RT for 12 h. The reaction was monitored by LCMS. After completion, the reaction mix-ture was filtered and the filtrate was concentrated to give crude tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8 -oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carb amate (270 mg) as a light yellow solid.

LCMS (ESI) calcd. for C₄₁H₅₆N₆O₈ [M+H] ⁺ m/z 761.4, found: 762.5.

Step 7: Synthesis of 5- ( (2²S, 6⁴S, 4S) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyeth yl) pyridin-3-yl trifluoromethanesulfonate

To a solution of crude tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8 -oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carb amate (270 mg, 0.35 mmol) in DCM (5 mL) were added DIEA (137 mg, 1.06 mmol) and PhN (Tf) ₂ (152 mg, 0.43 mmol) at 0-10℃. The resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure to obtain crude product which was purified by silica gel column eluting with (EtOAc/PE from 0%to 100%) to afford 5- ( (2²S, 6⁴S, 4S) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyet hyl) pyridin-3-yl trifluoromethanesulfonate (290 mg, 91 %) as a white foam.

LCMS (ESI) calcd. for C₄₂H₅₅F₃N₆O₁₀S [M+H] ⁺ m/z 893.4, found: 894.3.

Step 8: Synthesis of 5- ( (2²S, 6⁴S, 4S) -4-amino-1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3 ) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluo-romethanesulfonate

To a stirred solution of 5- ( (2²S, 6⁴S, 4S) -4- ( (tert-butoxycarbonyl) amino) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyet hyl) pyridin-3-yl trifluoromethanesulfonate (80 mg, 0.09 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 washed with sat. NaHCO₃ (3 mL) , brine (3 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product 5- ( (2²S, 6⁴S, 4S) -4-amino-1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl tri-fluoromethanesulfonate (91 mg, crude) as a yellow solid.

LCMS (ESI) calcd. for C₃₇H₄₇F₃N₆O₈S [M+H] + m/z 793.3, found: 794.3.

Step 9: Synthesis of tert-butyl (5S) -7- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carboxy late

To a solution of (S) -2- ( (S) -7- (tert-butoxycarbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-methylbutanoic acid (44 mg, 0.13 mmol) in DMF (2 mL) were added HATU (51 mg, 0.13 mmol) and DIEA (58 mg, 0.45 mmol) at 0-10 ℃. The resulting mixture was stirred at 0-10℃ for 10 min. Then 5- ( (2²S, 6⁴S, 4S) -4-amino-1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl tri-fluoromethanesulfonate (71 mg, 0.89 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 di-luted with brine and extracted with EtOAc (2 x 30 mL) , the combined organic phase was washed with sat-urated NaCl (100 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 afford tert-butyl (5S) -7- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carbox ylate (70 mg, 71 %) as a light yellow solid.

LCMS (ESI) calcd. for C₅₄H₇₅F₃N₈O₁₁S [M+H] + m/z 1101.5, found: 1102.4.

Step 10: Synthesis of 5- ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-4- ( (S) -3-methyl-2- ( (S) -2, 7-diazaspiro [4.4] nonan-2-yl) butanamido) -5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate

To a stirred solution of tert-butyl (5S) -7- ( (2S) -1- ( ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( ( (trifluoromethyl) sulfonyl) oxy) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3. 1.1] heptanacycloundecaphane-4-yl) amino) -3-methyl-1-oxobutan-2-yl) -2, 7-diazaspiro [4.4] nonane-2-carbox ylate (70 mg, 0.06 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 washed with sat. NaHCO₃ (3 mL) , brine (3 mL) , then dried over Na₂SO₄, following with concentration under reduced pressure to obtain crude product 5- ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-4- ( (S) -3-methyl-2- ( (S) -2, 7-diazaspiro [4.4] nonan-2-yl) butanamido ) -5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (63 mg, crude) as a yellow solid.

LCMS (ESI) calcd. for C₄₉H₆₇F₃N₈O₉S [M+H] + m/z 1001.5, found: 1002.3.

Step 11: Synthesis of (2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2² S, 6⁴S, 4S) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide trifluoromethanesulfonate

To a solution of lithium (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carboxylate (19 mg, 0.13 mmol) in DMF (2 mL) were added HATU (29 mg, 0.08 mmol) and DIEA (81 mg, 0.63 mmol) at 0-10℃. The re-sulting mixture was stirred at 0-10℃ for 10 min. Then 5- ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-4- ( (S) -3-methyl-2- ( (S) -2, 7-diazaspiro [4.4] nonan-2-yl) butanamido ) -5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-1²-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl trifluoromethanesulfonate (63 mg, 0.06 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 30 mL) , the combined organic phase was washed with saturated NaCl (100 mL) , then dried over Na₂SO₄, fol-lowing 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 afford tert-butyl (2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2 ²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-met hylbutanamide trifluoromethanesulfonate (25 mg, 31 %) as a light yellow solid.

LCMS (ESI) calcd. for C₅₆H₇₆F₃N₉O₁₀S [M+H] + m/z 1124.5, found: 1125.4.

Step 12: Synthesis of (2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2² S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

A mixture of (2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2 ²S, 6⁴S, 4S) -1¹-ethyl-1²- (5-hydroxy-2- ( (S) -1-methoxyethyl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-met hylbutanamide trifluoromethanesulfonate (25 mg, 0.022 mmol) , 5-ethynylpyrimidine (4.6 mg, 0.044 mmol) , CuI (0.6 mg, 0.003 mmol) and Pd (PPh₃) ₄ (3.9 mg, 0.003 mmol) in TEA/DMF (0.5 mL/2 mL) was stirred at 100℃ 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 pre-HPLC (ACN/H₂O (0.5 %NH₄HCO₃) from 20%to 95%in 30 min) to give (2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2 ²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (pyrimidin-5-ylethynyl) pyridin-3-yl) -10, 10-dimethyl-5, 7 -dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide (3 mg, 12.5%) as a white solid.

LCMS (ESI) calcd. for C₆₁H₇₉N₁₁O₇ [M+H] ⁺ m/z 1078.6, found: 1079.4.

¹H NMR (500 MHz, CDCl₃) δ 9.15 (t, J = 1.7 Hz, 1H) , 8.79 (d, J = 1.8 Hz, 2H) , 8.36 (d, J = 12.1 Hz, 1H) , 8.31 (d, J = 2.0 Hz, 1H) , 8.04 (d, J = 2.0 Hz, 1H) , 7.36 (d, J = 7.9 Hz, 1H) , 7.21 (d, J = 2.2 Hz, 1H) , 7.01 (dd, J = 7.9, 2.2 Hz, 1H) , 5.24 (q, J = 5.4 Hz, 1H) , 4.90 (d, J = 8.6 Hz, 1H) , 4.47 (q, J = 11.9 Hz, 1H) , 4.15 (q, J = 4.4 Hz, 2H) , 4.12 -4.06 (m, 1H) , 4.06 -4.03 (m, 2H) , 3.99 -3.89 (m, 2H) , 3.89 -3.82 (m, 2H) , 3.82 -3.78 (m, 1H) , 3.68 (d, J = 6.0 Hz, 1H) , 3.65 -3.55 (m, 5H) , 3.45 (dd, J = 7.4, 4.8 Hz, 1H) , 3.37 (d, J = 1.3 Hz, 2H) , 3.33 (s, 3H) , 3.09 (s, 2H) , 2.99 -2.92 (m, 1H) , 2.88 -2.79 (m, 3H) , 2.79 -2.66 (m, 2H) , 2.41 (t, J = 1.5 Hz, 3H) , 2.25 -1.91 (m, 9H) , 1.89 -1.81 (m, 3H) , 1.67 (d, J = 5.3 Hz, 3H) , 1.37 (t, J = 4.4 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 89

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6³S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacy cloundecaphane-4-yl) -3-methylbutanamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (6³S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate in the Step 1 of Example 90, the title compound was prepared by the same procedures as described for Example 90.

Example 90

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N - ( (6⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Step 1: Synthesis of (2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6⁴ S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -3-methylbutanamide

To a stirred solution of 5- ( (6⁴S, 4S, Z) -4- ( (2S) -2- (7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-methylbutanamido) -1¹-ethyl-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] heptanacycloundecaphane-12-yl) -6- ( (S) -1-methoxyethyl) pyridin-3-yl tri-fluoromethanesulfonate (80 mg, 0.071 mmol) and 4- (prop-2-yn-1-yl) morpholine (18 mg, 0.14 mmol) , CuI (2 mg, 0.011 mmol) , TEA (22 mg, 0.21 mmol) and Pd (PPh₃) ₄ (12 mg, 0.011 mmol) in DMF (2 mL) was stirred at 90℃ 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 pre-HPLC (eluting with CH₃CN/H₂O (0.1%NH₄HCO₃) from 20%to 70%) to give (2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (6 ⁴S, 4S, Z) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-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] heptanacycloundecaphane-4-yl) -3-methylbutanamide (19.1mg) as a white solid.

LCMS (ESI) calcd. for C₆₁H₈₀N₁₀O₇S [M+H] ⁺ m/z 1097.6, found: 1098.4.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H) , 8.40 (s, 1H) , 8.35 -8.18 (m, 1H) , 7.86 (s, 1H) , 7.75 (d, J = 8.3 Hz, 1H) , 7.58 (d, J = 8.5 Hz, 1H) , 5.93 (s, 1H) , 5.32 (s, 1H) , 4.73 (d, J = 10.2 Hz, 1H) , 4.49 (s, 1H) , 4.37 -4.20 (m, 2H) , 4.07 (d, J = 7.3 Hz, 1H) , 3.53 (dd, J = 26.3, 13.2 Hz, 5H) , 3.25 (s, 3H) , 2.88 -2.69 (m, 3H) , 2.67 -2.50 (m, 4H) , 2.36 (d, J = 14.5 Hz, 2H) , 2.27 -2.09 (m, 3H) , 2.02 -1.76 (m, 3H) , 1.66 (dd, J =33.9, 16.1 Hz, 3H) , 1.34 (d, J = 5.8 Hz, 3H) , 1.21 (s, 1H) , 0.99 -0.79 (m, 7H) , 0.58 (s, 1H) , 0.31 (d, J = 17.6 Hz, 3H) , 0.14 (s, 1H) .

Example 91

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6³S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dime-thyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazin acycloundecaphane-4-yl) -3-methylbutanamide

Substituting tert-butyl ( (6⁴S, 4S, Z) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa -6², 6³-diaza-2 (4, 2) -thiazola-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6³S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) c arbamate in the Step 1 of Example 90, the title compound was prepared by the same procedures as de-scribed for Example 90.

Example 92

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N - ( (2²S, 6³S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyri din-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -in dola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) -3-methylbutanamide

Substituting 4- (prop-2-yn-1-yl) morpholine with (R) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 1 of Example 91, the title compound was prepared by the same procedures as described for Example 91.

Example 93

(2S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) -3-methylbutanamide

Substituting tert-butyl ( (2²S, 6³S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate with tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate in the Step 1 of Example 92, the title compound was prepared by the same procedures as described for Example 92.

Example 94

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting (S) -2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -3-meth ylbutanoic acid with (S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) acetic acid in the Step 1 of Example 93, the title compound was prepared by the same procedures as described for Example 93.

Example 95

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6⁴S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) acetamide

Substituting (R) -1- (but-3-yn-2-yl) -4-methylpiperazine with 4- (prop-2-yn-1-yl) morpholine in the Step 1 of Example 94, the title compound was prepared by the same procedures as described for Example 94.

Example 96

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6³S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- (3-morpholinoprop-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) acetamide

Substituting tert-butyl ( (2²S, 6⁴S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1¹H-8-oxa-6², 6³-diaza-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (2, 4) -bicyclo [3.1.1] heptanacycloundecaphane-4-yl) carba mate with tert-butyl ( (2²S, 6³S, 4S) -1¹-ethyl-10, 10-dimethyl-5, 7-dioxo-1²- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) carbamate in the Step 1 of Example 95, the title compound was prepared by the same procedures as de-scribed for Example 95.

Example 97

(2S) -2-cyclopentyl-2- ( (S) -7- ( (2R, 3R) -3-cyclopropyl-1-methylaziridine-2-carbonyl) -2, 7-diazaspiro [4.4] nonan-2-yl) -N- ( (2²S, 6³S, 4S) -1¹-ethyl-1²- (2- ( (S) -1-methoxyethyl) -5- ( (R) -3- (4-methylpiperazin-1-yl) but-1-yn-1-yl) pyridin-3-yl) -10, 10-dimethyl-5, 7-dioxo-6¹, 6², 6³, 6⁴, 6⁵, 6⁶-hexahydro-1¹H-8-oxa-2 (4, 2) -morpholina-1 (5, 3) -indola-6 (1, 3) -pyridazinacycloundecaphane-4-yl) acetamide

Substituting 4- (prop-2-yn-1-yl) morpholine with (R) -1- (but-3-yn-2-yl) -4-methylpiperazine in the Step 1 of Example 96, the title compound was prepared by the same procedures as described for Example 96.

The following exemplary compounds was synthesized from different starting materials according to the method above (such as method for Example 1-30)

Table 4A. Exemplary Compounds Prepared by Methods of the Present Invention

Note: values may differ slightly from values found elsewhere in this application due to different measure-ments and rounding.

BIOLOGICAL ACTIVITY RESULTS

The following were used as reference compounds.

Ras: RAF1 HTRF Assay

This example is to verify the binding between RAS protein and its interacting protein (SOS1 or RAF1) . When RAS exists with SOS1 or RAF, the two interact to make the energy donor and receptor bound to it close enough, and then when the donor is excited by an external light source, energy resonance transfer occurs, thereby exciting the receptor and emitting a specific wavelength of emitted light, the FRET signal is detected.

Specific experimental methods: 20 nM purified RAS protein (e.g. KRAS-G12C, G12D, G12V, G12S, WT) was incubated with the drug to be screened (the drug was diluted in a 3-fold gradient to a final con-centration of 1000 nM) at room temperature for 1 h. Subsequently, 30 nM purified SOS1-Cat was added and incubated at room temperature for 0.5-1 h. After adding the detection antibody (PerkinElmer, Cisbio, HTRF antibody) , the value was measured according to the manufacturer's instructions.

The representative compound results

The reference compound (Ref. 1) and the representative Compound A (Example 16) significantly in-hibited the interaction of RAF1 with active RAS^Mutant protein or RAS^WT protein, and the result is shown in Figure 1.

The inhibitory IC₅₀ of the compounds of the examples of the present invention was shown in Table 5.

Table 5. RAS-GTP &Raf Disruption/HTRF Assay

*Key: A: 1 nM <IC₅₀ ≤ 10 nM; B: 10 nM < IC₅₀ ≤ 100 nM; C: 100 nM < IC₅₀ ≤ 1000 nM; D: IC₅₀ >1000 nM; E: not tested.

Cell viability assay

Selective screening using RAS-driven and RAS-non-driven cells: (1) RAS-driven cells, including cells with persistent RAS activation due to RAS mutations and upstream EGFR activation. Cells that are continuously activated due to RAS mutations, such as KRAS G12D (AsPC-1, HPAC, AGS, etc. ) mutant cells, KRAS G12C (NCI-H358, MIAPaCa-2, etc. ) KRAS G13D (LOVO, HCT15, etc. ) mutant cells, etc. Cells with continuous activation of RAS due to EGFR mutations, such as EGFREx19del (PC-9, etc. ) mu-tant cells, EGFRT790M/L858R (NCI-H1975, etc. ) mutant cells, etc.; (2) Non-RAS driven cells, including BRAFV600E (A375, SK, ) -MEL-3, etc. ) mutant cells, RASWT (BxPC-3, etc. ) cells, etc.

Specific experimental methods: The above cells were seeded in a 96-well plate at a density of 1000-10000 per well. Drugs were diluted in DMSO to make a 10 mM stock solution. Subsequently, the drug was diluted in a 3-fold gradient to a final concentration of 1000 nM. The cells were treated with the drug for 5 days. Cell viability was then detected by the MTS method.

The representative compound results

The reference compound (Ref. 1) and the representative Compound A (Example 16) significantly in-hibited the cell viability of KRAS mutant cells: MIA PACA-2 (KRAS G12C) , NCI-H358 (KRAS G12C) , NCI-H2122 (KRAS G12C) HPAF II (KRAS G12D) , AGS (KRAS G12D) , ASPC-1 (KRAS G12D) , HPAC (KRAS G12D) , LS174T (KRAS G12D) , SW480 (KRAS G12V) , SW620 (KRAS G12V) , CAL-62 (KRAS G12R) , LOVO (KRAS G13D) Calu6 (KRAS Q61K) and HCC827 (EGFR) . The result is shown in Figure 2.

The inhibitory IC₅₀ of the compounds of the examples of the present invention was shown in Table 6.

Table 6. Activity of Compounds of present invention in KRAS Cell viability assay

*Key: AA: IC₅₀ ≤ 1 nM; A: 1 nM <IC₅₀ ≤ 10 nM; B: 10 nM < IC₅₀ ≤ 100 nM; C: 100 nM < IC₅₀ ≤1000 nM; D: IC₅₀ > 1000 nM; E: not tested.

Anti-proliferation IC₅₀ Values of each cell line

Methods: The purpose of this cellular assay was to determine the effects of test compounds on the proliferation of human cancer cell lines NCI-H358 cells, AGS cells, HPAC cells, AsPC-1 cells, SW620 cells, and A375 cells over a 5-day treatment using Cell Counting Kit-8 (CCK8) . Cells were seeded at 2000 cells/well (NCI-H358) , 1000 cells/well (AGS) , 1500 cells/well (HAPC) , 3000 cells/well (AsPC-1) , 2000 cells/well (SW620) , 2000 cells/well (A375) in 96-well assay plates and incubated overnight. On the day of the assay, diluted compounds were then added in a final concentration of 0.5%DMSO. After 5 days incu-bation, a tenth of the volume of cell counting kit 8 (Dnjindo-CK04) was added into each well. Read the signal (OD450) using Biotek synergy H1 plate reader after incubation. IC₅₀ was determined by Graphpad 8.0.

Table 6A. Anti-proliferation IC₅₀ Values of reference compounds and Optimized compounds in each cell line

Results: Results from in vitro cell proliferation assays showed that Example 16, Example 17 and Example 18 exhibited a more potent inhibitory effect on cell growth compared to Ref. 1 and Ref. 2. Besides, the activity of Example 16 was more potent than Ref. 3; the activity of Example 17 was more potent than Ref. 4

In vivo efficacy and PD studies

After multiple batches of cell screening and activity testing, Compound A and B (Example 16 and Example 17) were selected for in vitro efficacy experiments with reference compounds Ref. 1 and Ref. 2 in this disclosure, and the differences and advantages of the disclosed compounds and clinical compounds were further compared.

Experimental Animal Models 1: Ref. 1 and Compound A in PDAC Tumor (HPAC^G12D)

Methods: Subcutaneous inoculation of 3 × 10⁶ HPAC cells in 0.1 mL DPBS (Dulbecco‘s Phos-phate-Buffered Saline) was performed in the right cervical dorsal region of each Balb/c nude mice. Ex-perimental animals were marked with ear tag numbers during inoculation as the sole identification for subsequent experiments. The in vivo efficacy study commenced with group administration on day 20 post-cell inoculation, with 5 mice per group receiving continuous treatment for 21 days. Tumor volume and body weight were measured twice weekly. T/C %= T/C × 100; TGI (%) = [1- (Treatending day -Treat-grouping day) / (Vehicleending day -Vehiclegrouping day) ] × 100.

Results: On day 21 drug administration, tumor-bearing mice in the vehicle group exhibited a mean tumor volume of 723 mm³. Significant antitumor efficacy with statistical differences was observed in the following treatment groups: Ref. 1 5 mg/kg (tumor volume = 183 mm³, TGI = 89.32%, T/C = 25.37%, p <0.0001) ; Compound A 0.1 mg/kg (tumor volume = 167 mm³, TGI = 92.02%, T/C = 23.10%, p < 0.0001) , Compound A 0.5 mg/kg (tumor volume = 26 mm³, TGI = 115.38%, T/C = 3.53%, p < 0.0001) , Compound A 1 mg/kg (tumor volume = 20 mm³, TGI = 116.27%, T/C = 2.81%, p < 0.0001) . Notably, Compound A demonstrated a clear dose-dependent relationship in tumor growth inhibition. The result is shown in Figure 3.

Experimental Animal Models 2: Ref. 2 and Compound A in PDAC Tumor (PK59^G12D)

Methods: Subcutaneous inoculation of 5 × 10⁶ PK59 cells in 0.1 mL DPBS (Dulbecco's Phos-phate-Buffered Saline) was performed in the right cervical dorsal region of each Balb/c nude mice. Ex-perimental animals were marked with ear tag numbers during inoculation as the sole identification for subsequent experiments. The in vivo efficacy study commenced with group administration on day 17 post-cell inoculation, with 5 mice per group receiving continuous treatment for 21 days. Tumor volume and body weight were measured twice weekly. T/C %= T/C × 100; TGI (%) = [1- (Treatending day -Treat-grouping day) / (Vehicleending day -Vehiclegrouping day) ] × 100.

Results: On day 21 drug administration, tumor-bearing mice in the vehicle group exhibited a mean tumor volume of 915 mm³. Significant antitumor efficacy with statistical differences was observed in the following treatment groups: Ref. 2 0.1 mg/kg (tumor volume = 224 mm³, TGI = 86.68%, T/C = 24.46%, p < 0.0001) ; Compound A 0.02 mg/kg (tumor volume = 303 mm³, TGI = 76.82%, T/C = 33.05%, p <0.0001) , Compound A 0.05 mg/kg (tumor volume = 110 mm³, TGI = 100.92%, T/C = 12.05%, p < 0.0001) , Compound A 0.1 mg/kg (tumor volume = 16 mm³, TGI = 112.79%, T/C = 1.70%, p < 0.0001) , Compound A 0.3 mg/kg (tumor volume = 7 mm³, TGI = 113.82%, T/C = 0.81%, p < 0.0001) . Notably, Compound A demonstrated a clear dose-dependent relationship in tumor growth inhibition. The result is shown in Figure 4.

Experimental Animal Models 3: Ref. 1, Ref. 2, Compound A and Compound B in PDAC Tumor (PK59^G12D)

Methods: Subcutaneous inoculation of 5 × 10⁶ HPAC cells in 0.1 mL DPBS (Dulbecco's Phos-phate-Buffered Saline) mixed with 50%Matrigel was performed in the right cervical dorsal region of each Balb/c nude mice. Experimental animals were marked with ear tag numbers during inoculation as the sole identification for subsequent experiments. The in vivo efficacy study commenced with group administra-tion on day 17 post-cell inoculation, with 5 mice per group receiving continuous treatment for 23 days. Tumor volume and body weight were measured twice weekly. T/C %= T/C × 100; TGI (%) =[1- (Treatending day -Treatgrouping day) / (Vehicleending day -Vehiclegrouping day) ] × 100.

Results: On day 23 drug administration, tumor-bearing mice in the vehicle group exhibited a mean tumor volume of 1678 mm³. Significant antitumor efficacy with was observed across treatment groups ex-cept for Ref. 2 0.1 mg/kg (tumor volume = 1495 mm³, TGI = 11.93%) : Ref. 1 5 mg/kg (tumor volume = 674 mm³, TGI = 65.12%) ; Ref. 1 25 mg/kg (tumor volume = 50 mm³, TGI = 105.49%) ; , Ref. 2 0.3 mg/kg (tumor volume = 527 mm³, TGI = 74.51%) , Compound A 0.1 mg/kg (tumor volume = 392 mm³, TGI = 83.41%) , Compound A 0.3 mg/kg (tumor volume = 70 mm³, TGI = 104.13%) , Compound B 0.1 mg/kg (tumor vol-ume = 374 mm³, TGI = 84.48%) , Compound B 0.3 mg/kg (tumor volume = 82 mm³, TGI = 103.45%) . The result is shown in Figure 5.

Experimental Animal Models 4: Ref. 1, Ref. 3, Ref. 4, Compound A and Compound B in NSCLC Tumor (LU99^G12C)

Methods: Subcutaneous inoculation of 5 × 10⁶ LU99 cells in 0.1 mL DPBS (Dulbecco's Phos-phate-Buffered Saline) mixed with 50%Matrigel was performed in the right cervical dorsal region of each Balb/c nude mice. Experimental animals were marked with ear tag numbers during inoculation as the sole identification for subsequent experiments. The in vivo efficacy study commenced with group administra-tion on day 8 post-cell inoculation, with 6 mice per group receiving continuous treatment for 14 days. Tu-mor volume and body weight were measured twice weekly. T/C %= T/C × 100; TGI (%) = [1- (Treatending day -Treatgrouping day) / (Vehicleending day -Vehiclegrouping day) ] × 100.

Results: On day 14 drug administration, tumor-bearing mice in the vehicle group exhibited a mean tumor volume of 1069 mm³. Antitumor efficacy of Compound A (TGI=32.11%, Compound A 0.01 mg/kg; TGI=109.42%, Compound A 0.05 mg/kg) was more potent than that of Ref. 3 (TGI=13.37%, Ref. 3 0.01 mg/kg; TGI=87.45%, Ref. 3 0.05 mg/kg) ; Antitumor efficacy of Compound B (TGI=57.43%, Compound B 0.05 mg/kg) was more potent than that of Ref. 4 (TGI=33.62%, Ref. 4 0.05 mg/kg) . The result is shown in Figure 6.

Brain metastasis intracranial model

The purpose of this assay is to determine whether brain exposure of the compounds of current inven-tion was sufficient to mediate regression of tumors in experimental Brain Metastases (BM) models.

Methods: Female BALB/c nude mice were anesthetized with xylazine hydrochloride (8 mg/kg) and Zoletil 50 (35 mg/kg) , receiving pre-and post-operative analgesia through butorphanol tartrate (1 mg/kg) . Following head fixation in a stereotaxic apparatus, surgical sites were disinfected with 70%ethanol and draped sterilely. A 1 cm sagittal incision exposed the parietal and occipital bones, which were cleaned with 3%hydrogen peroxide. A burr hole was drilled 2 mm right of the bregma and 0.5 mm posterior to the cor-onal suture using a dental drill. The cell suspension containing 3×10 NCI-H1373-luc cells in 3 μL DPBS with 20%Matrigel Matrix was carefully loaded into a Hamilton syringe, with external surfaces wiped with ethanol to prevent ectopic tumor formation. The needle was vertically inserted to 3 mm depth for con-trolled infusion over 1 minute (0.05 μL/sec) , followed by 1-minute dwell time before slow withdrawal. The injection site was sealed with cyanoacrylate glue, and the scalp was repositioned and sutured. Postopera-tive analgesia with meloxicam was administered for three days, with ear tags applied for identification. The efficacy study commenced on day 4 post-implantation, utilizing five mice per group for 21-day treatment.

Results: On day 21 post-grouping, tumor-bearing mice in the vehicle control group demonstrated a mean tumor bioluminescence intensity of 5.12×10 photons/sec. Significant antitumor efficacy with sta-tistical significance (p < 0.0001) was observed across treatment groups: Ref. 1 25 mg/kg (2.45×10 pho-tons/sec, TGI=113.40%, T/C=4.79%) , Compound A 0.1 mg/kg (5.68×10 photons/sec, TGI=105.86%, T/C=11.09%) , Compound A 0.5 mg/kg (8.86×10 photons/sec, TGI=117.06%, T/C=1.73%) , and Com-pound A 1 mg/kg (1.05×10 photons/sec, TGI=116.63%, T/C=2.05%) . The result is shown in Figure 7 and Figure 8.

Metabolic Stability In Vitro

The purpose of this experiment was to investigate the metabolic stability of the test compounds in liv-er microsomes and plasma of human, mouse, rat, canine and cynomolgus monkey.

Liver microsomal stability assay

The original stock solution of the test compound and the positive compound (prepared with 1 mg/mL DMSO) was diluted with DMSO to prepare a 0.25 mM working solution. General formula: mg/mL =(1000/M) mmol/L, M is the relative molecular mass of the compound. The metabolic stability of com-pounds in liver microsomes was evaluated by incubation them with liver microsomes of different species in vitro. After the chemical was incubated with liver microsomes for different times (0 min, 5 min, 15 min, 30 min, 45 min, 60 min) , the reaction was terminated by precooled acetonitrile (containing internal stand-ard) . After sample processed (protein precipitation method) , it was loaded into LC-MS for quantitative analysis of the compounds.

The elimination rate constant and clearance rate of the test compound in liver microsomes were cal-culated using the following formula:

a) Residual Rate (%) = peak area ratio of compound to internal standard at any time point/peak area ratio of compound to internal standard at 0 min*100%;

b) T_1/2 = 0.693/k_e, where k_e is the elimination rate constant and T_1/2 is the half-life;

c) Liver Microsomal Intrinsic Clearance (CL_int, _in _vitro) = 0.693/T_1/2/microsomal protein concentration (mg/mL) ;

The representative compound results

The results of liver microsome stability (Table 7) showed that the intrinsic clearance rate of most of the compounds of the present invention in different species (human, mouse, rat, dog, cynomolgus monkey) was generally lower than that of the reference compound (Ref. 1) , indicating that it had better stability in the liver microsomes of the above species.

Table 7. Liver Microsome Stability Data for Selected Compounds

*/: not tested

Plasma stability assay

The compounds were incubated with the plasma of different species (human, CD-1 mouse, SD rat, beagle dog and cynomolgus monkey) to evaluate the metabolic stability of the compounds in plasma. After the compound was incubated with plasma for different time (0 min, 3 min, 5 min, 15 min, 30 min, 60 min, 120 min) , the reaction was terminated by precooling acetonitrile (including internal standard) . The termi-nated reaction solution was purified by protein precipitation method, and the compounds were quantita-tively analyzed by LC-MS.

The results of plasma stability (Table 8) showed that the metabolism of Ref. 1 in rat plasma was rela-tively unstable (T_1/2=20.66 min) , while the compound of the present invention was T_1/2>120 min in rat plasma, and at the same time, the T_1/2 of the compounds of the present invention in the plasma of different species (human, CD-1 mouse, SD rat, beagle dog and cynomolgus monkey) were greater than 120 min.

Notably, the T_1/2 of Example 16 and Example 17 in human, mouse, rat, monkey and dog plasma were >120 min, which indicates that Example 16 and Example 17 are metabolically stable in the plasma of different species. Example 16 exhibits superior stability compared to Ref. 3 in liver microsomal metabolic systems of all species (human, CD-1 mouse, SD rat, beagle dog and cynomolgus monkey) . Example 16 exhibits superior stability compared to Ref. 2 in liver microsomal metabolic systems of human, CD-1 mouse, and cynomolgus monkey (Table 8) . Example 17 exhibits superior stability compared to Ref. 4 in liver microsomal metabolic systems of SD rats (Table 8)

In summary, it showed that the compounds of the present invention had good plasma stability of mul-tiple genera, and at the same time, compared with the reference compound (Ref. 1) , it had more excellent plasma stability of rats.

Table 8. Plasma Stability Data for Selected Compounds

*/: not tested

Pharmacokinetic study

Oral bioavailability (F) of Ref. 1, Ref. 2, Ref. 3, Ref. 4, Example 5, Example 16 and Example 17 was compared in ICR mice.

The above compounds were administered via caudal vein at a dose of 2 mg/kg, and orally at a dose of 10 mg/kg. Whole blood was collected from cheek veins at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, and 48 h after administration. And plasma samples were also prepared for the pharmacokinetics study of Ref. 1, Example 5, Example 16.

The established and verified LC-MS method was used to quantitatively analyze the above compounds in plasma or blood. The mobile phase system of H₂O (B) and acetonitrile (D) was utilized. The compounds were eluted by HPLC gradient with a rate of 0.8 mL·min^-1. And the detection of the ions was carried out in the negative ESI mode and Selected Ion Record (SIR) mode. MS conditions are as follows: Capillary volt-age, 1.5 kV; Cone voltage, 50 V; Desolvation temperature, 400℃; Desolvation Gas, 800 L/Hr. Pharmaco-kinetic parameters were calculated by WinNonlin.

The representative compound results

The plasma pharmacokinetic parameters of Ref. 1, Example 5 and Example 16 after single-dose ad-ministration in mice were shown in Table 9. After a single oral dose, T_1/2, C_max, AUC _(0-t) , AUC _(0-∞) and bio-availability (F) of Example 5 were 10 times, 3 times, 11 times, 10 times and 1 times of that of Ref. 1, re-spectively; T_1/2, C_max, AUC _(0-t) , AUC _(0-∞) and bioavailability (F) of Example 16 were 9 times, 4 times, 24 times, 23 times and 1 times of that of Ref. 1, respectively.

Compared with Ref. 1, Example 5 and Example 16 exhibited better pharmacokinetics in mice.

Table 9. Plasma PK Parameters of Compounds in ICR Mice

The boold pharmacokinetic parameters of Ref. 1, Ref. 2, Ref. 3, Ref. 4 and Example 17 after single-dose administration in mice were shown in Table 9A.

After a single vein dose, C_max, AUC _(0-∞) of Example 16 were 2.3 times, 1.2 times of those of Ref. 2, respectively. And after a single oral dose, C_max, AUC _(0-t) , AUC _(0-∞) and F of Example 16 were 1.7 times, 1.9 times, 1.8 times and 1.9 times of those of Ref. 2, respectively. And after a single vein dose, T_1/2 and Vd of Example 16 were 1.9 times and 2.5 times of those of Ref. 3, after a single oral dose, T_1/2 were 1.9 times of that of Ref. 3. The above data indicate that Example 16 (Plasma PK, Example 16 is evenly distributed in whole blood and plasma) has a higher peak concentration, higher exposure, higher bioavailability than Ref. 2 and a longer elimination half-life than Ref. 3 after a single dose administration in mice.

After a single vein dose, T_1/2, C_max, AUC _(0-t) , AUC _(0-∞) of Example 17 were 1.8 times, 1.5 times, 2.2 times and 2.3 times of those of Ref. 4; And after a single oral dose, T_1/2, C_max, AUC _(0-t) , AUC _(0-∞) and F of Example 17 were 2.1 times, 1.1 times, 2.7 times, 2.8 times and 1.2 times of those of Ref. 4. The above data indicate that Example 17 has a higher peak concentration, higher exposure, higher bioavailability and a longer elimination half-life than Ref. 4.

Table 9A. The Blood Pharmacokinetic Parameters of Compounds after Single-dose Administration in Mice.

All literatures mentioned in the present application are incorporated herein by reference, as though each one is individually incorporated by reference. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present in-vention.These equivalents also fall within the scope defined by the appended claims.

Claims

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 C_1-6 alkylene;

R⁸ and R⁹ are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, op-tionally substituted C_1-3 alkyl, or R⁸ and R⁹ combine with the atoms to which they are attached to form an optionally substituted C_3-6 cycloalkyl or a carbonyl;

R¹⁰ and R¹¹ are each independently selected from hydrogen, deuterium, halogen, hydroxy, cyano, op-tionally substituted C_1-3 alkyl, or R¹⁰ and R¹¹ combine with the atoms to which they are attached to form an optionally substituted C_3-6 cycloalkyl or a carbonyl;

R¹² and R¹³ are each independently selected from hydrogen, deuterium, halogen, hydroxy, optionally substituted C_1-3 alkyl, -O (C_1-6 alkyl) , -S (C_1-6 alkyl) or -N (C_1-6 alkyl) (C_1-6 alkyl) ; furthermore, the C_1-6 alkyl may be further optionally substituted;

R^A is optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 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 substi-tuted 8 to 10-membered fused bicyclic heteroaryl;

R^B is selected from hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, optionally sub-stituted C_3-6 cycloalkyl, or optionally substituted C_3-6 heterocycloalkyl (or 4 to 7-membered heterocycloal-kyl) ; or provided that when n exceeds 1, any two of R^B 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 C_1-3 alkyl;

X¹ is N or C;

X² is N or -CR^a-;

X³ is N or -CR^b-;

X⁴ is N or -CR^c-;

X⁵ is N or C;

X⁶ is S, O, N, or -CH-;

R^a, R^b, and R^c are each independently hydrogen, halogen, cyano, C_1-3 alkyl, C_1-3 alkoxyl, C_1-3 haloal-kyl, C_1-3 haloalkoxyl, C_3-6 cycloalkyl, or C_3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl) ;

R³ is absent, or selected from hydrogen, C_1-6 alkyl, or C_1-6 haloalkyl, provided that when X⁶ is O or S, R³ is absent;

E is a bond, or selected from N, or -CR^d-, wherein R^d is selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 alkoxyl, C_1-6 aminoalkyl, C_1-6 hydroxyalkyl, or -NR^eR^f; wherein R^e and R^f are independently selected from hydrogen, or optionally sub-stituted C_1-6 alkyl;

R⁴ is hydrogen, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 cycloalkenyl, optionally substituted C_3-10 heterocy-cloalkyl (or 4 to 12-membered heterocycloalkyl) , optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, or

R⁵ is hydrogen, C_1-6 alkyl or C_3-6 cycloalkyl, furthermore, the C_1-6 alkyl or C_3-6 cycloalkyl may be fur-ther optionally substituted;

or R⁴ and R⁵ combine with the atoms to which they are attached to form a ring, wherein the ring is se-lected 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) -, -CHR^g-or -C (R^g) ₂-, wherein R^g is optionally substituted C_1-6 alkyl;

R⁶ is hydrogen, or optionally substituted C_1-6 alkyl;

R⁷ is optionally substituted C_1-6 alkyl, optionally substituted C_1-6 heteroalkyl, optionally substituted C_3-10 cycloalkyl, optionally substituted C_3-10 heterocycloalkyl (or 3 to 10-membered heterocycloalkyl) , op-tionally 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.
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 ac-ceptable salt thereof, wherein the compound of formula (I) is a compound of formula (I-1)

wherein X¹, X², X³, X⁴, X⁵, X⁶, A, B, E, G, R^A, R^B, R³, R⁴, R⁵ and n are as defined in claim 1.
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 ac-ceptable salt thereof, wherein

B is optionally substitutedand

R^A is

wherein

R¹ is selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally substi-tuted C_3-6 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 -C_1-2 alkylene-C_3-6 cycloalkyl, optionally substituted -C_1-2 alkylene-C_3-6 heterocycloalkyl, optionally substituted -C_1-2 alkylene-5 to 8-membered aryl, optionally substituted -C_1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -C_1-2 alkylene-8 to 10-membered fused bicy-clic heteroaryl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl may be further optionally substituted;

in R¹, when the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, or C_1-6 hydroxyalkyl is further substituted, the substituent is selected from the group consisting of C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substituted C_3-6 cycloalkyl, optionally sub-stituted C_3-6 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 consist-ing of optionally substituted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl, optionally substi-tuted 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 C_3-6 heterocycloalkyl;

Y is -CH-or N;

R² is optionally substituted C_1-6 alkoxy, or optionally substituted C_1-6 alkyl; preferably, R² is optionally substituted C_1-6 alkyl; and

R^M and R^N are each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl, C_1-6 aminoalkyl, optionally substi-tuted C_3-6 cycloalkyl, optionally substituted C_3-6 heterocycloalkyl; furthermore, the C_1-6 alkyl, C_1-6 alkoxyl, C_1-6 haloalkyl, C_1-6 haloalkoxyl, C_1-6 hydroxyalkyl may be further optionally substituted. In some embodi-ments, R^M and R^N are each independently selected from hydrogen, and C_1-6 alkyl.
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 ac-ceptable salt thereof, wherein

R¹ is optionally substituted C_1-6 alkyl;

and, in R¹, the C_1-6 alkyl is further substituted, and the substituent is selected from optionally substi-tuted C_3-6 cycloalkyl, optionally substituted C_3-6 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.
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 ac-ceptable salt thereof, wherein

R¹ is optionally substituted C_1-6 alkyl;

in R¹, the C_1-6 alkyl is further substituted, and the substituent is optionally substituted C_3-6 heterocy-cloalkyl.
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 C₁ alkyl; and the C₁ alkyl is further substituted with optionally substituted C_3-6 heter-ocycloalkyl, wherein the heterocycloalkyl is saturated and the heterocycloalkyl is attached to the rest of the molecule via the N atom on the ring.
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 C₁ alkyl; and the C₁ alkyl is further substituted with optionally substituted C_3-6 heter-ocycloalkyl, 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 C_3-6 heterocycloalkyl is 5 to 7 menbered heterocycloalkyl and has l to 2 heteroatoms.
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 ac-ceptable salt thereof, wherein

R¹ is selected from the group consisting of
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 ac-ceptable salt thereof, wherein R¹ is C₁ alkyl substituted by C₆ heterocycloalkyl, optionally wherein the C₆ heterocycloalkyl is piperazine or morpholine.
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.
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 ac-ceptable salt thereof, wherein

is selected from the group consisting of:

is
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 ac-ceptable 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 se-lected 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
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 ac-ceptable salt thereof, wherein

X¹ is C, and/or X² is -CR^a-, and/or X³ is -CR^b, and/or X⁴ is -CR^c-, and/or X⁵ is -C-.
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 pharma-ceutically acceptable salt thereof, wherein, the compound is selected from any one of the compounds in Table 1.
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 pharma-ceutically 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.
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 pro-drug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, and a phar-maceutically acceptable carrier.
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.
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 neuro-endocrine 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.
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 cholangiocar-cinoma.
The compound according to any one of claims 1 to 15, or the stereoisomer thereof, the pharma-ceutically 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.
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 pharma-ceutical composition comprising the same.