Macrocyclic compounds as ras inhibitors for the treatment of cancer

Abstract

The present invention is related to 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, wherein the compound has a structure according to formula (I), and its use for the treatment of cancer.

Description

Docket No.: 127711.W0007RAS Inhibitors for the Treatment of CancerCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority from Application Nos. PCT / CN2024 / 116363, filed September 2, 2024; PCT / CN2025 / 092141, filed April 29, 2025, and PCT / CN2025 / 110667, filed July 25, 2025. The contents of the priority applications are incorporated by reference herein in their entirety.BACKGROUND OF THE INVENTION

[0002] RAS proteins (including KRAS4A, KRAS4B, HRAS, and NRAS) are small, membrane-bound guanine nucleotide-binding proteins that act as molecular switches by cycling between an active GTP -bound state and an inactive GDP -bound state. When a RAS protein binds to a GEF family protein such as SOS 1, 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 a RAS protein, activating the RAS protein, which plays a key role in regulating cell survival, proliferation, and differentiation 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 development, as they disrupt the guanine exchange cycle and lock RAS in the activated state, continuously activating downstream signaling pathways and leading to the development of tumors.

[0003] RAS protein mutations occur in approximately 19% of all cancers and play an important role in tumor occurrence and progression. Among them, KRAS is the most commonly mutated subtype, followed by NRAS and HRAS. KRAS mutations commonly occur in pancreatic ductal adenocarcinoma, lung adenocarcinoma, and colorectal adenocarcinoma, while NRAS mutations have a relatively higher frequency in hematologic malignancies such as chronic myeloid leukemia and acute myeloid leukemia, as well as in malignant melanoma, thyroid cancer, and laryngeal cancer. HRAS mutations are less common in human cancers, but have a relatively higher mutation rate in head and neck squamous cell carcinoma, bladder cancer, salivary gland carcinoma, and oral cancer.

[0004] Given the relevance of the RAS proteins in carcinogenesis and tumor development, there remains a need for effective RAS inhibitors to meet various clinical needs.SUMMARY OF THE INVENTION

[0005] Provided herein are Ras inhibitors. Without wishing to be bound by theory, these inhibitors are believed to act as molecular glues, which function by simultaneously binding to highly activated RAS (RAS-ON) proteins and a ubiquitously expressed protein in cells. This forms a tricomplex, which occupies binding sites for RAS-interacting proteins such as S0S1 and RAF 1. The tricomplex is also believed to keep a RAS protein in a locked state alone and therefore unable to activate downstream signaling pathways, thereby blocking RAS signaling pathway transmission and inhibiting tumor growth.

[0006] The approach described herein is believed to entail formation of a high affinity three-component complex between a synthetic ligand and two intracellular proteins which generally 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). In some embodiments, the RAS molecular glues described herein induce a new binding pocket in RAS by forming a three-component complex with high-affinity between the RAS protein and the cytosolic chaperone, cyclophilin A. Without being bound by theory, the inventors believe that one way the inhibitory effect on RAS is affected by compounds of the invention and the three- component complexes they form is by steric occlusion of the interaction site between RAS and downstream effector molecules, such as RAF and PI3K, which are required for propagating the oncogenic signal.

[0007] In one aspect, the present disclosure provides a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt, wherein the compound has a structure according to formula (I)wherein, - represents a double bond or single bond; 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 optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11 -memberedbicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; G is optionally substituted Ci-6 alkylene; - between U and T is a bond or absent; wherein when - between U and T is a bond, U or T are absent, or U andT are each independently O, S, -NR3or optionally substituted Ci-6 alkylene; or wherein - between U and T is absent, T is absent, and U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted 6-membered aryl, optionally substituted 5 to 6-membered heteroaryl, optionally substituted -C1.3 alkylene-O-Ci-6 alkyl, optionally substituted -C1.3 alkylene-O- C3-10 cycloalkyl, optionally substituted -C1.3 alkylene-O-3 to 10-membered heterocycloalkyl, optionally substituted -C1.3 alkylene-S-Ci-6 alkyl, optionally substituted -C1.3 alkylene-S-C3-io cycloalkyl, or optionally substituted -C1.3 alkylene-S-3 to 10-membered heterocycloalkyl; wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted; R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1.3 alkyl, or R8and R9combine with the atom(s) to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl; R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, and optionally substituted C1.3 alkyl, or R10and R11combine with the atom to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl; R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1.3 alkyl, -OR71, -SR72or -N(R73)R74; R71, R72, R73and R74are each independently Ci-6 alkyl, Ci-6 heteroalkyl, Ci-ehaloalkyl, or Ci-6 haloheteroalkyl, or R73and R74combine with the atom(s) to which they are attached to form an optionally substituted 3 to 10-membered heterocycloalkyl; wherein the 3 to 10-membered heterocycloalkyl has 0, 1, 2, 3, 4 or 5 heteroatom ring atom(s) other than the N atom; RAis optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; RBis hydrogen, Ci-6 alkyl, Ci-ealkoxyl, Ci-e haloalkyl, Ci-6 haloalkoxy 1, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or, when n is 2 or 3, any two RBcombine with the atoms to which they are attached to form a 3 to 6-membered ring, wherein the ring is optionally substituted with halogen, hydroxy, or C1.3 alkyl; X1is N or C; X2is N or - CRa-; X3is N or -CRb-; X4is N or C; X5is N or C; X6is N or C; Raand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl; R3is hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3-6halocycloalkyl, -C(O)C 1.3 alkyl, -S(O2), or -S(O2)Ci-3 alkyl;E is a bond, N, or -CRd-, wherein Rdis selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf, wherein Reand Rfare each independently hydrogen or optionally substituted Ci-6 alkyl; R4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-R6Rl^N membered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' ; R5is hydrogen, Ci-6 alkyl, or C3-6 cycloalkyl, wherein the Ci-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or wherein R4and R5combine with the atom(s) to which they are attached to form a ring, wherein the ring is 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; and wherein L is absent, - CH2-, -C(O)-, -CHRg-, or -C(Rg)2-, wherein Rgis optionally substituted Ci-6 alkyl; R6is hydrogen or optionally substituted Ci-6 alkyl; R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; or L, R6, and R7combine with the atom(s) 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 alkyl, or optionally substituted 4 to 11-membered bicyclic heteroalkyl.

[0008] In some embodiments, the compound has a structure according to formula (II):wherein Y is CH or N; Rlais hydrogen, Ci-6 alkyl, Ci-e alkoxyl, C 1.6 haloalky 1, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionallysubstituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl may be further optionally substituted; R2is optionally substituted Ci-6 alkoxy or optionally substituted Ci-6 alkyl; and RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, Ci- 6 alkyl, Ci-6 alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, and Ci-6 hydroxyalkyl may be further optionally substituted.

[0009] In some embodiments, the compound has a structure according to formula (Illa) or formula (Illb):hydrogen, Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2 alkylene-C3-6 cycloalkyl, optionally substituted -C1.2 alkylene-C3-6 heterocycloalkyl, optionally substituted - Ci-2 alkylene-5 to 8-membered aryl, optionally substituted -C1-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic aryl, or optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic heteroaryl; wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl may be further optionally substituted, and Raand Rbare each independently hydrogen, halogen, cyano, C1-3 alkyl, C1.3 alkoxyl, C1-3 haloalkyl, C1-3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl.

[0010] In some embodiments, the compound has a structure according to formula (IVaa), (IVab), (IVba) or (IVbb):, tionallyselected from the group consisting of hydrogen, Ci-6 alkyl, Ci-ealkoxyl, Ci-6 haloalky 1, Ci-6 haloalkoxy 1, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3- 6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2 alkylene- C3-6 cycloalkyl, optionally substituted -C1.2 alkylene-C3-6 heterocycloalkyl, optionally substituted -C1-2 alkylene-5 to 8-membered aryl, optionally substituted -C1-2 alkylene-5 to 8- membered heteroaryl, optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic heteroaryl; wherein the Ci-6 alkyl, Ci-e alkoxyl, Ci-ehaloalkyl, Ci-6 haloalkoxy 1, Ci-6 hydroxyalkyl may be further optionally substituted; in R1, when the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl is further substituted, the substituent is selected from the group consisting of Ci-6 alkyl, Ci^ alkoxyl, Ci-e haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionallysubstituted 8 to 10-membered fused bicyclic heteroaryl; optionally wherein the substituent is selected from the group consisting of optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; further optionally, the substituent is optionally substituted C3-6 heterocycloalkyl;

[0013] In some embodiments, Y is -CH- or N; R2is optionally substituted Ci-6 alkoxy or optionally substituted Ci-6 alkyl; optionally wherein R2is optionally substituted Ci-6 alkyl; and RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci- e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl; wherein the Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, or Ci-6 hydroxyalkyl is optionally substituted, further optionally wherein RMand RNare each independently selected from hydrogen or Ci-6 alkyl.

[0014] In some embodiments, R1is optionally substituted -C1.2 alkylene-3 to 6-membered heterocycloalkyl, optionally wherein the 3 to 6-membered heterocycloalkyl has the structure:wherein nl and n2 are each independently 1, 2, or 3, optionally wherein nl and n2 are each 2, and wherein ZRAis O, S, or NH; optionally wherein the C1.2 alkylene of R1is - CH2- or -CH(CH3)-; wherein optionally substituted means the group is unsubstituted or substituted with 1-4 substituent(s) selected from the group consisting of D, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl, further optionally, with 1-4 substituent(s) selected from the group consisting of D and Ci-6 alkyl, or, wherein R1is substituted Ci-6 alkyl, and is optionally substituted with one substituent of -CONR'R" and is unsubstituted or substituted with 1-4 substituent(s) selected from the group consisting of D, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl.

[0015] In some embodiments, R1is

[0016] In some embodiments, R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; optionally wherein the 3 to 10- membered cycloalkyl is cyclopropyl or cyclobutyl, and / or wherein the 3 to 10-membered heterocycloalkyl is a 4 to 5-membered heterocycloalkyl containing one heteroatom selected from O or S, optionally S, as a ring atom;wherein optionally substituted means unsubstituted or substituted with 1-4 substituents selected from the group consisting of D, halogen, -CN, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, -3 to 10-membered heterocycloalkenyl, - Ce-io aryl, -5 to 10-membered heteroaryl, -C1.4 alkylene-C3.10 cycloalkyl, -C1.4 alkylene-C3.10 cycloalkenyl, -C1.4 alkylene-3 to 10-membered heterocycloalkyl, -C1.4 alkylene-3 to 10- membered heterocycloalkenyl, -C1.4 alkylene-Ce-io aryl, and -C1.4 alkylene-5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of D, halogen, and Ci-6 alkyl; further optionally wherein optionally substituted means unsubstituted or substituted with 1-4 substituents selected from the group consisting of Ci-6 alkyl, Ce-io aryl, and 5 to 10- membered heteroaryl; wherein the aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of D, halogen, and Ci-6 alkyl.

[0017] In some embodiments,

[0018] In some embodiments, A is optionally substituted 5 to 6-membered heteroarylene, wherein 1-3 atoms of the heteroarylene are each independently N, O or S, optionally wherein A is optionally substituted 5-membered heteroarylene, wherein 1-3 atoms of the heteroarylene are each independently N, O or S, optionally wherein 1 of the atom of the heteroarylene is an N and 1 atom of the heteroarylene is O or S; further optionally wherein A is :

[0019] In some embodiments, when - between U and T is absent, T is absent, and U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted Ci-6 cycloalkyl, optionally substituted Ci-6 heterocycloalkyl, -C1.3 alkyl-O-Ci-6 alkyl, -C1-3 alkyl-O-Ci-6 cycloalkyl, or -C1.3 alkyl-O-Ci-6 heterocycloalkyl; wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, or Ci-6 heterocycloalkyl may be further optionally substituted;

[0020] In some embodiments, R13is each independently selected from -OR71or -NR73R74; R71, R73and R74are each independently, Ci-6 alkyl, Ci-6 heteroalkyl, or R73and R74combine to form a 3 to 10-membered heterocycloalkyl; wherein the Ci-6 alkyl, Ci-6 heteroalkyl and 3 to 10- membered heterocycloalkyl may be further optionally substituted, optionally wherein R13is

[0021] In some embodiments, X1is C; X2is -CRa-; X3is -CRb-; X4is -CRC-; and / or X5is - C-.

[0022] In some embodiments, the compound is selected from any one of the compounds in Table 1. In some embodiments, the compound is selected from any one 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, 58, 59-123, 124-194 or 243-244 of Table 1.

[0023] Also provided is a compound as defined herein. In another aspect, this disclosure provides the pharmaceutically acceptable salt of a compound as defined herein.

[0024] Also provided is use of the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt or pharmaceutical composition defined herein in the preparation of a medicament used for the treatment of cancer; the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt or pharmaceutical composition defined herein for use in treating cancer; and a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt, or pharmaceutical composition as defined herein.

[0025] In some embodiments, 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 (NSCLC), cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, and squamous cell lung carcinoma, or a combination thereof.

[0026] In some embodiments, the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, andcholangiocarcinoma.

[0027] In another aspect, the present invention provides a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein the compound has a structure according to formula (I);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 optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11 -membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene;G is optionally substituted Ci-6 alkylene;- between U and T is a bond or absent (i.e., there is no bond between U and T); when - between U and T is a bond, U and T are each independently absent, a bond, O, S, -NR3, or optionally substituted Ci-6 alkylene; when - between U and T is absent, T is absent, and U is optionally substitutedCi-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted 6-membered aryl, optionally substituted 5 to 6-membered heteroaryl, optionally substituted -C1.3 alkylene-O-Ci-6 alkyl, optionally substituted -C1.3 alkylene-O- C3-10 cycloalkyl, optionally substituted -C1.3 alkylene- 0-3 to 10-membered heterocycloalkyl, optionally substituted -C1.3 alkylene-S-Ci-6 alkyl, optionally substituted -C1.3 alkylene-S- C3-10 cycloalkyl, or optionally substituted -C1.3 alkylene-S-3 to 10-membered heterocycloalkyl; wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, or Ci-6 heterocycloalkyl may be further optionally substituted;R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1.3 alkyl; or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1.3 alkyl; or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1.3 alkyl, -OR71, -SR72or -N(R73)R74;R71, R72, R73and R74are each independently Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, or Ci-6 haloheteroalkyl; or R73and R74combine with the N atom to which they are attached to form an optionally substituted 3 to 10-membered heterocycloalkyl, wherein the 3 to 10-membered heterocycloalkyl has 0, 1, 2, 3, 4 or 5 heteroatom ring atom(s) other than the N atom;RAis optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl;RBis hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or provided that, when n is 2 or 3, any two of RBcombine 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 C1.3 alkyl;X1is N or C;X2is N or -CRa-;X3is N or -CRb-;X4is N or C;X5is N or C;X6is N, or C;Raand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl;R3is hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3-6 halocycloalkyl, - C(O)Ci-3 alkyl, -S(O2), or -S(O2)Ci-3alkyl;E is a bond, N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf; wherein Reand Rfare independently hydrogen, or optionally substituted Ci-6 alkyl;R4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl,R5is hydrogen, Ci-6 alkyl or C3-6 cycloalkyl, wherein the Ci-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is 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, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl, whereinL is absent, or -CH2-, -C(O)-, -CHRg- or -C(RS)2-, wherein Rgis optionally substituted Ci-6 alkyl;R6is hydrogen, or optionally substituted Ci-6 alkyl;R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10- membered heteroaryl; or L, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is 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.DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention provides a compound of formula (I):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.

[0029] In some embodiments, B is an optionally substituted 3 to 6-membered monocyclic heterocycloalkylene, optionally substituted 3 to 6-membered monocyclic heterocycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, optionally substituted 4 to 11-membered bicyclic heterocycloalkylene. In some embodiments, B is an optionally substituted 3 to 6-membered monocyclic heterocycloalkylene, or optionally substituted 4 to 11-membered bicyclic cycloalkylene. In some embodiments, B is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11-membered bicyclic alkylene, or optionally substituted 4 to 11 -membered bicyclic heteroalkylene.

[0031] In some embodiments, B is optionally substitutedor optionally

[0033] In some embodiments,

[0034] In some embodiments,

[0035] In some embodiments, R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1.3 alkyl; or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl. In some embodiments, R8and R9are each hydrogen.

[0036] In some embodiments, R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1.3 alkyl; or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl. In some embodiments, R10and R11are each hydrogen.

[0037] In some embodiments, R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1.3 alkyl, -OR71, -SR72or -NR73R74, wherein R71, R72, R73and R74are each independently Ci-6 alkyl, Ci-6 heteroalkyl, Ci-e haloalkyl, or Ci-6 haloheteroalkyl; or R73and R74combine with the N atom attached to them to form optionally substituted 3 to 10-membered heterocycloalkyl, wherein the 3 to 10-membered heterocycloalkyl has 0, 1, 2, 3, 4 or 5 heteroatom ring atom(s) other than the N atom. In some embodiments, R12is hydrogen. In some embodiments, R13is -OR71or -N(R73)R74.

[0038] In some embodiments, RAis optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 5 to 8-membered monocyclic aryl, optionally substituted 5 to 8-membered monocyclic heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl. In some embodiments, RAis optionally substituted 5 to 8- membered monocyclic aryl or optionally substituted 5 to 8-membered monocyclic heteroaryl.

[0039] RAunsubstituted or may be substituted with one or more of R2, RM, RN, Rlaor

[0040] In some embodiments, RAis

[0041] In some embodiments, Rlais hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalky 1, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10- membered fused bicyclic heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, and Ci-e hydroxyalkyl may be further optionally substituted.

[0042] In some embodiments, Rlais optionally substituted C2-4 alkynyl. In somealkyl (e.g., N-methyl or N-ethyl).

[0044] In some embodiments, R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-e hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8- membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1.2 alkylene-alkylamino, optionally substituted -C1.2 alkylene-C3-6 cycloalkyl, optionally substituted -C1.2 alkylene-3 to 6-membered heterocycloalkyl, optionally substituted -C1.2 alkylene-5 to 8-membered aryl, optionally substituted -C1.2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1.2 alkylene-8 to10-membered fused bicyclic aryl, or optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-ehaloalkoxyl, Ci-6 hydroxyalkyl may be further optionally substituted.

[0045] In some embodiments, R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8- membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -methylene-alkylamino, optionally substituted -methylene-Cs- 6 cycloalkyl, optionally substituted -methylene-3 to 6-membered heterocycloalkyl, optionally substituted -methylene-5 to 8-membered aryl, optionally substituted -methylene-5 to 8- membered heteroaryl, optionally substituted -methylene-8 to 10-membered fused bicyclic aryl, or optionally substituted -methylene-8 to 10-membered fused bicyclic heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl may be further optionally substituted.

[0046] In some embodiments, R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8- membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1.2 alkylene-C3-6 cycloalkyl, optionally substituted -C1.2 alkylene-3 to 6-membered heterocycloalkyl, optionally substituted -C1.2 alkylene-5 to 8- membered aryl, optionally substituted -C1.2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1.2 alkylene-8 to 10-membered fused bicyclic aryl, or optionally substituted -C1.2 alkylene-8 to 10-membered fused bicyclic heteroaryl. In some embodiments, R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl), wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxy alkyl (optionally the Ci-6 alkyl) may be further optionally substituted.

[0047] In some embodiments, R1is optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl. In some embodiments, R1is optionally substituted 6- membered aryl, or optionally substituted 5 to 6-membered heteroaryl. The 5 to 6-membered heteroaryl may contains 1, 2 or 3 heteroatoms (e.g., N).

[0048] In some embodiments, R1is optionally substituted -Ci-2 alkylene (e.g., -CH2- or - CH(CHa)-);-3 to 6-membered heterocycloalkyl; optionally wherein the 3 to 6-membered heterocycloalkyl has the structurewherein nl and n2 are each independently 1, 2 or 3 (optionally wherein nl and n2 are both 2), and ZRAis O, S or NH. In some embodiments, optionally substituted means the group is unsubstituted or substituted with one or more (such as 1, 2, 3, or 4) substituent(s) selected from the group consisting of deuterium, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl. In some embodiments, the substituent(s) are 1-4 substituent(s) selected from the group consisting of deuterium and Ci-6 alkyl.

[0049] In some embodiments, Rl1is optionally substituted -Cl -2 alkylene-3 to 6- membered heterocycloalkyl; optionally wherein, the 3 to 6-membered heterocycloalkyl has the structurewherein nl and n2 are each independently 1, 2 or 3 (optionally wherein nl and n2 are both 2), and ZRAis O, S or NH.

[0050] In some embodiments, R1is substituted Ci-6 alkyl. The Ci-6 alkyl may be substituted with one -CONRT1. In some embodiments, Rl is unsubstituted. In some embodiments, Rl substituted with one or more (such as 1, 2, 3, or 4) substituent(s) selected from the group consisting of deuterium, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl. The Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl (optionally, the Ci-6 alkyl) group of R1may be substituted with a substituent selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl. In some embodiments, the substituent optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, oroptionally substituted 8 to 10-membered fused bicyclic heteroaryl. In some embodiments, the substituent is optionally substituted C3-6 heterocycloalkyl.

[0051] In some embodiments, R1may be substituted with one or more (e.g., 1, 2 or 3) deuterium, halogen, Ci-6 alkyl, Ci-6 hydroxyalkyl, Ci-6 deuteroalkyl, or -C(O)-Ci-6 alkyl substituent(s).

[0052] In some embodiments, R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalky 1, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8- membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl. In some embodiments, the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl is substituted. In some embodiments, the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-e hydroxyalkyl is unsubstituted.

[0053] In some embodiments, RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl. The Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl may be further substituted or unsubstituted.

[0054] In some embodiments, RMand RNare each hydrogen. In some embodiments, RMand RNare each independently Ci-6 alkyl.

[0055] In some embodiments, Y is -CH- or N. In some embodiments, Y is N.

[0056] In some embodiments, R2is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl. In some embodiments, R2is optionally substituted Ci-6 alkyl.

[0057] In some embodiments, in R2, optionally substituted means unsubstituted or substituted with one or more (e.g., 1, 2 or 3) substituents selected from deuterium, Ci-6 alkoxy, Ci-6 deuteroalkoxy, and Ci-6 haloalkoxy.

[0058] In some embodiments, R2is Ci-6 alkyl substituted with one or more (e.g., 1, 2 or 3) substituents independently selected from the group consisting of deuterium, Ci-6 alkoxy, Ci-6 deuteroalkoxy, and Ci-6 haloalkoxy.

[0059] In some embodiments, B is yO H y or \ HNy , and RAis optionally substituted phenyl or optionally substituted 6-membered heteroaryl.

[0060] In some embodiments, R8, R9, R10, R11and R12are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1.3 alkyl. In some embodiments, R8, R9, R10, R11and R12are each hydrogen.

[0061] In some embodiments, R12and R13are each hydrogen. In some embodiments, one of R12or R13is H and the other is. In some embodiments, one of R12or R13is H

[0062] In some embodiments,

[0063] In some embodiments, the compound of formula (I) has a structure according to the formula:

[0064] In some embodiments, the compound of formula (I) is a compound of formula (1-1)or (1-2):

[0065] In some embodiments, the compound has a structure according to formula (II):wherein A, G, U, T, Y, X1, X2, X3, X4, X5, X6, Rla, R2, RM, RN, E, R4, R5and R13are as defined herein.

[0066] In some embodiments, the compound of formula (II) has a structure according to formula (II- 1) or formula (II-2) :wherein each of the variable positions are as defined herein.

[0067] In some embodiments, the compound of formula (II) is a compound of formula (Ila) or formula (lib) :wherein each of the variable positions are as defined herein.

[0068] In some embodiments, the compound of formula (Ila) has a structure according to formula (

[0069] In some embodiments, the compound of formula (lib) has a structure according to formula (lib- 1) or (IIb-2):

[0070] In some embodiments, the compound has a structure according to formula (Ila) or (lib), andA is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;G is optionally substituted Ci-6 alkylene;- between U and T is a bond or absent, wherein when - between U and T is a bond, U or T are absent, or U and T are each independently O, S, -NR3, or optionally substituted Ci-6 alkylene; or when - between U and T is absent, T is absent, and U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 10 membered Ci-6 heterocycloalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted 6-membered aryl, or optionally substituted 5 to 6-membered heteroaryl, -C1.3 alkylene-O-Ci-6 alkyl, -C1.3 alkylene-O-C3-6 cycloalkyl, or -C1.3 alkylene-O-4 to 6 membered heterocycloalkyl, wherein theCi-3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted;Y is -CH- or N;X1is N or C;X2is N or -CRa-;X3is N or -CRb-;X4 is N or C;X5is N or C;X6is N or C;Raand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl;Rlais hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, and Ci-6 hydroxyalkyl may be further optionally substituted;R2is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl;RMand RNare each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci- 6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, and Ci-6 hydroxyalkyl may be further optionally substituted;R3is hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3-6 halocycloalkyl, - C(O)Ci-3 alkyl, -S(O2), or -S(O2)Ci-3 alkyl;R13is each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1.3 alkyl, -OR71, -SR72or -NR73R74;R71, R72, R73and R74are each independently Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 haloalkyl, Ci-6 haloheteroalkyl, or R73and R74combine to form a 3 to 10-membered heterocycloalkyl, wherein the Ci-6 alkyl, Ci-6 heteroalkyl and 3 to 10-membered heterocycloalkyl may be further optionally substituted;E is a bond, N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf, wherein Reand Rfare each independently hydrogen, or optionally substituted Ci-6 alkyl;R4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-memberedR6RlL / N heteroaryl, or ' ; and R5is hydrogen, Ci-6 alkyl or C3-6 cycloalkyl, wherein the Ci-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; orR4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is 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, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl; and / orL is absent, -CH2-, -C(O)-, -CHRg- or -C(RS)2-, wherein Rgis optionally substituted Ci-6 alkyl; R6is hydrogen or optionally substituted Ci-6 alkyl; and R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; orL, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is 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, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl.

[0071] In some embodiments, X1is C.

[0072] In some embodiments, X2is -CRa-. In some embodiments, X2is -CH- or -CF-.

[0073] In some embodiments, X3is -CRb-. In some embodiments, X3is -CH- or -CF-),

[0074] In some embodiments, X4is C, and / or X5is C.

[0075] In some embodiments, Raand Rbeach independently hydrogen, halogen, cyano, Ci-3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, or C1.3 haloalkoxyl. In some embodiments, Raand Rbare each independently hydrogen or C1.3 alkyl.

[0076] In some embodiments of the present disclosure, X1, X2, X3, X4and X5are each - CH-, and RMand RNare each hydrogen.

[0077] In some embodiments, X6is N or C. In some embodiments, X6is N.

[0078] In some embodiments, - between U and T is a bond, and U and T are each independently O, S, -NR3or optionally substituted Ci-6 alkylene.

[0079] In some embodiments, - between U and T is a bond, U is optionally substituted Ci-6 alkylene, and T is O or optionally substituted Ci-6 alkylene.

[0080] In some embodiments, - between U and T is a bond, U is optionally substituted -CH2-, optionally substituted -(CH2)2- or optionally substituted -(CH2)3-, and T is O or optionally substituted -CH2- or O.

[0081] In some embodiments, U is substituted with C1.4 alkyl, halogen, or hydroxyl. In some embodiments, T is substituted with C1.4 alkyl or halogen (e.g., F).

[0082] In some embodiments, - between U and T is a bond, U is Ci-6 alkylene or Ci-6 haloalkylene, and T is O or Ci-6 alkylene.

[0083] In some embodiments, when - between U and T is absent, T is absent, U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted 6-membered aryl, optionally substituted 5 to 6-membered heteroaryl, optionally substituted -C1.3 alkylene-O-Ci-6 alkyl, optionally substituted -C1.3 alkylene-O-C3-6 cycloalkyl, optionally substituted -C1.3 alkylene-O-4 to 6-membered heterocycloalkyl, optionally substituted -C1.3 alkylene-O-Ci-6 alkyl, optionally substituted -C1.3 alkylene-O-C3-6 cycloalkyl, or optionally substituted -C1.3 alkylene-O-4 to 6-membered heterocycloalkyl, wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted.

[0084] In some embodiments, - between U and T is absent, T is absent, and U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, -C1.3 alkylene-O-Ci-6 alkyl, -Ci-3 alkylene-O-C3-6 cycloalkyl, or -C1.3 alkylene-O-4 to 6-membered heterocycloalkyl, wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted. In some embodiments, - between U and T is absent, T is absent, and U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, -C1.3 alkylene- O-Ci-6 alkyl, -C1.3 alkylene-O-C3-6 cycloalkyl, or -C1.3 alkylene-O-4 to 6-membered heterocycloalkyl, and optionally, at least one of heteroatoms in the heteroalkyl and / or the heterocycloalkyl is O.

[0085] In some embodiments, the compound has a structure according to formula (Illa) or formula (Illb):(Illb),wherein each of the variable positions are as defined herein.

[0086] In some embodiments, the compound has a structure according to formula (Illa- 1), (IIIa-2), (IIIb-1), or (IIIb-2):

[0087] In some embodiments, the compound has a structure according to formula (Illa) or (Illb),A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;G is optionally substituted Ci-6 alkylene;- between U and T is a bond or absent; when - between U and T is a bond, U or T are absent, or they are each independently O, S, -NR3or optionally substituted Ci-6 alkylene; when - between U and T is absent, T is absent, U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, -C1.3 alkylene-O-Ci-6 alkyl, -C1.3 alkylene-O-C3-6 cycloalkyl, or -C1.3 alkylene-O-4 to 6 membered heterocycloalkyl, wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted;Y is -CH- or N;X6is N or -CH-;Raand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl;R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, and Ci-e hydroxyalkyl may be further optionally substituted;R2is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl; and / orR3is selected from hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3-6 halocycloalkyl, -C(O)C 1.3 alkyl, -S(O2), or -S(O2)Ci-3 alkyl;R13is each independently selected from-OR71or -NR73R74;R71, R73and R74are each independently Ci-6 alkyl, Ci-6 heteroalkyl, or R73and R74combine to form a 3 to 10-membered heterocycloalkyl, wherein the Ci-6 alkyl, Ci-6 heteroalkyl and 3 to 10-membered heterocycloalkyl may be further optionally substituted;E is a bond N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-ehydroxyalkyl, or -NReRf, wherein Reand Rfare hydrogen, or optionally substituted Ci-6 alkyl;R4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl,R5is hydrogen, Ci-6 alkyl or C3-6 cycloalkyl, wherein the Ci-6 alkyl or C3-6 cycloalkyl may be further optionally substituted;R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is 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, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl; and / or wherein L is absent, -CH2-, -C(O)-, -CHRg-, or -C(RS)2-, wherein Rgis optionally substituted Ci-6 alkyl; R6is hydrogen, or optionally substituted Ci-6 alkyl; and R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is 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, or optionally substituted 4 to 11-membered bicyclic heterocycloalkyl.

[0088] In some embodiments, the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, C3-5 heterocycloalkyl (or 4 to 6-membered heterocycloalkyl), 3 to 6-membered heterocycloalkyl, 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, Ci- 6 heteroalkyl, C3-10 heterocycloalkyl, 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl or 4 to 11 -membered bicyclic heterocycloalkyl, the heteroatom is independently N, O or S, and the number of the heteroatom(s) is independently 1 to 4.

[0089] In some embodiments, the compound has a structure according to formula (IVaa) or formula (In some embodiments, the compound has a structure according to formula (IVaa-1), (IVaa-2), (IVab-1), or (IVab-2)whereinare defined as above.

[0090] In some embodiments, the compound has a structure according to formula (IVba) or formula (IVbb):

[0091] In some embodiments, the compound has a structure according to formula (IVba-1), (IVba-2), (IVbb-1), or (IVbb-2):wherein A, G, U, T, Y, Ra, Rb, X6, R1, R2, E, R4, R5and R13are defined as above.

[0092] In some embodiments, the compound has a structure according to formula (IVaa), (IVab), (IVba) or (IVbb),A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; and / orG is optionally substituted Ci-6 alkylene; and / or- between U and T is a bond or absent; when - between U and T is a bond, U or T are absent, or they are each independently O, S, -NR3or optionally substituted Ci-6 alkylene; when - between U and T is absent, when T is absent, U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, -C1.3 alkylene-O-Ci-6 alkyl, -C1.3 alkylene-O-Ci-6 cycloalkyl, or -C1.3 alkylene-O-4 to 6membered heterocycloalkyl, wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted; and / orY is -CH- or N; and / orX6is N or -CH-; and / orRaand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, 3 to 6-membered heterocycloalkyl; and / orR1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, or optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl, wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl may be further optionally substituted; and / orR2is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl; and / orR3is hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3-6 halocycloalkyl, - C(O)Ci-3 alkyl, -S(O2), or -S(O2)Ci-3alkyl; and / orR13is each independently -OR71or -NR73R74;R71, R73and R74are each independently Ci-6 alkyl or Ci-6 heteroalkyl; or R73and R74combine to form a 3 to 10-membered heterocycloalkyl, wherein the Ci-6 alkyl, Ci-6 heteroalkyl and 3 to 10-membered heterocycloalkyl may be further optionally substituted; and / orE is a bond N or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf, wherein Reand Rfare independently hydrogen, or optionallysubstituted Ci-6 alkyl; and / orR4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl,R5is hydrogen, Ci-6 alkyl or C3-6 cycloalkyl, wherein the Ci-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; and / orR4and R5combine 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; and / or whereinL is absent, -CH2-, -C(O)-, -CHRg-, or -C(RS)2-, wherein Rgis optionally substituted Ci-6 alkyl; and / orR6is hydrogen, or optionally substituted Ci-6 alkyl; and / orR7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; and / orL, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is 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, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl.

[0093] In some embodiments, in the 5 to 6-membered heterocycloalkylene, 5 to 6- membered heteroarylene, C3-5 heterocycloalkyl, 3 to 6-membered heterocycloalkyl, 5 to 6- membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, Ci-6 heteroalkyl, C3-10 heterocycloalkyl (or 3 to 10-membered heterocycloalkyl), 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl or 4 to 11 -membered bicyclic heteroalkyl, the heteroatom is independently N, O or S, and the number of the heteroatom(s) is independently 1 to 4.

[0094] In some embodiments, the 5 to 6-membered heterocycloalkylene contains one or two heteroatoms; optionally wherein each heteroatom is independently N, O, or S.

[0095] In some embodiments, A is optionally substituted 5 to 6-memberedheterocycloalkylene, the number of the heteroatom(s) is independently 1 to 2, and each heteroatom is independently N, O or S.

[0097] In some embodiments, A is optionally substituted 5 to 6-membered arylene.

[0098] In some embodiments, A is

[0099] In some embodiments, the 5 to 6-membered heteroarylene contains one, two or three (optionally one or two) heteroatoms; optionally wherein each heteroatom is independently N, O or S.

[0100] In some embodiments, A is optionally substituted 5 to 6-membered heteroarylene, the number of the heteroatom(s) is independently 1 to 3, and each heteroatom is independently N, O or S.

[0102] In some embodiments, A isIn some embodiments,

[0103] In some embodiments, A has the structure:wherein ZA1, ZA2and ZA3are each independently N, O, S, or CH; with the proviso that onlyone of ZA1, ZA2and ZA3is O or S. In some embodiments, ZA1is N, one of ZA2and ZA3is O or S, and the other of ZA2and ZA3is CH or N.

[0104] In some embodiments, G is optionally substituted Ci-6 alkylene. In some embodiments, G is optionally substituted -C(Ci-3alkyl)2-.

[0105] In some embodiments, G is unsubstituted or substituted with one or more deuterium atom(s).

[0107] In some embodiments, U or T is absent, or U and T are each independently O, S, - NR3, or optionally substituted Ci-6 alkylene.

[0108] In some embodiments, U is optionally substituted Ci-6 alkylene. In some embodiments, U is -CH2CH2-, -CH2CHOH-, -CH2C(CH3)2- or -CH2CF2-.

[0109] In some embodiments, T is O or Ci-6 alkylene. In some embodiments, T is O or - CH-.

[0110] In some embodiments of the present disclosure, Y is N.[OlH] In some embodiments of the present disclosure, X6is N.

[0112] In some embodiments of the present disclosure, R1is Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, Ci-e hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl.

[0113] In some embodiments, T is absent, U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4 to 6 membered heterocycloalkyl, -C1.3 alkylene-O-Ci-6 alkyl, -C1.3 alkylene-O-C3-6 cycloalkyl, or - C1.3 alkylene-O-4 to 6 membered heterocycloalkyl, wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted.

[0116] In some embodiments, R1is optionally substituted -C 1-2 alkylene- alkylamino, optionally substituted -C1.2 alkylene-C3-6 cycloalkyl, or optionally substituted -C 1-2 alkyl ene-3 to 6-membered heterocycloalkyl.

[0117] In some embodiments, R1is substituted with one or more substituents selected from the group consisting of deuterium, halogen, Ci-6 alkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, -OC(O)-Ci-6 alkyl,, C3-io cycloalkyl, and 3 to 10-membered heterocycloalkyl, or acombination thereof.

[0119] In some embodiments, R1is optionally substituted 4 to 5-membered heteroalkyl, or 5 to 6-membered heteroaryl.

[0120] In some embodiments, R1is substituted with one or more substituents selected from deuterium, halogen, Ci-6 alkyl, Ci-6 deuteroalkyl, and Ci-6 hydroxyalkyl, or a combination thereof, or two substituents on the same or adjacent atoms together with the atom(s) to which they are attached form a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3 to 10-membered heterocycloalkyl, or 3 to 10-membered heterocycloalkenyl.

[0121] In some embodiments, R1is

[0122] In some embodiments, R1is optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl, the number of the heteroatom(s) is independently 1 to 4, and each heteroatom is independently selected from N, O or S.

[0124] In some embodiments, R2is optionally substituted Ci-6 alkyl or optionallysubstituted Ci-6 alkoxy. In some embodiments, R2is O In some embodiments, R2is

[0125] In some embodiments, R3is hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3- 6 halocycloalkyl, -C(O)Ci-3 alkyl, -S(O2), or -S(O2)Ci-3 alkyl;

[0126] In some embodiments, R3is C1.3 alkyl. In some embodiments, R3is Ci-6 deuterated alkyl. In some embodiments, R3is

[0127] In some embodiments, R3is C1.3 haloalky. In some embodiments, R3is

[0128] In some embodiments, R3is C3-6 cycloalkyl; optionally wherein R3is

[0129] In some embodiments, R3is C3-6 halocycloalkyl; optionally wherein R3is

[0130] In some embodiments, R3is -C(O)Ci-3 alkyl; optionally wherein R3is0

[0131] In some embodiments, R3is -S(O2)Ci-3 alkyl; optionally wherein R3is 0

[0132] In some embodiments, each R13is independently -OR71or -NR73R74; wherein R71, R73and R74are each independently Ci-6 alkyl or Ci-6 heteroalkyl; or R73and R74combine to form a 3 to 10-membered heterocycloalkyl, wherein the Ci-6 alkyl, Ci-6 heteroalkyl and 3 to 10-membered heterocycloalkyl may be further optionally substituted.

[0134] In some embodiments of the present disclosure, E is a bond, N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf, wherein Reand Rfare each independently hydrogen, or optionally substituted Ci-6 alkyl. In some embodiments, E is a bond, N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy or Ci-6 alkyl.

[0135] In some embodiments, Rdis halogen. In some embodiments, Rdis -F, -Cl, -Br or -I; optionally wherein Rdis -F.

[0136] In some embodiments, Rdis Ci-6 alkyl. In some embodiments, Rdis, / ,^ , or H

[0137] In some embodiments, Rdis Ci-6 haloalkyl. In some embodiments, Rdis -CF3.

[0138] In some embodiments of the present disclosure, Rdis Ci-6 alkoxyl. In some embodiments,

[0139] In some embodiments, Rdis Ci-6 aminoalkyl. In some embodiments, Rdis

[0140] In some embodiments, one of Reor Rfis Ci-6 alkyl. In some embodiments, one ofReor R f is - » ,, , , optionally wherein the other of Reor R f is hydrogen.

[0141] In some embodiments, L is -CH2-, -C(O)-, -CHRS- or -C(RS)2-, wherein Rgis optionally substituted Ci-6 alkyl.

[0142] In some embodiments, R4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-R6RlL / N membered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' . In someR6RlL / N embodiments, R4is hydrogen, optionally substituted Ci-6 alkyl, or ' .

[0143] In some embodiments, R6is hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, R6is hydrogen or unsubstituted Ci-6 alkyl.

[0144] In some embodiments, R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl. In some embodiments, R7is Ci-6 alkyl or optionally substituted C3- 10 cycloalkyl.

[0145] In some embodiments, R4is hydrogen, optionally substituted Ci-6 alkyl, optionallysubstituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-R6RlL / N membered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' , wherein R6is hydrogen or optionally substituted Ci-6 alkyl; R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl.

[0146] In some embodiments, R4is optionally substituted with one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, and Ci-6 alkyl. In some embodiments, R4is hydrogen, Ci-6 alkyl, 3 to 6-membered heterocycloalkyl, 3 to 6-memberedR6Rl^N cycloalkyl, 6 to 10-membered aryl, 5 to 10-membered heteroaryl, or ' , wherein R6is hydrogen or Ci-6 alkyl; R7is Ci-6 alkylor 3- to 10-membered heterocycloalkyl, wherein the 3 to 10-membered heterocycloalkyl is optionally substituted by Ci-6 alkyl, 6 to 10-membered aryl, - CO-O-C3-6 cycloalkyl or -CO-O-Ci-6 alkyl; the 3 to 6-membered cycloalkyl is optionally substituted by hydroxyl, cyano, halogen, or Ci-6 alkyl; in 3 to 10-membered heterocycloalkyl, the heteroatom is independently N, O or S, and the number of the heteroatom(s) isR6RlL / N independently 1 to 3; optionally, R4is hydrogen, Ci-6 alkyl, or ' , wherein R6is hydrogen, or Ci-6 alkyl; R7is Ci-6 alkyl, or 3 to 10-membered heterocycloalkyl.

[0147] In some embodiments, in R4, C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl) contains 1 or 2 heteroatoms selected from the group consisting of N, O and S.

[0148] In some embodiments, R4is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, or optionally substituted C3-10 heterocycloalkyl; the heteroatom is N, O or S, and the number of the heteroatom(s) is independently 1 or 2. In some embodiments, R4is

[0149] In some embodiments of the present disclosure, R4is optionally substituted 6 to 10-membered aryl or optionally substituted 5 to 10-membered heteroaryl. In some embodiments,

[0150] In some embodiments of the present disclosure, R5is optionally substituted Ci-6 alkyl. In some embodiments, R5is I,,

[0151] In some embodiments of the present disclosure, R5is optionally substituted C3-6 cycloalkyl. In some embodiments, R5is

[0152] In some embodiments, in the ring formed by R4, R5and the atoms to which they are attached, the heterocycloalkyl or the bicyclic heterocycloalkyl contains 1, 2 or 3 heteroatom(s) selected from the group consisting of N, O and S.

[0153] In some embodiments of the present disclosure, R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10- membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl; the heteroatom is N, O or S, and the number of the heteroatom(s) is independently 1 to 3. In some embodiments, the ring

[0154] In some embodiments, R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl. In some embodiments, the 3 to 10-membered cycloalkyl is cyclopropyl or cyclobutyl, and the 3 to 10-membered heterocycloalkyl is a 4 to 5-membered heterocycloalkyl containing one heteroatom selected from O or S as the ring atom. In some embodiments, optionally substituted means unsubstituted or substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of deuterium, halogen, -CN, Ci-6 alkyl, -C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, 3 to 10-membered heterocycloalkenyl, Ce-io aryl, 5 to 10-membered heteroaryl, -Ci- 4 alkylene-C3.it) cycloalkyl, -C1.4 alkylene-C3.10 cycloalkenyl, -C1.4 alkylene-3 to 10-membered heterocycloalkyl, -C 1.4 alkylene-3 to 10-membered heterocycloalkenyl, -C1.4 alkylene-Ce-io aryl, and -C1.4 alkylene-5 to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one or more (such as1, 2, 3 or 4) substituents selected from the group consisting of deuterium, halogen, and Ci-6 alkyl. In some embodiments, the ring is substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of Ci-6 alkyl, Ce-io aryl, and 5 to 10-membered heteroaryl; wherein the aryl and heteroaryl is unsubstituted or substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of D, halogen, and Ci-6 alkyl.

[0155] In some embodiments, R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl; optionally, the ring is optionally substituted 3 to 4-membered cycloalkyl; further optionally, the ring is optionally substituted cyclopropyl; optionally, wherein optionally substituted means unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-4 alkyl, C i-4 deuteroalkyl, cyano, Ci-4 hydroxyalkyl, and Ci.4 haloalkyl.

[0156] In some embodiments, R4and R5combine with the atoms to which they are attached to form the ring

[0157] In some embodiments, R4and R5combine with the atoms to which they are attached to form the ring

[0158] In some embodiments, R4and R5combine with the atoms to which they are attached to form the ring, which is optionally further substituted with a linear or cyclic alkyl group, or an aryl group.

[0159] In some embodiments, R4and R5combine with the atoms to which they are attached to form the ring

[0160] In some embodiments, R4and R5combine with the atoms to which they are attached to form the ring, wherein X is C or N.

[0161] In some embodiments, R4and R5combine with the atoms to which they areattached to form the ring, wherein X is cyclopentyl or isopropyl.

[0162] In some embodiments of the present disclosure, R6is optionally substituted Ci-6_ | \_| alkyl; In some embodiments, R6is » or /

[0163] In some embodiments, R7is optionally substituted C3-10 cycloalkyl, or optionally substituted C3-10 heterocycloalkyl.

[0164] In some embodiments, R7is optionally substituted C3-10 heterocycloalkyl, which is optionally substituted with one or more Ci-6 alkyl, 6 to 10-membered aryl, -CO-O-C3-6 cycloalkyl or -CO-O-Ci-6 alkyl, and / or the substituents for C3-10 cycloalkyl are independently hydroxyl, cyano, halogen, or Ci-6 alkyl.

[0165] In some embodiments, in R7, C3-10 heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of N, O and S.

[0166] In some embodiments, R7is optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl; optionally wherein the C3-10 heterocycloalkyl optionally substituted by Ci-6 alkyl, Ce-io aryl , -CO-O-C3-6 cycloalkyl or -CO-O-Ci-6 alkyl; the C3-10 cycloalkyl optionally substituted by hydroxyl, cyano, halogen, or Ci-6 alkyl; in C3-10 heterocycloalkyl, the heteroatom is N, O or S, and the number of the heteroatom is independently 1 to 3.

[0167] In some embodiments of the present disclosure, R7is Ci-6 alkyl.

[0168] In some embodiments,

[0169] In some embodiments, R7is optionally substituted 3 to 6-membered heterocycloalkyl.

[0170] In some embodiments, in R7, the 3 to 6-membered heterocycloalkyl contains 1 or 2 heteroatom selected from N, O and S; optionally wherein R7is

[0171] In some embodiments of the present disclosure, R7is 3 to 6-membered heterocycloalkyl, optionally, the heteroatom is N, O or S, and the number of the heteroatom(s) is independently 1 or 2. In some embodiments, R7isOH

[0172] In some embodiments, R7is optionally substituted C3-6 cycloalkyl. In some

[0173] In some embodiments of the present disclosure, R7is C3-6 cycloalkyl; In some embodiments, R7is

[0174] In some embodiments, R7is optionally substituted Ce-io aryl. In some embodiments,

[0175] In some embodiments, R7is Ce-io aryl. In some embodiments, R7is^=^ L

[0176] In some embodiments, R7is optionally substituted Ci-6 alkyl or optionally substituted 3 to 6-membered heterocycloalkyl.

[0177] In some embodiments, R7is 3 to 6-membered heterocycloalkyl that is substituted with -C(O)R1and / or -NHC(O)R1, wherein R1is Ci-6 alkyl, -C2-ealkenyl, or C2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is unsubstituted or substituted with one or more (e.g., 1, 2, 3 or 4) substituents selected from the group consisting of deuterium, halogen, -CN, -OH, Ci-6 alkyl, Ci- e haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, and alkylamino.

[0178] In some embodiments, R7is 3 to 6-membered heterocycloalkyl optionally substituted with 6 to 10-membered aryl or -CO-O-Ci-6 alkyl.

[0179] In some embodiments, in R7, the 3- to 6-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N and O.

[0180] In some embodiments of the present disclosure, R7is Ci-6 alkyl or 3 to 6-membered heterocycloalkyl; the 3 to 6-membered heterocycloalkyl optionally substituted by 6 to 10- membered aryl or -CO-O-Ci-6 alkyl; in 3 to 6-membered heterocycloalkyl, the number of the heteroatom(s) is independently 1 or 2, and the heteroatom(s) are independently N or O.

[0182] In some embodiments of the present disclosure, L, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is 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, or optionally substituted 4 to 11-membered bicyclic heterocycloalkyl.

[0183] In some embodiments, the ring formed by L, R6and R7combined with the atoms to which they are attached is substituted with -C(O)R1; wherein R1is Ci-6 alkyl, -C2-ealkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or 3 to 10-membered heterocycloalky, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl is unsubstituted or is substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of deuterium, halogen, Ci- 6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, alkylamino, and C3-6 cycloalkyl.

[0186] In some embodiments of the present disclosure, the “halogen” is F, Cl, Br or I; optionally, the “halogen” is F.

[0187] In some embodiments of the present disclosure, the compound has a structure according to formula (Va) or formula (Vb):wherein the variables are as described above.

[0188] In some embodiments, X1, X2, X3, X4, X5, X6, A, B, E, G, L, U, T, Y, Ra, Rb, RA, RB, RMRNR1R2R3R4r5 R6R7R8R9R10R11R12R13R71R72R73R74an(JR in theformulae above each independently correspond to an X1, X2, X3, X4, X5, X6, A, B, E, G, L, U, T, Y, Ra, Rb, RA, RB, RM, RN, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R71, R72, R73, R74or n exemplified in a specific compound shown below or in the examples (e.g., examples 1 to 289).

[0189] The present invention also has some schemes derived from any combination of the above-mentioned variables.

[0190] The present invention also provides, but is not limited to, any one of the following compounds, 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

[0191] In some embodiments, the atom(s) in each of these compounds may exhibit their natural isotopic abundances. In some embodiments, one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of Formulas above and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature.Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0192] In some embodiments, R1is -(CH^-R1.

[0193] In some embodiments, the compound has a structure according to formula (Via),wherein U, T and R13are defined as above. In some embodiments, U is -CH2CH2-, - CH2CHOH-, -CH2C(CH3)2- or -CH2.CF2-.

[0194] In some embodiments, T is absent, O, or -CH-.

[0197] In some embodiments, the compound has a structure according to formula (VII):

[0198] In some embodiments, R of formula (VII) is, ,Q\_| <0_] OJAN_] OJAN_! OJV! <gHQyi

[0200] In some embodiments, the compound has a structure according to formula (VIII):(VIII).

[0201] In some embodiments, the compound has the structure:

[0202] In some embodiments, the compound has the structure:

[0203] In some embodiments, the compound has the structure:

[0204] In some embodiments, the compound has the structure:

[0205] In some embodiments, the compound has the structure:

[0206] In some embodiments, the compound has the structure:

[0207] In some embodiments, the compound has the structure:

[0208] In some embodiments, the compound has the structure:

[0209] In some embodiments, the compound has the structure:

[0210] In some embodiments, the compound has the structure:

[0211] In some embodiments, the compound of formula (I) is Compound A as defined in Table 1 below.

[0212] It is to be understood that the foregoing description of preferred embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present invention is not intended to be limited other than expressly set forth in the following claims.

[0213] The present invention provides a compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt, wherein the is selected from any one of the compounds listed in Table 1.Table 1. Exemplary Compounds of the Present InventionIll

[0214] In another aspect, the present invention also provides a pharmaceutical composition comprising 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, and a pharmaceutically acceptable carrier, optionally wherein the compound is selected from any one of the compounds in Table 1.

[0215] In another aspect, the present invention also provides a use of 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, or a pharmaceutical composition thereof, in the preparation of a medicament used for the treatment of cancer, optionally wherein the compound is selected from any one of the compounds in Table 1

[0216] In some embodiments, the cancer is a Ras-driven cancer. In some embodiments, wherein the cancer comprises a Ras mutation.

[0217] In some embodiments, the Ras mutation is at position 12, 13 or 61. In some embodiments, the Ras mutation is at position 12. In some embodiments of the present disclosure, the Ras mutation is G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R, or Q61L, or a combination thereof.

[0218] In some embodiments of the present disclosure, the Ras mutation is G12D, G12V, G12R, or a combination thereof.

[0219] In some embodiments of the present disclosure, 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.

[0220] In some embodiments of the present disclosure, the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0221] In some embodiments, the cancer is pancreatic ductal adenocarcinoma (PDAC) non-small cell lung cancer (NSCLC), or colorectal cancer (CRC).

[0222] In some embodiments of the present disclosure, the RAS protein is KRAS.

[0223] In some embodiments, the compound can be used in combination with an additional anti-cancer therapy.

[0224] In some embodiments, the additional anti-cancer therapy is an EGFR inhibitor, a second RAS inhibitor, a SHP2 inhibitor, a SO SI inhibitor, a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a P13K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORCl inhibitor, a BRAF inhibitor, a PD-Ll inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

[0225] 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 a compound of the present invention, 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, or a pharmaceutical composition thereof, compound or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt as defined above, or the pharmaceutical composition as defined above. In some embodiments, the compound is selected from any one of the compounds in Table 1.EXEMPLARY EMBODIMENTS

[0226] Embodiment 1. A compound, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt, wherein the compound is a compound of formula (I)wherein, - represents a double bond or single bond; n is 0, 1, 2, or 3;A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;B is selected from optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11- membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene;G is optionally substituted Ci-6 alkylene;- between U and T is a bond or null; when - between U and T is a bond, U or T are absent, or they are each independently selected from O, S, -NR3or optionally substituted Ci-6 alkylene; when - between U and T is null, T is absent, and U is selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted 3 to 10- membered heterocycloalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted 6-membered aryl, optionally substituted 5 to 6-membered heteroaryl, optionally substituted -C1.3 alkylene-O-Ci-6 alkyl, optionally substituted -C1.3 alkylene-O- C3-10 cycloalkyl, optionally substituted -C1.3 alkylene-O-3 to 10-membered heterocycloalkyl, optionally substituted -C1.3 alkylene-S-Ci-6 alkyl, optionally substituted -C1.3 alkylene-S-C3-io cycloalkyl, and optionally substituted -C1.3 alkylene-S-3 to 10-membered heterocycloalkyl; furthermore, the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted;R8and R9are each independently selected from the group consisting of hydrogen,deuterium, halogen, hydroxy, cyano, optionally substituted C1.3 alkyl, or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R10and R11are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, cyano, optionally substituted C1.3 alkyl, or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R12and R13are each independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, optionally substituted C1.3 alkyl, -OR71, -SR72or -N(R73)R74;R71, R72, R73and R74are each independently selected from the group consisting of Ci-6 alkyl, Ci-6 heteroalkyl, Ci-6 haloalky 1, Ci-6 haloheteroalkyl, or R73and R74combine with the N atom attached to them to form optionally substituted 3 to 10-membered heterocycloalkyl; wherein the 3 to 10-membered heterocycloalkyl has 0, 1, 2, 3, 4 or 5 heteroatom ring atom(s) other than the N atom;RAis optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl;RBis selected from hydrogen, Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-6 haloalkoxyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or provided that when n exceeds 1, any two of RBcombine with the atoms to which they are at-tached to form a 3 to 6-membered ring, wherein the ring can be optionally substituted with halo-gen, hydroxy, or C1.3 alkyl;X1is N or C;X2is N or -CRa-;X3is N or -CRb-;X4is N or C;X5is N or C;X6is N or C;Raand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl;R3is selected from hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3-6 halocycloalkyl, -C(O)C 1.3 alkyl, -S(O2), or -S(O2)Ci-3 alkyl;E is a bond, or selected from N, or -CRd-, wherein Rdis selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf; wherein Reand Rfare independently selected from hydrogen, or optionally substituted Ci-6 alkyl;R4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl,R6RL / N optionally substituted 5 to 10-membered heteroaryl, or 'R5is hydrogen, Ci-6 alkyl or C3-6 cycloalkyl, furthermore, the Ci-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6- membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl; whereinL is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(RS)2-, wherein Rgis optionally substituted Ci-6 alkyl;R6is hydrogen, or optionally substituted Ci-6 alkyl;R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6and R7combine 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 alkyl, optionally substituted 4 to 11-membered bicyclic heteroalkyl.

[0227] Embodiment 2. The compound of embodiment 1, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, thesolvate thereof or the solvate of the pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (II):whereinA, B, G, U, T, X1, X2, X3, X4, X5, X6, R3, RB, R8, R9, R10, R11, R12, R13, E and n are defined as in embodiment 1;Y is CH orN;Rlais selected from hydrogen, Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10- membered fused bicyclic heteroaryl; furthermore, the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci- 6 haloalkoxyl, and Ci-e hydroxyalkyl may be further optionally substituted;R2is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl;RMand RNare each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci^ alkoxyl, Ci-ehaloalkyl, Ci-6 haloalkoxyl, Ci-e hydroxyalkyl, Ci- 6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; furthermore, the Ci-6 alkyl, Ci^ alkoxyl, Ci-e haloalkyl, Ci-6 haloalkoxyl, and Ci-ehydroxyalkyl may be further optionally substituted;R4and R5are defined as in embodiment 1; preferably, R4and R5combine 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.

[0228] Embodiment 3. The compound of any one of embodiments 1 to 2, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, theprodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (Illa) or formula (Illb) :whereinA, G, U, T, X6, R3and E are defined as in embodiment 1;Y, R2, R4, R5and R13are defined as in any one of embodiments 1-2;R1is selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, Ci-e hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10- membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1.2 alkylene-C3-6 cycloalkyl, optionally substituted -C1.2 alkylene-C3-6 heterocycloalkyl, optionally substituted -C1.2 alkylene-5 to 8-membered aryl, optionally substituted -C1.2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1.2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic heteroaryl; furthermore, the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-ehaloalkoxyl, Ci-e hydroxyalkyl may be further optionally substitutedRaand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl.

[0229] Embodiment 4. The compound of any one of embodiments 1 to 3, 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 has a structure of formula (IVaa), (IVab), (IVba) or (IVbb):whereinA, G, U, T, X6, R3and E are defined as in embodiment 1;Y, R2, R4, R5and R13are defined as in any one of claims 1-2;R1, Raand Rbare defined as in embodiment 3.

[0230] Embodiment 5. The compound of any one of embodiments 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinB is optionally substitutedor optionally substitutedandwhereinR1is selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, Ci-e hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10- membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1.2 alkylene-C3-6 cycloalkyl, optionally substituted -C1.2 alkylene-C3-6 heterocycloalkyl, optionally substituted -C1.2 alkylene-5 to 8-membered aryl, optionally substituted -C1.2 alkylene-5 to 8-membered heteroaryl, optionally substituted -C1.2alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic heteroaryl; furthermore, the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl may be further optionally substituted; in R1, when the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl is further substituted, the substituent is selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10- membered fused bicyclic heteroaryl; preferably, the substituent is selected from the group consisting of optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; more preferably, the substituent is optionally substituted C3-6 heterocycloalkyl;Y is -CH- or N;R2is optionally substituted Ci-6 alkoxy, or optionally substituted Ci-6 alkyl; preferably, R2is optionally substituted Ci-6 alkyl; andRMand RNare each independently selected from hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci- 6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl; furthermore, the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl may be further optionally substituted. In some embodiments, RMand RNare each independently selected from hydrogen, and Ci-6 alkyl

[0231] Embodiment 6. The compound of any one of embodiments 5, 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, whereinR1is optionally substituted -C1.2 alkylene-3 to 6-membered heterocycloalkyl; wherein preferably, the 3 to 6-membered heterocycloalkyl has a structure ofwherein nl and n2 are each independently 1, 2 or 3 (preferably nl and n2 are both2), and ZRAis O, S or NH; preferably, Ci-2 alkylene is -CH2- or -CH(CHa)-; preferably, optionally substituted means the group is unsubstituted or substituted with one or more (such as 1, 2, 3, or 4) substituent(s) selected from the group consisting of D, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl, more preferably, with one or more (such as 1, 2, 3, or 4) substituent(s) selected from the group consisting ofD, Ci-6 alkyl, orR1is substituted Ci-6 alkyl, and preferably, the Ci-6 alkyl is substituted with one substituent of -CONR'R" and is unsubstituted or substituted with one or more (such as 1, 2, 3, or 4) substituent(s) selected from the group consisting of D, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl.

[0232] Embodiment 7. The compound of embodiment 5, 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, whereinR1is selected from the group consisting of

[0233] Embodiment 8. The compound of any one of embodiments 1, or a stereoisomerthereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinR4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; wherein preferably, the 3 to 10-membered cycloalkyl is cyclopropyl or cyclobutyl, and the 3 to 10-membered heterocycloalkyl is a 4 to 5-membered heterocycloalkyl containing one heteroatom selected from O or S (preferably S) as ring atom; preferably, optionally substituted means unsubtituted or being substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of D, halogen, - CN, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -C3-10 cycloalkyl, -3 to 10-membered heterocycloalkenyl, -Ce-io aryl, -5 to 10-membered heteroaryl, -C1.4 alkylene-Cs-io cycloalkyl, - C1.4 alkylene-C3.10 cycloalkenyl, -C1.4 alkylene-3 to 10-membered heterocycloalkyl, -C1.4 alkylene-3 to 10-membered heterocycloalkenyl, -C1.4 alkylene-Ce-io aryl, and -C1.4 alkylene-5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubtituted or being substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of D, halogen, Ci-6 alkyl; more preferably, optionally substituted means unsubtituted or being substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of Ci-6 alkyl, Ce-io aryl, 5 to 10-membered heteroaryl; wherein the aryl and heteroaryl is unsubtituted or being substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting ofD, halogen, Ci-6 alkyl.

[0234] Embodiment 9. The compound of any one of embodiments 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, whereinselected from the group consisting of

[0235] Embodiment 10. The compound of any one of embodiments 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinA is optionally substituted 5 to 6-membered heteroarylene, the heteroatom is independently selected from one or two of N, O and S, and the number of the heteroatom is independently 1 to 3 preferably, A is optionally substituted 5-membered heteroarylene, the heteroatom is independently selected from N, O and S, and the number of the heteroatom is independently 1to 2; preferably, one of the heteroatoms is N, and the other, if present, is O or S; more preferably, A is selected from the group consisting of

[0236] Embodiment 11. The compound of any one of embodiments 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 when - between U and T is null, T is absent, U is selected from the group consisting of optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted Ci-6 cycloalkyl, optionally substituted Ci-6 heterocycloalkyl, -C1.3 alkyl-O-Ci-6 alkyl, -C1-3 alkyl-O-Ci-6 cycloalkyl, -C1.3 alkyl-O-Ci-6 heterocycloalkyl; furthermore, the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted.

[0237] Embodiment 12. The compound of any one of embodiments 1, or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, asolvate thereof or a solvate of the pharmaceutically acceptable salt thereof, whereinR13is each independently selected from -OR71or -NR73R74;R71, R73and R74are each, independently, Ci-6 alkyl, Ci-6 heteroalkyl, or R73and R74combine to form a 3 to 10-membered heterocycloalkyl; furthermore, the Ci-6 alkyl, Ci-6 heteroalkyl and 3 to 10-membered heterocycloalkyl may be further optionally substituted.

[0238] Embodiment 13. The compound of any one of embodiments 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 X1is C, and / or X2is -CRa-, and / or X3is -CRb, and / or X4is -CRC-, and / or X5is -C-.

[0239] 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.

[0240] Embodiment 15. The compound of any one of embodiments 1 to 14, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, wherein, the compound is selected from compounds of Examples 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 28, 29, 30, 31, 32, 33, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59-123, 124-194 and 243-244 in Table 1.

[0241] Embodiment 16. A pharmaceutical composition comprising: the compound of any one of embodiments 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0242] Embodiment 17. A use of the compound according to any one of embodiment 1 to15, 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 in the preparation of a medicament used for the treatment of cancer

[0243] Embodiment 18. The use according to embodiment 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 (NSCLC), cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, and squamous cell lung carcinoma, or combinations thereof.

[0244] Embodiment 19. The use according to embodiment 18, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, and cholangiocarcinoma.

[0245] Embodiment 20. The compound of any one of embodiments 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same for use in treating cancer.

[0246] Embodiment 21. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of embodiments 1 to 15, or the stereoisomer thereof, the pharmaceutically acceptable salt thereof, the metabolite thereof, the prodrug thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition comprising the same.TERM DEFINITIONS

[0247] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as a skilled person in the art would understand the term.

[0248] As used herein, the term “pharmaceutically acceptable salt” refers to a salt prepared from a pharmaceutically acceptable base or acid. When the compound of the present invention is acidic, its corresponding salt can be prepared from pharmaceutically acceptable bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.

[0249] As used herein, the term “solvate” refers to solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent.

[0250] As used herein, an excipient that is useful in preparing a pharmaceutical composition may be generally safe, nontoxic and neither biologically nor otherwise undesirable, and may include a carrier that is acceptable for veterinary use as well as human pharmaceutical use.

[0251] A “pharmaceutically acceptable carrier” as used herein includes both one and more than one such carrier. The term “pharmaceutically acceptable carrier” also encompasses “pharmaceutically acceptable excipient” and “pharmaceutically acceptable diluent”. The particular carrier used in the pharmaceutical compositions of the present disclosure will depend upon the means and purpose for which the compounds of the present disclosure are being applied.

[0252] As used herein, unless otherwise specified, the term "optionally substituted" indicates unsubstituted or substituted with one or more (such as 1, 2, 3 or 4) substituents. Suitable substituents for each group can be found herein. Unless otherwise specified, exemplary substituents can be selected from the group consisting of D, halogen, -CN, -NO2, R1, -Ci-ialkylene-R.', -C2-4alkenylene-R1, -C2-4alkynylene-R1, -OR1, -OC(O)R\ -C(O)R\ - CO2FU -CON^RN -OC(O)NNR'R'\ -NRUC(O)R\ -NR'-C(O)NR"R"\ -NRiiC(O)2Ri- NH-C(NH2)=NBU -NR'C(NH2)=NFU -NH-C(NH2)=NR\ -S(O)R\ -S(O)2R\ - S(O)2NR1R11-NR1S(O)2RU, wherein R1, R11and R111are each independently H, Ci-6 alkyl, -C2-6 alkenyl, C2-e alkynyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, Ce-io aryl, 5 to 10-membered heteroaryl, -C1.4 alkylene- C3-10 cycloalkyl, -C1.4 alkylene-C3.10 cycloalkenyl, -C1.4 alkylene-3 to 10-membered heterocycloalkyl, -C 1.4 alkylene-3 to 10-membered heterocycloalkenyl, -C1.4 alkylene-Ce-io aryl, or -C1.4 alkylene-5 to 10-membered heteroaryl; or R\RU, R11and R111together with the atom to which they are attached to form C3-10 cycloalkyl, C3-10 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, Ce-io aryl, 5 to 10-membered heteroaryl, wherein the alkylene, alkenylene, alkynylene, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl can be unsubstituted or substituted with one or more (such as 1, 2, 3, 4, or 5) substituents selected from the group consisting of deuterium, halogen, -CN, -OH, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, amino, alkylamino, -C(O)Ci-6 alkyl, -OCi-6 alkyl, -OC(O)Ci-6 o II N=S— alkyl, -S(O)Ci-6alkyl, -S(O)2Ci.6alkyl, -COOCi-6 alkyl, ' I , 0x0 (=0), Ci-6alkylidene, Ci-6haloalkylidene, Ci-6 deuteroalkylidene, Ci-6 hydroxy alkylidene, Ci-6 aminoalkylidene, C3-6 cycloalkyl optionally substituted with one or more of D, halogen, -CN, -OH, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, and Ci-6 aminoalkyl, 3 to 6-membered heterocycloalkyl optionally substituted with one or more of D, halogen, -CN, -OH, Ci-6 alkyl,Ci-ehaloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxy alkyl, and Ci-6 aminoalkyl, 3 to 6-membered heterocycloalkenyl optionally substituted with one or more of D, halogen, -CN, -OH, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-e hydroxyalkyl, and Ci-6 aminoalkyl, phenyl, 5 to 6- membered heteroaryl optionally substituted with one or more of D, halogen, -CN, -OH, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-e hydroxyalkyl, or Ci-6 aminoalkyl. In some embodiments, said " optionally substituted" means that the group is substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=0), thio (=S), C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 deuterated alkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkenyl, C2-C4 alkyne, C3-C6 cycloalkyl, and 3 to 6-membered heterocycloalkyl.

[0253] 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. C1.20 means 1 to 20 carbon atoms). In some embodiments, an alkyl group is an alkyl having 1 to 12 alkyl carbon atoms, e.g., C1-12 alkyl. In some embodiments, the alkyl group is a Ci-6 alkyl (i.e., 6 carbon) group, or a C1.4 alkyl (i.e., 4 carbon) group. Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1 -dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl,1 -ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, l-ethyl-2-m ethylpropyl, 1,1,2- trimethylpropyl, 1,1 -dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl,2-ethylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2,3 -dimethylbutyl, n-heptyl, 2- methylhexyl, 3 -methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4- dimethylpentyl, 2,2-dimethylpentyl, 3, 3 -dimethylpentyl, 2-ethylpentyl, 3 -ethylpentyl, n-octyl, 2,3 -dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3- dimethylhexyl, 4.4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2- ethylpentyl, 2-methy 1-3 -ethylpentyl, n-nonyl, 2-methyl -2-ethylhexyl, 2-methyl -3-ethylhexyl,2.2-diethylpentyl, n-decyl, 3, 3 -di ethylhexyl, 2,2-diethylhexyl, and the isomers of branched chains thereof; optionally an alkyl group is a lower alkyl having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1 -dimethylpropyl, 1,2-dimethylpropyl, 2,2- dimethylpropyl, 1 -ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, l-ethyl-2-m ethylpropyl,1.1.2-trimethylpropyl, 1,1 -dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, and 2,3- dimethylbutyl. The alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point; optionally the substituent group(s) is alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxyl,heterocyclic, cycloalkylthio, heterocyclic alkylthio or an oxo group.

[0254] The term “alkylene” refers to a saturated linear or branched aliphatic hydrocarbon group having two radicals formed by removing two hydrogen atoms from the group (e.g., two hydrogen atoms from the same carbon atom or from two different carbon atoms of the parent alkane). The linear or branched chain groups contain 1 to 20 carbon atoms; optionally 1 to 12 or 1 to 6 carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylidene (- CH2CH2CH2CH2-). The alkylene groups can be substituted or unsubstituted. When substituted, the substituent group(s) is optionally one or more, optionally one to five or 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, heterocyclic alkoxyl, cycloalkylthio and heterocyclic alkylthio.

[0255] As used herein, the term “alkenyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond; for example, vinyl, 1- propenyl, 2- propenyl, 1-2-, 3-butenyl, etc., optionally C2-20 alkenyl, C2-12 alkenyl, or C2-6 alkenyl. The alkenyl groups can be substituted or unsubstituted. When substituted, the substituent group(s) is optionally one or more, optionally one to five, further optionally one to three, group(s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocyclic, cycloalkylthio, heterocyclic alkylthio, and oxo group.

[0256] The term “alkenylene” refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, optionally C2-20 alkenylene, moreoptionally C2-12 alkenylene, and most optionally C2-6 alkenylene. Examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2, -CE^CElCEbCEb, - CH2CH=CHCH2- etc. The alkenylene group can be substituted or unsubstituted. When substituted, the substituent group(s) is optionally one or more, optionally one to five, further optionally 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, heterocyclic alkoxyl, cycloalkylthio and heterocyclic alkylthio.

[0257] As used herein, the term “alkynyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1- propynyl, 2-propynyl, 1-2-, or 3-butynyl etc., optionally C2-20 alkynyl, further optionally C2-12 alkynyl, and optionally C2-6 alkynyl. The alkynyl group can be substituted or unsubstituted.When substituted, the substituent group(s) is optionally one or more, optionally one to five, optionally 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, heterocyclic alkoxyl, cycloalkylthio, and heterocyclic alkylthio.

[0258] As used herein, the term “aryl” refers to a 6 to 14-membered (or Ce-u) 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. Optionally, aryl is 6 to 10-membered (or Ce-io), such as phenyl and naphthyl, optionally phenyl. The aryl can be fused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to the parent structure is aryl.Representative examples include, but are not limited to, the following substituents:

[0259] The aryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is optionally one or more, optionally one to five, optionally 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, and cycloalkoxyl, heterocyclic, alkoxyl, cycloalkylthio and heterocyclic alkylthio.

[0260] The term “arylene” is a divalent group which is connected to the rest of the molecule through two single bonds, and the rest definitions are the same as the term “aryl”.

[0261] 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). Optionally a heteroaryl is 5 to 10-membered, optionally 5 or 6-membered, for example, thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolylfuryl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl.Representative examples include, but are not limited to, the following substituents:

[0262] The heteroaryl group can be substituted or unsubstituted. When substituted, the substituent group(s) is optionally one or more, optionally one to five, further optionally 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, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio and -NReRf.

[0263] 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”.

[0264] The term "bicyclic" is intended to include spiro, fused-ring or bridged-ring.

[0265] As used herein, the term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0266] As used herein, the term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0267] As used herein, the term “bridged” refers to two rings that share three adjacent ring atoms with one another.

[0268] 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 (referred to as C3-20), optionally 3 to 12 carbon atoms (referred to as C3-12), further optionally 3 to 10 carbon atoms (referred to as C3-10), or further optionally 3 to 8 carbon atoms (referred to as C3- s) or 3 to 6 carbon atoms (referred as C3-6). In some embodiments, cycloalkyl is monocyclic cycloalkyl. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. In some embodiments, cycloalkyl is polycyclic cycloalkyl (such as bicyclic cycloalkyl). In some embodiments, cycloalkyl is a spiro cycloalkyl, a fused cycloalkyl or a bridged cycloalkyl. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring. The cycloalkylcan 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 indanylacetic, tetrahydronaphthalene, benzocycloheptyl and so on. The cycloalkyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is optionally one or more, optionally one to five, optionally 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, heterocyclic, cycloalkylthio, heterocyclic alkylthio, and oxo group.

[0269] 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”.

[0270] “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. Optionally a spiro cycloalkyl is 6 to 14-membered, and further optionally 7 to 10-membered. According to the number of common spiro atoms, a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and optionally refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, further optionally 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:

[0271] “Fused Cycloalkyl” refers to a 5 to 20-membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Optionally, a fused cycloalkyl group is 6 to 14- membered, further optionally 7 to 10-membered. According to the number of membered rings, fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl,and optionally refers to a bicyclic or tricyclic fused cycloalkyl, further optionally 5- membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following substituents:

[0272] “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 may have one or more double bonds but no completely conjugated pi-electron system. Optionally, a bridged cycloalkyl is 6 to 14-membered, and further optionally 7 to 10-membered. According to the number of membered rings, bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and optionally refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, further optionally a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:

[0273] 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, optionally one to five, further optionally one to three carbon ring atoms being replaced with heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is 0, 1, or 2) as ring atoms, but excluding -O-O-,-O-S-or -S-S- in the ring, the remaining ring atoms being C. Optionally, heterocyclyl is a 3 to 12-membered ring having 1 to 4 heteroatoms; optionally a 3 to 10-membered ring having 1 to 3 heteroatoms; optionally a 4 to 8-membered ring having 1 to 3 heteroatoms; furtheroptionally a 5 to 6-membered ring having 1 to 2 heteroatoms. In some embodiments, heterocycloalkyl / heterocyclyl is monocyclicheterocycloalkyl / heterocyclyl. Representative examples of monocyclic heterocyclyls or heterocycloalkyl include, but are not limited to, oxetanyl, azabutyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on. In some embodiments, heterocycloalkyl / heterocyclyl is polycyclic heterocycloalkyl / heterocyclyl (such as bicyclic heterocycloalkyl / heterocyclyl). In some embodiments, heterocycloalkyl / heterocyclyl is a spiro heterocycloalkyl / heterocyclyl, a fused heterocycloalkyl / heterocyclyl or a bridged heterocycloalkyl / heterocyclyl. Polycyclic heterocyclyl or heterocycloalkyl includes the heterocyclyl having a spiro ring, fused ring or bridged ring. Examples of such heterocyclyl groups are I-NQ>FN. When the heterocyclyl has substituents, the substituents may be attached to any atom in the ring, provided that a stable chemical structure results.

[0274] The term “heterocycloalkylene” is a divalent group which is connected to the rest of the molecule by two single bonds, and the rest of the definitions are the same as the term “heterocycloalkyl”.

[0275] “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, optionally one to five, further optionally one to three heteroatoms selected from the group consisting of N, O, and S(O)m. (wherein m is 0,1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. Optionally a spiro heterocyclyl is 6 to 14-membered, and optionally 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 optionally refers to mono-spiro heterocyclyl or dispiro heterocyclyl, optionally 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:

[0276] “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, optionally one to five, optionally 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. Optionally a fused heterocyclyl is 6 to 14-membered, and further optionally 7 to 10-membered. According to the number of membered rings, fused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, optionally refers to bicyclic or tricyclic fused heterocyclyl, optionally 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused heterocyclyl. Representative examples of fused heterocyclyl include, but are not limited to, the following substituents:

[0277] As used herein, the ring of said heterocyclyl can be fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring-bound to the parent structure is heterocyclyl. Representative examples include, but are not limited to the following substituents:

[0278] The heterocyclyl is optionally substituted or unsubstituted. When substituted, the substituent group(s) is optionally one or more, optionally one to five, further optionally 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, cycloalkoxyl, heterocyclic alkoxyl, cycloalkylthio, heterocyclic alkylthio.

[0279] “Bridged Heterocyclyl” refers to a 5 to 14-membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms, the rings can have one or more double bonds, but have no completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is 0, 1, or 2) as ring atoms, the remaining ring atoms being C. Optionally a bridged heterocyclyl is 6 to 14-membered, and further optionally 7 to 10-membered. According to the number of membered rings, bridged heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and optionally refers to bicyclic, tricyclic or tetracyclic bridged heterocyclyl, optionally bicyclic or tricyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following substituents:

[0280] As used herein, the term “Ci-6 haloalkoxyl” refers to an alkoxyl group in which one or more hydrogen atoms are replaced by a halogen, for example, -OCF3.

[0281] 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.

[0282] As used herein, the term “Ci-6 alkoxyCi-6 alkyl” refers to a Ci- 6 alkyl group in which one or more hydrogen atoms are replaced by Ci-6 alkoxy or a Ci-6 alkoxy group in which one or more hydrogen atoms are replaced by Ci-6 alkyl.

[0283] As used herein, the term “alkoxy” refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci-6 alkoxy means a straight or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of “alkoxy” as used herein include, but not limited to, methoxy, ethoxy, prop- 1 -oxy, pro-2-oxy, pentoxy, hexyloxy, and the like.

[0284] As used herein, the term “aminoalkyl” refers to an alkyl moiety substituted by one or more amino moieties, for example, -CEEINEE).

[0285] As used herein, the term “alkylamino” refers to an amino group substituted by oneor more alkyl such as NH(Ci-6alkyl) or N(Ci-ealkyl)2. Examples of alkylamino include, but are not limited to -NH(CH3) and -N(CH3)2.

[0286] As used herein, the term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0287] As used herein, the term "oxo" means =0, in which an oxygen atom replaces two hydrogen atoms on the same carbon atom.

[0288] As used herein, the term “bond” refers to a covalent bond using a sign of “ — ”. In some embodiments, - represents a double bond or single bond.

[0289] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure. In case of conflict, the present specification, including definitions, will control. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Throughout this specification and embodiments, the words “have” and “comprise,” or variations such as “has,” “having,” “comprises,” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. All publications and other references mentioned herein are incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference in its entirety. Although a number of documents are cited herein, this citation does not constitute an admission that any of these documents forms part of the common general knowledge in the art. As used herein, the term “approximately” or “about” as applied to one or more values of interest refers to a value that is similar to a stated reference value. In some embodiments, the term refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context.

[0290] According to the present disclosure, back-references in the dependent claims are meant as short-hand writing for a direct and unambiguous disclosure of each and every combination of claims that is indicated by the back-reference. Further, headers herein are created for ease of organization and are not intended to limit the scope of the claimed invention in any manner.

[0291] In order that this invention may be better understood, the following examples are set forth. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.EXAMPLESMethods of Synthesis

[0292] The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents are as defined above unless otherwise indicated. Unless explicitly stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in chemistry.

[0293] General synthetic procedure for preparing compounds as formula (II) are shown in Scheme 1:Scheme 1

[0294] Scheme 1 illustrates the preparation of compound of formula (II). The coupling of compounds of formula (I) can be obtained through standard Suzuki coupling conditions (e.g., Pd(dppf)C12 and K2CO3) to provide compound of formula (II). Compound of formula (2) was coupled with compound of formula (3) under Suzuki coupling conditions (e.g., Pd(dppf)C12 and K2CO3) to give compound of formula (4), which was converted to compound of formula (5) in the presence of iodization reagents, such I2 or NIS. Deprotection of compound of formula (5) to provide compound of formula (6), such as hydrolysis of the ester with LiOH-OH, or with TBAF deprotecting silicon protective group on hydroxyl group. Compound of formula (8) was attained by a routine coupling condition between compound of formula (6)and amine of formula (7) with coupling reagents, such as HATU, EDCI / HOBt or PyBOP, etc, in the presence of an organic base, such as EtsN, DIPEA or pyridine, which was hydrolyzed to provide acid of formula (9) under a base, such as LiOH-ELO. 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 (e.g., Pd(dppf)C12 and K2CO3) to provide compound of formula (11). Compound of formula (11) was coupled with compound of formula (12) under Suzuki coupling conditions (e.g., Pd(dppf)C12 and K2CO3) to give compound of formula (13), which was converted to compound of formula (14) with alkylate reagents, such iodomethane or iodoethane, in the presence of an inorganic base, such as CS2CO3. Deprotection of compound (14) can afford compound of formula (15) in the presence of an acid, such as TFA. Compound of formula (II) can be obtained by a coupling reaction between acid of formula (16) and compound of formula (15) with coupling reagents, such as HATU, EDCI / HOBy, PyBOP or COMU, in the presence of a base, such as TEA, DIPEA, pyridine or 2,6-lutidine.Preparation of IntermediatesIntermediate A: 3-(5-bromo-2-iodo-lH-indol-3-yl)-2,2-dimethylpropyl acetateStep 1: Synthesis of (5-bromo-lH-indol-3-yl)methanol

[0295] To a solution of 5-bromo-U / -indole-3-carbaldehyde (100.0 g, 0.45 mol) in premixed solvents THF / MEOH (1 L, V: V = 4: 1) was stirred at 0 °C for 5 mins, then NaBE (20.0g, 0.53 mol) was added into the above solution at room temperature. The resulting mixture was stirred at 0 °C for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with HzO (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 NazSO-i and concentrated to give the crude product (5-bromo- U / -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 CLHxBrNO [M-H]+m / z 224.07,found: 224.10.Step 2: Synthesis of methyl 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropanoate

[0296] To a solution of ((l-methoxy-2-methylprop-l-en-l-yl)oxy)trimethylsilane (157.3 g, 0.90 mol) in dry THF (150 mL) under N2 atmosphere, the reaction mixture was stirred at -40 °C for 5 mins, then (5-bromo-U / -indol-3-yl)methanol (107.5 g, 0.48 mol) in dry THF (50 mL) was added under N2 atmosphere, After 10 mins, TMSOTf (90.0 g, 0.40 mol) in dry THF (50 mL) was added into the above solution by dropwise at nitrogen atmosphere. The reaction mixture was stirred at this temperature for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was warmed to room temperature and diluted with NaHCO? solution (100 mL), then the resulting mixture was extracted with EtOAc (100 mL x 4). The organic layer was separated, dried over anhydrous Na SCh and concentrated to give the crude product, which was further purified by silica gel chromatography eluting with petroleum ether / EtO Ac (from 0% to 20%) to obtain methyl 3-(5-bromo-U / -indol-3-yl)-2,2-dimethylpropanoate (98g, 70%) as a yellow solid. LCMS (ESI) calcd. for CuHieBrNCh [M+H]+m / z 310.19, found: 310.20.Step 3: Synthesis of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropan-l-ol

[0297] To a solution of methyl 3-(5-bromo-U / -indol-3-yl)-2,2-dimethylpropanoate (98g, 0.32 mol) and LiBHj (40g, 1.82 mol) was added in dry THF (300 mL) at room temperature, the reaction mixture was stirred at 80 °C for 12h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature, quenched with NH4CI 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 Na?SO4 and concentrated to give the crude product 3-(5-bromo-U / -indol-3-yl)-2,2-dimethylpropan-l-ol (91.3g, 99%) as a light-yellow solid. The crude product was proceeded to the next reaction without purification. LCMS (ESI) calcd. for CnHieBrNO [M+H]+m / z 282.18, found: 282.40.Step 4: Synthesis of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate

[0298] To a solution of 3-(5-bromo-U / -indol-3-yl)-2,2-dimethylpropan-l-ol (91.3g, 0.31 mol) in dry DCM (150 mL) at room temperature under N2 atmosphere, then DIPEA (62.7g, 0.49 mol), DMAP (4.0g, 0.03 mol) and AC2O (24.0 g, 0.31 mol) was added into the above solution under N2 atmosphere. The reaction mixture was stirred at room temperature for 3h. The reaction was monitored by LCMS. After completion, The reaction mixture was diluted with NaHCO? solution ( 100 mL), then the resulting mixture was extracted with DCM (100 mL x 4), the combined organic phase was washed with saturated NaCl (50 mL), then died over with Na2SO4, following with concentration under reduced pressure to obtain crude one, which was purified by silica gel column eluting with petroleum ether / EtOAc (from 0% to 20%) toafford 3-(5-bromo-l#-indol-3-yl)-2,2-dimethylpropyl acetate (82.0 g, 79%) as a white solid.

[0299] LCMS (ESI) calcd. for CisHisBrNCh [M+H]+m / z 324.22, found: 324.60Step 5: Synthesis of 3-(5-bromo-2-iodo-lH-indol-3-yl)-2,2-dimethylpropyl acetate

[0300] To a solution of 3-(5-bromo-U / -indol-3-yl)-2,2-dimethylpropyl acetate (10.0 g, 0.03 mol), AgSCECFs (9.5g, 0.04 mol) and NaHCOs (3.2g, 0.04 mol) in THF (50 mL) was stirred for 5 mins under ice-water bath, then b (7.1 g, 0.03 mol) in THF (10 ml) was added by dropwise into the above solution. The reaction was stirred at the above temperature for Ih, the reaction was monitored by LCMS. After completion, The reaction was diluted with EtOAc (10 mL) and H2O (10 mL), then filtered, the filtrate was extracted with EtOAc (20 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 15%) to obtain 3-(5-bromo-2-iodo-U / -indol-3-yl)-2,2-dimethylpropyl acetate (11.4 g, 83%) as a light yellow solid. LCMS (ESI) calcd. for Ci5Hi7BrINO2 [M-H]+m / z 448.11, found: 448.00Intermediate B: methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoateStep 1. Preparation of methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoate

[0301] To a solution of activated Zn dust (22 g, 334 mmol) and DMF (100 mL) was added to a 250 mL three-necked round-bottomed flask and purged with N2, then a solution of I2 (1.5 g, 6.08 mmol) in DMF (5 mL) was added to the above solution. The mixture was stirred for 10 min at rt, then a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (20 g, 60.79 mmol) in DMF (200 mL) was added dropwise over a period of 10 min. The mixture was heated at 35°C and stirred for 2 h, then the reaction was cooled to rt. Transfer the liquid to another 500 mL three-necked round-bottomed flask and purged with N2, and a solution of Pd(PPh3)C12 (2.1 g, 3.04 mmol) and 2,4-dibromothiazole 2 (17.7 g, 72.95 mmol) in DMF (100 mL) was added dropwise over a period of 10 min. The reaction was stirred at 50°C for 16 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 500 mL). The organic layers were combined, washed with saturated NaCl (2 x 500 mL), dried over anhydrous Na2SO4 andconcentrated 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 CuHnBrlS CUS [M+H]+m / z 365.01, found: 367.3Intermediate C: (S)-4-(m ethoxy carbonyl)-2, 3 -diazabicyclo[3.1. l]heptan-2-ium 2, 2, 2-tri fluoroacetateStep 1. Preparation of 3-oxocyclobutane-l-carbonyl chloride

[0302] To a stirred solution of 3 -oxocyclobutane- 1 -carboxylic acid (50 g, 438.60 mmol) in DCM (500 mL) and DMF (321 mg, 4.39 mmol) was added (COC1)2 (83.51 g, 657.89 mmol), the resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was used to next step without purification. LCMS (ESI) calcd. for C5H5CIO2 [M+H]+m / z 133.00, found: 133.4. Step 2.Preparation of 3-(2-diazoacetyl)cyclobutan-l-one

[0303] To a stirred solution of crude 3-oxocyclobutane-l-carbonyl chloride in THF (250 mL) and CH3CN (250 mL) was added TMSCHN2 (2M in hexanes, 285 mL, 570.18 mmol) dropwise at 0°C. The resulting mixture was stirred at rt for 18 h. After completion, the reaction solution was concentrated under reduced pressure to give the residual, the residual was purified by silica gel column (eluting with EtOAc / PE from 0% to 50%) to afford 3-(2- diazoacetyl)cyclobutan-l-one (60.2 g, 99.5 %) as a yellow oil. LCMS (ESI) calcd. forC6H6N2O2 [M+H]+m / z 139.04, found: 139.4.Step 3. Preparation of 2-(3-oxocyclobutyl)acetic acid

[0304] 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°C, the reaction mixture was stirred at rt for 18 h. After completion, the reaction solution was concentrated under reduced pressure to give the residual, the residual was diluted with H2O and acidified with HC1 (2N) to pH = 2. The resulting mixture was extracted with EtOAc (5*300 mL). The organic layers were combined and dried over Na2SO4, following with concentration under reduced pressure to afford crude 2-(3-oxocyclobutyl)acetic acid (55. 8g, 99.9 %) as a brown oil.LCMS (ESI) calcd. for C6H8O3[M+H]+m / z 129.13, found: 129.4.Step 4. Preparation of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one

[0305] To a stirred solution of 2-(3-oxocyclobutyl)acetic acid (52.0 g, 406.3 mmol), CS')-4- benzyloxazolidin-2-one (71.9 g, 406.3 mmol), 4-Dimethylaminopyridine (5.0 g, 40.6 mmol) and triethylamine (141.2 mL, 1015.6 mmol) in DCM (1 L) was added 2-Chloro-l- methylpyridinium iodide (135.0 g, 528.1 mmol) in portions at 0°C. The reaction mixture was stirred at R.T. for 4 h. After completion, the reaction solution was diluted with H2O and extracted with DCM, the combined organic phase was washed with H2O dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give (5)-4-benzyl-3-(2- (3-oxocyclobutyl)acetyl)oxazolidin-2-one (68 g 58.3 %) as a yellow oil.

[0306] LCMS (ESI) calcd. for CI6HI7NO4[M+H]+m / z 288.1, found: 288.5.Step 5. Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one

[0307] 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 NaBHj (6.5 g, 172.5 mmol) in portions at 0°C. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was diluted with H2O then concentrated under reduced pressure to remove THF. The residual was extracted with EtOAc, the combined organic phase was dried over Na2SO4, following with concentration under reduced pressure to obtain CS')-4- benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (45 g, 99.3 %) as a light yellow oil.

[0308] 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

[0309] To a stirred solution of fS')-4-benzyl-3-(2-(3 -hydroxy cy cl obutyl)acetyl)oxazolidin-2-one (48.0 g, 156.8 mmol) and DIEA (43.3 g, 249.1 mmol) in DCM (500 mL) was added 4- Dimethylaminopyridine (16.2 g, 132.9 mmol) and tosyl chloride (34.8 g, 182.7 mmol) at 0°C.The reaction mixture was stirred at r.t. for 14 h. After completion, the reaction solution was diluted with H2O and extracted with DCM, the combined organic phase was washed with H2O dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 30%) to give (5)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, 84.3 %) as a yellow oil.

[0310] 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

[0311] To a stirred solution of (5)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2- oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, 139.8 mmol) in N-Methyl-2- pyrrolidone (650 mL) was added Lithium bromide (24.3 g, 279.6 mmol), the resulting mixture was stirred at 65°C for 13 h. The reaction was monitored by LCMS. After completion, the reaction solution was diluted with H2O and extracted with EtOAc, the combined organic phase was washed with NaCl (aq.) dried over Na2SC>4, 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 (5)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (42 g, 85.3 %) as a light yellow oil.

[0312] LCMS (ESI) calcd. for Ci6Hi8BrNO3[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

[0313] To a stirred solution of (5)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2- one (30.0 g, 85.5 mmol) in THF (300 mL) was added LDA (2 M in THF, 111.0 mmol) was added dropwise over a period of 15 minutes at -78 oC under N2 condition. The reaction mixture was stirred at -78°C for 30 mins, then a solution of Di-tert-Butyl azodi carb oxy late (23.6 g, 102.6 mmol) in DCM (50 mL) was added rapidly. The reaction mixture was stirred at - 78°C for 30 mins, then l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (310 mL, 2565.0 mmol) was added dropwise at -78°C. The reaction mixture was stirred at r.t. for 14 h. After completion, the reaction solution was quenched with water (200 mL), then LiOH ELO (10.8 g, 256.5 mmol) was added and the reaction solution was stirred at r.t. for 2 h. After completion, the reaction solution was diluted with brine (200 mL) and washed with tert-Butyl methyl ether 2 times, the aqueous phase was acidified to pH = 3-4 with 2 N HC1. The resulting mixture was extracted with EtOAc, washed with water and brine, then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product (5)-2,3-bis(tert-butoxycarbonyl)- 2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid, which was used directly for the next step.

[0314] LCMS (ESI) calcd. for C16H26N2O6 [M+H]+m / z 343.39, found: 343.5.Step 9. Preparation of 2,3 -di-tert-buty 14-methyl (S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylate

[0315] To a stirred solution of crude product fS')-2,3-bis(tert-butoxycarbonyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylic acid (27.0 g, 78.9 mmol) in DMF (300 mL) was added K2CO3 (27.3 g, 197.4 mmol) and lodomethane (10 mL, 157.8 mmol) at r.t.. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 23%) to give 2,3 -di -tert-butyl 4-methyl (5)-2,3- diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylate (5.6 g, 18.45 % in two-steps) as a light yellow oil.

[0316] 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

[0317] To a stirred solution of 2,3-di-tert-butyl 4-methyl (5)-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 (5)-4-(m ethoxy carbonyl)-2, 3 -diazabicyclo[3.1.1 ]heptan- 2-ium 2,2,2-trifluoroacetate (7.2 g) as a yellow solid.

[0318] LCMS (ESI) calcd. for C15H23BO4 [M+H]+m / z 157.09, found: 157.4.Intermediate D: (S)-3-(2-(5-(benzyloxy)-2-(l-methoxyethyl)pyridin-3-yl)-5-bromo- l-(2,2,2-trifluoroethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetateStep 1: Synthesis of (S)-2-(l-methoxyethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridine

[0319] To a stirred solution of (S)-3-bromo-2-(l-methoxyethyl)pyridine (80.1 g, 370.83 mmol) and ILPi (113.1 g, 445.00 mmol) in 1,4-dioxane (1000 mL) were added Pd(dppf)C12 (23.1 g, 31.52 mmol) and KOAc (109.2 g, 1.11 mol). The reaction was stirred at 100 °C for 18 h under N2 atmosphere. The reaction was monitored by LCMS. After completion, the reactionsolution was concentrated under reduced pressure to give the residual which was purified by neutral AI2O3 column (eluting with EtOAc / PE from 0% to 100%) to afford (S)-2-(l- methoxyethyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (130.8 g) as a brown oil.

[0320] LCMS (ESI) calcd. for C14H22BNO3 [M+H]+m / z 264.2, found: 264.5Step 2: Synthesis of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-lH-indol-3-yl)-2,2- dimethylpropyl acetate

[0321] To a stirred solution of 3-(5-bromo-2-iodo-lH-indol-3-yl)-2,2-dimethylpropyl acetate (12.2 g, 27.17 mmol), (S)-2-(l-methoxyethyl)-3-(4,4,5,5-tetramethyl-l,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)C12 (2.0 g, 2.72 mmol) at rt. The reaction mixture was stirred at 90 °C under N2 for 18 h. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-di oxane 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-(l-methoxyethyl)pyridin-3-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (10.5 g, 84.1 %) as a yellow solid.

[0322] LCMS (ESI) calcd. for C23H27BrN2O3 [M+H]+m / z 459.1, found: 459.5.Step 3: Synthesis of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)- lH-indol-3-yl)-2, 2 -dimethylpropyl acetate

[0323] To a stirred solution of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-lH- 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 2-Iodo- 1,1,1 -trifluoroethane (8.5 g, 40.64 mmol) at 0 °C, 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-2-(2-(l- methoxyethyl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (10.4 g, 79.0 %) as a brown solid.

[0324] LCMS (ESI) calcd. for C25H2sBrF3N2O3 [M+H]+m / z 541.1, found: 541.5.Step 4: Synthesis of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)- lH-indol-3-yl)-2,2-dimethylpropan-l-ol

[0325] To a solution of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-l-(2,2,2- trifluoroethyl)-lH-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 ELO (2.7 g, 64.26 mmol) at 0-10 °C, the resulting mixture was stirred at 0-10 °C for 20 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 HC1. 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-2-(2-(l- methoxyethyl)pyridin-3-yl)-l -(2, 2, 2-tri fluoroethyl)- lH-indol-3-yl)-2,2-dimethylpropan-l-ol (5.0 g, 52.0 %) as a yellow solid.

[0326] LCMS (ESI) calcd. for C23H26BrF3N2O2 [M+H]+m / z 499.1, found: 499.6.Step 5: Synthesis of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)- lH-indol-3-yl)-2, 2 -dimethylpropyl acetate

[0327] To a stirred solution of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-l- (2,2,2-trifhioroethyl)-lH-indol-3-yl)-2,2-dimethylpropan-l-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 , the resulting mixture was stirred at rt for 18 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 EA / PE from 0% to 50%) to give (S)-3- (5-bromo-2-(2-(l -methoxy ethyl)pyridin-3-yl)- 1-(2, 2, 2-tri fluoroethyl)-lH-indol-3-yl)-2, 2- dimethylpropyl acetate (5.1 g, 94.3 %) as a pale yellow solid.

[0328] LCMS (ESI) calcd. for C25H28BrF3N2O3[M+H]+m / z 541.1, found: 541.5.

[0329] To a stirred solution of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-l- (2,2,2-trifluoroethyl)-lH-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 °C under N2 for 24 h. The reaction 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 7: Synthesis of (S)-3-(5-bromo-2-(5-hydroxy-2-(l-methoxyethyl)pyridin-3-yl)-l-(2,2,2- trifluoroethyl)-lH-indol-3-yl)-2, 2 -dimethylpropyl acetate

[0330] To a stirred solution of crude (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-l- (2,2,2-trifluoroethyl)-lH-indol-2-yl)-6-(l-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 concentration under reduced pressure to obtain the crude (S)-3-(5-bromo-2-(5- hydroxy-2-(l -methoxy ethyl)pyri din-3 -yl)-l -(2, 2, 2-tri fluoroethyl)- lH-indol-3-yl)-2, 2-dimethylpropyl acetate (3.4 g, 80.9 % ) as a yellow solid.

[0331] LCMS (ESI) calcd. for C25H2sBrF3N2O4[M+H]+m / z 557.1, found: 557.6.Step 8: Synthesis of (S)-3-(2-(5-(benzyloxy)-2-(l-methoxyethyl)pyridin-3-yl)-5-bromo-l-(2,2,2- trifluoroethyl)-lH-indol-3-yl)-2, 2 -dimethylpropyl acetate

[0332] To a stirred solution of crude (S)-3-(5-bromo-2-(5-hydroxy-2-(l- methoxyethyl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-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 °C 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-(l-methoxyethyl)pyridin-3-yl)-5- bromo-l-(2,2,2-trifluoroethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (3.2 g, 79.4 %) as a yellow foam.

[0333] LCMS (ESI) calcd. for C32H34BrF3N2O4[M+H]+m / z 647.2, found: 647.6 Intermediate E: (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine "Intermediate EStep 1. Preparation of (S)-l-(3-bromopyridin-2-yl)ethan-l-ol

[0334] To a stirred solution of TEA (151.76 g, 1.50 mol) was added FA (13.81 g, 299.96 mmol) at 0 °C. Then (S,S)-N-(p-Toluenesulfonyl)-l,2-diphenylethanediamine(chloro)(p- cymene)ruthenium(II) (800 mg, 1.25 mmol) was added into the reaction mixture, the resulting mixture was stirred at 40 °C under N2 for 0.5 h. l-(3-bromopyridin-2-yl)ethan-l-one (25.00 g, 124.98 mmol) was added into the reaction mixture, the resulting mixture was stirred at 40°C under N2 for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (500 mL), washed with saturated NH4C1 (300 x 3 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 25%) to give (S)-l-(3- bromopyridin-2-yl)ethan-l-ol (28.80 g, 95.0 %) as a yellow oil.

[0335] LCMS (ESI) calcd. for C7H6BrNO [M+H]+m / z 200.98, found: 202.1.Step 2. Preparation of (S)-3-bromo-2-(l-methoxyethyl)pyridine

[0336] To a stirred solution of (S)-l-(3-bromopyridin-2-yl)ethan-l-ol (23.80 g, 117.82mmol) in THF (240 mL) was added NaH (60% in oil, 7.07 g, 176.73 mmol) portion wisely at 0°C, the resulting mixture was stirred at 0°C for 1 h. CH3I (33.45 g, 235.64 mmol) was added into the reaction mixture at 0°C, the resulting mixture was stirred at rt for 15 h. The reaction mixture was quenched with H2O (50 mL) at 0°C and extracted with EtOAc (2*200 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 25%) to give (S)-3-bromo-2-(l-methoxyethyl)pyridine (23.39 g, 91.9 %) as a light yellow oil.

[0337] LCMS (ESI) calcd. for CsHwBrNO [M+H]+m / z 214.99, found: 216.3.Step 3. Preparation of (S)-3-bromo-2-(l-methoxyethyl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine

[0338] To a stirred solution of (S)-3-bromo-2-(l-methoxyethyl)pyridine (12.00 g, 55.56 mmol) fhPi (15.53 g, 61.11 mmol) in THF (180 mL) was added [Ir(COD)(OMe)]2 (737 mg, 1.11 mmol) and dtbpy (895 mg, 3.33 mmol) at rt , the resulting mixture was stirred at 75°C under N2 for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give crude (S)-3-bromo-2-(l -methoxy ethyl)-5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (20.9 g) as an orange oil.

[0339] LCMS (ESI) calcd. for Ci4H2iBBrNO3[M+H]+m / z 341.08, found: 342.4Step 4. Preparation of (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid

[0340] To a stirred solution of crude (S)-3-bromo-2-(l-methoxyethyl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (16.20 g, 47.51 mmol) in THF (150 mL) and H2O (150 mL) were added NH4OAc (14.60 g, 190.03 mmol ) and NaIO4(40.60 g, 190.03 mmol) at 0°C, the resulting mixture was stirred at rt for 3h. The reaction was monitored by LCMS. After completion, the reaction mixture was extracted with EtOAc (2x300 mL). The organic layers were combined, washed with brine, dried over Na2SO4and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid (10.98 g, 89.2%) as a yellow solid.

[0341] LCMS (ESI) calcd. for C8HnBBrNO3[M+H]+m / z 259.00, found: 260.3.Step 5. Preparation of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine

[0342] To a stirred solution of (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid (3.00 g, 11.58 mmol) in CH3CN (45 mL) was added NIS (3.13 g, 13.90 mmol) at rt, the resulting mixture was stirred at 75°C for 20h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with sat. aq. Na2SO3and concentrated to give the residue. The residue was extracted with EtOAc (2*30 mL). The organic layers were combined and washed with brine, then dried over Na2SO4and concentrated to give the crudeproduct which was purified by silica gel column (eluting with EtOAc / PE from 0% to 20%) to give (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (2.65 g, 67.1%) as a brown solid.

[0343] LCMS (ESI) calcd. for C8H9BrINO3[M+H]+m / z 340.89, found: 342.3.Intermediate F : (R)-l-(but-3-yn-2-yl)-4-cyclopropylpiperazinestep 1 step 2 Intermediate FStep 1: Synthesis of (S)-but-3-yn-2-yl me thane sulfonate

[0344] To a stirred solution of (S)-but-3-yn-2-ol (500 mg, 7.13 mmol) in DCM (7.5 mL) and DIEA (1.80 g, 17.83 mmol) was added MsCI (980 mg, 8.56 mmol), the resulting mixture was stirred at rt for 3 h. 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 10%) to give (S)-but-3-yn-2-yl methanesulfonate (783 mg, 74.2%) as a brown oil.

[0345] LCMS (ESI) calcd. for C5H8O3S [M+H]+m / z 149.0, found: 149.3.Step 2: Synthesis of (R)-l-(but-3-yn-2-yl)-4-cyclopropylpiperazine

[0346] To a stirred solution of (S)-but-3-yn-2-yl methanesulfonate (783 mg, 5.29 mmol) in THF (20 mL) was added 1 -cyclopropylpiperazine (3.60 g, 28.52 mmol) drop wisely at rt, the resulting mixture was stirred at 75 °C for 16 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)-l-(but-3-yn-2-yl)-4- cyclopropylpiperazine (497 mg, 52.5 %) as a yellow crystal.

[0347] LCMS (ESI) calcd. for CHHI8N2[M+H]+m / z 179.2, found: 179.4.Intermediate G: 3 -(2-((M)-5-(benzyloxy)-2-((S)- 1 -methoxy ethyl)pyri din-3 -yl)- 1 -(2- ((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indol-3-yl)-2,2-dimethylpropyl acetateStep 1: General procedure for preparation of 1,4 f -trioxaspiro [4.5] decane

[0348] A mixture of tetrahydro-4H-pyran-4-one (50 g, 499.42 mmol, 1 eq.), ethane-1,2- diol (31.00 g, 499.42 mmol, 1 eq.) and TsOH (8.60 g, 49.94 mmol, 0.1 eq.) in toluene (400 mL) was stirred at 100 °C for 16 h. TLC indicated Reactant 1 was consumed completely and one new spot formed. After cooling to room temperature, the benzene layer was decanted from the dark oil in the bottom of the flask and was concentrated. The resulting oil was taken up in DCM (500 mL) and shaken in a separatory funnel. The DCM layer was decanted from the insoluble oil. The DCM layer was concentrated to give yellow oil. The crude product was used to next step without purification, l,4,8-trioxaspiro[4.5]decane (32 g, crude) was obtained as yellow oil.

[0349] 'H NMR: (400 MHz, DMSO-tL) 5: 1.61 (t, J= 5.6 Hz, 4H), 3.59-3.66 (m, 4H), 3.82-3.89 (m, 4H).Step 2: General procedure for preparation of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethan-l-ol

[0350] To a solution of l,4,8-trioxaspiro[4.5]decane (30 g, 208.09 mmol, 1 eq.) in THF (300 mL) was added BH3-DMS (10 M, 0.95 eq.), TMSOTf (2.31 g, 10.40 mmol, 0.05 eq.) was dropped in 2 min at -78 °C under N2. The mixture was stirred at -78 °C for 16 hr under N2 atmosphere. TLC indicated no compound 2 was consumed, and one major new spot with larger polarity was detected. The reaction mixture was quenched by MeOH (20 mL) at 0 °C and was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was used to next step without purification. 2-((tetrahydro-2H- pyran-4-yl)oxy)ethan-l-ol (30 g, crude) was obtained as yellow oil.

[0351] 'H NMR: (400 MHz, CHLOROFORM-t / ) 5: 1.56-1.60 (m, 2H), 1.84-1.93 (m, 2H), 3.43-3.56 (m, 2H), 3.57-3.58 (m, 3H), 3.71-3.73 (m, 2H), 3.92-3.96(m, 2H).Step 3: General procedure for preparation of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl 4- methylbenzenesulfonate

[0352] To a solution of 2-((tetrahydro-2H-pyran-4-yl)oxy)ethan-l-ol (30 g, 205.22 mmol, 1 eq.) in DCM (200 mL) was added TEA (62.30 g, 615.66 mmol, 3 eq.), TsCl (39.12 g, 205.22 mmol, 1 eq.) and DMAP (2.51 g, 20.52 mmol, 0.1 eq.) slowly. The mixture was stirred at 0 °C for 16 h. LC-MS showed 2-((tetrahydro-2H-pyran-4-yl)oxy)ethan-l-ol was consumed completely and -21% of desired compound was detected. The reaction mixture was quenched by addition HC1 (IM) to adjust pH=6 and then diluted with H2O 500 mL and extracted with DCM 900 mL (300 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, Commercial hexanes: ethyl acetate=5 / l to 3 / 1). 2-((tetrahydro-2H- pyran-4-yl)oxy)ethyl 4-methylbenzenesulfonate (19.47 g, 30.65% yield, 97.035% purity) was obtained as colorless oil.

[0353] LCMS: calcd. for C14H20O5S [M+H]+m / z: 300.1, found: 301.2.HPLC: (Purity: 97.05%).1H NMR: (400 MHz, DMSO-tL) 5: 1.24-1.33 (m, 2H), 1.72 (d, J= 12.8 Hz, 2H), 2.42 (s, 3H), 3.24-3.31 (m, 2H), 3.37-3.40 (m, 1H), 3.58 (s, 2H), 3.72-3.76(m, 2H), 4.11-4.13 (m, 2H), 7.48 (d, J= 8.0 Hz, 2H), 7.79 (d, J= 8.0z, 2H).Step 4: General procedure for preparation of 3-(5-bromo-2-(2-((S)-l-methoxyethyl)pyridin-3- yl) -l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate

[0354] A mixture of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-lH-indol-3-yl) - 2,2-dimethylpropyl acetate (16.0 g, 34.8 mmol, 1.0 eq), 2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl 4-methylbenzenesulfonate (13.0 g, 39.9 mmol, 1.15 eq), Cs2CO3 (22.7 g, 69.7 mmol, 2.0 eq) and DMF (250 mL) at 25 °C. The mixture was stirred at 60 °C for 5 h. LCMS showed that the starting material was consumed and two peaks (Rtl = 0.644 min, about 40%, Rt2 = 0.700 min, about 45%) showed desired mass. The reaction mixture was quenched by addition water 250 mL at 25 °C, and then diluted with EA (250 mL x 3). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. It was purified by column chromatography (SiO2, hexanes: EA = 3 / 1 to 0 / 1) to give 3-(5-bromo-2-((R)-2-((S)-l- methoxy ethyl)pyri din-3 -yl) -l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2,2- dimethylpropyl acetate (3.80 g, 17% yield, less polar, Rt = 0.696 min) as yellow oil and the 3- (5-bromo-2-(2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- lH-indol-3-yl)-2,2-dimethylpropyl acetate (16.5 g, 79% yield) as yellow oil.LCMS: calcd. for C30H39BrN2O5 [M+H]+ m / z: 587.20, found: Rtl = 0.644 min, 589.0, Rt2 = 0.700 min, 589.2. 1H NMR: (400 MHz, CHLOROFORM-d) 5 : 8.81 (dd, JI = 4.8 Hz, J2 = 1.6 Hz, 1H), 7.80-7.77 (m, 2H), 7.37-7.29 (m, 3H), 4.10-3.96 (m, 3H), 3.83-3.77 (m, 2H), 3.70-3.60 (m, 3H), 3.57-3.52 (m, 1H), 3.36-3.26 (m, 3H), 3.02 (s, 3H), 2.72 (d, J = 14.4 Hz, 1H), 2.28 (d, J = 14.4 Hz, 1H), 2.00 (s, 3H), 1.75-1.70 (m, 2H), 1.47 (d, J = 6.0 Hz, 3H), 1.44- 1.36 (m, 2H), 0.82 (d, J = 16.4 Hz, 6H).Step 5: Synthesis of ((M)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-l-(2-((tetrahydro-2H- pyran-4-yl)oxy)ethyl)-lH-indol-2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)boronic acid

[0355] To a stirred solution of 3-(5-bromo-2-((M)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l- (2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (atropisomer 2) (4.10 g, 8.44 mmol) , ELPi (3.22 g, 12.7 mmol) in THF (60 mL) was added [Ir(COD)(OMe)]2 (283 mg, 0.420 mmol) and dtbpy (339 mg, 1.27 mmol) at rt , the resulting mixture was stirred at 75 °C under N2 for 23 h. The reaction was monitored by LCMS. After completion, the mixture was used directly at next step.Step 6: Synthesis of 3-(5-bromo-2-((M)-5-hydroxy-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(2- ( tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2, 2 -dimethylpropyl acetate

[0356] To a stirred solution of crude ((M)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-l- (2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-2-yl)-6-((S)-l -methoxy ethyl)pyri din-3 - yl)boronic acid in THF (60 mL) was added H2O2 (1.91 g, 16.9 mmol, 30% in water ) at 0 °C, the resulting mixture was stirred at 0 °C for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was extracted with EtOAc (2x50 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product 3-(5-bromo-2-((M)-5-hydroxy-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(2-((tetrahydro- 2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate which was used directly at next step.

[0357] LCMS (ESI) calcd. for C3oH39BrN206[M+H]+ m / z 602.20, found: 603.8.Step 7: Synthesis of 3-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-5-bromo-l- (2-( tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2, 2 -dimethylpropyl acetate

[0358] To a stirred solution of 3-(5-bromo-2-((M)-5-hydroxy-2-((S)-l- m ethoxy ethyl)pyri din-3 -yl)- 1 -(2-((tetrahy dro-2H-pyran-4-yl)oxy)ethyl)- 1 H-indol-3 -yl)-2,2- dimethylpropyl acetate (crude) in CH3CN (40 mL) was added Cs2CO3(4.16 g, 12.7 mmol ) and BnBr (1.58 g, 9.28 mmol) at rt, the resulting mixture was stirred at rt for 20 h. The reaction was monitored by LCMS. After completion, the mixture was filtered. The filtrate was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 50%) to give 3-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin- 3-yl)-5-bromo-l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (3.1 g, 53%, 3 steps) as a yellow oil.

[0359] LCMS (ESI) calcd. for C37H45BrN2O6 [M+H]+ m / z 692.25, found: 693.6.Step 8: Synthesis of 3-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(2-( tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH- indol-3-yl)-2, 2 -dimethylpropyl acetate

[0360] To a stirred solution of 3-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3- yl)-5-bromo-l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (3.10 g, 4.48 mmol) in 1,4-dioxane (40 mL) was added Pd(dppf)C12 (328 mg, 0.448 mmol ) and KOAc (1.32 g, 13.4 mmol) and Bis(pinacolato)diboron (1.71 g, 6.72 mmol). The reaction was stirred at 95 °C for 16 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, the residual was diluted with H2O and extracted with EtOAc (50 mL x 3), 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 60% to afford 3-(2-((M)-5- (benzyloxy)-2-((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)- 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (3.1 g, 94 %) as a brown oil.

[0361] LCMS (ESI) calcd. for C43H57BN2O8 [M+H]+m / z 740.42, found: 742.2.Intermediates H&I : (2R,3S)-3-methyloxetane-2-carboxylic acid & (2S,3S)-3- methyloxetane-2-carboxylic acidIntermediate H Intermediate IStep 1: Synthesis of (R) -2 -bromopropan- l-ol

[0362] To a stirred solution of (R)-2-bromopropanoic acid (3.60 g, 20.0 mmol) in THF (50 mL) was added BHa / SMe2 (2.2 mL, 22 mmol, 10M) at 0 °C. The resulting mixture was stirred at rt overnight. The reaction solution was quenched with 1 M HC1 aqueous 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 which was purified by silica gel column eluting with EtOAc / PE from 0% to 20% to afford (R)-2-bromopropan-l-ol (2.1 g, 76 %) as a colorless oil.

[0363] XH NMR (400 MHz, CDC13) 5 4.27-4.18 (m, 1H), 3.78-3.66 (m, 2H), 1.69 (d, = 6.8 Hz, 3H).Step 2: Synthesis of 1 -benzyl 3 -(tert-butyl) 2-diazomalonate

[0364] To a stirred solution of benzyl tert-butyl malonate (2.50 g, 10.0 mmol) and P-ABSA (2.40 g, 10.0 mmol) in CH3CN (25 mL) was added TEA (3.03 g, 30.0 mmol) at 0 °C. The mixture was warmed to rt and stirred overnight, 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 10% in 20 min) to obtain 1-benzyl 3 -(tert-butyl) 2-diazomalonate (2.40 g, yield: 87%) as a colorless oil.

[0365] LCMS (ESI) calcd. for C14H16N2O4 [M+H]+ m / z 276.11, found 221 ,4[M+H-56]+. Step 3: Synthesis of 1 -benzyl 3 -(tert-butyl) 2-((R)-2-bromopropoxy)malonate

[0366] To a stirred solution of 1-benzyl 3 -(tert-butyl) 2-diazomalonate (552 mg, 2.00 mmol) in toluene (5 mL) was added (A)-2-bromopropan-l-ol (306 mg, 2.20 mmol) and Rh2(OAc)4 (9 mg, 0.02 mmol) at 0 °C. The reaction mixture was heated to 60 °C and stirred for 6 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 10%) to give 1-benzyl 3 -(tert-butyl) 2-((R)-2-bromopropoxy)malonate (450 mg, 58 % ) as a colorless oil.

[0367] LCMS (ESI) calcd. for Ci7H23BrO5[M+H]+m / z 386.07, found: 331.4[M+H-56]+.Step 4: Synthesis of 2 -benzyl 2 -(tert-butyl) (3S)-3-methyloxetane-2,2-dicarboxylate

[0368] To a stirred solution of 1-benzyl 3 -(tert-butyl) 2-((R)-2 -brom opropoxy)mal onate (13.2 g, 34.1 mmol) in DMF (250 mL) was added NaH (1.5 g, 37.5 mmol, 60%), the resulting mixture was stirred at rt overnight. The reaction solution was poured into 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 10%) to give 2-benzyl 2-(tert- butyl) (3S)-3-methyloxetane-2,2-di carboxylate (3.5 g, 33%) as a colorless oil.

[0369] LCMS (ESI) calcd. for C17H22O5 [M+H]+m / z 306.15, found: 251.4[M+H-56]+.Step 5: Synthesis of (3S)-2-((benzyloxy)carbonyl)-3-methyloxetane-2-carboxylic acid

[0370] To a stirred solution of 2-benzyl 2-(tert-butyl) (3S)-3-methyloxetane-2,2- dicarboxylate (1.00 g, 3.27 mmol) in DCM (10 mL) was added TFA (3 mL), the resulting mixture was stirred at rt for 3 h. The resulting mixture was concentration under reduced pressure to obtain crude (3S)-2-((benzyloxy)carbonyl)-3-methyloxetane-2-carboxylic acid (910 mg, >100%) as a colorless oil.

[0371] LCMS (ESI) calcd. for C13H14O5 [M+H]+m / z 250.08, found: 251.4.Step 6: Synthesis of benzyl (2R,3S)-3-methyloxetane-2-carboxylate & benzyl (2S,3S)-3- methyloxetane-2-carboxylate

[0372] To a stirred solution of (3S)-2-((benzyloxy)carbonyl)-3-methyloxetane-2-carboxylic acid (1.00 g, 4.00 mmol) in 1,4-dioxane (40 mL) was added DMAP (976 mg, 2.00 mmol) at rt. The reaction mixture was stirred at 100 °C under N2 overnight. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to 15% to afford benzyl (2R,3S)-3-methyloxetane-2-carboxylate (200 mg, 24%) (enantiomer 1) as a colorless oil and (2S,3S)-3-methyloxetane-2-carboxylate (150 mg, 18%) (enantiomer 2) as a colorless oil.

[0373] enantiomer 1 : LCMS (ESI) calcd. for C12H14O3 [M+H]+m / z 206.09, found: 207.4. enantiomer 2: LCMS (ESI) calcd. for C12H14O3 [M+H]+m / z 206.09, found: 207.4. Step 7: Synthesis of (2R,3S)-3-methyloxetane-2-carboxylic acid

[0374] To a stirred solution of benzyl (2R,3S)-3-methyloxetane-2-carboxylate (150 mg, 0.727 mmol) (enantiomer 1) in EtOAc (10 mL) were added Pd(OH)2 (30 mg, 10%). The resulting mixture was heated to 50 °C and stirred overnight under H2 atmosphere (1 atm). The mixture was cooled to rt and filtered. The filtrate was concentrated to obtain (2R,3S)-3- methyloxetane-2-carboxylic acid (80 mg, 95%) as colorless oil.

[0375] LCMS (ESI) calcd. for C5H8O3[M-H]' m / z 116.05, found: 115.2.Step 8: Synthesis of (2S,3S)-3-methyloxetane-2-carboxylic acid

[0376] To a stirred solution of benzyl (2S,3S)-3-methyloxetane-2-carboxylate (300 mg, 1.45 mmol) (enantiomer 2) in EtOAc (10 mL) were added Pd(OH)2 (100 mg, 10%). The resulting mixture was heated to 50 °C and stirred overnight under H2 atmosphere (1 atm). The mixture was cooled to rt and filtered. The filtrate was concentrated to obtain (2S,3S)-3- methyloxetane-2-carboxylic acid (170 mg, 100%) as colorless oil.

[0377] LCMS (ESI) calcd. for C5H8O3[M-H]' m / z 116.05, found: 115.2.Intermediate J: methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-morpholinopropanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylateStep 1: General procedure for preparation of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxy carbonyl)amino)-3-morpholinopropyl acetate

[0378] To a solution of tert-butyl (4R,5R)-4-(acetoxymethyl)-5-(4-bromothiazol-2-yl)- 1,2,3- oxathiazolidine-3 -carboxylate 2,2-dioxide (9.0 g, 19.68 mmol, 1 eq) in MeCN (90 mL) was added dropwise morpholine (3.43 g, 39.36 mmol, 3.46 mL, 2 eq) in MeCN (34 mL) at 25 °C. The mixture was stirred at 25 °C for 4 h. LCMS showed the starting material was consumed completely and ~ 66% of desired MS was found. TLC (DCM: MeOH = 9: 1, UV, Pl Rf = 0.32) indicated Reactant 1 was consumed completely and some new spots formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, DCM: MeOH = 1 / 0 to 9 / 1 ~ 1 / 1) to give (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxy carbonyl)amino)-3-morpholinopropyl acetate (9.6 g, 89.29% yield) as an off-white solid.

[0379] LCMS: calcd. for CnIMrNsChS [M+H]+m / z: 463.1, found: 465.9.^ NMR: (400 MHz, CHLOROFORM^ / ) 5: 8.46-8.65 (m, 2 H), 7.28 (s, 1 H), 5.33-5.39 (m, 1 H), 4.69 (dd, J =10.8, 8.8 Hz, 1 H), 4.36 (d, J= 10.8 Hz, 1 H), 3.96-4.04 (m, 6 H), 3.76-3.86 (m, 2 H), 3.67- 3.72 (m, 4 H), 3.29-3.40 (m, 6 H), 2.78-2.84 (m, 2 H), 2.33-2.38 (m, 2 H), 2.01 (s, 3 H), 1.58 (s, 9 H).Step 2: General procedure for preparation of tert-butyl ((lS,2S)-l-(4-bromothiazol-2-yl)-3- hydroxy-l-morpholinopropan-2-yl) carbamate

[0380] To a stirred solution of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxy carbonyl)amino)-3-morpholinopropyl acetate (9.6 g, 20.67 mmol, 1 eq) in THF (50 mL) was added a solution of LiOHftO (1.74 g, 41.35 mmol, 2.0 eq) in H2O (50 mL) dropwise at 0 °C. The mixture was stirred at 25 °C for 3 h. LCMS showed -13% of Reactant 1 remained and -76% of desired compound was detected. TLC (DCM: MeOH = 9: 1, UV, Pl Rf = 0.51) indicated Reactant 1 was consumed completely and two new spots formed. The pH value of reaction mixture was neutralized to 7 with Sat.aq.Na^PCh. The mixture was extracted with DCM (200 mL x 5), dried over Na2SO4, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiCh, DCM: MeOH= 1 / 0 to 2 / 1) to give tert-butyl ((1 S,2S)-l-(4-bromothiazol-2-yl)-3-hydroxy-l-morpholinopropan-2-yl)carbamate (6.8 g, 68.54% yield) as a yellow oil.

[0381] LCMS: calcd. for Ci5H24BrN3O4S [M+H]+m / z: 421.1, found: 423.1.1H NMR: (400 MHz, DMSO-Jt,) 8: 7.83 (s, 1 H), 6.49 (d, J= 9.2 Hz, 1 H), 4.55-4.71 (m, 1 H), 4.04-4.12 (m, 1 H), 3.86-3.94 (m, 1 H), 3.47 (s, 5 H), 3.13-3.18 (m, 1 H), 2.52 (s, 2 H), 2.26 (d, J= 4.8 Hz, 2 H), 1.42 (s, 9 H).Step 3: General procedure for preparation of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-morpholinopropanoic acid

[0382] To a solution of tert-butyl ((lS,2S)-l-(4-bromothiazol-2-yl)-3-hydroxy-l- morpholinopropan-2-yl)carbamate (6.0 g, 14.21 mmol, 1 eq) in Acetone (60 mL) was added Jones reagent (2.5 M, 11.37 mL, 2 eq) dropwise at 0 °C. The mixture was stirred at 25 °C for 1 h. LCMS (ES32464-7-P1A) showed the starting material was consumed and -56% of desired MS was detected. TLC (DCM: MeOH = 20: 1, UV, Pl Rf = 0.15) indicated one new spot formed. The reaction mixture was quenched by addition IPA (4 mL) at 25°C, and then diluted with water (100 mL) and extracted with DCM (120 mL x 5). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. It was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0-8% MeOH / DCM gradient @ 35 mL / min) to give (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-morpholinopropanoic acid (2.55 g, 37.83% yield) as a white solid.

[0383] LCMS: calcd. for CisFfeBrNsOsS [M+H]+m / z: 435.1, found: 438.1.HPLC: (Purity: 91.96%). SFC: RT = 3.225, 97.22% ee value. 'H NMR: (400 MHz, DMSO-t / 6) 8: 12.32-12.92 (m, 1 H), 7.81 (s, 1 H), 7.28 (d, J= 9.2 Hz, 1 H), 4.63 (t, J= 9.2 Hz, 1 H), 4.25 (d, J= 9.6 Hz, 1 H), 3.47-3.56 (m, 4 H), 2.50-2.57 (m, 2 H), 2.30 (d, J= 5.2 Hz, 2 H), 1.41 (s, 9 H).Step 4: General procedure for preparation of methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2- ( tert-butoxycarbonyl)amino)-3-morpholinopropanoyl)-2, 3-diazabicyclo[ 3.1.1 ]heptane-4- carboxylate

[0384] To a solution of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3- morpholinopropanoic acid (4) (436 mg, 1.00 mmol) in DMF (6 mL) were added methyl (S)- 2,3-diazabicyclo[3.1.1]heptane-4-carboxylate HC1 salt (212 mg, 1.10 mmol), TEA (404 mg, 4.00 mmol) and HATU (494 mg, 1.30 mmol) at 0-10 °C. The resulting mixture was stirred at 0- 10 °C for 1 h. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 15 mL), the combined organic phase was washed with brine (10 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 70% to afford methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3- morpholinopropanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (400 mg, 70%) as a white solid.

[0385] LCMS (ESI) calcd. for C22H32BrN5O6S [M+H]+m / z 573.13, found: 574.5.Intermediate K: methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tertbutoxycarbonyl)amino)-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoyl)-2,3- diazabicyclo[3.1.1 ]heptane-4-carboxylateIntermediate KStep 1: General procedure for preparation of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxy carbonyl)amino)-3-(7-oxa-2-azaspiro[ 3.5 ]nonan-2-yl)propyl acetate

[0386] To a solution of tert-butyl (4R,5R)-4-(acetoxymethyl)-5-(4-bromothiazol-2-yl)-l,2,3 -oxathiazolidine-3 -carboxylate 2,2-dioxide (15 g, 32.80 mmol, 1 eq.) in CH3CN (200 mL) wasadded 7-oxa-2-azaspiro[3.5]nonane (10.43 g, 82.00 mmol, 2.5 eq.) and the mixture was stirred at 20 °C for Ih. LCMS showed the starting material consumed and 29% of desired mass was observed. The mixture was concentrated on vacuo to give the residue and then EtOAc (200 mL) and saturated aqueous NaEbPC solution (100 mL) was added. The mixture was stirred at 60 °C for Ih. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the residue. The residue was purified by prep-HPLC (Column: 88-Biosepur Phosphoramidite C18 250x50mm, 10pm, Condition: water (0.2%FA)-ACN, Begin B: 22, End B: 52, Gradient Time (min): 21, 100%B Hold Time (min): 5, flow rate (ml / min): 100) to give (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(7-oxa-2- azaspiro[3.5]nonan-2-yl)propyl acetate (11.2 g, 22.20 mmol, 67.69% yield) as a colorless oil.

[0387] LCMS: calcd. for C2oH3oBrN305S [M+H]+m / z: 503.1, found: 504.1.XH NMR: (400 MHz, METHANOL-^) 8 1.47 (s, 9H), 1.77 (t, J= 5.2 Hz, 4H), 1.96 (s, 3H), 3.21-3.24 (m, 2H), 3.29-3.31 (m, 2H), 3.57-3.61 (m, 4H), 3.75 (dd, J= 11.2, 7.6 Hz, IH), 4.06-4.14 (m, 3H), 4.24 (dd, J= 11.6, 4.0 Hz, IH), 7.59 (s, IH).Step 2: General procedure for preparation of tert-butyl ((lS,2S)-l-(4-bromothiazol-2-yl)-3- hydroxy-1 -(7 -oxa-2 -azaspiro [ 3.5 ]nonan-2-yl)propan-2-yl)carbamate

[0388] To a solution of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3- (7- oxa-2-azaspiro[3.5]nonan-2-yl)propyl acetate (16.00 g, 31.72 mmol, 1 eq.) in THF (40 mL) and MeOH (40 mL) was added LiOHH2O (2.00 g, 47.58 mmol, 1.5 eq.) in water (20 mL). The mixture was stirred at 20 °C for 0.5 h. LCMS showed the reaction was completed. The mixture was adjusted to pH 5-6 with saturated aqueous NaftPCL solution. The mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filter and concentrated in vacuo to give tert-butyl ((1 S,2S)-l-(4- bromothiazol-2-yl)-3 -hydroxy- 1- (7-oxa-2-azaspiro[3.5]nonan-2-yl)propan-2-yl)carbamate (14 g, crude) as a white solid.

[0389] LCMS: calcd. for Ci8H28BrN3O4S [M+2+H]+m / z: 461.1, found: 464.1.1H NMR: (400 MHz, CHLOROFORM-; / ) 5 1.46 (s, 9H), 1.75 (t, J= 5.2 Hz, 4H), 3.16-3.18 (m, 2H), 3.26-3.30 (m, 2H), 3.43-3.54 (m, 2H), 3.56-3.60 (m, 4H), 4.03-4.07 (m, IH), 4.09-4.15 (m, 2H), 5.17-5.20 (m, IH), 7.27 (s, IH).Step 3: General procedure for preparation of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoic acid

[0390] To a solution of tert-butyl ((lS,2S)-l-(4-bromothiazol-2-yl)-3-hydroxy-l-(7-oxa-2- azaspiro[3.5]nonan-2-yl)propan-2-yl)carbamate (14.00 g, 30.28 mmol, 1 eq.) in acetone (200 mL) was added Jones reagent (2.5 M, 24.22 mL, 2 eq.) dropwise at 0 °C and the mixture was stirred at 0 °C for Ih. LCMS showed the reaction was completed. The mixture wasconcentrated and then water (200 mL) was added. The mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (50 mL), dried over ISfeSCU, filtered and concentrated in vacuo to give the residue, it was purified by prep-HPLC (Column:88-Biosepur Phosphoramidite C18 250x50mm, 10pm, Condition: water (0.2% FA)- ACN, begin B: 22, end B: 52, gradient time (min): 21, 100% B hold time (min): 5, flow rate (ml / min): 100) to give (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(7- oxa-2-azaspiro[3.5]nonan-2-yl)propanoic acid (4.1 g, 8.61 mmol, 28.4% yield) as an off-white solid.

[0391] LCMS: calcd. for CisIMrNsChS [M+2+H]+m / z: 475.1, found: 478.0.HPLC: (purity: 87.07%). SFC: (ee: 100%).1H NMR: (400 MHz, DMSO-tL) 5 1.35 (s, 9H), 1.61-1.64 (m, 4H), 3.01-3.04 (m, 2H), 3.05-3.09 (m, 2H), 3.41-3.43 (m, 4H), 4.18-4.21 (m, 1H), 4.39- 4.41 (m, 1H), 6.76-6.80 (m, 1H), 7.80 (s, 1H).Step 4: Synthesis of methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoyl)-2, 3- diazabicyclo[ 3.1.1 ]heptane-4-carboxylate

[0392] To a solution of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3- (7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoic acid (1.40 g, 2.94 mmol) in DMF (15 mL) were added methyl (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate HC1 salt (623 mg, 3.23 mmol), TEA (1.19 g, 11.8 mmol) and HATU (1.45 g, 3.82 mmol) at 0-10 °C. The resulting mixture was stirred at 0-10 °C for 1 h. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 15 mL), the combined organic phase was washed with brine (10 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 methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate (1.4 g, 77%) as a yellow solid.

[0393] LCMS (ESI) calcd. for C25H36BrN5O6S [M+H]+m / z 613.16, found: 616.2.Intermediate L: (lR,2S,3R)-2-methyl-3-(pyridin-4-yl)cyclopropane-l -carboxylic acidStep 1: General procedure for preparation of tert-butyl (E)-3-(pyridin-4-yl)acrylate

[0394] To a stirred yridine-4-carbaldehyde (10 g, 93.36 mmol, 1 eq.) and tert-butyl 2- (triphenyl-phosphanylidene) acetate (38.65 g, 102.73 mmol, 1.1 eq.) in THF (250 mL). The mixture was stirred at 40 °C for 2 h. The reaction was monitored by TLC and 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 / n-Hexane from 0% to 10% to afford the crude compound, then following with re-crystallization from solvent DMF (8 mL) at 0 °C for 2 h to afford tert-butyl (E)-3-(pyridin-4-yl)acrylate (16 g, 84 % yield) as a white solid.

[0395] LCMS: (ESI) calcd. for C12H15NO2 [M+H]+ m / z 205.1, found: 206.0.1H NMR (400 MHz, DMSO-tL) 5: 1.49 (9 H, s), 6.78 (1 H, d, J= 16.0 Hz), 7.52 (1 H, d, J= 16.0 Hz), 7.72 - 7.63 (2 H, m), 8.64 - 8.53 (2 H, m).Step 2: General procedure for preparation of tert-butyl (1R,2S,3R and lS,2R,3S)-2-methyl-3- (pyridin-4-yl) cyclopropane- 1 -carboxylate

[0396] To a solution of ethyldiphenyl sulfonium tetrafluoroborate (47.1 g, 155.9 mmol, 2 eq.) in DME (200 mL) and DCM (10 mL) was added LDA (2 M, 58.46 mL, 1.5 eq.) at -78 °C under N2 atmosphere and stirred for 30 min. Then tert-butyl (E)-3-(pyridin-4-yl)acrylate (16 g, 77.95 mmol, 1 eq.) in DCM (10 mL) was added to the solution stirred at 25 °C for another 2 h under nitrogen protection. LCMS showed ~0% of reactant 1 remained. Several new peaks were shown on LC-MS and desired compound was detected. The reaction mixture was quenched by addition NH4CI (500 mL) at 0°C, and then diluted with DCM 200 mL and extracted with DCM (500 mL x3). The combined organic layers were washed with NaCl 400 mL (200 mL x2), dried over Na2SO4, filter and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 21-Welch Xtimate C18 250x80mm, 10 pm; mobile phase: [H2O (0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient: 28%-51% B over 25.0 min) to provide tert-butyl (1R,2S,3R and lS,2R,3S)-2-methyl-3-(pyridin-4-yl)cyclopropane-l- carboxylate (4.5 g, 24.74% yield) was obtained as yellow oil.

[0397] LCMS: calcd. for C14H19NO2 [M+H]+m / z: 234.1, found: 234.1, crude LCMS.^H NMR: (400 MHz, DMSO-t / 6)5: 0.90 (d, J= 6.4 Hz, 3H), 1.77-1.82 (m, 1H), 2.21 (t, J= 4.8 Hz, 1H), 2.67-2.71 (m, 1H), 7.49 (d, J= 4.4 Hz, 2H), 8.56 (d, J= 5.2 Hz, 2H).Step 3: General procedure for preparation of tert-butyl (lR,2S,3R)-2-methyl-3-(pyridin-4- yl) cyclopropane- 1 -carboxylate & tert-butyl (lS,2R,3S)-2-methyl-3-(pyridin-4-yl) cyclopropane-1 -carboxylate

[0398] The residue from previous was separated by SFC (condition: column: DAICEL CHIRALPAK IG (250mm x 30mm, 10 um); mobile phase: [CO2-IPA]; B%: 10%, isocratic elution mode), tert-butyl (lR,2S,3R)-2-methyl-3-(pyridin-4-yl)cyclopropane-l- carboxylate(130 mg, 43.3% yield, SFC RT = 1.289) and tert-butyl (lS,2R,3S)-2-methyl-3-(pyridin-4- yl)cyclopropane-l- carboxylate (125 mg, 41.7% yield, SFC RT = 1.393) was obtained both as white solid.

[0399] tert-butyl (lR,2S,3R)-2-methyl-3-(pyridin-4-yl)cyclopropane-l-carboxylate:SFC: (Rt = 1.289 min, ee: 99.48%). 'H NMR: (400 MHz, DMSO-d6) 8: 0.88 (d, J = 6.4 Hz, 3H), 1.42 (s, 9H), 1.67-1.73 (m, 1H), 2.12 (t, J = 4.8 Hz, 1H), 2.54-2.58 (m, 1H), 7.28-7.27 (m, 2H), 8.44 - 8.45 (m, 2 H). tert-butyl (lS,2R,3S)-2-methyl-3-(pyridin-4-yl) cyclopropane- 1- carb oxy late: SFC: (Rt = 1.393 min, ee: 98.00%). 'H NMR: (400 MHz, DMSO-d6) 6: 0.88 (d, J = 6.4 Hz, 3H), 1.42 (s, 9H), 1.67-1.73 (m, 1H), 2.13 (t, J = 4.8 Hz, 1H), 2.54-2.57 (m, 1H), 7.28-7.27 (m, 2H), 8.44 - 8.45 (m, 2 H).Step 4: General procedure for preparation of ( 1R,2S, 3R)GZ-methyl-3f pyridineyl) cyclopropane^ -carboxy lie acid

[0400] To a solution of tert-butyl (lR,2S,3R)-2-methyl-3-(pyridin-4-yl)cyclopropane -1- carboxylate (110 mg, 0.471 mmol, 1 eq.) in DCM (3 mL) was added TFA (1.54 g, 13.46 mmol, 1 mL) at 25 °C. The mixture was stirred at 25 °C for 16 h. LCMS showed Reactant 1 was consumed completely and ~ 82% of desired mass was detected. The reaction mixture concentrated under reduced pressure to give a residue. It was purified by prep-HPLC (column: 40-WePure Biotech XP tC18 150 x 30 mm, 7 pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient: 0%-20% B over 10.0 min) to give (lR,2S,3R)-2-methyl-3-(pyridin-4- yl)cyclopropane-l -carboxylic acid (34.0 mg, 40.70% yield) as a white solid.

[0401] LCMS: ealed. for C10H11NO2 [M+H]+m / z: 177.1, found: 178.2.HPLC: (Purity: 100.00%). SFC: (Rt = 2.048 min, ee: 98.66%).^ NMR: (400 MHz, DMSO4) 6: 0.89 (d, J= 6.4 Hz, 3 H), 1.70-1.82 (m, 1 H), 2.14 (t, J= 5.2 Hz, 1 H), 2.64 (dd, J= 9.6, 4.8 Hz, 1 H), 7.38 (d, J= 6.0 Hz, 2 H), 8.40 - 8.60 (m, 2 H), 11.65 - 13.06 (m, 1 H).Intermediate M: (lR,2S,3R)-2-methyl-3-(pyridin-4-yl)cyclopropane-l -carboxylic acidStep 1: General procedure for preparation of tert-butyl (E)-3-(oxazol-4-yl)acrylate

[0402] To a solution of oxazole-4-carbaldehyde (14.5 g, 149 mmol, 1 eq) in THF (200 mL) was added tert-butyl 2-(triphenyl-15-phosphaneylidene)acetate (84.34 g, 224.06 mmol, 1.5 eq). The mixture was stirred at 40 °C under N2 for 2 h. TLC (PEZEtOAc = 3 / 1) showed the material was consumed and there were two new spots observed. The reaction mixture was concentrated in vacuo to give the crude product. It was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0-30% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to give tert-butyl (E)-3-(oxazol-4-yl)acrylate (16 g, 81.96 mmol, 54.9% yield) both as colorless oil.

[0403] 'H NMR: (400 MHz, CDCh) 8 1.53 (s, 9H), 6.59 (d, J= 15.6 Hz, 1H), 7.42 (d, J= 15.2 Hz, 1H), 7.81 (s, 1H), 7.90 (s, 1H).Step 2: General procedure for preparation of compound tert-butyl (1R,2S,3R and lS,2R,3S)-2- methyl-3-(oxazol-4-yl)cyclopropane-l- carboxylate and compound tert-butyl (lR,2R,3R)-2- methyl-3-(oxazol-4-yl) cyclopropane-1 -carboxy late

[0404] To a solution of ethyldiphenyl sulfonium tetrafluoroborate (37.2 g, 123 mmol, 2 eq) in DME (200 mL) and DCM (20 mL) was added LDA (61.5 mL, 123 mmol, 2 eq, 2 M in THF) at -78 °C under N2. After stirring at -78 °C for 30 min, to the mixture was added tert-butyl (E)-3-(oxazol-4-yl)acrylate (12 g, 61.5 mmol, 1 eq, in 100 mL of DME) dropwise at -78 °C. The mixture was stirred at 20 °C under N2 for 1 h. LCMS showed that the reaction was complete. The reaction was quenched with saturated NH4CI aq. (500 mL) at 20 °C under N2. The mixture was extracted with EtOAc (500 mL x 3). The combined organic layer was washed with brine (500 mL) and dried over Na2SO4, filtered, the filtrate was concentrated in vacuo to give the residue. It was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0-10% Ethyl acetate / Commercial hexanes gradient @ 80 mL / min) to give tert-butyl (lR,2R,3R and lS,2S,3S)-2-methyl-3-(oxazol-4-yl)cyclopropane-l- carboxylate (1.5 g, 6.72 mmol, 10.93% yield) and tert-butyl (1R,2S,3R and 75,2A,35' )-2-methyl-3-(oxazol-4-yl)cyclopropane-l -carboxylate (10 g, impurity), it was further purified by prep-HPLC (column: 21-Welch Xtimate C18 250^80 mm, 10pm; mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:30%-62% B over 21.0 min ) to give tert-butyl (1R,2S,3R and 1S,2R,3S )-2- methyl-3-(oxazol-4-yl) cyclopropane- 1 -carboxylate (5.00 g, 22.39 mmol, 36.43% yield) both as colorless oil.

[0405] LCMS: calcd. for C12H17NO3 [M+H]+m / z: 223.1, found: 224.0.^ NMR (tert-butyl (1R,2S,3R and lS,2R,3S)-2-methyl-3-(oxazol-4-yl)cyclopropane-l- carboxylate)'. (400 MHz, CDCh) 6 1.07 (d, J= 6.4 Hz, 3H), 1.47 (s, 9H), 1.70-1.75 (m, 1H), 1.82 (t, J= 4.8 Hz, 1H), 2.48 (dd, J= 8.8, 4.8 Hz, 1H), 7.51 (s, 1H), 7.80 (s, IH^H NMR (tert-butyl (lR,2R,3R)-2- methyl-3-(oxazol-4-yl) cyclopropane-l-carboxylate)'. (400 MHz, CDCh) 6 1.30 (d, J= 6.4 Hz, 3H), 1.48 (s, 9H), 1.70-1.80 (m, 1H), 2.10-2.15 (m, 1H), 2.20-2.30 (m, 1H), 7.79 (s, 1H), 7.75(s, 1H).Step 3: General procedure for preparation of (1R,2S,3R and lS,2R,3S)-2-methyl-3-(oxazol-4- yl) cyclopropane-1 -carboxylic acid

[0406] To a solution of tert-butyl (1R,2S,3R and lS,2R,3S)-2-methyl-3-(oxazol-4- yl)cyclopropane-l -carboxylate (5.00 g, 22.39 mmol) in DCM (30 mL) was added TFA (10 mL). The mixture was stirred at 20 °C for 3 h. LCMS showed that the reaction was complete. The reaction mixture was concentrated in vacuo to give (1R,2S,3R and lS,2R,3S)-2-methyl-3- (oxazol-4-yl)cyclopropane-l -carboxylic acid (3.7 g, 22.13 mmol, 98.9% yield) as yellow oil.

[0407] LCMS: calcd. for C8H9NO3[M+H]+m / z: 167.1, found: 168.0.^ NMR: (400 MHz, DMSO-tL) 5 1.00 (d, J= 6.4 Hz, 3H), 1.60-1.70 (m, 1H), 1.79 (t, J= 4.8 Hz, 1H), 2.38 (dd, J= 8.8, 4.8 Hz, 1H), 8.02 (s, 1H), 8.28 (s, 1H).Step 4: General procedure for preparation of benzyl (1R,2S,3R and lS,2R,3S)-2-methyl-3- (oxazol-4-yl) cyclopropane- 1 -carboxylate

[0408] To a solution of (1R,2S,3R and lS,2R,3S)-2-methyl-3-(oxazol-4-yl)cyclopropane - 1 -carboxylic acid (3.70 g, 22.1 mmol, 1 eq and bromomethylbenzene (3.79 g, 22.1 mmol, 1 eq) in DMF (100 mL) was added CS2CO3 (21.6 g, 66.4 mmol, 3 eq . The mixture was stirred at 20 °C for 1 h. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (50 mL) and it was extracted with EtOAc (50 mL x3), the combined organic layer was washed with brine (50 mL) and dried over Na2SO4, filtered. The filtrate was concentrated in vacuo to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate / Commercial hexanes gradient @ 60 mL / min) to give benzyl (1R,2S,3R and lS,2R,3S)-2-methyl-3-(oxazol- 4-yl)cyclopropane-l -carboxylate (4.1 g, 15.94 mmol, 72.0% yield) as colorless oil.

[0409] LCMS: calcd. for C8H9NO3[M+H]+m / z: 257.1, found: 257.9.^ NMR: (400 MHz, CDCh) 5 1.12 (d, J = 6.4 Hz, 3H), 1.80-1.90 (m, 1H), 1.99 (t, J= 4.8 Hz, 1H), 2.62 (dd, J = 9.6, 4.8 Hz, 1H), 5.12 (s, 2H), 7.30-7.50 (m, 5H), 7.53 (s, 1H), 7.82 (s, 1H).Step 5: General procedure for preparation of benzyl (lR,2S,3R)-2-methyl-3-(oxazol-4-yl) cyclopropane-1 -carboxylate and benzyl (lS,2R,3S)-2-methyl-3- (oxazol-4-yl) cyclopropane- 1- carboxylate

[0410] Benzyl (lR,2S,3R)-2-methyl-3-(oxazol-4-yl)cyclopropane-l -carboxylate (990 mg, 3.85 mmol, eq) was separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: [CCh-MeOH (0.1% NH3H2O)]; B%: 15%, isocratic elution mode) to give benzyl (lR,2S,3R)-2-methyl-3-(oxazol-4-yl)cyclopropane-l-carboxylate (400 mg, 1.55 mmol, 40.4% yield, peak 1, retention time = 1.865 min) and benzyl (lS,2R,3S)-2-methyl-3- (oxazol-4-yl)cyclopropane-l -carboxylate (380 mg, 1.48 mmol, 38.4% yield, peak 2, retention time = 2.120 min) both as colorless oil.

[0411] LCMS: calcd. for C8H9NO3 [M+H]+m / z: 257.1, found: 257.9benzyl (1R,2S,3R)- 2-methyl-3-(oxazol-4-yl)cyclopropane-l-carboxylate:SFC: (ee: 98.7%). 'H NMR: (400 MHz, CDC13) 5 1.11 (d, J = 6.4 Hz, 3H), 1.80-1.90 (m, 1H), 1.99 (t, J = 4.8 Hz, 1H), 2.60-2.70 (m, 1H), 5.16 (s, 2H), 7.30-7.50 (m, 5H), 7.52 (s, 1H), 7.81 (s, lH).benzyl (lS,2R,3S)-2-methyl-3- (oxazol-4-yl)cyclopropane-l -carboxylate :SFC: (ee: 99.3%). 'H NMR: (400 MHz, CDCL) 8 1.12 (d, J = 6.4 Hz, 3H), 1.80-1.90 (m, 1H), 1.99 (t, J = 4.8 Hz, 1H), 2.60-2.70 (m, 1H), 5.16 (s, 2H), 7.30-7.50 (m, 5H), 7.53 (s, 1H), 7.81 (s, 1H).Step 6: General procedure for preparation of ( 1R,2S, 3R)-2-methyl-3-(oxazol-4-yl)cyclopropane -1-carboxylic acid

[0412] To a solution of benzyl (lR,2S,3R)-2-methyl-3-(oxazol-4-yl)cyclopropane-l- carboxylate (0.3 g, 1.17 mmol, 1 eq in MeOH (3 mL) Water (3 mL) THF (3 mL) was added LiOH-H2O (73.4 mg, 1.75 mmol, 1.5 eq). The mixture was stirred at 20 °C for 1 hr. LCMS showed that the reaction was complete. The mixture was added with HC1 aq. (IM) till pH = 8, then the mixture was concentrated in vacuo to remove MeOH and THF. The residue was diluted with water (20 mL) and it was added with HC1 aq. (IM) till pH = 2, then extracted with EtOAc (20 mL x 3). The combined organic layer was dried over ISfeSCU, filtered. The filtrate was concentrated in vacuo to give (lR,2S,3R)-2-methyl-3-(oxazol-4-yl)cyclopropane-l- carboxylic acid (165 mg, 0.987 mmol, 84.7% yield) as an off-white solid.

[0413] LCMS: calcd. for C8H9NO3[M+H]+m / z: 167.1, found: 168.1. ^NMR: (400 MHz, DMSO k) 5 1.00 (d, J= 6.4 Hz, 3H), 1.60-1.70 (m, 1H), 1.79 (t, J= 4.8 Hz, 1H), 2.30-2.40 (m, 1H), 8.02 (s, 1H), 8.28 (s, 1H), 12.28 (brs, 1H).Preparation of compoundsIntermediate of Example 3: Synthesis of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-olStep 1. Preparation of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol

[0414] A mixture of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (200 mg, 0.59 mmol), 2-methylbut-3-yn-2-ol (99 mg, 1.17 mmol), K2CO3 (243 mg, 1.76 mmol), Pd(PPh3)2Ch (41 mg, 0.059 mmol) and Cui (11 mg, 0.059 mmol) in THF (4.5 mL) was stirred at 65°C under N2 for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 40%) to give (S)-4-(5-bromo-6-(l- methoxyethyl)pyri din-3 -yl)-2-methylbut-3-yn-2-ol (160 mg, 91.3%) as a brown solid.

[0415] LCMS (ESI) calcd. for CnHieBrNCh [M+H]+m / z 297.04, found: 298.4.Intermediate of Example 5: Synthesis of tert-butyl (S)-3-((5-bromo-6-((S)-l- methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylateStep 1. Preparation of tert-butyl (S)-3-ethynylpyrrolidine-l-carboxylate

[0416] To a stirred solution of tert-butyl (R)-3-formylpyrrolidine-l -carboxylate (1 g, 5.0 mmol) and K2CO3 (1.4 g, 10.0 mmol) in MeOH (15 mL) was added dimethyl (l-diazo-2- oxopropyl)phosphonate (1.2 g, 6.0 mmol) at RT. The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (30 mL), then dried over Na2SC>4, following with concentration under reduced pressure to obtain crude product tert-butyl (S)-3-ethynylpyrrolidine-l -carboxylate (980 mg) as a yellow oil.

[0417] 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)-l-methoxyethyl)pyridin-3- yl)ethynyl)pyrrolidine-l -carboxylate

[0418] A mixture of tert-butyl (S)-3-ethynylpyrrolidine-l -carboxylate (980 mg, 5.0 mmol), (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (1.7 g, 5.0 mmol), Cul (96 mg, 0.5 mmol) TEA (1.0 g, 10.0 mmol) and Pd PPhs^Ch (352 mg, 0.5 mmol) in THF (20 mL) was stirred at 50°C under N2 for 2 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 25%) to give tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l- carboxylate (1.8 g, 90 % in 2 steps) as a brown oil.LCMS (ESI) calcd. for CifeBr^Ch [M+H]+m / z 409.1, found: 409.6.

[0419] The following intermediates in Table 2 were prepared using the method described above in step for the preparation of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2- methylbut-3-yn-2-ol or tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3- yl)ethynyl)pyrrolidine-l-carboxylate and utilizing the appropriate starting materials and modifications.Table 2. Certain Intermediates containing alkynyl group of the Present inventionIntermediate of Example 15: Synthesis of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3- yl)prop-2-yn-l-yl)morpholineStep 1. Preparation of 3-bromo-2-((S)-l-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2- yl)oxy)prop-l-yn-l-yl)pyridine

[0420] A mixture of (5)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (10.00 g, 29.24 mmol), 2-(prop-2-yn-l-yloxy)tetrahydro-2H-pyran (4.92 g, 35.09 mmol), Cui (0.45 g, 2.34 mmol), TEA (8.88 g, 8.73 mmol) and Pd(PPh3)2Cl2(1.64 g, 2.34 mmol) in THF (120.00 mL) was stirred at 50°C for 4h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 3% in 20 min) to obtain 3 -bromo-2-((5)- 1 -methoxy ethyl)-5 -(3 -((tetrahy dro-2H-pyran-2-yl)oxy)prop- 1 -yn- 1 - yl)pyridine (10.10 g, yield: 97.5%) as a yellow oil.

[0421] LCMS (ESI) calcd. for Ci6H2oBrN03[M+H]+m / z 354.1, found 354.5.Step 2. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol

[0422] To a solution of 3-bromo-2-(fS')- l-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2- yl)oxy)prop-l-yn-l-yl)pyridine (10.10 g, 28.51 mmol) in MeOH (100.00 mL) was added TsOH (19.64 g, 114.05 mmol) at 0°C, the mixture was stirred at room temperature for 5 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with DCM (50.00 mL) and H2O (150.00 mL) and extracted with DCM (50 mL x 3), the combined layers were washed with saturated NaCl (150.00 mL), dried over Na2SC>4, concentrated to obtain (5)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, yield: 92.2%) as a yellow oil.

[0423] LCMS (ESI) calcd. for CiiHi2BrNO2[M+H]+m / z 270.0, found 270.3.Step 3. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4- methylbenzenesulfonate

[0424] To a solution of (5)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, 26.28 mmol) in THF (100.00 mL) were added TsCl (10.02 g, 52.57 mmol) and KOH (2.95 g, 52.57 mmol) at 0°C, the mixture was stirred at 0°C for 2 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with EtOAc (50.00 mL) and water (100.00 mL), then extracted with EA (50.00 mL x 3). The combined organic phase was washed with brine (100.00 mL), dried over Na2SO4 and concentrated under reduced pressure. The residual was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 30% in 30 min) to obtain (5)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3- yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (10.50 g, yield: 94.2%) as a brown solid.

[0425] LCMS (ESI) calcd. for Ci8Hi8BrNO4S [M+H]+m / z 424.0, found 424.8.Step 4. Preparation of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l- yl)morpholine

[0426] 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 (5)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3- yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (1.58 g, 3.74 mmol) in DCM (10 mL) at rt, theresulting mixture was stirred at rt for 16 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressureto give the residual which was purified by silica gel column chromatography (eluting with EtOAc / PE from 0% to 40%) to obtain (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine (980 mg, yield: 77.5%) as a brown oil.LCMS (ESI) calcd. for CisHwBrNCh [M+H]+m / z 339.1, found 339.6.

[0427] The following intermediates in Table 3 were prepared using the method described above in step for the preparation of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2- yn-l-yl)morpholine and utilizing the appropriate starting materials and modifications.Table 3. Certain Intermediates containing alkynyl group of the Present inventionIntermediate: Synthesis of N-(dimethylcarbamoyl)-N-methyl-L-valinePd(OH)2 / CMeOHStep 1. Preparation of benzyl N-(dimethylcarbamoyl)-N-methyl-L-valinate

[0428] A mixture of benzyl (2S)-3-methyl-2-(methylamino)butanoate (500 mg, 2.26 mmol) and dimethylcarbamyl chloride (1.215 g, 11.3 mmol) in THF (5 mL), was added TEA (2.286 g, 22.59 mmol and DMAP (276.02 mg, 2.26 mmol) in portions under nitrogen atmosphere. The reaction mixture was stirred at 65°C for 12 h under nitrogen atmosphere, then quenched with water (100 ml) and 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.

[0429] LCMS (ESI) calcd. for C16H25N2O3 [M+H]+m / z 293.2, found: 293.4.Step 2. Preparation ofN-(dimethylcarbamoyl)-N-methyl-L-valine

[0430] A mixture of benzyl N-(dimethylcarbamoyl)-N-methyl-L-valinate (400 mg, 1.37 mmol) and palladium hydroxide on carbon (400 mg, 2.85 mmol) in MeOH (10 mL) was stirred for 4 h under hydrogen atmosphere. The reaction mixture was 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

[0431] The following compounds in Table 4 were prepared according to the representative procedure described 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

[0432] 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 below, the embodiments formed by the combination of the invention with other chemical synthesis methods, and the equivalent substitution methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, embodiments of the present invention. To those skilled in the art, various changes and improvements to the specific embodiments of the present invention without departing from the spirit and scope of the invention will be obvious and shall also be regarded as the scope of protection of the present invention.Example 15: (lr,2R,3S)-N-((64S,4S,Z)-12-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop- l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-15,16-dihydro-14H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(8,l)-pyrrolo[3,2,l-ij]quinolina-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide

[0433] Substituting tert-butyl (R)-4-(but-3-yn-2-yl)piperazine-l -carboxylate with (R)-4- (but-3-yn-2-yl)morpholine in the Step 24 of Example 148, the title compound was prepared by the same procedures as described for Example 148.

[0434] LCMS (ESI) calcd. for C49H59N7O6S[M+H]+m / z 873.42, found: 875.5. NMR (400 MHz, DMSO-tL) 5 8.77 (s, 1H), 8.41 (d, J= 8.7 Hz, 1H), 8.25 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.45 (s, 1H), 5.92 (d, J= 11.6 Hz, 1H), 5.39-5.29 (m, 2H), 4.67 (d, J= 10.7 Hz, 1H), 4.49-4.45 (m, 1H), 4.41-4.36 (m, 1H), 4.17 -4.11 (m, 1H), 3.66-3.49 (m, 7H), 3.24 (s, 3H), 3.11-2.84 (m, 6H), 2.67-2.59 (m, 2H), 2.43-2.37 (m, 1H), 2.35-2.10 (m, 5H), 2.01-1.92 (m, 2H), 1.57-1.51 (m, 1H), 1.45-1.34 (m, 4H), 1.17-1.03 (m, 7H), 0.91-0.79 (m, 4H), 0.37 (s, 3H).Example 21: (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7- diazaspiro[4.4]nonan-2-yl)-N-((7S,9S,15S)-21-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3- yl)-19,19-dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro- 12H,18H,23H-ll,15-epimino-3,7:12,14-dimethano-2,26- (metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)-3-methylbutanamideStep 1: Synthesis of (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2, 7- diazaspiro[ 4.4 ]nonan-2-yl)-N-((7S, 9S, 15S)-21-(2-( (S)-l -methoxyethyl)-5- ( triethylsilyl)ethynyl)pyridin-3-yl)-19, 19-dimethyl-l 0, 16-dioxo-4.5. 7.8.9.10.13.14.15.16.19.20.24.25 -tetradecahydro- 12H, 18H, 23H-11, 15-epimino-3, 7: 12, 14- dimethano-2, 26-(metheno) [ 1,12 ]dioxa[ 4,18 ]diazacyclodocosino[ 7, 8-a ]indolizin-9-yl)-3- methylbutanamide

[0435] A mixture of 5-((7S,9S,15S)-9-((S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l- methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-3-methylbutanamido)-19,19- dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H,18H,23H- [ll,15]epimino[3,7: 12,14]dimethano[2,26](metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8- a]indolizin-21-yl)-6-((S)-l-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (30 mg, 0.026 mmol), triethyl(ethynyl)silane (19 mg, 0.13 mmol), Cui (2 mg, 0.0011 mmol) and Pd(PPh3)4(6 mg, 0.0053 mmol) and TEA (8 mg, 0.079 mmol) in DMF (1.5 mL) was stirred at 100°C for 1 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column (eluting with DCM / MeOH from 0% to 10%) to give (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l- methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-((7S,9S,15S)-21-(2-((S)-l- methoxyethyl)-5-((triethylsilyl)ethynyl)pyri din-3 -yl)- 19, 19-dimethyl-10,16-di oxo-4.5.7.8.9.10.13.14.15.16.19.20.24.25-tetradecahydro-12H,18H,23H-ll,15-epimino-3,7:12,14- dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)-3- methylbutanamide (16 mg, 54.7%) as a brown oil.

[0436] LCMS (ESI) calcd. for C64H91N9O7 [M+H]+ m / z 1126.7, found: 1127.8.Step 2: Synthesis of (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2, 7- diazaspiro[ 4.4 ]nonan-2-yl)-N-((7S, 9S, 15S)-2 l-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)- 19, 19 -dime thy l-l 0, 16-dioxo-4,5, 7,8,9,10, 13, 14, 15, 16, 19,20,24,25-tetradecahydro- 12H, 18H, 23H-11, 15-epimino-3, 7:12, 14-dimethano-2, 26- (metheno)[ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-9-yl)-3-methylbutanamide

[0437] To a stirred solution of (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2- carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-((7S,9S,15S)-21-(2-((S)-l-methoxyethyl)-5- ((triethylsilyl)ethynyl)pyri din-3 -yl)- 19,19-dimethyl- 10,16-dioxo-4.5.7.8.9.10.13.14.15.16.19.20.24.25-tetradecahydro-12H,18H,23H-ll,15-epimino-3,7:12,14- dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)-3- methylbutanamide (15 mg, 0.013 mmol) in THF (0.5 mL) was added TBAF (IM, 0.04 mL, 0.04 mmol), the resulting mixture was stirred at rt for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the residue which 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-l-methylaziridine-2-carbonyl)-2,7- diazaspiro[4.4]nonan-2-yl)-N-((7S,9S,l 5S)-21-(5-ethynyl-2-((S)-l -methoxy ethyl)pyridin-3- yl)-19,19-dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H, 18H,23H- 11 , 15 -epimino-3 ,7 : 12, 14-dimethano-2,26- (metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)-3-methylbutanamide (2.1 mg) as a white solid.

[0438] LCMS (ESI) calcd. for C58H77N9O7 [M+H]+ m / z 1012.6, found: 1012.5.Example 22: (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7- diazaspiro[4.4]nonan-2-yl)-N-((7S,9S,15S)-21-(2-((S)-l-methoxyethyl)-5-(3- morpholinoprop-l-yn-l-yl)pyridin-3-yl)-19,19-dimethyl-10,16-dioxo-4.5.7.8.9.10.13.14.15.16.19.20.24.25-tetradecahydro-12H,18H,23H-ll,15-epimino- 3,7:12,14-dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin- 9-yl)-3-methylbutanamideStep 1: Synthesis of methyl (S)-3-((S)-4-(l-(3-acetoxy-2,2-dimethylpropyl)-2-(5-(benzyloxy)-2- ((S)-l-methoxyethyl)pyridin-3-yl)-5, 6-dihydro-4H-pyrrolo [ 3, 2, l-ij]quinolin-8-yl)morpholin-2- yl)-2-( ( tert-butoxycarbonyl)amino)propanoate

[0439] To a stirred solution of (S)-3-(2-(5-(benzyloxy)-2-(l-methoxyethyl)pyridin-3-yl)- 8-bromo-5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-l-yl)-2,2-dimethylpropyl acetate (2.5 g, 4.14 mmol), methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-morpholin-2-yl)propanoate (1.4 g, 4.97 mmol) and CS2CO3 (4.1 g, 12.42 mmol) in 1,4-dioxane (75 mL) were added Ruphos Pd G3(346 mg, 0.41 mmol) and Ruphos (387 mg, 0.83 mmol) at rt, the reaction mixture was stirred at 100 °C under N2 for 16 h. After completion, the reaction solution was concentrated under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 70%) to afford methyl (S)-3-((S)-4-(l-(3-acetoxy-2,2- dimethylpropyl)-2-(5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-5,6-dihydro-4H- pyrrolo[3,2,l-ij]quinolin-8-yl)morpholin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (1.9 g, 58.0 %) as a yellow foam.

[0440] LCMS (ESI) calcd. for C46H60N4O9 [M+H]+m / z 813.4, found: 814.4.Step 2: Synthesis of (S)-3-((S)-4-(2-(5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(3- hydroxy-2, 2 -dimethylpropyl) -5, 6-dihydro-4H-pyrrolo[ 3, 2, l-ij]quinolin-8-yl)morpholin-2-yl)-2- ( tert-butoxycarbonyl)amino)propanoic acid

[0441] To a solution of methyl (S)-3-((S)-4-(l-(3-acetoxy-2,2-dimethylpropyl)-2-(5- (benzyloxy)-2-((S)-l -methoxy ethyl)pyridin-3-yl)-5,6-dihydro-4H-pyrrolo[3, 2,1 -ij]quinolin-8- yl)morpholin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (1.9 g, 2.40 mmol) in THF (15mL), MeOH (5 mL) and H2O (10 mL) was added LiOH (504 mg, 12.00 mmol) at 0-10 °C, the resulting mixture was stirred at rt for 4h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the residue. The residue was diluted with H2O (30 mL) and acidified to pH = 4-5 with 2 N HC1. The resulting mixture was extracted with EtOAc (25 mL x 2), the combined organic phase was washed with saturated NaCl (50 mL), then dried over Na2SO4 and concentrated to give crude (S)-3-((S)-4-(2-(5-(benzyloxy)-2- ((S)-l-methoxyethyl)pyridin-3-yl)-l-(3-hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H- pyrrolo[3,2,l-ij]quinolin-8-yl)morpholin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.7 g) as a brown foam.

[0442] LCMS (ESI) calcd. for C43H56N4O8 [M+H]+m / z 757.4, found: 758.3.Step 3: Synthesis of methyl (S)-2-((S)-3-((S)-4-(2-(5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-( 3-hydroxy-2, 2-dimethylpropyl)-5, 6-dihydro-4H-pyrrolo[ 3, 2, l-ij]quinolin-8- yl)morpholin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo [3.1.1 ]heptane-4-carboxylate

[0443] To a solution of crude (S)-3-((S)-4-(2-(5-(benzyloxy)-2-((S)-l- methoxyethyl)pyridin-3-yl)-l-(3-hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H-pyrrolo[3,2,l- ij]quinolin-8-yl)morpholin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.7 g, 2.30 mmol) and methyl (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (575 mg, 2.53 mmol) in DMF (25 mL) were added DIEA (1.5 g, 11.51 mmol) and HATU (1.3 g, 3.46 mmol) at rt. The resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction was diluted with H2O (250 mL x 3) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with brinr (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 100%) to afford methyl (S)-2-((S)-3-((S)-4-(2- (5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(3-hydroxy-2,2-dimethylpropyl)-5,6- dihydro-4H-pyrrolo[3,2,l-ij]quinolin-8-yl)morpholin-2-yl)-2-((tert- butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (1.8 g, 89.0 %) as a yellow foam.

[0444] LCMS (ESI) calcd. for CsoHeeNeCh [M+H]+m / z 895.5, found: 896.6.Step 4: Synthesis of (S)-2-((S)-3-((S)-4-(2-(5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)- l-( 3-hydroxy-2, 2 -dimethylpropyl) -5, 6-dihydro-4H-pyrrolo[ 3, 2, l-ij]quinolin-8-yl)morpholin-2- yl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2, 3-diazabicyclo[ 3.1.1 ]heptane-4-carboxylic acid

[0445] To a solution of methyl (S)-2-((S)-3-((S)-4-(2-(5-(benzyloxy)-2-((S)-l- methoxyethyl)pyridin-3-yl)-l-(3-hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H-pyrrolo[3,2,l- ij]quinolin-8-yl)morpholin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (1.8 g, 2.04 mmol) in THF (18 mL) and H2O (9 mL) was added LiOH-ILO (256 mg, 6.11 mmol) at 0-10 °C, 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 residue. The residue was diluted with H2O (50 mL) and acidified to pH = 4-5 with 2 N HC1. The resulting mixture 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 crude (S)-2-((S)-3-((S)-4-(2-(5-(benzyloxy)-2-((S)-l- methoxyethyl)pyridin-3-yl)-l-(3-hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H-pyrrolo[3,2,l- ij]quinolin-8-yl)morpholin-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylic acid (1.7 g, 98.6%) as a yellow foam.

[0446] LCMS (ESI) calcd. for C49H64N6O9 [M+H]+m / z 881.5, found: 882.3.Step 5: Synthesis of tert-butyl ((7S,9S, 15S)-2 l-(5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3- yl)-19, 19-dimethyl-10,16-dioxo-4,5, 7,8,9, 10, 13, 14, 15,16, 19,20,24,25-tetradecahydro- 12H, 18H, 23H-11, 15-epimino-3, 7:12, 14-dimethano-2, 26- (metheno)[ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-9-yl)carbamate

[0447] To a solution of TCFH (2.0 g, 7.04 mmol) in CH3CN (60 mL) was added a solution of crude (S)-2-((S)-3-((S)-4-(2-(5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(3- hydroxy-2,2-dimethylpropyl)-5,6-dihydro-4H-pyrrolo[3,2,l-ij]quinolin-8-yl)morpholin-2-yl)- 2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1 ]heptane-4-carboxylic acid (1.6 g, 1.76 mmol) and NMI (1.2 g, 14.01 mmol) in CH3CN (100 mL) at rt. The reaction mixture was stirred at rt for 1 h. The reaction was monitored by LCMS. After completion, the reaction was concentrated under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 65%) to afford (700 mg, 46.0 %) as a white foam.

[0448] LCMS (ESI) calcd. for C49H62N6O8 [M+H]+m / z 863.5, found: 864.3.Step 6: Synthesis of tert-butyl ((7S,9S,15S)-21-(5-hydroxy-2-((S)-l-methoxyethyl)pyridin-3-yl)- 19, 19 -dime thy l-l 0, 16-dioxo-4,5, 7,8,9,10, 13, 14, 15, 16, 19,20,24,25-tetradecahydro- 12H, 18H, 23H-11, 15-epimino-3, 7:12, 14-dimethano-2, 26- (metheno)[ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-9-yl)carbamate

[0449] To a stirred solution of tert-butyl ((7S,9S,15S)-21-(5-(benzyloxy)-2-((S)-l- methoxyethyl)pyridin-3-yl)-19,19-dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25- tetradecahy dro- 12H, 18H,23H- 11,15 -epimino-3 ,7 : 12, 14-dimethano-2,26- (metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)carbamate (700 g, 0.81 mmol) in IPA (15 mL) was added Pd(OH)2 / C (10%, 100 mg) at rt , the resulting mixture was stirred at 85 °C for 17 h. The reaction was monitored by LCMS. After completion, the reaction mixture was filtered and the filtrate was concentrated to give crude tert-butyl ((7S,9S,15S)-21 -(5-hydroxy-2-((S)- 1 -methoxy ethyl)pyri din-3 -yl)- 19,19-dimethyl- 10,16-dioxo-4.5.7.8.9.10.13.14.15.16.19.20.24.25-tetradecahydro-12H,18H,23H-ll,15-epimino-3,7:12,14- dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9- yl)carbamate (654 mg) as a pale yellow foam.

[0450] LCMS (ESI) calcd. for C42H56N6O8[M+H]+m / z 773.4, found: 774.3.Step 7: Synthesis of 5-((7S,9S, 15S)-9-((tert-butoxycarbonyl)amino)-19, 19 -dimethyl- 10, 16- dioxo-4, 5, 7, 8, 9, 10,13,14, 15,16, 19,20, 24, 25-tetradecahydro-12H, 18H, 23H-11, 15-epimino- 3, 7: 12, 14-dimethano-2, 26-(metheno) [ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-21- yl)-6-( (S)-l-methoxyethyl)pyridin-3-yl trifluoromethanesulfonate

[0451] To a solution of crude tert-butyl ((7S,9S,15S)-21-(5-hydroxy-2-((S)-l- methoxyethyl)pyridin-3-yl)-19,19-dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25- tetradecahy dro- 12H, 18H,23H- 11,15 -epimino-3 ,7 : 12, 14-dimethano-2,26- (metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)carbamate (654 mg, 0.85 mmol) in DCM (12 mL) were added DIEA (219 mg, 1.69 mmol) and PhN(Tf)2 (302 mg, 0.85 mmol) at 0-10 °C. 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 65%) to afford 5-((7S,9S,15S)-9-((tert-butoxycarbonyl)amino)-19,19-dimethyl-10,16- dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H,18H,23H-ll,15-epimino- 3,7: 12,14-dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-21- yl)-6-((S)- 1-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (576 mg, 75.0 %) as a pale brown foam.

[0452] LCMS (ESI) calcd. for C43H55F3N6O10S [M+H]+m / z 905.4, found: 906.3.Step 8: Synthesis of 5-((7S,9S,15S)-9-amino-19,19-dimethyl-10,16-dioxo-4.5. 7.8.9.10.13.14.15.16.19.20.24.25 -tetradecahydro- 12H, 18H, 23H-11, 15-epimino-3, 7: 12, 14- dimethano-2, 26-(metheno) [ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-21-yl)-6-( (S)- l-methoxyethyl)pyridin-3-yl trifluoromethanesulfonate

[0453] To a solution of crude 5-((7S,9S,15S)-9-((tert-butoxycarbonyl)amino)-19,19- dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H,18H,23H- ll,15-epimino-3,7: 12,14-dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8- a]indolizin-21-yl)-6-((S)- 1-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (280 mg, 0.31 mmol) in DCM (3 mL) were added TFA (1 mL) at rt. The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (20 mL) and basified with sat. aq. NaHCCL to pH = 7-8. The organic layer was separated, dried over anhydrous Na2SO4and concentrated to give crude 5-((7S,9S,15S)-9-amino-19,19-dimethyl-10,16-dioxo-4.5.7.8.9.10.13.14.15.16.19.20.24.25-tetradecahydro-12H,18H,23H-ll,15-epimino-3,7: 12,14-dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-21-yl)-6-((S)- 1-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (240 mg, 96.3%) as a yellow foam.

[0454] LCMS (ESI) calcd. for CssIL FsNeOsS [M+H]+m / z 805.3, found: 805.9.Step 9: Synthesis of tert-butyl (5S)-7-((2S)-l-(((7S,9S,15S)-21-(2-((S)-l-methoxyethyl)-5- (((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)-19,19-dimethyl-10,16-dioxo-4.5. 7.8.9.10.13.14.15.16.19.20.24.25 -tetradecahydro- 12H, 18H, 23H-11, 15-epimino-3, 7: 12, 14- dimethano-2, 26-(metheno) [ 1,12 ]dioxa[ 4,18 ]diazacyclodocosino[ 7, 8-a [indolizin-9-yl) amino) - 3-methyl-l-oxobutan-2-yl)-2, 7 -diazaspiro [ 4.4 [nonane-2-carboxylate

[0455] To a solution of (S)-2-((S)-7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)- 3 -methylbutanoic acid (139 mg, 0.43 mmol) in DMF (3 mL) were added HATU (216 mg, 0.57 mmol) and DIEA (185 mg, 1.43 mmol) at 0-10 °C. The resulting mixture was stirred at 0-10 °C for 10 min. Then 5-((7S,9S,15S)-9-amino-19,19-dimethyl-10,16-dioxo-4.5.7.8.9.10.13.14.15.16.19.20.24.25-tetradecahydro-12H,18H,23H-ll,15-epimino-3,7:12,14- dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-21-yl)-6-((S)- 1-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (240 mg, 0.30 mmol) in DMF (3 mL) 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 (5S)-7-((2S)-l-(((7S,9S,15S)-21-(2-((S)-l-methoxyethyl)-5- (((trifluoromethyl)sulfonyl)oxy)pyri din-3 -yl)- 19,19-dimethyl- 10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H,18H,23H-ll,15-epimino-3,7:12,14- dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)amino)-3- methyl-l-oxobutan-2-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (136 mg, 40.8 %) as a brown foam.

[0456] LCMS (ESI) calcd. for C55H75F3N8O11S [M+H]+m / z 1113.5, found: 1114.7.Step 10: Synthesis of 5-((7S,9S,15S)-19,19-dimethyl-9-((S)-3-methyl-2-((S)-2, 7- diazaspiro[ 4.4 ]nonan-2-yl)butanamido)-10,16-dioxo-4, 5, 7, 8,9, 10,13,14,15,16,19,20, 24,25- tetradecahydro-12H, 18H, 23H-[11,15 ]epimino[ 3, 7:12, 14 [dimethano [2 ,26] (metheno) [ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-21-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl trifluoromethane sulfonate

[0457] To a solution of crude tert-butyl (5S)-7-((2S)-l-(((7S,9S,15S)-21-(2-((S)-l- m ethoxy ethyl)-5-(((trifluoromethyl)sulfonyl)oxy)pyri din-3 -yl)- 19,19-dimethyl- 10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H,18H,23H-ll,15-epimino-3,7: 12,14- dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8-a]indolizin-9-yl)amino)-3-methyl-l-oxobutan-2-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (136 mg, 0.12 mmol) in DCM (2 mL) were added TFA (0.6 mL) at rt. The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (20 mL) and basified with sat. aq. NaHCOs to pH = 7-8. The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give crude 5-((7S,9S,15S)-19,19-dimethyl-9-((S)-3-methyl-2-((S)-2,7-diazaspiro[4.4]nonan-2- yl)butanamido)-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro- 12H,18H,23H-[11.15]epimino[3,7: 12,14]dimethano[2,26](metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8- a]indolizin-21-yl)-6-((S)-l-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (108 mg, 88.9%) as a yellow foam.

[0458] LCMS (ESI) calcd. for C50H67F3N8O9S [M+H]+m / z 1013.5, found: 1014.3.Step 11: Synthesis of 5-((7S,9S,15S)-9-((S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine- 2-carbonyl)-2, 7 -diazaspiro [4.4]nonan-2-yl)-3-methylbutanamido)-19, 19 -dime thy I- 10, 16- dioxo-4, 5, 7, 8, 9, 10,13,14, 15,16, 19,20, 24, 25 -tetradecahydro- 12H, 18H, 23H-[11.15 ]epimino[ 3, 7:12, 14 dimethano [2 ,26] (metheno) [ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-21-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl trifluoromethane sulfonate

[0459] To a solution of lithium (2R,3R)-3-cyclopropyl-l-methylaziridine-2-carboxylate (26 mg, 0.18 mmol) in DMF (2 mL) were added HATU (86 mg, 0.23 mmol) and DIEA (48 mg, 0.37 mmol) at 0-10 °C. The resulting mixture was stirred at 0-10 °C for 10 min. Then 5- ((7S,9S,15S)-19,19-dimethyl-9-((S)-3-methyl-2-((S)-2,7-diazaspiro[4.4]nonan-2- yl)butanamido)-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro- 12H,18H,23H-[11.15]epimino[3,7: 12,14]dimethano[2,26](metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8- a]indolizin-21-yl)-6-((S)-l-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (108 mg, 0.11 mmol) in DMF (2 mL) 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 20 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 DCM / MeOH from 0% to 10%) to afford 5-((7S,9S,15S)-9-((S)-2-((S)-7- ((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-3- methylbutanamido)-19,19-dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25- tetradecahydro- 12H, 18H,23H-[ll,15]epimino[3,7: 12,14]dimethano[2,26](metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8- a]indolizin-21-yl)-6-((S)-l-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (63 mg,52.4 %) as a yellow foam.

[0460] LCMS (ESI) calcd. for C57H76F3N9O10S [M+H]+m / z 1136.5, found: 1137.4.Step 12: Synthesis of (2S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2, 7- diazaspiro[ 4.4 ]nonan-2-yl)-N-((7S, 9S, 15S)-21-(2-( (S)-l -methoxy ethyl) -5 -( 3-morpholinoprop- l-yn-l-yl)pyridin-3-yl)-19, 19 -dime thy I- 10, 16-dioxo-4,5, 7,8,9, 10, 13, 14, 15, 16, 19,20,24,25- tetradecahydro-12H, 18H, 23H-11, 15-epimino-3, 7: 12, 14-dimethano-2,26-(metheno)[ 1, 12 ]dioxa[ 4, 18 ]diazacyclodocosino[7, 8-a]indolizin-9-yl)-3-methylbutanamide

[0461] A mixture of 5-((7S,9S,15S)-9-((S)-2-((S)-7-((2R,3R)-3-cyclopropyl-l- methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-3-methylbutanamido)-19,19- dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H,18H,23H- [ll,15]epimino[3,7: 12,14]dimethano[2,26](metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8- a]indolizin-21-yl)-6-((S)-l-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (32 mg, 0.028 mmol), 4-(prop-2-yn-l-yl)morpholine (7 mg, 0.056 mmol), Cui (2 mg, 0.0085 mmol) and Pd(PPh3)4 (5 mg, 0.0042 mmol) and TEA (9 mg, 0.085 mmol) in DMF (1.5 mL) was stirred at lOOoC 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 80% in 30 min) to give (2S)-2-((S)-7- ((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)-N- ((7 S, 9 S, 15 S)-21 -(2-((S)- 1 -methoxy ethyl)-5 -(3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -yl)-19,19- dimethyl-10,16-dioxo-4,5,7,8,9,10,13,14,15,16,19,20,24,25-tetradecahydro-12H,18H,23H- ll,15-epimino-3,7: 12,14-dimethano-2,26-(metheno)[l,12]dioxa[4,18]diazacyclodocosino[7,8- a]indolizin-9-yl)-3-methylbutanamide (8 mg) as a white solid.

[0462] LCMS (ESI) calcd. for C63H86NIO08[M+H]+ m / z 1111.7, found: 1112.4.^ NMR (400 MHz, DMSO-tL) 5 8.77 (s, 1H), 7.85 (s, 1H), 7.63 (d, J= 66.4 Hz, 2H), 6.93 (s, 1H), 6.78 (s, 1H), 6.35 (s, 1H), 5.42 (s, 2H), 4.53 (s, 1H), 4.30 (d, J= 7.2 Hz, 2H), 3.78 (s, 2H), 3.68 - 3.48 (m, 9H), 3.19 (dd, J= 21.9, 13.4 Hz, 3H), 2.98 (s, 3H), 2.86 (d, J= 19.7 Hz, 5H), 2.71 (d, J= 8.4 Hz, 2H), 2.63 (s, 2H), 2.45 (d, J= 8.6 Hz, 2H), 2.31 (s, 2H), 2.24 - 2.11 (m, 4H), 2.08 (dd, J= 20.3, 6.7 Hz, 4H), 1.87 (s, 3H), 1.79 - 1.55 (m, 4H), 1.37 (dd, J= 27.5, 4.9 Hz, 4H), 1.23 (s, 4H), 0.94 - 0.84 (m, 3H), 0.81 (dd, J= 12.5, 6.5 Hz, 3H), 0.72 (s, 1H), 0.68 - 0.48 (m, 6H), 0.29 (d, J= 7.2 Hz, 3H), 0.11 (s, 2H).Example 35: (2R,3S)-N-((64S,3S,4S,Z)-l2-((M)-2-((S)-l-methoxyethyl)-5-(3- morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6- azaspiro [3.3] heptan-6-yl)-l L(2-((tetrahydr o-2H-pyran-4-yl)oxy)ethyl)- 11H-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3- methyloxetane-2-carboxamideStep 1: Synthesis of tert-butyl (4R)-4-((4-bromothiazol-2-yl)(hydroxy)methyl)-2,2- dimethyloxazolidine-3-carboxylate

[0463] To a stirred solution of 2,4-dibromothiazole (2.67 g, 10.0 mmol) in THF (20 mL) was added i-PrMgBr (1 M in THF, 11 mL, 11 mmol) was added dropwise at -10 °C under N2 condition. The reaction mixture was stirred at -10 °C for 30 mins, then a solution of tert-butyl (4R)-4-((4-bromothiazol-2-yl)(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (2.29 g, 10.0 mmol) in THF (10 mL) was added dropwise at -10 °C under N2 condition. The reaction mixture was stirred at -10 °C for 30 mins. After completion, the reaction solution was quenched with water (50 mL). The resulting mixture was extracted with EtOAc, washed with brine, 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 20%) to give tert-butyl (4R)-4-((4-bromothiazol-2-yl)(hydroxy)methyl)-2,2-dimethyloxazolidine-3- carboxylate (2.85 g, 72% ) as a light yellow oil.

[0464] LCMS (ESI) calcd. for Ci4H2iBrN2O4S [M+H]+m / z 392.04, found: 293.4 [M+H- 100]+.Step 2: Synthesis of tert-butyl (R)-4-(4-bromothiazole-2-carbonyl)-2,2-dimethyloxazolidine-3- carboxylate

[0465] To a stirred solution of crude product tert-butyl (4R)-4-((4-bromothiazol-2- yl)(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (2.85 g, 7.25 mmol) in DCM (40 mL) was added DMP (6.15 g, 14.5 mmol) at 0 °C. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was washed with sat. Na2S2Ch aqueous, sat. Na2COs aqueous brine, dried and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl (R)-4-(4-bromothiazole-2-carbonyl)-2,2-dimethyloxazolidine-3-carboxylate (2.40 g, 85%) as a white solid.

[0466] LCMS (ESI) calcd. for CwHwBr^CUS [M+H]+m / z 390.02, found: 391.4.Step 3: Synthesis of tert-butyl (( 1R,2R)-1 -(4-bromothiazol-2-yl)-l , 3-dihydroxypropan-2- y I) carbamate

[0467] To a stirred solution of crude product tert-butyl (R)-4-(4-bromothiazole-2- carbonyl)-2,2-dimethyloxazolidine-3-carboxylate (2.40 g, 6.13 mmol) in THF (30 mL) was added DIBALH (9.2 mL, 9.20 mmol, IM in THF) by dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. After completion, the reaction solution was quenched with water and 1 M HC1 aqueous. The resulting mixture was extracted with EtOAc, washed with brine, then dried over Na2SO4, following with concentration under reduced pressure to give tert-butyl ((lR,2R)-l-(4-bromothiazol-2-yl)-l,3-dihydroxypropan-2-yl)carbamate (2.40 g, 100% ) as a colorless oil.

[0468] LCMS (ESI) calcd. for CwHwBr^CUS [M+H]+m / z 390.02, found: 391.4.Step 4: Synthesis of tert-butyl (( 1R,2R)-1 -(4-bromothiazol-2-yl)-l , 3-dihydroxypropan-2- y I) carbamate

[0469] To a stirred solution of tert-butyl ((lR,2R)-l-(4-bromothiazol-2-yl)-l,3- dihydroxypropan-2-yl)carbamate (2.40 g, 6.10 mmol) in MeOH (30 mL) was added TsOH (105 mg, 0.61 mmol). The reaction mixture was heated to 50 °C and stirred overnight. After completion, the reaction solution was concentrated under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 65%) to give tert-butyl ((lR,2R)-l-(4-bromothiazol-2-yl)-l,3-dihydroxypropan-2-yl)carbamate (1.30 g, 60% ) as a white solid.

[0470] LCMS (ESI) calcd. for CiiHi7BrN2O4S [M+H]+m / z 352.01, found: 297.2[M+H- 56]+.Step 5: Synthesis of (2R,3R)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3- hydroxypropyl acetate

[0471] To a stirred solution of tert-butyl ((lR,2R)-l-(4-bromothiazol-2-yl)-l,3- dihydroxypropan-2-yl)carbamate (18.6 g, 52.7 mmol) in DCM (300 mL) was added TEA (16.0 g, 158 mmol) and AcCl (4.96 g, 63.2 mmol) at 0 °C. The reaction mixture was warm to rt and stirred overnight. After completion, the reaction solution was concentrated under reducedpressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give (2R,3R)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3- hydroxypropyl acetate (13.5 g, 65%) as a white solid.

[0472] LCMS (ESI) calcd. for CnHwBr^OsS [M+H]+m / z 394.02, found: 339.3.Step 6: Synthesis of tert-butyl (4R,5R)-4-(acetoxymethyl)-5-(4-bromothiazol-2-yl)-l,2,3- oxathiazolidine-3-carboxylate 2-oxide

[0473] To a stirred solution of (2R,3R)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-hydroxypropyl acetate (13.5 g, 34.2 mmol) in DCM / CEECN (100 mL / 100 mL) was added SOCI2 (10.2 g, 85.4 mmol) was added dropwise at -40 °C under N2 condition. The reaction mixture was stirred at -40 °C for 10 mins, then pyridine (10.8 g, 136.8 mmol) was added dropwise at -40 °C under N2 condition. The reaction mixture was stirred at - 40 °C for 30 mins. After completion, the reaction solution was quenched with water (10 mL). The resulting mixture was extracted with EtOAc, washed with brine, then dried over Na2SO4, following with concentration under reduced pressure to obtain tert-butyl (4R,5R)-4- (acetoxymethyl)-5-(4-bromothiazol-2-yl)-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (15.0 g, 99%) as a light yellow oil.

[0474] LCMS (ESI) calcd. for Ci3Hi7BrN2O6S2 [M+H]+m / z 439.97, found: 385.3.Step 7: Synthesis of tert-butyl (4R,5R)-4-(acetoxymethyl)-5-(4-bromothiazol-2-yl)-l,2,3- oxathiazolidine-3-carboxylate 2, 2 -dioxide

[0475] To a stirred solution of tert-butyl (4R,5R)-4-(acetoxymethyl)-5-(4-bromothiazol-2- yl)-l,2,3-oxathiazolidine-3-carboxylate 2-oxide (15.0 g, 34.0 mmol) in CH3CN / H2O (150 mL / 150 mL) was added Ruthenium(III) Chloride Hydrate (383 mg, 1.70 mmol) and NaICU (8.73 g, 40.8 mmol) at 0 °C. The reaction mixture was warm to rt and stirred overnight. The mixture was extracted with EtOAc, washed with brine, 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 20%) to give tert-butyl (4R,5R)-4-(acetoxymethyl)-5- (4-bromothiazol-2-yl)- 1,2, 3 -oxathiazolidine-3 -carboxylate 2,2-dioxide (13.2 g, 85% ) as a white solid.

[0476] LCMS (ESI) calcd. for Ci3Hi7BrN2O7S2 [M+H]+m / z 455.97, found: 401.3.Step 8: Synthesis of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa- 6-azaspiro[3.3 ]heptan-6-yl)propyl acetate

[0477] To a stirred solution of tert-butyl (4R,5R)-4-(acetoxymethyl)-5-(4-bromothiazol-2- yl)-l,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (12.6 g, 27.6 mmol) in CH3CN (200 mL) was added 2-oxa-6-azaspiro[3.3]heptane (6.82 g, 68.9 mmol) at 0 °C under N2 condition. The reaction mixture was stirred at rt for 2 h, then the mixture was concentrated. The residue was dissolved in EtOAc (200 mL). To the mixture was added NaH7PO4 aqueous (100 mL). Thereaction mixture was heated to 60 °C and stirred at for 5 h. After completion, the resulting mixture was extracted with EtOAc, washed with brine, 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 40%) to give (2S,3S)-3-(4-bromothiazol-2-yl)-2- ((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl acetate (3.5 g, 27% ) as a white solid.

[0478] LCMS (ESI) calcd. for CisIMrNsOsS [M+H]+m / z 475.08, found: 476.5. Step 9: Synthesis of tert-butyl ((lS,2S)-l-(4-bromothiazol-2-yl)-3-hydroxy-l-(2-oxa-6- azaspiro[ 3.3 ]heptan-6-yl)propan-2-yl)carbamate

[0479] To a stirred solution of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propyl acetate (1.90 g, 4.00 mmol) in TElF / MeOEl / EhO (20 mL / 20 mL / 20 mL) was added KOH (560 mg, 10.0 mmol) at 0 °C and stirred 1 hour. The mixture was extracted with EtOAc, washed with brine, then dried over Na2SO4, following with concentration under reduced pressure to give tert-butyl ((1S,2S)- l-(4-bromothiazol-2-yl)-3-hydroxy-l-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-2- yl)carbamate (1.7 g, 98% ) as a white solid.

[0480] LCMS (ESI) calcd. for Ci6H24BrN3O4S [M+H]+m / z 433.07, found: 434.5.Step 10: Synthesis of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2- oxa-6-azaspiro[3.3 ]heptan-6-yl)propanoic acid

[0481] To a stirred solution of tert-butyl ((lS,2S)-l-(4-bromothiazol-2-yl)-3-hydroxy-l-(2- oxa-6-azaspiro[3.3]heptan-6-yl)propan-2-yl)carbamate (400 mg, 0.921 mmol) in acetone was added Jone’s reagents (0.8 mL) at 0 °C and stirred 2 hours. The mixture concentration under reduced pressure. The residue was purified by C18 (0.1% NH4HCO3 aqueous / CH3CN) to give (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)propanoic acid (200 mg, 48%) as a green solid.

[0482] LCMS (ESI) calcd. for Ci6H22BrN3O5S [M+H]+m / z 447.05, found: 448.4.Step 11: Synthesis of methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3 ]heptan-6-yl)propanoyl)-2, 3- diazabicyclo[ 3.1.1 ]heptane-4-carboxylate

[0483] To a solution of (2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3- (2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoic acid (1.86 g, 4.14 mmol) in DMF (15 mL) were added methyl (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate HC1 salt (1.18 g, 4.56 mmol), TEA (1.67 g, 16.6 mmol) and HATU (2.05 g, 5.37 mmol) at 0-10 °C. The resulting mixture was stirred at 0-10 °C for 1 h. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 30 mL), the combined organic phase was washed with brine (100 mL), then dried over Na2SO4, following with concentration under reduced pressure toobtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to 70% to afford methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate (1.45 g, 60%) as a white solid.

[0484] LCMS (ESI) calcd. for C23H32BrN5O6S [M+H]+m / z 585.13, found: 586.7.Step 12: Synthesis of methyl (S)-2-((2S,3S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-((M)-5- (benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propanoyl)-2, 3 -diazabicyclo [ 3.1.1 ]heptane-4-carboxylate

[0485] A mixture of 3-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l-(2- ((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- indol-3-yl)-2,2-dimethylpropyl acetate (500 mg, 0.676 mmol), K2CO3 (414 mg, 2.03 mmol) and Pd(dppf)C12 (50 mg, 0.068 mmol) in toluene (15 mL), dioxane (5 mL) and H2O (5 mL) was stirred at 90 °C under N2 for 5 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 10%) to give (S)-2-((2S,3S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-((M)-5- (benzyloxy)-2-((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)- 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (480 mg, 63 %) as a yellow solid.

[0486] LCMS (ESI) calcd. for C60H77N7O12S [M+H]+m / z 1119.54, found: 1122.0.Step 13: Synthesis of (S)-2-((2S,3S)-3-(4-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin- 3-yl)-3-(3-hydroxy-2,2-dimethylpropyl)-l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol- 5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propanoyl)-2, 3 -diazabicyclo [ 3.1.1 ]heptane-4-carboxylic acid

[0487] To a solution of (S)-2-((2S,3S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-((M)-5- (benzyloxy)-2-((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)- 1 -(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (520 mg, 0.464 mmol) in MeOH (10 mL), THF (5 mL) and H2O (5 mL) was added LiOH-ELO (97 mg, 2.32 mmol) at 0-10 °C, the resulting mixture was stirred at 0-10 °C for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 4-5 with 1 N HC1. The resulting mixture was extracted with EtOAc (15 mL x 2), the combined organic phase was washed with saturated NaCl (10 mL), then dried over Na2SO4 and concentrated to give the (S)-2-((2S,3S)-3- (4-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-3-(3-hydroxy-2,2- dimethylpropyl)-l-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-5-yl)thiazol-2-yl)-2- ((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (480 mg, 97%) as a white solid.

[0488] LCMS (ESI) calcd. for C57H73N7O11S [M+H]+m / z 1063.51, found: 1065.6.

[0489] To a solution of TCFH (300 mg, 1.07 mmol) in ACN (80 mL) was added a solution of (S)-2-((2S,3S)-3-(4-(2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)-3-(3- hydroxy-2, 2-dimethylpropyl)-l-(2-((tetrahy dro-2H-pyran-4-yl)oxy)ethyl)-lH-indol-5- yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (380 mg, 0.357 mmol) and NMI (146 mg, 1.78 mmol) in ACN (5 mL) at 0 °C, the reaction was gradually improved temperature to room temperature and stirred for 45 min. 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 100% to afford tert-butyl ((64S,3S,4S,Z)-l2-((M)-5-(benzyloxy)-2-((S)-l-methoxyethyl)pyridin-3-yl)- 10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (130 mg, 33%) as a white solid.

[0490] LCMS (ESI) calcd. for C57H71N7O10S [M+H]+m / z 1045.50, found: 1047.6.

[0491] To a stirred solution of tert-butyl ((64S,3S,4S,Z)-l2-((M)-5-(benzyloxy)-2-((S)-l- methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)- indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (130 mg, 0.124 mmol) in CH3OH (5 mL) was added Pd / C (30 mg, 10%). The reaction mixture was stirred at 50 °C under EE atmosphere (1 atm) overnight. After completion, the reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl ((64S,3S,4S,Z)-l2-((M)-5-hydroxy-2- ((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan- 6-yl)-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thi azola- l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (110 mg, 93%) as a white solid.

[0492] LCMS (ESI) calcd. for C50H65N7O10S [M+H]+m / z 955.45, found: 956.8.Step 16: Synthesis of (5M)-5-((64S,3S,4S,Z)-4-((tert-butoxycarbonyl)amino)-10,10-dimethyl- 5, 7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)~ l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[ 3.1.1 ]heptanacycloundecaphane-l2-yl)-6-( (S)-l-methoxyethyl)pyridin-3-yl trifluoromethane sulfonate

[0493] To a stirred solution of tert-butyl ((64S,3S,4S,Z)-l2-((M)-5-hydroxy-2-((S)-l- methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)- indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (110 mg, 0.115 mol) in DCM (5 mL) was added PhN(Tf)2 (41 mg, 0.115 mmol) and TEA (23 mg, 0.23 mmol) at 0 °C. The resulting mixture was stirred at rt under N2 for 2 h. The mixture was concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 100%) to give (5M)-5-((64S,3S,4S,Z)-4-((tert-butoxycarbonyl)amino)- 10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1 ]heptanacycloundecaphane- 12-yl)-6-((S)- 1 -m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (80 mg, 64 %) as a white solid.

[0494] LCMS (ESI) calcd. for C51H64F3N7O12S2 [M+H]+ m / z 1087.40, found: 1089.2.Step 17: Synthesis of tert-butyl ((64S,3S,4S,Z)-l2-((M)-2-((S)-l-methoxyethyl)-5-(3- morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-3-(2-oxa-6- azaspiro[ 3.3 heptan-6-yl)-!1-(2-( ( tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62, 63-diaza- 2(4, 2)-thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)carbamate

[0495] A mixture of (5M)-5-((64S,3S,4S,Z)-4-((tert-butoxycarbonyl)amino)-10,10- dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1 ]heptanacycloundecaphane- 12-yl)-6-((S)- 1 -m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (80 mg, 0.072 mmol), Cui (4 mg, 0.02 mmol), TEA (36 mg, 0.36 mmol) and Pd(PPh3)4 (8 mg, 0.0072 mmol) in DMF (3 mL) was stirred at 100°C for 4 hours 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 MeOH / DCM from 0% to 10%) to give tert-butyl ((64S,3S,4S,Z)-l2-((M)-2-((S)- 1 -m ethoxy ethyl)-5 -(3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo-3-(2- oxa-6-azaspiro[3.3]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4- yl)carbamate (60 mg, 78 %) as a white solid.

[0496] LCMS (ESI) calcd. for C57H74N8OIOS[M+H]+m / z 1062.52, found: 1063.9.Step 18: Synthesis of (64S,3S,4S,Z)-4-amino-l2-((M)-2-((S)-l-methoxyethyl)-5-(3- morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)- l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)~ indola-6(2, 4)-bicyclo[ 3.1.1 ]heptanacycloundecaphane-5, 7 -dione

[0497] To a stirred solution of tert-butyl ((64S,3S,4S,Z)-l2-((M)-2-((S)-l-methoxyethyl)-5- (3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -y 1 ) - 10 , 10-dimethyl-5 , 7-dioxo-3 -(2-oxa-6- azaspiro[3.3]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (60 mg, 0.056 mmol) in dichloromethane (3 mL) was added TFA (1 mL) drop wisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated. The residue was dissolved in EtOAc (10 mL) The mixture was washed with sat.NaHCCL aqueous (2 mL), brine, dried and concentrated to give (64S,3S,4S,Z)-4-amino-l2-((M)-2-((S)-l-methoxyethyl)-5-(3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-3 -(2-oxa-6-azaspiro[3.3 ]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thi azola- ^S, 3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacy cl oundecaphane-5, 7-dione (45 mg, 83%) as a white solid.

[0498] LCMS (ESI) calcd. for C52H66N8O8S[M+H]+m / z 962.47, found: 963.9.Step 19: Synthesis of (2S,3S)-N-((64S,3S,4S,Z)-l2-((M)-2-((S)-l-methoxyethyl)-5-(3- morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-3-(2-oxa-6- azaspiro[ 3.3 heptan-6-yl)-!1-(2-( ( tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62, 63-diaza- 2(4, 2)-thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-3- methyloxetane-2-carboxamide

[0499] To a stirred solution of (64S,3S,4S,Z)-4-amino-l2-((M)-2-((S)-l-methoxyethyl)-5- (3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -yl)- 10, 10-dimethyl-3 -(2-oxa-6-azaspiro[3.3]heptan-6- yl)-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)- indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5, 7-dione (35 mg, 0.036 mmol) and (2S,3S)-3-methyloxetane-2-carboxylic acid (8 mg, 0.073 mmol) and TEA (11 mg, 0.11 mmol) in DMF (1.5 mL) was added HATU (21 mg, 0.34 mmol) at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was purified by pre-HPLC (ACN / HjO (0.5 % NH4HCO3) from 20% to 95% in 30 min) to give (2S,3S)-N-((64S,3S,4S,Z)-l2-((M)-2-((S)-l- methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2- oxa-6-azaspiro[3.3]heptan-6-yl)-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3- methyloxetane-2-carboxamide (14 mg, 23%) as a white solid.

[0500] LCMS (ESI) calcd. for C57H72N8OioS[M+H]+m / z 1060.51, found: 1062.6.1H NMR (400 MHz, DMSO-tL) 5 8.77 (s, 1H), 8.43 (s, 1H), 8.04 (d, J= 8.1 Hz, 1H), 7.93 (s, 1H), 7.77-7.67 (m, 2H), 7.59 (d, J= 8.6 Hz, 1H), 6.01 (d, J= 10.4 Hz, 1H), 5.26 (d, J= 8.1 Hz, 1H), 5.02 (d, J= 8.6 Hz, 1H), 4.86-4.77 (m, 2H), 4.60-4.51 (m, 4H), 4.48-4.44 (m, 1H), 4.27-4.10 (m, 4H), 3.65-3.43 (m, 11H), 3.39-3.34 (m, 2H), 3.24 (s, 5H), 3.15 -3.02 (m, 3H), 2.96-2.94 (s, 2H), 2.69-2.63 (m, 1H), 2.50 (s, 3H), 2.41-2.30 (m, 3H), 2.22-2.14 (m, 1H), 1.87 (t, J= 10.3 Hz, 1H), 1.56-1.52 (m, 1H), 1.45-1.42 (m, 1H), 1.34 (d, J= 5.9 Hz, 3H), 1.16-0.96 (m, 5H), 0.91 (s, 3H), 0.28 (s, 3H).Example 36: (2S,3S)-N-((64S,3S,4S,Z)-12-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop- l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5,7-dioxo-ll-(2-((tetrahydro-2H- pyran-4-yl)oxy)ethyl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamide

[0501] Substituting methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate with methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)- 2-((tert-butoxycarbonyl)amino)-3-morpholinopropanoyl)-2,3-diazabicyclo[3.1.1]heptane-4- carboxylate in the Step 12 of Example 35, the title compound was prepared by the same procedures as described for Example 35.

[0502] LCMS (ESI) calcd. for C56H72N8OIOS[M+H]+m / z 1048.51, found: 1050.5.^ NMR (400 MHz, DMSO-t / e) 5 8.77 (s, 1H), 8.35 (s, 1H), 8.19 (d, J= 8.8 Hz, 1H), 7.94 (s, 1H), 7.77- 7.68 (m, 2H), 7.59 (d, J= 8.9 Hz, 1H), 5.99 (d, J= 11.0 Hz, 1H), 5.46 (br s, 1H), 5.06 (d, J= 8.8 Hz, 1H), 4.86-4.79 (m, 1H), 4.61-4.48 (m, 2H), 4.44 (d, J= 15.1 Hz, 1H), 4.25-4.01 (m, 4H), 3.65-3.50 (m, 11H), 3.45-3.32 (m, 3H), 3.25-3.04 (m, 6H), 2.97-2.87 (m, 1H), 2.78-2.69 (m, 2H), 2.60-2.55 (m,lH), 2.51 (s, 4H), 2.44-2.40 (m, 4H), 2.34-2.21 (m, 3H), 2.17-2.10 (m, 1H), 1.60-1.45 (m, 3H), 1.34 (d, J= 6.0 Hz, 3H), 1.09-0.87 (m, 5H), 0.87 (s, 3H), 0.34 (s, 3H).Example 40: ( 1 R.2S.3R)-\-((64S.3S.4S.Z)-l l-ethyl-12-((R)-2-((S)-l- methoxyethyl)-5- ((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2-methyl-3-(pyridin-4-yl)cyclopropane-l- carboxamideStep 1: General procedure for preparation of compound (lR,2S,3R)-N-((64S,3S,4S,Z)-ll-ethyl -12-((R)-2-((S)-l-methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10- dimethyl-5, 7-dioxo-3-(2-oxa-6-azaspiro[ 3.3 ]heptan-6-yl)-HH-8-oxa-62, 63-diaza-2(4,2)- thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2-methyl-3- (pyridin-4-yl) cyclopropane- 1 -carboxamide

[0503] To a solution of (64S,3S,4S,Z)-4-amino-ll-ethyl-12-((R)-2-((S)-l-methoxyethyl) - 5 -((R)-3 -morpholinobut- 1 -yn- 1 -yl)pyri din-3 -y 1 ) - 10 , 10-dimethyl-3 -(2-oxa-6- azaspiro[3.3]heptan-6-yl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-5, 7-dione (1) (60 mg, 0.068 mmol, 1 eq and (lR,2S,3R)-2-methyl-3-(pyridin-4-yl)cyclopropane-l-carboxylic acid (12 mg, 0.068 mmol, 1 eq) in CH3CN (3 mL) was added NMI (11 mg, 0.137 mmol, 2 eq and TCFH (23 mg, 0.082 mmol, 1.2 eq at 0 °C, the resulting mixture was stirred at 25 °C for 0.5 h. LCMS showed that the reaction was complete. The reaction mixture was diluted with water (20 mL) and it was extracted with EtOAc (20 mL x3). The combined organic layer was washed with brine (20 mL) and dried over Na2SO4, filtered. The filtrate was concentrated in vacuo to give the crude product. It was purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [H2O (lOmM NH4HCO3)-ACN]; gradient: 45%-75% B over 11.0 min) to give the desired product (30 mg, 93.2% purity). Then it was further purified by prep-HPLC (column: Welch Xtimate C18 150*25mm*5um;mobile phase: [H2O (0.225% FA)-ACN];gradient: 20%- 40% B over 12.0 min) to give (lR,2S,3R)-N-((64S,3S,4S,Z)-ll-ethyl-12-((R)-2-((S)-l- methoxyethyl)-5-((R)-3 -morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo-3 - (2-oxa-6-azaspiro[3.3]heptan-6-yl)-llH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2-methyl-3-(pyridin-4-yl)cyclopropane- 1-carboxamide (22.53 mg, 31.78% yield) as a white solid.

[0504] LCMS: calcd. for C58H69N9O7S [M+H]+m / z: 1035.5, found: 1036.3.HPLC: (Purity: 100%). SFC: (Rt = 1.426 min, ee: 98.72%).XH NMR: (400 MHz, CHLOROFORM^ / ) 5 : 8.81 (d, J= 2.0 Hz, 1H), 8.55-8.70 (m, 2H), 7.60-7.65 (m, 2H), 7.44 (s, 1H), 7.39 (d, J= 8.4 Hz, 1H), 7.15-7.20 (m, 1H), 7.05-7.10 (m, 2H), 5.60-5.65 (m, 1H), 5.37 (d, J= 6.8 Hz, 1H), 4.70- 4.90 (m, 6H), 4.30-4.40 (m, 1H), 4.20-4.28 (m, 2H), 4.00-4.10 (m, 1H), 3.70-3.90 (m, 9H),3.40-3.50 (m, 5H), 3.15-3.25 (m, 1H), 2.80-2.90 (m, 2H), 2.55-2.75 (m, 5H), 2.40-2.50 (m, 2H), 2.15-2.20 (m, 1H), 2.00-2.10 (m, 1H), 2.70-2.80 (m, 3H), 1.50-1.60 (m, 3H), 1.46 (d, J= 6.0 Hz, 3H), 0.90-1.10 (m, 9H), 0.42 (s, 3H).Example 41: (2S,3S)-N-((64S,3S,4S,Z)-ll-ethyl-12-((R)-2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamideStep 1: General procedure for preparation of 3-(5-bromo-l-ethyl-2-((R)-2-((S)-l-methoxyethyl) pyridin-3-yl)-lH-indol-3-yl)-2, 2 -dimethylpropyl acetate

[0505] To a solution of (S)-3-(5-bromo-2-(2-(l-methoxyethyl)pyridin-3-yl)-lH-indol-3-yl) -2,2-dimethylpropyl acetate (7.4 g, 16.11 mmol, 1 eq) in DMF (100 mL) was added CS2CO3 (10.50 g, 32.22 mmol, 2 eq) and EtI (3.77 g, 24.16 mmol, 1.93 mL, 1.5 eq). The mixture was stirred at 25 °C for 16 h. LCMS showed the starting material was consumed completely and ~ 41+40% of desired compound was found. TLC (n-hexane: EtOAc = 1 : 1, 12, Pl Rf = 0.45, P2 Rf = 0.40) indicated two new spots formed. The reaction mixture was combined with this batch and worked up together. The reaction mixture was diluted with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (600 mL), dried over Na2SO4, filter and concentrated under reduced pressure to give a residue. It waspurified by column chromatography (SiCh, Commercial hexanes: Ethyl acetate = 1 / 0 to 7 / 3) to provide 3 -(5-bromo- 1 -ethyl-2-((R)-2-((S)- 1 -methoxy ethyl) pyri din-3 -yl)- lH-indol-3 -yl)-2,2- dimethylpropyl acetate (3.1 g, 37.51% yield) as a yellow solid and 3-(5-bromo-l-ethyl-2-((S)- 2-((S)-l -methoxy ethyl) pyridin-3-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (5.6 g, 42.79% yield) as an orange solid.

[0506] LCMS: calcd. for C25H3iBrN2O3[M+H]+m / z: 486.2, found: 489.2.^ NMR: (400 MHz, CHLOROFORMS) 5: 8.83 (dd, J= 4.8, 1.6 Hz, 1H), 7.79 (d, J= 1.6 Hz, 1H), 7.68 (dd, J= 7.6, 2.0 Hz, 1H), 7.32-7.39 (m, 2H), 7.23-7.27 (m, 1H), 4.08-4.15 (m, 1H), 3.93-4.03 (m, 1H), 3.80-3.91 (m, 1H), 3.58-3.70 (m, 2H), 3.05 (s, 3H), 2.72 (d, J= 14.4 Hz, 1H), 2.32 (d, J= 14.4 Hz, 1H), 1.99 (s, 3H), 1.49 (d, J= 6.0 Hz, 3H), 1.20 (t, J= 6.8 Hz, 3H) 0.81 (d, J= 18.8 Hz, 6H).Step 2: General procedure for preparation of ((R)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-5- bromo-l-ethyl-lH-indol-2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)boronic acid

[0507] To a stirred solution of 3-(5-bromo-l-ethyl-2-((R)-2-((S)-l-methoxyethyl)pyridin-3- yl) -lH-indol-3-yl)-2,2-dimethylpropyl acetate (3.10 g, 6.36 mmol, 1 eq.) and fhPi (2.42 g, 9.54 mmol, 1.5 eq) in THF (50 mL) was added dtbpy (256 mg, 0.954 mmol, 0.15 eq.) and chloroiridium; (lZ,5Z)-cycloocta-l,5-diene (213.6 mg, 0.318 mmol, 0.05 eq.) in portions at 25 °C under N2. The resulting mixture was stirred at 75 °C for 16 h. LCMS showed the Reactant was consumed and -65% of desired compound was detected. TLC (DCM: MeOH = 9: 1, 12, Rf = 0.44) indicated two new spots formed. The reaction mixture was concentrated under reduced pressure to give a residue. It was purified by column chromatography (SiCh, DCM: MeOH = 1 / 0 to 19 / 1) to give ((R)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-l- ethyl-lH-indol-2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)boronic acid (4.3 g, 89.09% yield) as an orange solid.

[0508] LCMS: calcd. for C25H32BBrN2O5[M+H]+m / z: 530.2, found: SS U^H NMR: (400 MHz, CHLOROFORMS) 5: 9.11 (d, J= 1.6 Hz, 1H), 8.03 (d, J= 1.6 Hz, 1H), 7.78 (d, J= 1.6 Hz, 1H), 7.30-7.35 (m, 1H), 7.21-7.26 (m, 1H), 4.68 (s, 2H), 4.10-4.15 (m, 1H), 3.92-4.01 (m, 1H), 3.82-3.91 (m, 1H), 3.65 (d, J= 7.2Hz, 2H), 3.06 (s, 3H), 2.70 (d, J= 14.0 Hz, 1H), 2.31 (d, J= 14.4 Hz, 1H), 1.96 (s, 3H), 1.48 (d, J= 6.4 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H), 0.79 (d, J = 19.2 Hz, 6H).Step 3: General procedure for preparation of 3-(5-bromo-l-ethyl-2-((R)-5-iodo-2-((S)-l- methoxyethyl)pyridin-3-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate

[0509] To a stirred solution of ((R)-5 -(3 -(3 -acetoxy -2, 2-dimethylpropyl)-5 -bromo- 1 -ethyl - lH-indol-2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)boronic acid (3.30 g, 6.21 mmol, 1 eq) and chloroamine-T (17.50 g, 62.12 mmol, 10 eq) in THF (40 mL) was added a solution of Nal (9.31 g, 62.12 mmol, 10 eq) in water (20 mL) in portions at 0 °C under an air atmosphere. Theresulting mixture was stirred at 50 °C for 16 h under an argon atmosphere. LCMS showed Reactant was consumed completely and -9% of desired compound was detected. TLC (n- hexane: EtOAc = 4: 1, UV, Pl Rf = 0.25) indicated many new spots formed. The reaction mixture was combined with this batch and worked up together. The resulting mixture was concentrated under reduced pressure to remove THF and then diluted with Na2S2O3(300 mL), extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (600 mL) and dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, Commercial hexanes: Ethyl acetate = 1 / 0 to 17 / 3) to give 3-(5-bromo-l-ethyl-2-((R)-5-iodo-2-((S)-l- methoxyethyl)pyridin-3-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (1.75 g, 41.34% yield) as a light-yellow solid.

[0510] LCMS: calcd. for C25H3oBrIN203[M+H]+m / z: 612.1, found: eiS.l^H NMR: (400 MHz, CHLOROFORM-tZ) 5: 9.00 (d, J= 2.0 Hz, 1 H), 7.98-8.05 (m, 1 H), 7.79 (d, J= 2.0 Hz, 1 H) 7.33-7.39 (m, 1 H), 7.23-7.26 (m, 1 H), 3.86-4.10 (m, 3 H), 3.61-3.73 (m, 2 H), 3.06 (s, 3 H), 2.72 (d, J= 14.4 Hz, 1 H), 2.30 (d, J= 14.4 Hz, 1 H), 2.02 (s, 3 H), 1.46 (d, J= 6.0 Hz, 3 H) 1.21 (t, J= 7.2 Hz, 3 H) 0.82 (d, J= 15.6 Hz, 6 H).Step 4: General procedure for preparation of 3-(5-bromo-l-ethyl-2-((R)-2-((S)-l- methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-lH-indol-3-yl)-2,2- dimethylpropyl acetate

[0511] To a solution of (R)-4-(but-3-yn-2-yl)morpholine (297.87 mg, 2.14 mmol, 1.05 eq) in DMSO (15 mL) was added (S)-3-(5-bromo-l-ethyl-2-(5-iodo-2-(l-methoxyethyl)pyridin-3- yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (1.25 g, 2.04 mmol, 1 eq), Cui (77.63 mg, 407.61 pmol, 0.2 eq), TEA (2.06 g, 20.38 mmol, 2.84 mL, 10 eq) and Pd(PPh3)4(471.02 mg, 407.61 pmol, 0.2 eq) at 25 °C under N2. The mixture was stirred at 25 °C for 16 h under N2 atmosphere. LCMS showed the reactant 1 was consumed completely, ~ 52 % of desired MS and -21% of PPh3O was detected. TLC (EtOAc, UV, Pl Rf = 0.28) indicated one new spot formed. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. It was purified by column chromatography (SiO2, DCM: MeOH =1 / 0 to 4 / 1) to give 3-(5-bromo-l-ethyl-2-((R)-2-((S)-l- methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l- yl)pyridin-3-yl)-lH-indol-3-yl)-2,2- dimethylpropyl acetate (2.7 g, crude) as a brown oil. LCMS showed the obtained compound contained - 57 % of desired compound and -30% of PPh3O.

[0512] LCMS: calcd. for C33H42BrN3O4[M+H]+m / z: 623.2, found: 626.2.^ NMR: (400 MHz, CHLOROFORMS) 5: 8.84 (d, J= 2.0 Hz, 1H), 7.81 (d, J= 1.6 Hz, 1H), 7.70 (d, J= 2.4 Hz, 1H), 7.34-7.39 (m, 1H), 7.25-7.28 (m, 1H), 4.07-4.12 (m, 1H), 3.96-4.04 (m, 1H), 3.87-3.95 (m, 1H), 3.65-3.82 (m, 7H), 3.08 (s, 3H), 2.71-2.83 (m, 3H), 2.57-2.65 (m, 2H), 2.33 (d, J = 14.0 Hz, 1H), 2.03 (s, 3H), 1.52-1.45 (m, 6H), 1.22 (t, J= 7.2 Hz, 3H), 0.83 (d, J= 13.2 Hz, 6H).Step 5: General procedure for preparation of 3-(l-ethyl-2-((R)-2-((S)-l-methoxyethyl)-5-((R)~ 3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-5-( 4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH- indol-3-yl)-2, 2 -dimethylpropyl acetate

[0513] To a stirred solution of 3-(5-bromo-l-ethyl-2-((R)-2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (0.9 g, 1.44 mmol, 1 eq) and EhPi (548.85 mg, 2.16 mmol, 1.5 eq) in DMSO (15 mL) was added KOAc (282.83 mg, 2.88 mmol, 2 eq) and Pd(dppf)C12 (105.43 mg, 144.09 pmol, 0.1 eq) at 25 °C under N2. The resulting mixture was stirred at 80 °C for 4 h. LCMS showed ~ 16% of desired MS, ~ 32% of reactant 1, ~ 7% of de-Br byproduct and -24% of PPI13O was detected. The mixture was stirred at 80 °C for 16 h. LCMS (ES32464-60-P1C) showed - 18% of desired MS, - 27% of reactant 1, - 7.7% of de-Br byproduct and -21% of PPI13O was detected. The reaction mixture from ES32464-54 was combined with this batch and worked up together. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (lOOmL x 3). The combined organic layers were washed with brine (300mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. It purified by prep-HPLC (column: 41- WePure Biotech XP tC18 150x40mm, 7pm; mobile phase: [H2O (0.05% NHsHjO+ IOmM NH4HCO3)-ACN]; gradient: 63%-83% B over 12.0 min) to give 3-(l-ethyl-2-((R)-2-((S)-l- methoxyethyl)-5-((R)-3-morpholinobut- 1 -yn- 1 -yl) pyridin-3-yl)-5-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate (0.39 g, 35.46% yield) as a brown solid. HNMR and LCMS showed the obtained compound was contain - 61% of 3-(l- ethyl-2-((R)-2-((S)- 1 -methoxy ethyl)-5-((R)-3 -morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- 5 - (4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-lH-indol-3-yl)-2,2-dimethylpropyl acetate and -27% of (3-(3-acetoxy-2,2-dimethylpropyl)-l- ethyl-2-((R)-2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- lH-indol-5-yl)boronic acid.

[0514] LCMS: calcd. for C39H54BN3O6 [M+H]+m / z: 671.4, found: 673.5.^ NMR: (400 MHz, CHLOROFORM^ / ) 5: 8.79-8.89 (m, 1 H), 8.00-8.25 (m, 1 H), 7.64-7.76 (m, 2 H), 7.35- 7.44 (m, 1 H), 3.97-4.10 (m, 2 H), 3.87-3.95 (m, 1 H), 3.65-3.86 (m, 7 H), 3.02-3.11 (m, 3 H), 2.88 (d, J= 13.6 Hz, 1 H), 2.71-2.83 (m, 2 H), 2.50-2.70 (m, 2 H), 2.32 (d, J= 14.0 Hz, 1 H), 1.99-2.06 (m, 3 H), 1.43-1.52 (m, 6 H), 1.38 (s, 8 H), 1.18-1.24 (m, 3 H), 0.77-0.88 (m, 6 H).

[0515] To a stirred solution of 3-(l-ethyl-2-((R)-2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)-5 -(4,4,5, 5-tetram ethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1H- indol-3-yl)-2,2-dimethylpropyl acetate (290.0 mg, 431.76 pmol, 1 eq), methyl (S)-2-((2S,3S)- 3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (303.87 mg, 518.11 pmol, 1.2 eq) and K2CO3 (179.01 mg, 1.30 mmol, 3 eq) in toluene (16 mL) / dioxane (8 mL / BLO (8 mL) was added Pd(dppf)C12 (31.59 mg, 43.18 pmol, 0.1 eq) at 25 °C under N2. The reaction mixture was stirred at 90 °C for 16 h under N2. LCMS showed Reactant 1 was consumed completely and ~ 17% of desired mass was detected. TLC (DCM: MeOH= 19: 1, UV, Pl Rf = 0.30) many new spots formed. The reaction solution was concentrated under reduced pressure to remove 1,4- di oxane and toluene, the residue was diluted with H2O (100 mL) and extracted with EtOAc (60 mL x 3), the combined organic phase was washed with brine (200 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product. It was purified by column chromatography (SiCh, DCM: MeOH = 1 / 0 to 24 / 1) to give methyl (S)-2- ((2S,3S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-l-ethyl-2-((R)-2-((S)-l-methoxyethyl)-5- ((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-lH-indol-5-yl)thiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate (252.0 mg, 32.20% yield) as a yellow solid.

[0516] LCMS: calcd. for C56H74N8O10S [M+H]+m / z: 1050.5, found: 1052.9. NMR: (400 MHz, CHLOROFORM-; / ) 5: 8.82-8.85 (m, 1H), 8.10-8.27 (m, 1H), 7.82 (d, J= 92 Hz, 1H), 7.72 (d, J= 2.0 Hz, 1H), 7.54-7.65 (m, 1H), 7.43-7.52 (m, 1H), 7.39 (s, 1H), 5.47-5.76 (m, 1H), 5.31 (s, 1H), 4.66-4.76 (m, 4H), 4.25-4.45 (m, 1H), 4.15-4.21 (m, 1H), 4.02-4.07 (m, 1H), 3.90-3.97 (m, 1H), 3.72-3.82 (m, 9H), 3.50-3.63 (m, 3H), 3.04-3.10 (m, 3H), 2.73-2.84 (m, 3H), 2.54-2.69 (m, 3H), 2.29-2.43 (m, 2H), 1.86-2.03 (m, 4H), 1.49-1.51 (m, 3H), 1.47 (s, 6H), 1.13-1.37 (m, 9H), 0.76-1.00 (m, 9H).Step 7: General procedure for preparation of (S)-2-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3- (4-(l-ethyl-3-(3-hydroxy-2 , 2-dimethylpropyl)-2-( (R)-2-( (S)-l-methoxyethyl)-5-( (R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-lH-indol-5-yl)thiazol-2-yl)-3-(2-oxa-6- azaspiro[ 3.3 ]heptan-6-yl)propanoyl)-2, 3-diazabicyclo[ 3.1.1 ]heptane-4-carboxylic acid

[0517] To a solution of methyl (S)-2-((2S,3S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl) -1- ethyl-2-((R)-2-((S)- 1 -methoxy ethyl)-5-((R)-3 -morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- 1H- indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6- yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (232.0 mg, 220.68 pmol, 1 eq) in THF (8 mL) and H2O (8 mL) was added LiOHftO (46.30 mg, 1.10 mmol, 5 eq) at 0 °C. The mixture was stirred at 25 °C for 4.5h. LCMS showed Reactant 1 was consumed completely and ~ 68% of desired mass was detected. The reaction mixture was concentrated under reducedpressure to remove THF. The residue was diluted with water (20 mL) and extracted with EtOAc (15mL x 2). The aqueous phase was lyophilizated to give (S)-2-((2S,3S)-2-((tert- butoxycarbonyl)amino) -3-(4-(l-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-((R)-2-((S)-l- methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-lH-indol-5-yl)thiazol-2-yl)-3- (2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (280.0 mg, 95.62% yield, Li salt) as a little brown solid. The obtained compound was used for next step without further purification.

[0518] LCMS: calcd. for C53H70N O9S [M+H]+m / z: 994.5, found: 996.0.1H NMR: (400 MHz, METHANOL-^) 8: 8.75 (s, 1H), 8.21-8.40 (m, 1H), 7.88-8.00 (m, 1H), 7.78-7.87 (m, 1H), 7.69 (s, 1H), 7.46-7.53 (m, 1H), 5.40-5.53 (m, 1H), 4.74 (s, 4H), 4.52-4.62 (m, 1H), 4.31- 4.45 (m, 1H), 4.15 (d, J= 5.2 Hz, 2H), 3.71-3.93 (m, 7H), 3.49-3.64 (m, 4H), 3.17-3.27 (m, 2H), 3.05 (s, 3H), 2.74-2.87 (m, 3H), 2.62 (s, 3H), 2.25-2.35 (m, 2H), 2.02-2.12 (m, 1H), 1.71- 1.84 (m, 2H), 1.46 (s, 12H), 1.40 (s, 3H), 1.24 (s, 3H), 0.78 (d, J= 19.6Hz, 6H).Step 8: General procedure for preparation of tert-butyl ((64S,3S,4S,Z)-ll-ethyl-12-((R)-2-((S)~ l-methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-3- (2-oxa-6-azaspiro[3.3]heptan-6-yl)-llH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)carbamate

[0519] To a solution of TCFH (235.41 mg, 839.02 pmol, 3 eq) in MeCN (48 mL) was added a solution of (S)-2-((2S,3S)-2-((tert-butoxycarbonyl)amino)-3-(4-(l-ethyl-3-(3-hydroxy- 2,2-dimethylpropyl)-2-((R)-2-((S)-l-methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin- 3-yl)-lH-indol-5-yl)thiazol-2-yl)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylic acid (278.34 mg, 279.67 pmol, 1 eq) and NMI (114.81 mg, 1.40 mmol, 111.46 pL, 5 eq) in MeCN (2 mL) at 0 °C, the reaction was gradually improved temperature to 25 °C and stirred for 2 h. LCMS showed Reactant 1 was consumed completely and ~ 40% of desired mass was detected. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filter and concentrated under reduced pressure to give the crude product confirmed with LCMS. The crude product was purified by prep-HPLC (column: 40-WePure Biotech XP tC18 150 x 30mm, 7pm; mobile phase: [H2O (0.05% NHsHjO+ IOmM NH4HCO3)-ACN]; gradient: 50%-90% B over 10.0 min) to give tert- butyl((64S,3 S,4S,Z)- 11 -ethyl- 12-((R)-2-((S)- 1 -methoxy ethyl)-5-((R)-3 - morpholinobut- 1 -yn- l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-llH-8-oxa- 62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4- yl)carbamate (60.0 mg, 21.38% yield) as a white solid.LCMS: calcd. for C53H6 N O8S [M+H]+m / z: 976.5, found: 977.6.

[0520] SFC: RT = 1.297, 100.00% ee value d NMR: (400 MHz, CHLOROFORM-tZ) 5:8.82 (s, 1H), 8.51 (s, 1H), 7.62-7.73 (m, 2H), 7.36-7.44 (m, 2H), 5.87 (d, J= 8.4 Hz, 1H), 5.32- 5.37 (m, 1H), 4.77-4.89 (m, 2H), 4.74 (s, 4H), 4.38 (d, J= 6.4 Hz, 1H), 4.17-4.27 (m, 2H), 3.93-4.00 (m, 1H), 3.64-3.86 (m, 6H), 3.59 (d, J= 8.0 Hz, 2H), 3.43 (s, 3H), 3.19-3.31 (m, 3H), 2.70-2.81 (m, 2H), 2.58-2.68 (m, 2H), 2.38-2.50 (m, 2H), 2.11-2.22 (m, 1H), 1.64-1.83 (m, 1H), 1.37-1.52 (m, 18H), 1.00 (s, 3H), 0.94 (t, J= 6.8 Hz, 3H), 0.35-0.43 (m, 3H).Step 9: General procedure for preparation of (64S,3S,4S,Z)-4-amino-ll-ethyl-12-((R)-2-((S)-l- methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-(2-oxa-6- azaspiro[3.3 ]heptan-6-yl)-HH-8-oxa-62, 63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2, 4)- bicyclo[3.1.1 ]heptanacycloundecaphane-5, 7 -dione

[0521] To a solution of tert-butyl ((64S,3S,4S,Z)-ll-ethyl-12-((R)-2-((S)-l-methoxyethyl) -5-((R)-3 -morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo-3 -(2-oxa-6- azaspiro[3.3]heptan-6-yl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (60.0 mg, 61.40 pmol, 1 eq) in HFIP (2 mL) was added TFA (70.01 mg, 613.99 pmol, 10 eq). The mixture was stirred at 25 °C for 3 h. LCMS showed Reactant 1 was consumed completely and -91% of desired compound was detected. The reaction mixture was concentrated by N2. The residue was dissolved in EtOAc (20 mL). The mixture was washed with Sat.aq.NaHCCL aqueous (20 mL), brine (20 mL), dired over Na2SO4 and concentrated to give (64S,3S,4S,Z)-4-amino-ll-ethyl-12-((R)-2-((S)-l- methoxy ethyl) -5 -((R)-3 -morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- 10, 10-dimethyl-3 -(2-oxa-6- azaspiro[3.3]heptan-6-yl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-5, 7-dione (50.0 mg, 90.06% yield) as a yellow solid.

[0522] LCMS: calcd. for C48H6oN806S [M+H]+m / z: 876.4, found: 877.4.Step 10: General procedure for preparation of (2S,3S)-N-((64S,3S,4S,Z)-ll-ethyl-12-((R)-2- ((S)-l-methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5, 7- dioxo-3-(2-oxa-6-azaspiro[3.3 ]heptan-6-yl)-l lH-8-oxa-62, 63-diaza-2(4,2)-thiazola-l(5,3)~ indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamide

[0523] To a stirred solution of (64S,3S,4S,Z)-4-amino-ll-ethyl-12-((R)-2-((S)-l- methoxy ethyl) -5 -((R)-3 -morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- 10, 10-dimethyl-3 -(2-oxa-6- azaspiro[3.3]heptan-6-yl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-5, 7-dione (50.0 mg, 57.01 pmol, 1 eq) in MeCN (2 mL) was added (2S,3S)-3-methyloxetane-2-carboxylic acid (7.28 mg, 62.71 pmol, 1.1 eq), NMI (9.36 mg, 114.01 pmol, 2.0 eq) and TCFH (19.19 mg, 68.41 pmol, 1.2 eq) at 25 °C, the resulting mixture was stirred at 25 °C for 0.5 h. LCMS showed Reactant 1 was consumed completely and - 30 % of desired mass was detected. TLC (DCM: MeOH= 9: 1, UV, Pl Rf = 0.28) showed many new spots formed. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15mL x 3). The combined organic layers were washed with brine(50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. It was purified by prep-TLC (SiCh, DCM: MeOH = 9:1) to give a crude product (35 mg) confirmed with LCMS. The crude product (35 mg) was purified by prep-HPLC (column: Welch Xtimate Cl 8 150 x 25 mm x 5 pm;mobile phase: [H2O(0.225% FA)-ACN]; gradient:23%-43% B over 12.0 min) to give the product (11 mg). LCMS, HNMR, HPLC and SFC showed the obtained product (11 mg) was the desired compound. The (9.2 mg, 83% purity) was purified by prep-HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 pm; mobile phase: [H2O (0.225% FA)-ACN]; gradient:22%-42% B over 12.0 min) to give the product (4.6 mg). LCMS showed the obtained product (4.6 mg) was the desired compound. The product (11 mg) and product (4.6 mg) was mixed to give (2S,3S)-N-((64S,3S,4S,Z)-ll-ethyl-12-((R)-2- ((S)-l -methoxy ethyl)-5-((R)-3-morpholinobut-l-yn-l-yl)pyridin-3-yl)- 10,10-dimethyl-5, 7- di oxo-3 -(2-oxa-6-azaspiro[3.3 ]heptan-6-yl)- 1 lH-8-oxa-62,63 -diaza-2(4,2)-thiazola- 1(5,3)- indola-6(2,4)-bicyclo[3.1. l]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamide (14.68 mg, 25.83% yield) as a white solid.

[0524] LCMS: calcd. for CssHeeNsOsS [M+H]+m / z: 974.5, found: 975.5.HPLC: (Purity: 97.83%). SFC: RT = 1.298, 100.00% ee value^H NMR: (400 MHz, CHLOROFORM-tZ) 5: 8.81 (d, J= 2.0 Hz, 1H), 8.49 (s, 1H), 8.33 (d, J= 7.2 Hz, 1H), 7.60-7.68 (m, 2H), 7.42 (s, 1H), 7.37 (d, J= 8.8 Hz, 1H), 5.51 (d, = 7.2 Hz, 1H), 5.41 (d, J= 11.2 Hz, 1H), 5.18 (d, J= 8.8 Hz, 1H), 4.96 (dd, J= 8.0, 6.0 Hz, 1H), 4.90 (d, J= 10.4 Hz, 1H), 4.81-4.87 (m, 1H), 4.70-4.76 (m, 4H), 4.34-4.44 (m, 2H), 4.20-4.23 (m, 1H), 4.02 (s, 1H), 3.74-3.86 (m, 5H), 3.58-3.67 (m, 3H), 3.49 (s, 2H), 3.42 (s, 4H), 3.33 (d, J= 8.0 Hz, 2H), 3.22 (d, J= 14.0 Hz, 1H), 2.72-2.88 (m, 3H), 2.56-2.72 (m, 3H), 2.42-2.50 (m, 2H), 2.15-2.25 (m, 1H), 1.79-1.82 (m, 1H), 1.51 (s, 3H), 1.45 (d, 7= 6.0 Hz, 3H), 1.27 (d, 7= 7.2 Hz, 3H), 1.02 (s, 3H), 0.93 (t, 7= 7.2 Hz, 3H), 0.40 (s, 3H).Example 42: (2S,3S)-N-((64S,3S,4S,Z)-12-((R)-2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-ll-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-HH-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3- methyloxetane-2-carboxamide

[0525] Substituting 4-(prop-2-yn-l-yl)morpholine with (R)-4-(but-3-yn-2-yl)morpholine in the Step 17 of Example 35, the title compound was prepared by the same procedures as described for Example 35.

[0526] LCMS: calcd. for C58H74N8O10S [M+H]+m / z: 1075.5, found: 1075.5.HPLC: (Purity: 96.17%). SFC: (Rt = 1.428 min, ee: 100%).'H NMR: (400 MHz, CHLOROFORM-tZ) 5 : 8.81 (d, J= 1.6 Hz, 1H), 8.49 (s, 1H), 8.34-8.31 (m, 1H), 7.64-7.61 (m, 2H), 7.42 (s, 1H), 4.38 (d, J= 8.8 Hz, 1H), 5.52 (d, J= 6.8 Hz, 1H),5.42-5.40 (m, 1H), 5.20-5.17 (m, 1H), 4.97 (dd, Ji = 8.0 Hz, . / 2= 6.0 Hz, 1H), 4.92-4.88 (m, 1H), 4.87-4.83 (m, 1H), 4.73 (s, 4H), 4.43-4.40 (m, 2H), 4.34-4.27 (m, 2H), 4.02 (s, 1H), 3.89- 3.61 (m, 12H), 3.46-3.42 (m, 5H), 3.33 (d, J= 8.4 Hz, 3H), 3.28-3.20 (s, 3H), 3.12-3.07 (m, 1H), 2.80-2.75 (s, 2H), 2.70-2.61 (s, 2H), 2.49-45 (s, 2H), 2.23-2.16 (s, 1H), 1.81-1.76 (m, 1H), 1.45 (d, .7= 6.0 Hz, 7H), 1.27 (d, = 7.2 Hz, 6H), 1.22-1.10 (m, 1H), 1.12 (s, 3H), 0.40 (s, 3H).Example 43: (2S,3S)-N-((64S,3S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5,7-dioxo-l1-(2- ((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)- indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2- carboxamideStep 1: Synthesis of tert-butyl ((64S,3S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5, 7-dioxo-f-(2- ((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)carbamate

[0527] To a stirred solution of 5-((64S,3S,4S,Z)-4-((tert-butoxycarbonyl)amino)-10,10- dimethyl-3-morpholino-5,7-dioxo-l1-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa- 62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-l2- yl)-6-((S)- 1-m ethoxy ethyl)pyri din-3 -yl trifluoromethanesulfonate (150 mg, 0.14 mmol), (R)-4- (but-3-yn-2-yl)morpholine (29 mg, 0.21 mmol), Pd(PPh3)4 (16 mg, 0.01 mmol) and Cui (5 mg, 0.03 mmol) in 1,4-DMF (3 mL) was added TEA (71 mg, 0.70 mmol) at r.t.. The reaction mixture was stirred at 95 °C under N2 for 1 h. 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 ISfeSCU, following 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,3S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((R)-3-morpholinobut- l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5,7-di oxo-11-(2- ((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (120 mg, 80.8 %) as a white solid.

[0528] LCMS (ESI) calcd. ]+m / z 1065.5, found: 1065.9.Step 2: Synthesis of (64S,3S,4S, methoxyethyl)-5-((R)-3-morpholinobut- l-yn-l-yl)pyridin-3-yl)-10, 10-d -(2-((lelrahydro-2H-pyran-4- yl) oxy) ethyl) -I1H-8-oxa-62, 63-d ,3)-indola-6(2, 4)- bicyclo[3.1.1 ]heptanacyclound

[0529] To a stirred solution of tert-butyl ((64S,3S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((R)- 3-morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5,7-dioxo-l1-(2- ((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (120 mg, 0.11 mmol) in dichloromethane (3 mL) was added TFA (1 mL) slowly at r.t., the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product (63S,4S,Z)-4- amino- 1 ^ethyl- 12-(2-((S)- 1 -methoxy ethyl)-5-(3 -((tetrahydro-2H-pyran-4-yl)oxy)prop- 1 -yn- 1 - yl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexahydro-l1EI-8-oxa-2(4,2)-thiazola-l(5,3)- indola-6(l,3)-pyridazinacycloundecaphane-5, 7-dione (108 mg, crude ) as a light yellow solid. Step 3: Synthesis of (2S,3S)-N-((64S,3S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5, 7-dioxo-R-(2- ((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamide

[0530] To a stirred solution of (64S,3S,4S,Z)-4-amino-l2-(2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-3 -morpholino- 11-(2-((tetrahydro-2H- pyran-4-yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-5, 7-dione (80 mg, 0.08 mmol) and (2S,3S)-3- methyloxetane-2-carboxylic acid (10 mg, 0.09 mmol) and TEA (34 mg, 0.33 mmol) in DMF (3 mL) was added HATU (47 mg, 0.12 mmol) at r.t., and the resulting mixture was stirred at r.t. 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 (2S,3S)-N-((64S,3S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-((R)-3-morpholinobut-l-yn-l- yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5,7-dioxo-l1-(2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamide (17 mg, 19.3 %) as a white solid.

[0531] LCMS (ESI) calcd. for C57H74N8O10S [M+H]+m / z 1063.5, found: 1065.0.1!! NMR(400 MHz, DMSO-t / e) d 8.11 (d, J = 1.7 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J = 6.4 Hz, 1H), 7.95 (s, 1H), 7.80 - 7.69 (m, 2H), 7.61 (d, J = 8.6 Hz, 1H), 6.00 (d, J = 11.0 Hz, 1H), 5.50 (s, 1H), 5.09 (d, J = 8.7 Hz, 1H), 4.91 - 4.82 (m, 1H), 4.57 (d, J = 4.2 Hz, 2H), 4.45 (d, J = 15.4 Hz, 1H), 4.27 - 4.06 (m, 5H), 3.79 (dd, J = 14.1, 7.0 Hz, 1H), 3.57 (dt, J = 11.7, 6.6 Hz, 11H), 3.45 (d, J = 10.9 Hz, 3H), 3.21 (s, 3H), 3.12 (dd, J = 20.7, 11.0 Hz, 3H), 2.97 (d, J = 16.2 Hz, 2H), 2.75 (s, 2H), 2.61 (d, J = 5.2 Hz, 3H), 2.47 (s, 3H), 2.31 (d, J = 11.7 Hz, 3H), 2.19 - 2.11 (m, 2H), 1.59 (d, J = 10.4 Hz, 2H), 1.45 (d, J = 12.6 Hz, 2H), 1.39 - 1.31 (m, 6H), 1.26 - 1.00 (m, 7H), 0.89 (s, 3H), 0.37 (s, 3H).Example 54: (2S,3S)-N-((64S,3S,4S,Z)-12-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop- l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5,7-dioxo-ll-(2-((tetrahydro-2H- pyran-4-yl)oxy)ethyl)-HH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2-carboxamide

[0532] Substituting methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate with methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)- 2-((tert-butoxycarbonyl)amino)-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate in the Step 12 of Example 35, the title compound was prepared by the same procedures as described for Example 35.

[0533] LCMS (ESI) calcd. for CsfeNsOwS [M+H]+m / z 1088.54, found: 1090.7.^ NMR (400 MHz, DMSO ) 8 8.76 (d, J= 1.7 Hz, 1H), 8.43 (s, 1H), 8.25 (d, J= 7.8 Hz, 1H), 7.92 (s, 1H), 7.75-7.68 (m, 2H), 7.59 (d, J= 8.8 Hz, 1H), 6.00 (d, J= 10.9 Hz, 1H), 5.24 (d, J= 7.6 Hz, 1H), 5.02 (d, J= 8.7 Hz, 1H), 4.86-4.83 (m, 2H), 4.60-4.56 (m, 1H), 4.48-4.44 (m, 1H), 4.26-4.13 (m, 4H), 3.61-3.34 (m, 16H), 3.25 (s, 3H), 3.16-2.87 (m, 9H), 2.70-2.67 (m, 1H), 2.57-2.48 (m, 4H), 2.40-2.30 (m, 2H), 2.20-2.16 (m, 1H), 1.84-1.82 (m, 1H), 1.67 (s, 3H), 1.51-1.41 (m, 2H), 1.34 (d, J= 6.0 Hz, 3H), 1.21 (s, 2H), 1.13-0.91 (m, 8H), 0.28 (s, 3H).Example 55: (2S,3S)-N-((64S,3S,4S,Z)-12-(2-((S)-l-methoxyethyl)-5-((R)-3- morpholinobut-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(7-oxa-2- azaspiro[3.5]nonan-2-yl)-ll-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-HH-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3- methyloxetane-2-carboxamide

[0534] Substituting methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate with methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)- 2-((tert-butoxycarbonyl)amino)-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate in the Step 12 and substituting 4-(prop-2-yn-l- yl)morpholine with (R)-4-(but-3-yn-2-yl)morpholine in the Step 17 of Example 35, the title compound was prepared by the same procedures as described for Example 35.

[0535] LCMS (ESI) calcd. for C6OH78N8OIOS[M+H]+m / z 1102.56, found: HOdJ^HNMR (400 MHz, DMSO-t / e) 5 8.75 (s, 1H), 8.43 (s, 1H), 8.25 (d, J= 7.8 Hz, 1H), 7.93 (s, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.59 (d, J= 8.7 Hz, 1H), 6.00 (d, J= 11.3 Hz, 1H), 5.24 (d, J= 7.8 Hz, 1H), 5.02 (d, J= 8.6 Hz, 1H), 4.86-4.83 (m, 2H), 4.56 (s, 1H), 4.46 (d, J= 14.7 Hz, 1H), 4.26- 4.12 (m, 4H), 3.79-3.74 (m, 1H), 3.62-3.30 (m, 15H), 3.22 (s, 3H), 3.18-2.94 (m, 7H), 2.89 (d, J= 6.8 Hz, 2H), 2.69-2.49 (m, 6H), 2.38-2.31 (m, 4H), 2.21-2.16 (m, 1H), 1.84-1.78 (m, 1H), 1.67 (s, 3H), 1.56-1.52 (m, 1H), 1.43-1.28 (m, 7H), 1.11-0.89 (m, 8H), 0.29 (s, 3H).Example 56: (2S,3S)-N-((64S,3S,4S,Z)-12-(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-l- yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(7-oxa-2- azaspiro[3.5]nonan-2-yl)-ll-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-HH-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3- methyloxetane-2-carboxamide

[0536] Substituting methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate with methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)-3-(7-oxa-2-azaspiro[3.5]nonan-2-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate in the Step 12 and substituting 4-(prop-2-yn-l- yl)morpholine with N,N,2,2-tetramethylbut-3-ynamide in the Step 17 of Example 35, the title compound was prepared by the same procedures as described for Example 35.

[0537] LCMS (ESI) calcd. for C6oH78N8OioS[M+H]+m / z 1102.56, found: 1004.9.1H NMR (400 MHz, DMSO-tL) 5 8.75 (s, 1H), 8.42 (s, 1H), 8.25 (d, J= 7.9 Hz, 1H), 7.93 (s, 1H), 7.74 (d, J= 8.6 Hz, 1H), 7.66 (s, 1H), 7.58 (d, J= 8.6 Hz, 1H), 6.01 (d, J= 10.8 Hz, 1H), 5.24 (d, J = 8.0 Hz, 1H), 5.02 (d, J= 9.0 Hz, 1H), 4.85-4.80 (m, 2H), 4.58-4.41 (m, 3H), 4.24-4.09 (m, 4H), 3.60-3.29 (m, 15H), 3.23 (s, 3H), 3.14-2.90 (m, 14H), 2.70-2.63 (m, 1H), 2.57-2.52 (m, 1H), 2.40-2.36 (m, 4H), 2.21-2.15 (m, 1H), 1.82 (t, J= 9.1 Hz, 1H), 1.67 (s, 4H), 1.56-1.39 (m, 8H), 1.34 (d, J= 6.0 Hz, 3H), 1.10-0.89 (m, 8H), 0.29 (s, 3H).Example 73: (2S,3S)-N-((64S,3S,4S,Z)-12-(5-((R)-3-(4-cyclopropylpiperazin-l-yl)but-l- yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-3-(2-oxa-6- azaspiro[3.3]heptan-6-yl)-ll-(2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-HH-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3- methyloxetane-2-carboxamide

[0538] Substituting 4-(prop-2-yn-l-yl)morpholine with (R)-l-(but-3-yn-2-yl)-4- cyclopropylpiperazine in the Step 17 of Example 35, the title compound was prepared by the same procedures as described for Example 35.

[0539] LCMS (ESI) calcd. for C6iH79N9O9S[M+H]+m / z 1113.57, found: lllS.S^H NMR (400 MHz, DMSO-tL) 5 8.72 (d, J= 1.8 Hz, 1H), 8.43 (s, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.93 (s, 1H), 7.74 (d, J= 8.6 Hz, 1H), 7.64 (s, 1H), 7.58 (d, J= 8.8 Hz, 1H), 6.01 (d, J= 10.8 Hz, 1H), 5.26 (d, J= 8.2 Hz, 1H), 5.02 (d, J= 8.8 Hz, 1H), 4.83 (dd, J= 13.7, 8.6 Hz, 2H), 4.61- 4.52 (m, 5H), 4.45 (d, J= 14.6 Hz, 1H), 4.27-4.08 (m, 5H), 3.79-3.75 (m, 1H), 3.58-3.31 (m, 9H), 3.25-3.23 (m, 5H), 3.12-2.86 (m, 6H), 2.68-2.65 (m, 1H), 2.60-2.52 (m, 5H), 2.39-2.29 (m, 3H), 2.25-2.16 (m, 1H), 1.90-1.85 (m, 1H), 1.57-1.50 (m, 2H), 1.39-1.27 (m, 7H), 1.08- 0.87 (m, 8H), 0.35-0.23 (m, 8H).Example 76: (2S,3S)-N-((64S,3S,4S,Z)-12-(5-((R)-3-(4-cyclopropylpiperazin-l-yl)but-l- yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-3-morpholino-5,7-dioxo-ll- (2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-llH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methyloxetane-2- carboxamide

[0540] Substituting methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)-3-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate with methyl (S)-2-((2S,3S)-3-(4-bromothiazol-2-yl)- 2-((tert-butoxycarbonyl)amino)-3-morpholinopropanoyl)-2,3-diazabicyclo[3.1.1]heptane-4- carboxylate in the Step 12 and substituting 4-(prop-2-yn-l-yl)morpholine with (R)-l-(...

Claims

CLAIMS1. 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, wherein the compound has a structure according to formula (I)wherein, - represents a double bond or single bond; 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 optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11 -membered bicyclic cycloalkylene, or optionally substituted 4 to 11 -membered bicyclic heterocycloalkylene;G is optionally substituted Ci-6 alkylene;- between U and T is a bond or absent; wherein when - between U and T is a bond, U or T are absent, or U and T are each independently O, S, -NR3or optionally substituted Ci-6 alkylene; or wherein - between U and T is absent, T is absent, and U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted 6-membered aryl, optionally substituted 5 to 6-membered heteroaryl, optionally substituted -C1.3 alkylene-O-Ci-6 alkyl, optionally substituted -C1.3 alkylene-O- C3-10 cycloalkyl, optionally substituted -C1.3 alkylene- 0-3 to 10-membered heterocycloalkyl, optionally substituted -C1.3 alkylene-S-Ci-6 alkyl, optionally substituted -C1.3 alkylene-S-C3-io cycloalkyl, or optionally substituted -C1.3 alkylene- S-3 to 10-membered heterocycloalkyl; wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, Ci-6 heterocycloalkyl may be further optionally substituted;R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1.3 alkyl, or R8and R9combine with the atom(s) to which they areattached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, and optionally substituted C1.3 alkyl, or R10and R11combine with the atom to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1.3 alkyl, -OR71, -SR72or -N(R73)R74;R71, R72, R73and R74are each independently Ci-6 alkyl, Ci-6 heteroalkyl, Ci-e haloalkyl, or Ci-6 haloheteroalkyl, or R73and R74combine with the atom(s) to which they are attached to form an optionally substituted 3 to 10-membered heterocycloalkyl; wherein the 3 to 10- membered heterocycloalkyl has 0, 1, 2, 3, 4 or 5 heteroatom ring atom(s) other than the N atom;RAis optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl;RBis hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; or, when n is 2 or 3, any two RBcombine with the atoms to which they are attached to form a 3 to 6-membered ring, wherein the ring is optionally substituted with halogen, hydroxy, or C1.3 alkyl;X1is N or C;X2is N or -CRa-;X3is N or -CRb-;X4is N or C;X5is N or C;X6is N or C;Raand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl;R3is hydrogen, C1.3 alkyl, C3-6 cycloalkyl, C1.3 haloalkyl, C3-6 halocycloalkyl, -C(O)Ci-3 alkyl, -S(O2), or -S(O2)Ci-3alkyl;E is a bond, N, or -CRd-, wherein Rdis selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf, wherein Reand Rfare each independently hydrogen or optionally substituted Ci-6 alkyl;R4is hydrogen, optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionallysubstituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionallyR6substituted 5 to 10-membered heteroaryl, or;R5is hydrogen, Ci-6 alkyl, or C3-6 cycloalkyl, wherein the Ci-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or wherein R4and R5combine with the atom(s) to which they are attached to form a ring, wherein the ring is 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; and whereinL is absent, -CH2-, -C(O)-, -CHRS-, or -C(RS)2-, wherein Rgis optionally substituted Ci-6 alkyl;R6is hydrogen or optionally substituted Ci-6 alkyl;R7is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; or L, R6, and R7combine with the atom(s) 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 alkyl, or optionally substituted 4 to 11-membered bicyclic heteroalkyl.

2. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of claim 1, wherein the compound has a structure according to formula (II):Y is CH orN;Rlais hydrogen, Ci-6 alkyl, Ci-e alkoxyl, Ci-6 haloalky 1, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; wherein the Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, or Ci-6 hydroxyalkyl may be further optionally substituted;R2is optionally substituted Ci-6 alkoxy or optionally substituted Ci-6 alkyl; andRMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; wherein the Ci-6 alkyl, Ci-e alkoxyl, Ci-ehaloalkyl, Ci-e haloalkoxyl, and Ci-e hydroxyalkyl may be further optionally substituted.

3. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of claim 1 or 2, wherein the compound has a structure according to formula (Illa) or formula (Illb):whereinR1is hydrogen, Ci-6 alkyl, Ci-ealkoxyl, Ci-6 haloalky 1, Ci-6 haloalkoxy 1, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2 alkylene- C3-6 cycloalkyl, optionally substituted -C1.2 alkylene-C3-6 heterocycloalkyl, optionally substituted -C1-2 alkylene-5 to 8-membered aryl, optionally substituted -C1-2 alkylene-5 to 8- membered heteroaryl, optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic aryl, or optionally substituted -C1-2 alkylene-8 to 10-membered fused bicyclic heteroaryl;wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, or Ci-e hydroxyalkyl may be further optionally substituted, andRaand Rbare each independently hydrogen, halogen, cyano, C1.3 alkyl, C1.3 alkoxyl, C1.3 haloalkyl, C1.3 haloalkoxyl, C3-6 cycloalkyl, or 3 to 6-membered heterocycloalkyl.

4. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-3, wherein the compound has a structure according to formula (IVaa), (IVab), (IVba) or (IVbb):

5. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-4, whereinB is optionally substitutedor optionally substitutedand whereinwhereinR1is selected from the group consisting of hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-e haloalkoxyl, Ci-e hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10- membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclicheteroaryl, optionally substituted -Ci-2 alkylene-C3-6 cycloalkyl, optionally substituted -Ci-2 alkylene-C3-6 heterocycloalkyl, optionally substituted -Ci-2 alkylene-5 to 8-membered aryl, optionally substituted -Ci-2 alkylene-5 to 8-membered heteroaryl, optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic aryl, and optionally substituted -Ci-2 alkylene-8 to 10-membered fused bicyclic heteroaryl; wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalky 1, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl may be further optionally substituted; in R1, when the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl is further substituted, the substituent is selected from the group consisting of Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10- membered fused bicyclic heteroaryl; optionally wherein the substituent is selected from the group consisting of optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; further optionally, the substituent is optionally substituted C3-6 heterocycloalkyl;Y is -CH- or N;R2is optionally substituted Ci-6 alkoxy or optionally substituted Ci-6 alkyl; optionally wherein R2is optionally substituted Ci-6 alkyl; andRMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl; wherein the Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, or Ci-6 hydroxyalkyl is optionally substituted, further optionally wherein RMand RNare each independently selected from hydrogen or Ci-6 alkyl.

6. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 3-5, whereinR1is optionally substituted -C1.2 alkylene-3 to 6-membered heterocycloalkyl, optionally wherein the 3 to 6-membered heterocycloalkyl has the structure:wherein nl and n2 are each independently 1, 2, or 3, optionally wherein nl and n2 are each 2, and wherein ZRAis O, S, or NH; optionally wherein the Ci-2 alkylene of R1is -CH2- or -CH(CHa)-; wherein optionally substituted means the group is unsubstituted or substituted with 1-4 substituent(s) selected from the group consisting of D, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl, further optionally, with 1-4 substituent(s) selected from the group consisting of D and Ci-6 alkyl, or, wherein R1is substituted Ci-6 alkyl, and is optionally substituted with one substituent of -CONR'R" and is unsubstituted or substituted with 1-4 substituent(s) selected from the group consisting of D, halogen, -CN, Ci-6 alkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, and C1.4 deuterated alkyl.

7. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 3-5, whereinR1is8. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-7, wherein R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, or optionally substituted 3 to 10- membered heterocycloalkyl; optionally wherein the 3 to 10-membered cycloalkyl is cyclopropyl or cyclobutyl, and / or wherein the 3 to 10-membered heterocycloalkyl is a 4 to 5-membered heterocycloalkyl containing one heteroatom selected from O or S, optionally S, as a ring atom; wherein optionally substituted means unsubstituted or substituted with 1-4 substituents selected from the group consisting of D, halogen, -CN, -Ci-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, - C3-10 cycloalkyl, -3 to 10-membered heterocycloalkenyl, -Ce-io aryl, -5 to 10-membered heteroaryl, -C1.4 alkylene-C3.10 cycloalkyl, -C1.4 alkylene-C3.10 cycloalkenyl, -C1.4 alkylene-3 to 10-membered heterocycloalkyl, -C 1.4 alkylene-3 to 10-membered heterocycloalkenyl, -C1.4 alkylene-Ce-io aryl, and -C1.4 alkylene-5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of D, halogen, and Ci-6 alkyl; further optionally wherein optionally substituted means unsubstituted or substituted with 1-4 substituents selected from the group consisting of Ci-6 alkyl, Ce-io aryl, and 5 to 10- membered heteroaryl; wherein the aryl and heteroaryl is unsubstituted or substituted with 1-4 substituents selected from the group consisting of D, halogen, and Ci-6 alkyl.

9. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-8, wherein10. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-9, wherein A is optionally substituted 5 to 6-membered heteroarylene, wherein 1-3 atoms of the heteroarylene are each independently N, O or S, optionally wherein A is optionally substituted 5-membered heteroarylene, wherein 1-3 atoms of the heteroarylene are each independently N, O or S, optionally wherein 1 of the atom of the heteroarylene is an N and 1 atom of the heteroarylene is O or S;11. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-10, wherein when - between U and T is absent, T is absent, and U is optionally substituted Ci-6 alkyl, optionally substituted Ci-6 heteroalkyl, optionally substituted Ci-6 cycloalkyl, optionally substituted Ci-6 heterocycloalkyl, -C1.3 alkyl-O-Ci-6 alkyl, -C1.3 alkyl-O-Ci-6 cycloalkyl, or -C1.3 alkyl-O-Ci-6 heterocycloalkyl; wherein the C1.3 alkyl, Ci-6 alkyl, Ci-6 cycloalkyl, or Ci-6 heterocycloalkyl may be further optionally substituted; further optionally wherein U is12. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-11, whereinR13is each independently selected from -OR71or -NR73R74;R71, R73and R74are each independently, Ci-6 alkyl, Ci-6 heteroalkyl, or R73and R74combine to form a 3 to 10-membered heterocycloalkyl; wherein the Ci-6 alkyl, Ci-6 heteroalkyl and 3 to 10-membered heterocycloalkyl may be further optionally substituted,13. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt according to any one of claims 1-12, wherein X1is C;X2is -CRa-;X3is -CRb-;X4is -CRC-; and / orX5is -C-.

14. 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, wherein the compound is selected from any one of the compounds in Table 1.

15. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of claim 14, wherein the compound is selected from any one 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, 58, 59-123, 124-194 or 243-244 of Table 1.

16. The compound of any one of claims 1-15.

17. The pharmaceutically acceptable salt of any one of claims 1-15.

18. A pharmaceutical composition comprising the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable saltaccording to any one of claims 1 to 17 and a pharmaceutically acceptable carrier.

19. Use of the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt according to any one of claims 1 to 17, or the pharmaceutical composition according to claim 18, in the preparation of a medicament used for the treatment of cancer.

20. The compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1 to 17, or the pharmaceutical composition of claim 18, for use in treating cancer.

21. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, or solvate of the pharmaceutically acceptable salt of any one of claims 1-17, or the pharmaceutical composition of claim 18.

22. The use of claim 19, the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, solvate of the pharmaceutically acceptable salt, or pharmaceutical composition for use of claim 20, or the method of claim 21, 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 (NSCLC), cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, and squamous cell lung carcinoma, or a combination thereof.

23. The use of claim 19, the compound, stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, solvate, solvate of the pharmaceutically acceptable salt, or pharmaceutical composition for use of claim 20, or the method of claim 21,wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, and cholangiocarcinoma.

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