Condensed macrocyclic compounds as ras inhibitors for the treatment of cancer

Abstract

The present invention relates to condensed macrocyclic compounds and therapeutic uses thereof. The present invention discloses a compound of formula (I), or a stereoisomer, pharma- ceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharma- ceutically acceptable salt, and their use for the preparation of a medicament of treatment of cancer. Provided herein are compounds that function as inhibitors of RAS and RAS mutants. (I)

Description

CONDENSED MACROCYCLIC COMPOUNDS AS RAS INHIBITORS FOR THE TREATMENT OF CANCER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority from Application Nos. PCT / CN2024 / 124791, filed October 14, 2024, and PCT / CN2025 / 095776, filed May 19, 2025. The contents of these priority applications are incorporated by reference herein in their entirety. TECHNICAL FIELD

[0002] The present invention belongs to the field of medicine, and specifically relates to condensed macrocyclic compounds and their stereoisomers, as well as related pharmaceutically acceptable salts, solvates, eutectic forms, or deuterated compounds, and to their use in the treat- ment of RAS protein-mediated diseases. BACKGROUND

[0003] The RAS family (including KRAS4A, KRAS4B, HRAS, and NRAS) is a family of 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 RAS binds to a GEF family protein such as SOS1, its conformation changes, and its affinity for GDP is reduced. This causes RAS to dissociate from GDP and binding to GTP, 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 (and therefore activation of) RAS, 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.

[0004] RAS mutations occur in approximately 19% of all cancers and play an important role in tumor occurrence and progression. Among them, KRAS is the most commonly mutated subtype, followed by NRAS and HRAS. KRAS mutations commonly occur in pancreatic duc- tal adenocarcinoma, lung adenocarcinoma, and colorectal adenocarcinoma, while NRAS muta- tions have a relatively higher frequency in hematologic malignancies such as chronic myeloidleukemia and acute myeloid leukemia, as well as in malignant melanoma, thyroid cancer, and laryngeal cancer. HRAS mutations have a relatively higher mutation rate in head and neck squamous cell carcinoma, bladder cancer, salivary gland carcinoma, and oral cancer.

[0005] Given the key role of the RAS family of proteins in cancer occurrence and progres- sion, there remains a need for the development of RAS inhibitors. SUMMARY OF THE INVENTION

[0006] Provided herein are Ras inhibitors that function as molecular glues. The approach described herein entails formation of a high affinity three-component complex between a syn- thetic ligand, and two intracellular proteins that do not interact under normal physiological con- ditions – 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 high-affinity three-component complex between the Ras protein and the cytosolic chaperone, cyclophilin A. Without being bound by theory, the in- ventors believe that one way the inhibitory effect on Ras is effected by compounds of the in- vention 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 re- quired for propagating the oncogenic signal.

[0007] In the first aspect, the present invention provides a compound of formula (I):or a stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein is a double bond or single bond; n is 0, 1, 2, or 3;A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substi- tuted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; B is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substi- tuted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11-membered bicy- clic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; G is optionally substituted C1-6alkylene;between U and T is a bond (i.e.,is) or null (i.e., there is no bond between U and T); whenbetween U and T is a bond, U and T are each independently absent, a bond, O, S, -NR3, or optionally substituted C1-6alkylene; when between U and T is null, T is absent, and U is optionally substitutedC1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6heteroalkyl, option- ally substituted C3-6cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, op- tionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl; W and Q are each independently a linker; R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3alkyl; or R8and R9combine with the atoms to which they are at- tached to form an optionally substituted C3-6cycloalkyl or a carbonyl; R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3alkyl; or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6cycloalkyl or a carbonyl; R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, option- ally substituted C1-3alkyl, -O(optionally substituted C1-6alkyl), -S(optionally substituted C1-6alkyl) or -N(optionally substituted C1-6alkyl)(optionally substituted C1-6alkyl); RAis optionally substituted C3-6cycloalkyl, 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 option- ally substituted 8 to 10-membered fused bicyclic heteroaryl; RBis hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, optionally substituted C3-6cycloalkyl, or optionally substituted C3-6heterocycloalkyl (or 4 to 7-membered heterocycloalkyl); or, when n exceeds 1, any two of RBcombine with the atoms to which theyare attached to form a 3 to 6-membered ring, wherein the ring may be optionally substituted with halogen, hydroxy, or C1-3alkyl; 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, C1-3alkyl, C1-3alkoxyl, C1-3haloalkyl, C1-3haloalkoxyl, C3-6cycloalkyl, or C3-6heterocycloalkyl (or 4 to 7-membered heterocycloalkyl); R3is hydrogen, C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C3-6halocycloalkyl, - C(O)C1-3alkyl, -S(O2), or -S(O2)C1-3alkyl; E is absent, a bond, orwherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-3alkyl, optionally substituted C1-3alkoxyl, C1-3aminoalkyl, or C1-3hydroxyalkyl; R4is a bond, optionally substituted C1-6alkylene, optionally substituted C1-6het- eroalkylene, optionally substituted C1-6haloalkylene, optionally substituted C2-6alkenylene, op- tionally substituted C2-6haloalkenylene, optionally substituted C3-10cycloalkylene, optionally substituted C3-10cycloalkenylene, optionally substituted C3-10heterocycloalkylene (or 4 to 12- membered heterocycloalkylene), optionally substituted 6 to 10-membered arylene, optionally substituted 5 to 10-membered heteroarylene, or , optionally wherein R7is the at-tachment site to Q; R5is hydrogen, optionally substituted C1-6alkyl, or optionally substituted C3-6cyclo- alkyl; or E, R4and R5combine together to form a group of -Rr2- or -Rr1-Rr2-; wherein Rr1is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, or C1-2alkylene-N(C1-3alkyl); and Rr2is a ring selected from optionally substituted 3 to 10-membered cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, and optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; wherein L4is N(R6) or C(R6)2; L is absent, O, -CH2-, -C(O)-, -CHRg-, or -C(Rg)2-; wherein Rgis optionally substi- tuted C1-6alkyl. In some embodiments, L is O or -C(O)-. R6is each independently hydrogen or optionally substituted C1-6alkyl; R7is a bond, -R72-, or -R71-R72-; wherein R71is C1-3alkylene; and R72is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substi- tuted 6 to 10-membered arylene, or optionally substituted 5 to 10-membered heteroarylene; or L, N, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cy- cloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene.

[0008] In the second aspect, the present invention provides a pharmaceutical composition comprising the compound according to the first aspect, or a stereoisomer, pharmaceutically ac- ceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically ac- ceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] In the third aspect, the present invention provides a use of the compound according to the first aspect, or a stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, in the preparation of a medicament used for the treatment of cancer. DETAILED DESCRIPTION OF THE INVENTION

[0010] In one aspect, the present invention provides a compound of formula (I):or a stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0011] In some embodiments, L4is N(R6).

[0012] In some embodiments,. In some embodi- ments,

[0013] In some embodiments, L is absent, -CH2-, -C(O)-, -CHRg- or -C(Rg)2-; wherein Rgis optionally substituted C1-6alkyl. In some embodiments, L is -C(O)-.

[0014] In some embodiments, when L4is N(R6) (i.e., L is ab-sent, -CH2-, -C(O)-, -CHRg- or -C(Rg)2-; wherein Rgis optionally substituted C1-6alkyl. In some embodiments, L is -C(O)-.

[0015] In some embodiments, when L4is C(R6)2(i.e.,L is ab- sent, O, -CH2-, -C(O)-, -CHRg- or -C(Rg)2-; wherein Rgis optionally substituted C1-6alkyl. In some embodiments, L is -O-.

[0016] In some embodiments, B is optionally substituted 3 to 6-membered monocyclic het- erocycloalkylene, optionally substituted 3 to 6-membered monocyclic heterocycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene. In some embodiments, B is optionally substituted 3 to 6-membered monocyclic heterocycloalkylene or optionally substituted 4 to 11-membered bicyclic cycloalkylene.

[0017] In some embodiments, B is optionally substituted 3 to 6-membered heterocycloal- kylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4to 11-membered bicyclic alkylene, or optionally substituted 4 to 11-membered bicyclic het- eroalkylene.

[0018] In some embodiments, the compound of formula (I) is a compound of formula (I-1) or (I-2):

[0019] In some embodiments, B is

[0020] In some embodiments, B is optionally substituted or optionally substi-tuted

[0021] In some embodiments, B is, deuteratedor deuteratedIn some embodiments, B is

[0022] In some embodiments, W is a linker with a length of 1, 2, 3, or 4 chain atoms.

[0023] In some embodiments, W is a linker comprising 1, 2, 3, or 4 units selected from the group consisting of -O-, -NH-, -N(C1-4alkyl)-, -CH2-, -CH(C1-4alkyl)-, -CH(C3-6cycloalkyl)-, - C(O)-, and -S(O)2- (with provision that the composed linker is stable).

[0024] In some embodiments, W isIn some embodiments, W is optionally wherein W is connected to Evia -CO-.

[0025] In some embodiments, Q is a linker with a length of 1, 2, 3, 4, 5, 6, 7 or 8 chain at- oms. In some embodiments, Q is a linker with a length of 2, 3, 4, 5, or 6 chain atoms.

[0026] In some embodiments, Q is a linker comprising -(CH2)m-; wherein m is 1, 2, 3, 4, 5, 6, 7 or 8, optionally 2, 3, 4, 5, or 6, further optionally 2 or 3; and 0, 1, 2 or 3 -CH2- unit(s), op- tionally 0 or 1 -CH2- unit, in the linker is replaced with -O- or -NH-.

[0027] In some embodiments, Q is a linker of -(CH2)m-; wherein m is 1, 2, 3, 4, 5, 6, 7 or 8, optionally 2, 3, 4, 5, or 6, further optionally is 2 or 3; and 1, 2 or 3 -CH2- unit(s), optionally 1 or 2 -CH2- units, further optionally 1 -CH2- unit, in the linker is replaced with -O- or -NH-.

[0028] In some embodiments, in Q, at least one -CH2- unit in the linker is unreplaced.

[0029] In some embodiments, Q is -O-, -NH-, -(CH2)m2-, -(CH2)m1-O-(CH2)m2-, -(CH2)m1- NH-(CH2)m2-, -(CH2)m1-O-(CH2)m2-O-(CH2)m3-, -(CH2)m1-NH-(CH2)m2-O-(CH2)m3-, or - (CH2)m1-NH-(CH2)m2-NH-(CH2)m3-; wherein m1 and m3 are each independently 0 or 1, m2 is1, 2, 3, 4, 5, 6, 7 or 8 (optionally 1 or 2), with the provision that m1+m2+m3 is 1, 2, 3, 4, 5, 6, 7 or 8 (optionally 2, 3 or 4).

[0030] In some embodiments, R8and R9are each independently hydrogen, deuterium, hal- ogen, hydroxy, cyano, or optionally substituted C1-3alkyl; or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6cycloalkyl or a carbonyl. In some embodiments, R8and R9are hydrogen.

[0031] In some embodiments, R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3alkyl; or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6cycloalkyl or a car- bonyl. In some embodiments, R10and R11are hydrogen.

[0032] In some embodiments, R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1-3alkyl, -O(optionally substituted C1-6alkyl), -S(op- tionally substituted C1-6alkyl) or -N(optionally substituted C1-6alkyl)( optionally substituted C1-6alkyl). In some embodiments, R12and R13are hydrogen.

[0033] In some embodiments, RAis optionally substituted C3-6cycloalkyl, optionally sub- stituted 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.

[0034] In some embodiments, in RA, optionally substituted means unsubstitued or substit- ued with one or more of R2, RM, RN, R1aor

[0035] In some embodiments, RAis

[0036] In some embodiments, R1ais hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, option- ally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, and C1-6hydroxyalkyl may be further optionally substituted.

[0037] In some embodiments, R1ais optionally substituted C2-4alkynyl. In some embodi- ments, R1ais

[0038] In some embodiments, RAis

[0039] In some embodiments, R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, option- ally 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-mem- bered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2alkylene- alkylamino, optionally substituted -C1-2alkylene-C3-6cy- cloalkyl, optionally substituted -C1-2alkylene-3 to 6-membered heterocycloalkyl, optionally substituted -C1-2alkylene-5 to 8-membered aryl, optionally substituted -C1-2alkylene-5 to 8- membered heteroaryl, optionally substituted -C1-2alkylene-8 to 10-membered fused bicyclic aryl, or optionally substituted -C1-2alkylene-8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl may be further optionally substituted.

[0040] In some embodiments, R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, option- ally 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-mem- bered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -methylene-alkylamino, optionally substituted -methylene-C3-6cycloal- kyl, optionally substituted -methylene-3 to 6-membered heterocycloalkyl, optionally substi- tuted -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 option- ally substituted -methylene-8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6alkyl,C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl may be further optionally sub- stituted.

[0041] In some embodiments, R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, option- ally 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-mem- bered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2alkylene-C3-6cycloalkyl, optionally substituted -C1-2alkylene-3 to 6- membered heterocycloalkyl, optionally substituted -C1-2alkylene-5 to 8-membered aryl, option- ally substituted -C1-2alkylene-5 to 8-membered heteroaryl, optionally substituted -C1-2alkylene- 8 to 10-membered fused bicyclic aryl, or optionally substituted -C1-2alkylene-8 to 10-mem- bered fused bicyclic heteroaryl. In some embodiments, R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, 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, R1is optionally substituted C1-6alkyl, optionally substituted C1-6alkoxyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6haloalkoxyl, or optionally substituted C1-6hydroxyalkyl.

[0042] In some embodiments, R1is optionally substituted -C1-2alkylene-3 to 6-membered heterocycloalkyl; optionally wherein the 3 to 6-membered heterocycloalkyl has a structure of wherein n1and n2are each independently 1, 2 or 3, optionallywherein n1and n2are both 2, and ZRAis O, S or NH; optionally wherein C1-2alkylene is -CH2- or –CH(CH3)-; wherein, 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, halo- gen, -CN, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and C1-4deuterated alkyl, optionally with one or more (such as 1, 2, 3, or 4) substituent(s) selected from the group consisting of D and C1-6alkyl.

[0043] In some embodiments, R1’is optionally substituted 3 to 6-membered heterocycloal- kyl; optionally wherein the 3 to 6-membered heterocycloalkyl has a structure ofwherein n1and n2are each independently 1, 2 or 3, optionally wherein n1and n2are both 2, and ZRAis O, S or NH.

[0044] In some embodiments, R1is substituted C1-6alkyl, optionally wherein the C1-6alkyl is substituted with one substituent of -CONRiRiiand 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, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and C1-4deuterated alkyl.

[0045] In some embodiments, in R1, when the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, or C1-6hydroxyalkyl, optionally the C1-6alkyl, is further substituted, the substitu- ent is C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoal- kyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6heterocycloalkyl, option- ally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, op- tionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10- membered fused bicyclic heteroaryl. In some embodiments, the substituent is optionally substi- tuted C3-6cycloalkyl, optionally substituted C3-6heterocycloalkyl, 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 is optionally substituted C3-6heterocycloal- kyl.

[0046] In some embodiments, in R1, optionally substituted means unsubstituted or being substituted with one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of deuterium, halogen, C1-6alkyl, C1-6hydroxyalkyl, C1-6deuteroalkyl, and -C(O)-C1-6alkyl.

[0047] In some embodiments, R1’is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, option- ally 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-mem- bered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl;wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl may be further optionally substituted.

[0048] In some embodiments, RMand RNare each independently hydrogen, halogen, hy- droxy, cyano, carboxyl, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxy- alkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3 to 6- membered heterocycloalkyl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloal- koxyl, C1-6hydroxyalkyl may be further optionally substituted.

[0049] In some embodiments, RMand RNare each independently hydrogen or C1-6alkyl.

[0050] In some embodiments, Y is -CH- or N. In some embodiments, Y is N.

[0051] In some embodiments, R2is optionally substituted C1-6alkoxy or optionally substi- tuted C1-6alkyl. In some embodiments, R2is optionally substituted C1-6alkyl.

[0052] In some embodiments, in R2, optionally substituted means unsubstituted or being substituted with one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of deuterium, C1-6alkoxy, C1-6deuteroalkoxy, and C1-6haloalkoxy.

[0053] In some embodiments, R2is C1-6alkyl substituted with one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of deuterium, C1-6alkoxy, C1-6deuteroalkoxy, and C1-6haloalkoxy.

[0054] In some embodiments, B isRAis optionally substituted phenyl or optionally substituted 6-membered heteroaryl.

[0055] In some embodiments, R8, R9, R10, R11, R12and R13are each independently hydro- gen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3alkyl. In some embodi- ments, R8, R9, R10, R11, R12and R13are each independently hydrogen.

[0056] In some embodiments, the compound of formula (I) is a compound of formula (I-3):

[0057] In some embodiments, the compound of the present invention is a compound of for- mula (II):wherein A, B, G, U, T, Y, E, Q, X1, X2, X3, X4, X5, X6, R1a, R2, RM, RN, R4and R5are defined as above.

[0058] In some embodiments, the compound of formula (II) is a compound of formula (II- 1) or formula (II-2):

[0059] In some embodiments, the compound of formula (II) is a compound of formula (IIa) or formula (IIb):wherein A, G, U, T, Y, E, Q, X1, X2, X3, X4, X5, X6, R1a, R2, RM, RN, R4, and R5are defined as above.

[0060] In some embodiments, the compound of formula (IIa) is a compound of formula (IIa-1) or (IIa-2):

[0061] In some embodiments, the compound of formula (IIb) is a compound of formula (IIb-1) or (IIb-2):

[0062] In some embodiments, in formula (IIa) or (IIb),A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substi- tuted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; and / or G is optionally substituted C1-6alkylene; and / or between U and T is a bond or null; when between U and T is a bond, U or T is absent, or they are each inde- pendently O, S, -NR3or optionally substituted C1-6alkylene; when between U and T is null, T is absent, and U is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6heteroalkyl, option- ally substituted C3-6cycloalkyl, optionally substituted 3 to 6-membered C1-6heterocycloalkyl, optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl; and / or Q is a linker; and / or Y is -CH- or N; and / or X1is N or C; and / or X2is N or -CRa-; and / or X3is N or -CRb-; and / or X4is N or C; and / or X5is N or C; and / or X6is N or C; and / or Raand Rbare each independently hydrogen, halogen, cyano, C1-3alkyl, C1-3alkoxyl, C1-3haloalkyl, C1-3haloalkoxyl, C3-6cycloalkyl, or 3 to 6-membered heterocycloalkyl; and / or R1ais hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hy- droxyalkyl, C1-6aminoalkyl, optionally substituted C2-4alkynyl, optionally substituted C3-6cy- cloalkyl, 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 C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, and C1-6hy- droxyalkyl may be further optionally substituted; and / or R2is optionally substituted C1-6alkoxy or optionally substituted C1-6alkyl; and / or RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, op- tionally substituted C3-6cycloalkyl, or optionally substituted 3 to 6-memberedheterocycloalkyl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, and C1-6hydroxyalkyl may be further optionally substituted; and / or R3is hydrogen, C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C3-6halocycloalkyl, - C(O)C1-3alkyl, -S(O2), or -S(O2)C1-3alkyl; and / or E is absent, a bond, or; wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-3alkyl, optionally substituted C1-3alkoxyl, C1-3aminoalkyl, or C1-3hydroxyalkyl; and / or R4is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C1-6haloalkylene, optionally substituted C2-6alkenylene, optionally sub- stituted C2-6haloalkenylene, optionally substituted C3-10cycloalkylene, optionally substituted C3-10cycloalkenylene, optionally substituted C3-10heterocycloalkylene (or 4 to 12-membered heterocycloalkylene), optionally substituted 6 to 10-membered arylene, optionally substituted 5 to 10-membered heteroarylene, orand / or R5is hydrogen, optionally substituted C1-6alkyl, or optionally substituted C3-6cyclo- alkyl; or E, R4and R5combine together to form a group of -Rr2- or -Rr1-Rr2-; wherein Rr1is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, or C1-2alkylene-N(C1-3alkyl); and Rr2is optionally substituted 3 to 10-membered cycloalkylene, optionally substi- tuted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloal- kenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substi- tuted 4 to 11-membered bicyclic heterocycloalkylene; wherein L4is N(R6) or C(R6)2; L is absent, -CH2-, -C(O)-, -CHRg, - or -C(Rg)2-, wherein Rgis optionally substi- tuted C1-6alkyl; and / or R6is hydrogen or optionally substituted C1-6alkyl; and / or R7is a bond, -R72- or -R71-R72-; wherein R71is C1-3alkylene; and R72is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substi- tuted 6 to 10-membered arylene, or optionally substituted 5 to 10-membered heteroarylene; or L, N, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cy- cloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene.

[0063] In some embodiments, X1is C; and / or X2is -CRa-, optionally -CH- or -CF-; and / or X3is -CRb-, optionally -CH- or -CF-; and / or X4is C; and / or X5is C.

[0064] In some embodiments, Raand Rbare each independently hydrogen, halogen, cyano, C1-3alkyl, C1-3alkoxyl, C1-3haloalkyl, or C1-3haloalkoxyl. In some embodiments, Raand Rbare each independently hydrogen or C1-3alkyl.

[0065] In some embodiments, X1, X2, X3, X4and X5are -CH-; RMand RNare hydrogen.

[0066] In some embodiments, X6is N or C. In some embodiments, X6is N.

[0067] In some embodiments, when between U and T is a bond, U and T are each independently O, S, -NR3or optionally substituted C1-6alkylene.

[0068] In some embodiments, when between U and T is a bond, U is optionally substituted C1-6alkylene, and T is O or optionally substituted C1-6alkylene.

[0069] In some embodiments, when 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.

[0070] In some embodiments, substituent for U is selected from C1-4alkyl, halogen, and hydroxyl; and / or substituent for T is selected from C1-4alkyl and halogen (e.g., F).

[0071] In some embodiments, when between U and T is a bond, U is C1-6alkylene or C1-6haloalkylene, and T is O or C1-6alkylene.

[0072] In some embodiments, when between U and T is null, T is absent, and U is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6heteroalkyl, optionally substituted C3-6cycloalkyl, optionally substituted 4 to 6-membered heterocycloalkyl, optionally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl.

[0073] In some embodiments, when between U and T is null, T is absent, and U is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6heteroalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4 to 6-membered heterocycloalkyl.

[0074] In some embodiments, when between U and T is null, T is absent, and U is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, or optionally substituted C1-6heteroalkyl; optionally wherein at least one hereoatom in the heteroalkyl is O.

[0075] In some embodiments, the compound of the present invention is a compound of for- mula (III):wherein A, B, G, U, T, Y, E, Q, n, X1, X2, X3, X4, X5, X6, RB, R1, R2, RM, RN, R4and R5are de- fined as above.

[0076] In some embodiments, the compound of formula (III) is a compound of formula (IIIa) or formula (IIIb):wherein A, G, U, T, Y, E, Q, Ra, Rb, X6, R1, R2, R4, and R5are defined as above.

[0077] In some embodiments, the compound of formula (IIIa) is a compound of formula (IIIa-1) or (IIIa-2), and the compound of formula (IIIb) is a compound of formula (IIIb-1) or (IIIb-2):

[0078] In some embodiments, in formula (IIIa) or (IIIb), A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substi- tuted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; and / or G is optionally substituted C1-6alkylene; and / or between U and T is a bond or null; when between U and T is a bond, U or T is absent, or they are each inde- pendently O, S, -NR3or optionally substituted C1-6alkylene; when between U and T is null, T is absent, and U is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, or optionally substituted C1-6heteroalkyl; and / or Q is a linker; and / or Y is -CH- or N; and / or X6is N or -CH-; and / orRaand Rbare each independently hydrogen, halogen, cyano, C1-3alkyl, C1-3alkoxyl, C1-3haloalkyl, C1-3haloalkoxyl, C3-6cycloalkyl, or 3 to 6-membered heterocycloalkyl; and / or R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydrox- yalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substi- tuted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, and C1-6hydroxyalkyl may be further optionally substituted; and / or R2is optionally substituted C1-6alkoxy or optionally substituted C1-6alkyl; and / or R3is hydrogen, C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C3-6halocycloalkyl, - C(O)C1-3alkyl, -S(O2), or -S(O2)C1-3alkyl; and / or E is absent, a bond, or; wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-3alkyl, optionally substituted C1-3alkoxyl, C1-3aminoalkyl, or C1-3hydroxyalkyl; and / or R4is a bond, -R42- or -R41-R42-; wherein R41is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, or C1-2alkylene-N(C1-3alkyl); and R42is optionally substi- tuted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C1-6haloal- kylene, optionally substituted C2-6alkenylene, optionally substituted C2-6haloalkenylene, op- tionally substituted C3-10cycloalkylene, optionally substituted C3-10cycloalkenylene, optionally substituted C3-10heterocycloalkylene (or 4 to 12-membered heterocycloalkylene), optionally substituted 6 to 10-membered arylene, optionally substituted 5 to 10-membered heteroarylene,R5is hydrogen, optionally substituted C1-6alkyl, or optionally substituted C3-6cyclo- alkyl; or E, R4and R5combine together to form a group of -Rr2- or -Rr1-Rr2-; wherein Rr1is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, or C1-2alkylene-N(C1-3alkyl); and Rr2is a ring selected from optionally substituted 3 to 10-membered cycloalkylene,optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6- membered cycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, and optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; and / or wherein L4is N(R6) or C(R6)2; L is absent, -CH2-, -C(O)-, -CHRg-, or -C(Rg)2-, wherein Rgis optionally substituted C1-6alkyl; and / or R6is hydrogen or optionally substituted C1-6alkyl; and / or R7is a bond, -R72- or -R71-R72-; wherein R71is C1-3alkylene; and R72is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substi- tuted 6 to 10-membered arylene, or optionally substituted 5 to 10-membered heteroarylene; or L, N, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cy- cloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene. Furthermore, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered het- eroarylene, C3-5 heterocycloalkyl (or 4 to 6-membered heterocycloalkyl), 3 to 6-membered het- erocycloalkyl, 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, C1-6heteroalkyl, C3-10heterocycloalkyl, 5 to 10-membered heteroaryl, 3 to 10-membered heterocy- cloalkyl, or 4 to 11-membered bicyclic heterocycloalkyl, the heteroatom is independently se- lected from one or more of N, O and S, and the number of heteroatoms is independently 1 to 4.

[0079] In some embodiments, the compound of the present invention is a compound of formula (IVaa) or formula (IVab):optionally, the compound of formula (IVaa) is a compound of formula (IVaa-1) or (IVaa-2), and the compound of formula (IVab) is a compound of formula (IVab-1) or (IVab-2)wherein A, G, U, T, Y, E, Q, Ra, Rb, X6, R1, R2, R4, and R5are defined as above.

[0080] In some embodiments, the compound of the present invention is a compound of for- mula (IVba) or formula (IVbb):optionally, the compound of formula (IVba) is a compound of formula (IVba-1) or (IVba-2), and the compound of formula (IVbb) is a compound of formula (IVbb-1) or (IVbb-2)wherein A, G, U, T, Y, E, Q, Ra, Rb, X6, R1, R2, R4, and R5are defined as above.

[0081] In some embodiments, in formula (IVaa), (IVab), (IVba), or (IVbb), A is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substi- tuted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene; and / or G is optionally substituted C1-6alkylene; and / or between U and T is a bond or null;when between U and T is a bond, U or T is absent, or they are each inde- pendently O, S, -NR3or optionally substituted C1-6alkylene; when between U and T is null, T is absent, and U is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, or optionally substituted C1-6heteroalkyl; and / or Q is a linker; and / or Y is -CH- or N; and / or X6is N or -CH-; and / or Raand Rbare each independently hydrogen, halogen, cyano, C1-3alkyl, C1-3alkoxyl, C1-3haloalkyl, C1-3haloalkoxyl, C3-6cycloalkyl, or 3 to 6-membered heterocycloalkyl; and / or R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydrox- yalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substi- tuted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl may be further optionally sub- stituted; and / or R2is optionally substituted C1-6alkoxy or optionally substituted C1-6alkyl; and / or R3is hydrogen, C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C3-6halocycloalkyl, - C(O)C1-3alkyl, -S(O2), or -S(O2)C1-3alkyl; and / or E is absent, a bond, or wherein Rdis hydrogen, halogen, hydroxy, cyano,carboxyl, optionally substituted C1-3alkyl, optionally substituted C1-3alkoxyl, C1-3aminoalkyl, or C1-3hydroxyalkyl; and / or R4is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C1-6haloalkylene, optionally substituted C2-6alkenylene, optionally sub- stituted C2-6haloalkenylene, optionally substituted C3-10cycloalkylene, optionally substituted C3-10cycloalkenylene, optionally substituted C3-10heterocycloalkylene (or 4 to 12-memberedheterocycloalkylene), optionally substituted 6 to 10-membered arylene, optionally substituted 5 to 10-membered heteroarylene, or ; and / orR5is hydrogen, optionally substituted C1-6alkyl, or optionally substituted C3-6cyclo- alkyl; or E, R4and R5combine together to form a group of -Rr2- or -Rr1-Rr2-; wherein Rr1is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, or C1-2alkylene-N(C1-3alkyl); and Rr2is a ring selected from optionally substituted 3 to 10-membered cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6- membered cycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, and optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; and / or wherein L4is N(R6) or C(R6)2; L is absent, -CH2-, -C(O)-, -CHRg-, or -C(Rg)2-, wherein Rgis optionally substituted C1-6alkyl; and / or R6is hydrogen or optionally substituted C1-6alkyl; and / or R7is a bond, -R72- or -R71-R72-; wherein R71is C1-3alkylene; and R72is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substi- tuted 6 to 10-membered arylene, or optionally substituted 5 to 10-membered heteroarylene; or L, N, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cy- cloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene.

[0082] Furthermore, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered het- eroarylene, C3-5heterocycloalkyl, 3 to 6-membered heterocycloalkyl, 5 to 6-membered het- eroaryl, 8 to 10-membered fused bicyclic heteroaryl, C1-6heteroalkyl, C3-10heterocycloalkyl (or 3 to 10-membered heterocycyoalkyl), 5 to 10-membered heteroaryl, 3 to 10-membered hetero- cycloalkyl or 4 to 11-membered bicyclic heteroalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1 to 4.

[0083] In some embodiments, the 5 to 6-membered heterocycloalkylene contains one or two heteroatoms; optionally wherein the heteroatom is each independently N, O, or S.

[0084] In some embodiments, A is optionally substituted 5 to 6-membered heterocycloal- kylene, the heteroatom is independently one or two of N, O, and S, and the number of heteroa- toms is independently 1 or 2.

[0085] In some embodiments, in A, the optionally substituted 5 to 6-membered heterocy- cloalkylene is

[0086] In some embodiments, A is optionally substituted 5 to 6-membered arylene.

[0087] In some embodiments, in A, the optionally substituted 5 to 6-membered arylene is, , In some embodiments, the optionally substi- tuted 5 to 6-membered arylene in A is

[0088] In some embodiments, the 5 to 6-membered heteroarylene contains one, two or three (optionally one or two) heteroatoms; optionally wherein the heteroatom is each inde- pendently N, O, or S.

[0089] In some embodiments, A is optionally substituted 5 to 6-membered heteroarylene, optionally wherein the heteroatom is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1 to 3.

[0090] In some embodiments, the optionally substituted 5 to 6-membered heteroarylene in

[0091] In some embodiments, A In someembodiments, A is

[0092] In some embodiments, G is optionally substituted C1-6alkylene. In some embodi- ments, G is optionally substituted -C(C1-3alkyl)2-. In some embodiments, G is -C(C1-3alkyl)2-.

[0093] In some embodiments, in G, optionally substituted means unsubstitued or being substituted with one or more deuterium.

[0094] In some embodiments, G is

[0095] In some embodiments, when between U and T is a bond, U or T is absent, or they are each independently O, S, -NR3- or optionally substituted C1-6alkylene.

[0096] In some embodiments, when between U and T is a bond, U is optionally substituted C1-6alkylene; optionally wherein U is -CH2CH2-, -CH2CHOH-, or -CH2C(CH3)2-.

[0097] In some embodiments, when between U and T is a bond, T is O or option- ally substituted C1-6alkylene. In some embodiments, T is O or optionally substituted meth- ylene. In some embodiments, T is O, -CH2- or -CF2-.

[0098] In some embodiments, in U and T, optionally substituted means unsubstitued or substituted with one or more substituents selected from deuterium, hydroxy, halogen (e.g., F) and C1-4alkyl.

[0099] In some embodiments, Y is N.

[0100] In some embodiments, X6is N.

[0101] In some embodiments, R1is C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, or optionally substi- tuted 3 to 6-membered heterocycloalkyl.

[0102] In some embodiments, when between U and T is null, T is absent, and U is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 4 to 6 membered heterocycloalkyl.

[0103] In some embodiments, when between U and T is null, U is

[0104] In some embodiments, R1is

[0105] In some embodiments, R1is optionally substituted -C1-2alkylene- alkylamino, op- tionally substituted -C1-2alkylene-C3-6cycloalkyl, or optionally substituted - C1-2alkylene-3 to 6- membered heterocycloalkyl.

[0106] In some embodiments, substituents for R1is D, halogen, C1-6alkyl, C1-6deuteroal- kyl, C1-6hydroxyalkyl, -C(O)-C1-6alkyl, C3-10cycloalkyl, or 3 to 10-membered het-erocycloalkyl.

[0107] In some embodiments, R1is

[0108] In some embodiments, R1is optionally substituted 4 to 5-membered heteroalkyl or 5 to 6-membered heteroaryl.

[0109] In some embodiments, substituents for R1is D, halogen, C1-6alkyl, C1-6deuteroal- kyl, or C1-6hydroxyalkyl; or two substituents on the same atom or adjacent atoms together with the atoms to which they are attached form C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-mem- bered heterocycloalkyl, or 3 to 10-membered heterocycloalkenyl.

[0110] In some embodiments, R1is

[0111] 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 bicy- clic aryl or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; optionally wherein the heteroatom is independently selected from one or two of N, O and S, and the num- ber of heteroatoms is independently 1 to 4.

[0112] In some embodiments, R1is

[0113] In some embodiments, R2is optionally substituted C1-6alkyl or optionally substi- tuted C1-6 alkoxy. In some embodiments, R2is , optionally

[0114] In some embodiments, R3is hydrogen, C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C3-6halocycloalkyl, -C(O)C1-3alkyl, -S(O2), or -S(O2)C1-3alkyl.

[0115] In some embodiments, R3is C1-3alkyl. In some embodiments, R3is C1-6deuterated alkyl. In some embodiments, R3is

[0116] In some embodiments, R3is C1-3haloalkyl. In some embodiments, R3is

[0117] In some embodiments, R3is C3-6cycloalkyl. In some embodiments, R3is

[0118] In some embodiments, R3is C3-6halocycloalkyl. In some embodiments, R3is

[0119] In some embodiments, R3is -C(O)C1-3alkyl. In some embodiments, R3is.

[0120] In some embodiments, R3is -S(O2)C1-3alkyl. In some embodiments, R3is

[0121] In some embodiments, E is absent, a bond, orwherein Rdis hydrogen, hal- ogen, hydroxy, cyano, carboxyl, optionally substituted C1-3alkyl, optionally substituted C1-3alkoxyl, C1-3aminoalkyl, or C1-3hydroxyalkyl. In some embodiments, E is absent, a bond, orwherein Rdis optionally substituted C1-3alkyl, optionally substituted C1-3alkoxyl, C1-3aminoalkyl, or C1-3hydroxyalkyl.

[0122] In some embodiments, Rdis halogen. In some embodiments, Rdis -F, -Cl, -Br or -I. In some embodiments, Rdis -F.

[0123] In some embodiments, Rdis C1-6alkyl. In some embodiments, Rdis

[0124] In some embodiments, Rdis C1-6haloalkyl. In some embodiments, Rdis -CF3.

[0125] In some embodiments, Rdis C1-6alkoxyl. In some embodiments, Rdis

[0126] In some embodiments, Rdis C1-6aminoalkyl. In some embodiments, Rdis

[0127] In some embodiments, E is absent or a bond.

[0128] In some embodiments, E is ; wherein Rdis hydrogen, optionally wherein R5is C1-6alkyl.

[0129] In some embodiments, E iswherein Rdis C1-6alkyl, optionally wherein R5is hydrogen.

[0130] In some embodiments, L is -CH2-, -C(O)-, -CHRg-, or -C(Rg)2-, wherein Rgis op- tionally substituted C1-6alkyl. In some embodiments, L is -C(O)-.

[0131] In some embodiments, R4is optionally substituted C1-6alkylene, optionally substi- tuted C1-6heteroalkylene, optionally substituted C1-6haloalkylene, optionally substituted C2-6alkenylene, optionally substituted C2-6haloalkenylene, optionally substituted C3-10cycloal- kylene, optionally substituted C3-10cycloalkenylene, optionally substituted C3-10heterocycloal- kylene (or 4 to 12-membered heterocycloalkylene), optionally substituted 6 to 10-membered arylene, optionally substituted 5 to 10-membered heteroarylene, or. In some em- bodiments, R4is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene,

[0132] In some embodiments, R7is the attachment site to Q.

[0133] In some embodiments, R7is optionally substituted C1-6alkylene, optionally substi- tuted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 6 to 10-membered arylene, or option- ally substituted 5 to 10-membered heteroarylene.

[0134] In some embodiments, R6is hydrogen or optionally substituted C1-6alkyl. In some embodiments, R6is hydrogen or C1-6alkyl. In some embodiments, R6is C1-6alkyl.

[0135] In some embodiments, R7is optionally substituted C1-6alkylene, optionally substi- tuted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 6 to 10-membered arylene, or option- ally substituted 5 to 10-membered heteroarylene. In some embodiments, R7is C1-6alkylene, op- tionally substituted C3-10cycloalkylene, or optionally substituted 3 to 10-membered heterocy- cloalkylene.

[0136] In some embodiments, R4is optionally substituted C1-6alkylene, optionally substi- tuted C1-6heteroalkylene, optionally substituted C1-6haloalkylene, optionally substituted C2-6alkenylene, optionally substituted C2-6haloalkenylene, optionally substituted C3-10cycloal- kylene, optionally substituted C3-10cycloalkenylene, optionally substituted C3-10heterocycloal- kylene (or 4 to 12-membered heterocycloalkylene), optionally substituted 6 to 10-membered arylene, optionally substituted 5 to 10-membered heteroarylene, or In some em-bodiments, R4is wherein R6is hydrogen or optionally substi-tuted C1-6alkyl; R7is optionally substituted C1-6alkylene, optionally substituted C1-6heteroal- kylene, optionally substituted C3-10cycloalkylene, optionally substituted C3-10heterocycloal- kylene, optionally substituted 6 to 10-membered arylene, or optionally substituted 5 to 10- membered heteroarylene.

[0137] In some embodiments, in R4, optionally substituted means unsubstituted or substi- tuted by one or more substituents selected from the group consisting of hydroxyl, cyano, halo- gen, and C1-6alkyl. In some embodiments, R4is C1-6alkylene, 3 to 6-membered heterocycloal- kylene, 3 to 6-membered cycloalkylene, 6 to 10-membered arylene, 5 to 10-membered het- eroarylene, or(optionally6wherein R is each independently hydrogen or C1-6alkyl; and R7is C1-6alkylene or 3 to 10-membered heterocyclo- alkylene; wherein the 3 to 10-membered heterocycloalkylene is optionally substituted by C1-6alkyl, 6 to 10-membered aryl, -CO-O-C3-6cycloalkyl or -CO-O-C1-6alkyl; the 3 to 6-membered cycloalkylene is optionally substituted by hydroxyl, cyano, halogen, or C1-6alkyl; in 3 to 10- membered heterocycloalkylene, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1 to 3. In some embodiments, R4is C1-6alkylene or (optionally wherein R6iseach independently hydrogen or C1-6alkyl; R7is C1-6alkylene or 3 to 10-membered heterocy- cloalkylene.

[0138] In some embodiments, in R4, C3-10heterocycloalkylene (or 4 to 12-membered heter- ocycloalkylene) contains 1 or 2 heteroatoms selected from the group consisting of N, O and S.

[0139] In some embodiments, R4is optionally substituted C1-6alkylene, optionally substi- tuted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, or optionally substituted C3-10heterocycloalkylene; the heteroatom is N, O or S, and the number of heteroatoms is inde- pendently 1 or 2. In some embodiments, in R4, the optionally substituted C1-6alkylene, option- ally substituted C1-6heteroalkylene, optionally substituted C3-10cycloalkylene, or optionally substituted C3-10heterocycloalkylene is

[0140] In some embodiments, R4is optionally substituted 6 to 10-membered aryl or option- ally substituted 5 to 10-membered heteroaryl. In some embodiments, in R4, is the optionally substituted 6 to 10-membered aryl or optionally substituted 5 to 10-membered heteroaryl is

[0141] In some embodiments, R5is optionally substituted C1-6alkyl. In some embodiments, in R5, the optionally substituted C1-6alkyl is optionally

[0142] In some embodiments, R5is optionally substituted C3-6cycloalkyl. In some embodi- ments, in R5, the optionally substituted C3-6cycloalkyl is

[0143] In some embodiments, in the ring formed by R4, R5and E, the heterocycloalkyl or the bicyclic heterocycloalkyl contains 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S.

[0144] In some embodiments, E, R4and R5combine together to form a group of -Rr2- or - Rr1-Rr2-; wherein Rr1is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, or C1-2alkylene-N(C1-3alkyl); and Rr2is a ring selected from optionally substituted 3 to 10- membered cycloalkylene, optionally substituted 3 to 10-membered heterocycloalkylene,optionally substituted 4 to 11-membered bicyclic cycloalkylene, and optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; the heteroatom is N, O or S; and the number of heteroatoms is independently 1 to 3; optionally wherein the ring (Rr2) isfurther op- tionally or

[0145] In some embodiments, E, R4and R5combine together to form a ring as defined for Rr2(i.e., E, R4and R5combine together to form Rr2).

[0146] In some embodiments, E, R4and R5combine together to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkylene. In some embodiments, the ring is optionally substituted 3 to 4-membered cycloalkylene. In some embodiments, the ring is op- tionally substituted cyclopropylene; wherein optionally substituted means unsubstituted or sub- stituted with one or more substituents selected from the group consisting of C1-4alkyl, C1-4deu- teroalkyl, cyano, C1-4hydroxyalkyl, and C1-4haloalkyl.

[0147] In some embodiments, E, R4and R5combine together to form Rr2, and Rr2is optionally

[0148] In some embodiments, R6is optionally substituted C1-6alkyl. In some embodiments, R6isor .

[0149] In some embodiments, R7is optionally substituted C3-10cycloalkylene or optionally substituted C3-10heterocycloalkylene.

[0150] In some embodiments, in R7, substituents for C3-10heterocycloalkylene are selected from the group consisting of C1-6alkyl, 6 to 10-membered aryl, -CO-O-C3-6cycloalkyl and - CO-O-C1-6alkyl, and / or substituents for C3-10cycloalkylene are selected from the group con- sisting of hydroxyl, cyano, halogen, and C1-6alkyl.

[0151] In some embodiments, in R7, C3-10heterocycloalkylene contains 1 to 3 heteroatoms selected from the group consisting of N, O and S.

[0152] In some embodiments, R7is optionally substituted C3-10cycloalkylene or optionally substituted C3-10heterocycloalkylene, optionally wherein the C3-10heterocycloalkylene isoptionally substituted by C1-6alkyl, C6-10aryl , -CO-O-C3-6cycloalkyl, or -CO-O-C1-6alkyl; the C3-10cycloalkylene is optionally substituted by hydroxyl, cyano, halogen, or C1-6alkyl; in C3-10heterocycloalkylene, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1 to 3.

[0153] In some embodiments, R7is a bond.

[0154] In some embodiments, R7is optionally substituted C1-6alkylene.

[0155] In some embodiments, R7is -CH(R74)-C0-5 alkylene and -CH(R74)- is the attachment to L; wherein R74is H or defined as the substituents for C1-6alkylene in R7.

[0156] In some embodiments, in R7, substituents for C1-6alkylene is selected from the group consisting of optionally substituted C1-6aminoalkyl, optionally substituted C1-6alkyl, op- tionally substituted -NH-C(O)-C1-6alkyl, optionally substituted -N(C1-3alkyl)-C(O)-C1-6alkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3 to 10-membered heterocycloal- kyl, optionally substituted -NH-C(O)-C3-10cycloalkyl, optionally substituted -NH-C(O)-3 to 10-membered heterocycloalkyl, optionally substituted -N(C1-3alkyl)-C(O)-C3-10cycloalkyl, and optionally substituted -N(C1-3alkyl)-C(O)-3 to 10-membered heterocycloalkyl; wherein option- ally substituted means unsubstituted or substituted by one or more substituents selected from the group consisting of D, halogen, -CN, Ri, -C(O)Ri-S(O)Ri, and -S(O)2R; wherein Riis C1-6alkyl, -C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and 3 to 10-membered heterocycloalky; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalky is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atoms in the group is substituted with substituents selected from the group consisting of D, halogen, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hy- droxyalkyl, C1-6aminoalkyl, alkylamino, and C3-6cycloalkyl.

[0157] In some embodiments, whenR74is H or optionally substituted -NH-C(O)-C1-6alkyl, optionally substituted -N(C1-3alkyl)-C(O)-C1-6alkyl, option- ally substituted -NH-C(O)-C3-10cycloalkyl, optionally substituted -NH-C(O)-3 to 10-mem- bered heterocycloalkyl, optionally substituted -N(C1-3alkyl)-C(O)-C3-10cycloalkyl, or option- ally substituted -N(C1-3alkyl)-C(O)-3 to 10-membered heterocycloalkyl; wherein optionally substituted means unsubstituted or substituted by one or more substituents selected from the group consisting of D, halogen, -CN, and C1-6alkyl.

[0158] In some embodiments, when , R74is H or optionally substituted C1-6aminoalkyl, optionally substituted C3-10cycloalkyl, or optionally substituted 3 to 10-membered heterocycloalkyl; wherein optionally substituted means unsubstituted or sub- stituted by one or more substituents selected from the group consisting of -C(O)Ri, -S(O)Ri, and -S(O)2Ri; wherein Riis C1-6alkyl, -C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, or 3 to 10- membered heterocycloalky; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalky is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atoms in the group is substituted with substituents selected from the group consisting of D, halogen, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, alkylamino, and C3-6cycloalkyl.

[0159] In some embodiments, in R74, optionally substituted C1-6aminoalkyl is -C1-3al- kylene-NH(R75) or -C1-3alkylene-N(C1-3alkyl)(R75); wherein R75is H, -C(O)Ri, -S(O)Ri, or - S(O)2Ri.

[0160] In some embodiments, in R74, optionally substituted 3 to 10-membered heterocyclo- alkyl iswherein n7a and n7b are each independently 1, 2 or 3 (optionally wherein n7a and n7b are both 1 or 2), and R75is H, -C(O)Ri, -S(O)Ri, or -S(O)2Ri.

[0161] In some embodiments, R7is

[0162] In some embodiments, R7is optionally substituted 3 to 6-membered heterocycloal- kylene.

[0163] In some embodiments, in R7, the 3 to 6-membered heterocycloalkylene contains 1 or 2 heteroatoms selected from N, O, and S. In some embodiments, R7is

[0164] In some embodiments, R7is 3 to 6-membered heterocycloalkylene, optionally wherein the heteroatom is N, O, or S, and the number of heteroatoms is independently 1 or 2.In some embodiments, R7is, wherein n7 = 0, 1 or 2. In some embodiments, n7 = 1. In some embodiments, R7issome embodiments, R7is wherein n7 = 0, 1 or 2, optionally 1, and * refers to theattachment to Q.

[0165] In some embodiments, R7is . In some embodiments, R7isand * refers to the attachment to Q; wherein R73is defined as the substituents forthe 3 to 6-membered heterocycloalkylene.

[0166] In some embodiments, R7is optionally substituted C3-6cycloalkylene. In some em- bodiments, in R7, the C3-6cycloalkylene is

[0167] In some embodiments, R7is C3-6cycloalkylene. In some embodiments, R7is

[0168] In some embodiments, R7is optionally substituted C6-10arylene. In some embodi- ments, in R7, the C6-10 arylene is

[0169] In some embodiments, R7 is C6-10 arylene. In some embodiments, R7 is

[0170] In some embodiments, R7is optionally substituted C1-6alkylene or optionally substi- tuted 3 to 6-membered heterocycloalkylene.

[0171] In some embodiments, in R7, substituents for the 3 to 6-membered heterocycloal- kylene is selected from the group consisting of Ri, -C(O)Ri, -C(O)ORi, -S(O)Ri, -S(O)2Ri, and - NHC(O)Ri, optionally -C(O)R and -NHC(O)Ri, wherein Riis C1-6alkyl, -C2-6alkenyl, C2-6al- kynyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-mem- bered heterocycloalkenyl, C6-10aryl, or 5 to 10-membered heteroaryl, optionally C1-6alkyl, -C2-6alkenyl, or C2-6alkynyl, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, C6-10 aryl, or 5 to 10-membered heteroaryl; optionally wherein the alkyl, alkenyl, or alkynyl is un- subtituted or one or more (such as 1, 2, 3 or 4) of H atoms in the group is substituted with sub- stituents selected from the group consisting of deuterium, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl (such as -C(CH3)2N(CH3)2), and C1-6alkylamino.

[0172] In some embodiments, in R7, substituents for the 3 to 6-membered heterocycloal- kylene is optionally substituted 5 to 10 membered heteroaryl, optionally substituted 6 to 10 membered aryl, optionally substituted -CO-C1-6alkyl, or optionally substituted -CO-O-C1-6al- kyl. In some embodiments, the substituent is 6 to 10-membered aryl or -CO-O-C1-6alkyl.

[0173] In some embodiments, R73is Ri, -C(O)Ri, -C(O)ORi, -S(O)Ri, or -S(O)2Ri, option- ally Ri, -C(O)Ri, -S(O)Ri, or -S(O)2Ri; wherein Riis C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered hetero- cycloalkenyl, C6-10 aryl, or 5 to 10-membered heteroaryl; wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10- membered heterocycloalkenyl, C6-10aryl, or 5 to 10-membered heteroaryl is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atoms in the group is substituted with substituents se- lected from the group consisting of deuterium, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl (such as -C(CH3)2N(CH3)2), and C1-6al- kylamino.

[0174] In some embodiments, R73is Ri. In some embodiments, Riis C6-10 aryl or 5 to 10- membered heteroaryl. In some embodiments, the C6-10 aryl or 5 to 10-membered heteroaryl is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atoms in the group is substituted with substituents selected from the group consisting of deuterium, halogen, -CN, C1-6alkyl, C1-6haloalkyl, and C1-6deuteroalkyl.

[0175] R73is -C(O)Ri, -C(O)ORi, -S(O)Ri, or -S(O)2Ri, optionally -C(O)Ri, or -S(O)2Ri; wherein Riis C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10- membered heterocycloalkyl, or 3 to 10-membered heterocycloalkenyl; optionally wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-membered het- erocycloalkyl, or 3 to 10-membered heterocycloalkenyl is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atom in the group is substituted with substituents selected from the group consisting of deuterium, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl (such as -C(CH3)2N(CH3)2), and C1-6alkylamino.

[0176] In some embodiments, in R7, the 3 to 6-membered heterocycloalkylene comprises 1 or 2 heteroatoms selected from N and O.

[0177] In some embodiments, R7is C1-6alkylene or 3 to 6-membered heterocycloalkylene; the 3 to 6-membered heterocycloalkylene is optionally substituted by one or more 5 to 10 membered heteroaryl, 6 to 10 membered aryl optionally substituted, -CO-; optionally by one or more 6 to 10-membered aryl or -CO-O-C1-6alkyl; in 3 to 6-membered heterocycloalkylene; the heteroatom is independently selected from one or two of N and O, and the number of heteroa- toms is independently 1 or 2.

[0178] In some embodiments, R7is

[0179] In some embodiments, L, N, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloal- kylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloal- kylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene.

[0180] In some embodiments, substituents for the ring formed by L, N, R6and R7com- bined with the atoms to which they are attached is -C(O)Ri; wherein Riis C1-6alkyl, -C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, and 3 to 10-membered heterocycloalky; wherein the al- kyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalky is unsubtituted or one or more (such as 1, 2, 3 or 4) of H atom in the group being substituted with substituents selected from the group consisting of D, halogen, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, C1-6aminoalkyl, alkylamino, or C3-6cycloalkyl.

[0181] In some embodiments,

[0182] In some embodiments,

[0183] In some embodiments, the “halogen” is F, Cl, Br or I. In some embodiments, the “halogen” is F.

[0184] In some embodiments, the compound of the present invention is a compound of for- mula (Va) or (Vb), or the compound is a compound of formula (Va’) or (Vb’):wherein the variables are as described above.

[0185] In some embodiments, each variable (e.g., X1, X2, X3, X4, etc.) in the formulae men- tioned herein is independently a corresponding group in the specific compounds shown below or in compounds of the examples.

[0186] In some embodiments, 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, R7and n are each independently corresponding groups in specific compounds shown below or in compounds 1 to 58.

[0187] The present invention also has some schemes derived from any combination of the above-mentioned variables.

[0188] In another aspect, the present invention also provides, but is not limited to, the fol- lowing compounds, and stereoisomers or pharmaceutically acceptable salts thereof:

[0189] In some compounds of Formulas above, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic 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 Formu- las above and embodiments thereof. For example, different isotopic forms of hydrogen(H) in- clude 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 ad- vantages, 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.

[0190] In some embodiments, R1is -(CH2)-R1’. In some embodiments, R1is -(CH(CH3))- R1’.

[0191] In some embodiments, the compound of the present invention is a compound of for- mula (VIa) or (VIb), or the compound is a compound of formula (VIa’) or (VIb’):

[0192] In some embodiments, U is -CH2CH2-, -CH2CHOH-, -CH2C(CH3)2- or -CH2CF2-.

[0193] In some embodiments, T is absent, O or -CH-.

[0194] In some embodiments, Za1and Za2are each independently O or CH2.

[0195] In some embodiments, W is optionally substituted C1-6alkyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6heteroalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments, at least one hereoatom in the heteroalkyl or heterocycloalkyl is N.

[0196] In some embodiments, W is

[0197] In some embodiments, R2’is optionally substituted C1-6alkyl, optionally substituted C1-6alkenyl, optionally substituted C1-6alkynyl, or optionally substituted C1-6heteroalkyl.

[0198] In some embodiments, R2’is

[0199] In some embodiments, R3’is optionally substituted C3-6cycloalkyl or optionally substituted 3 to 10-membered heterocycloalkyl.

[0200] In some embodiments, R3’is

[0201] In some embodiments, R1’is：

[0202] In some embodiments, the compound of formula (Vb) is a compound of formula (VII):

[0203] In some embodiments, R1’of formula (VII) is：

[0204] In some embodiments, the compound of the present invention is a compound of for- mula (VIII):

[0205] In some embodiments, R1’is：

[0206] In some embodiments, the compound of formula (I) is Compound A as defined be- low.

[0207] It is to be understood that the foregoing description of 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.

[0208] The present invention provides a Compound A, or a stereoisomer, pharmaceutically acceptable salt, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein the Compound A is selected from any one of the following compounds in Table 1: Table 1. Exemplary Compounds of the Present invention

[0209] In another aspect, the present invention also provides a pharmaceutical composition comprising a compound, or a stereoisomer, pharmaceutically acceptable salt, or solvate thereof, or a solvate of the pharmaceutically acceptable salt as defined above, and a pharma- ceutically acceptable carrier, wherein the compound is the Compound A as defined above.

[0210] In another aspect, the present invention also provides a use of a compound, or a ste- reoisomer, pharmaceutically acceptable salt, or solvate thereof, or a solvate of the pharmaceuti- cally acceptable salt, or the pharmaceutical composition as defined above, in the preparation of a medicament used for the treatment of cancer, wherein the compound is the Compound A as defined above.

[0211] In some embodiments, the cancer is a Ras-driven cancer.

[0212] In some embodiments, the cancer comprises a Ras mutation.

[0213] In some embodiments, the Ras mutation is at position 12, 13, or 61.

[0214] In some embodiments, the Ras mutation is at position 12.

[0215] In some embodiments, the Ras mutation is G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R or Q61L, or any combination thereof.

[0216] In some embodiments, the Ras mutation is G12D, G12V, or G12R, or a combina- tion thereof.

[0217] In some embodiments, 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 tu- mor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma.

[0218] In some embodiments, the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0219] In some embodiments, the Ras protein is KRAS.

[0220] In some embodiments, compound of the present invention may be used in combina- tion with an additional anti-cancer therapy.

[0221] In some embodiments, the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a Pl3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

[0222] 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 therapeuti- cally effective amount of a compound of the present invention, or a stereoisomer, pharmaceuti- cally acceptable salt, or solvate thereof, or a solvate of the pharmaceutically acceptable salt as defined above, or the pharmaceutical composition as defined above, wherein the compound is the Compound A as defined above.

[0223] In some embodiments, the cancer is a Ras-driven cancer.

[0224] In some embodiments, the cancer comprises a Ras mutation.

[0225] In some embodiments, the Ras mutation is at position 12, 13, or 61.

[0226] In some embodiments, the Ras mutation is at position 12.

[0227] In some embodiments, the Ras mutation is G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R or Q61L, or any combination thereof.

[0228] In some embodiments, the Ras mutation is G12D, G12V, or G12R, or a combina- tion thereof.

[0229] In some embodiments, 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 tu- mour, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovariancancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syn- drome, or squamous cell lung carcinoma.

[0230] In some embodiments, the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0231] In some embodiments, the Ras protein is KRAS.

[0232] In some embodiments, the method is provided of treating a Ras protein-related dis- order in a subject in need thereof.

[0233] In some embodiments, the method further comprises administering an additional anti-cancer therapy.

[0234] In some embodiments, the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a Pl3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof. Term Definitions

[0235] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.

[0236] The term “pharmaceutically acceptable salts” refers to salts prepared from pharma- ceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the pre- sent invention is basic, its corresponding salt can be conveniently prepared from pharmaceuti- cally acceptable non-toxic acids, including inorganic and organic acids.

[0237] The term “solvate” refers to solvent addition forms that contain either stoichio- metric or non-stoichiometric amounts of solvent.

[0238] A “pharmaceutically acceptable excipient” refers to an excipient that is useful in preparing a pharmaceutical composition that is generally safe, nontoxic and neither biologi- cally nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.

[0239] A “pharmaceutically acceptable carrier” 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 inthe pharmaceutical compositions of the present disclosure will depend upon the means and pur- pose for which the compounds of the present disclosure are being applied.

[0240] As used herein, unless otherwise specified, the term “optionally substituted” refers to unsubtituted or being substituted with one or more (such as 1, 2, 3 or 4) substituents. Suita- ble substituents for each group can be found herein. Unless otherwise specified, exemplary substituents can be selected from the group consisting of D, halogen, -CN, -NO2, Ri, -C1-4al- kylene-Ri, -C2-4alkenylene-Ri, -C2-4alkynylene-Ri, -NRiRii, -ORi, -OC(O)Ri, -C(O)ORi, - C(O)Ri, -CO2Ri, -CONRiRii, -OC(O)NRiRii, -NRiiC(O)Ri, -NRi-C(O)NRiiRiii, -NRiiC(O)2Ri, - NH-C(NH2)=NH, -NRiC(NH2)=NH, -NH-C(NH2)=NRi, -S(O)Ri, -S(O)2Ri, -S(O)2NRiRii, or -NRiS(O)2Rii; wherein Ri, Riiand Riiiare each independently H, C1-6alkyl, -C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-mem- bered heterocycloalkenyl, C6-10aryl, 5 to 10-membered heteroaryl, -C1-4alkylene-C3-10cycloal- kyl, -C1-4alkylene-C3-10cycloalkenyl, -C1-4alkylene-3 to 10-membered heterocycloalkyl, -C1-4alkylene-3 to 10-membered heterocycloalkenyl, -C1-4alkylene-C6-10aryl, or -C1-4alkylene-5 to 10-membered heteroaryl; or Riand Rii, Riiand Riiitogether with the atom to which they are at- tached form C3-10cycloalkyl, C3-10cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10- membered heterocycloalkenyl, C6-10 aryl, or 5 to 10-membered heteroaryl; wherein the al- kylene, alkenylene, alkynylene, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo- alkyl, heterocycloalkenyl, aryl and heteroaryl may be unsubtituted or one or more (such as 1, 2, 3 or 4) or all of H atoms in the group may be substituted with substituents selected from the group consisting of D, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hy- droxyalkyl, C1-6aminoalkyl, amino, alkylamino, -C(O)C1-6alkyl, -OC1-6alkyl, -OC(O)C1-6al- kyl, -S(O)C1-6alkyl, -S(O)2C1-6alkyl, -COOC1-6alkyl, oxo (=O), C1-6alkylidene, C1-6haloalkylidene, C1-6deuteroalkylidene, C1-6hydroxyalkylidene, C1-6aminoalkylidene, C3-6cy- cloalkyl optionally substituted with one or more of D, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, and C1-6aminoalkyl, 3 to 6-membered hetero- cycloalkyl optionally substituted with one or more of D, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, and C1-6aminoalkyl, 3 to 6-membered hetero- cycloalkenyl optionally substituted with one or more of D, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, and C1-6aminoalkyl, phenyl, 5 to 6-membered heteroaryl optionally substituted with one or more of D, halogen, -CN, -OH, C1-6alkyl, C1-6haloalkyl, C1-6deuteroalkyl, C1-6hydroxyalkyl, and C1-6aminoalkyl. In some embodiments,“optionally substituted” means that the group is substituted by one or more substituents se- lected from the group consisting of deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, C1-C4alkoxy, C1-C4deuter- ated alkyl, C1-C4haloalkoxy, C2-C4alkenyl, C2-C4alkyne, C3-C6cycloalkyl, and 3 to 6-mem- bered heterocycloalkyl.

[0241] The term “alkyl” refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups having the number of carbon atoms designated. C1-20means 1 to 20 carbon atoms. In some embodiments, an alkyl group is an alkyl having 1 to 12 carbon at- oms (i.e., C1-12alkyl); 1 to 6 carbon atoms (i.e., C1-6alkyl); or 1 to 4 carbon atoms (i.e., C1-4al- kyl). Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopro- pyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dime- thylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dime- thylpentyl, 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-dime- thylhexyl, 3,3-dimethylhexyl, 4.4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- methyl-2-ethylpentyl, 2-methy1-3-ethylpentyl, n-nonyl, 2-methy1-2-ethylhexyl, 2-methy1-3- ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and the isomers of branched chain thereof. In some embodiments, 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-dime- thylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1.2-dimethylbutyl, 2,2-dimethyl- butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3- dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) may be substituted at any available connection point. In some embodi- ments, the substituent group(s) are selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloal- kyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo.

[0242] The term “alkylene” refers to a divalent saturated linear or branched aliphatic hy- drocarbon group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent alkane. The straight or branched chain group may have 1 to 20 carbon atoms, optionally 1 to 12 carbon atoms, further optionally 1 to 6 carbon at- oms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (- CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylidene (- CH2CH2CH2CH2-). The alkylene group may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., 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, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

[0243] The term “alkenyl” refers to an alkyl that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2- propenyl, 1-2-, or 3-butenyl group. In some embodiments, the alkenyl is a C2-20alkenyl (e.g., C2-12alkenyl or C2-6alkenyl). The alkenyl group may be substituted or unsubstituted. When substituted, the number of sub- stituent group(s) may be one or more (e.g., one to five or one to three) group(s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, al- kylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo.

[0244] The term “alkenylene” refers to a di-radical (i.e., divalent) alkene group that is con- ceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent alkene. Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2, -CH=CHCH2CH2, and -CH2CH=CHCH2-. The alkenylene group may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five or one to three) group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hy- droxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

[0245] The term “alkynyl” refers to an alkyl that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-2-, and 3-bu- tynyl. The alkynyl may be C2-20alkynyl (e.g., C2-12alkynyl or C2-6alkynyl). The alkynyl groupmay be substituted or unsubstituted. When substituted, the substituent group(s) may be one or more (e.g., one to five or one to three) group(s) independently selected from the group consist- ing of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cyclo- alkylthio and heterocylic alkylthio.

[0246] The term “aryl” refers to a 6 to 14-membered (or C6-14) all-carbon monocyclic ring or a polycyclic fused ring. A “fused” ring system having two or more rings, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring in the system. An aryl group has a completely conjugated pi-electron system. In some embodiments, the aryl is 6 to 10-membered (or C6-10), for example phenyl or naphthyl. The aryl may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring. Representative examples of structures comprising aryl groups include, but are not limited to, the following:

[0247] The aryl group may be substituted or unsubstituted. When substituted, the number of substituent group(s) is optionally one or more (e.g., one to five or one to three) substituent(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, het- eroaryl, cycloalkoxyl, heterocylicalkoxyl, cycloalkylthio and heterocylic alkylthio.

[0248] The term “arylene” refers to a di-radical (i.e., divalent) aryl group that is conceptu- ally formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent aryl.

[0249] 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. The heteroaryl may have, e.g., 5 to 14 ring atoms. In some embodiments, the heteroaryl is 5 to 10-membered or 5 or 6-membered. In some embodiments, the heteroaryl is thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolylfuryl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, im- idazolyl, tetrazolyl, and the like. The heteroaryl may be fused with the ring of an aryl, hetero- cyclyl or cycloalkyl, wherein the ring bound to the parent structure is heteroaryl.Representative examples of structures comprising a heteraryl group include, but are not limited to, the following:

[0250] The heteroaryl group may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five or one to three) substitu- ent(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, al- kylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NReRf.

[0251] The term “heteroarylene” refers to a di-radical (i.e., divalent) heteroaryl group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent heteroaryl. The term “bicyclic” includes spiro, fused-ring, or bridged-ring structures. “Spiro” refers to two rings that share one ring atom (e.g., carbon). “Fused” refers to two rings that share two adjacent ring atoms with one another. “Bridged” refers to two rings that share three adjacent ring atoms with one another.

[0252] The term “cycloalkyl” refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms (i.e., C3-20), optionally 3 to 12 carbon atoms (i.e., C3-12), further optionally 3 to 10 carbon atoms (i.e., C3-10), 3 to 8 carbon at- oms(i.e., C3-8), or 3 to 6 carbon atoms (i.e., C3-6). In some embodiments, cycloalkyl is monocy- clic cycloalkyl. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexa- dienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. In some embodiments, cycloalkyl is pol- ycyclic cycloalkyl (e.g., bicyclic cycloalkyl). In some embodiments, cycloalkyl is a spiro cy- cloalkyl, a fused cycloalkyl, or a bridged cycloalkyl. Polycyclic cycloalkyl includes a cycloal- kyl having a spiro ring, fused ring or bridged ring. The cycloalkyl may be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure iscycloalkyl. Representative examples include, but are not limited to, indanylacetic, tetrahy- dronaphthalene, benzocycloheptyl, and so on. The cycloalkyl may be substituted or unsubsti- tuted. When substituted, the number of substituent group(s) is one or more (e.g., one to five or one to three) substituent(s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloal- kyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cyeloalkylthio, heterocylic alkylthio and oxo.

[0253] The term “cycloalkylene” refers to a di-radical (i.e., divalent) cycloalkyl group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent cycloalkyl.

[0254] “Spiro Cycloalkyl” refers to a 5 to 20-membered polycyclic group with rings that are 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. In some embodiments, a spiro cycloalkyl is 6 to 14-membered (e.g., 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. In some embodi- ments, the spiro cycloalkyl is a mono-spiro cycloalkyl or di-spiro cycloalkyl. In some embodi- ments, the spiro cycloalkyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-mem- bered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiro cyclo- alkyl. Representative examples of spiro cycloalkyl include, but are not limited to, the follow- ing:

[0255] “Fused Cycloalkyl” refers to a 5 to 20-membered polycyclic hydrocarbon system having two or more rings, wherein each ring in the system shares an adjacent pair of carbon at- oms with another ring. The one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. A fused cycloalkyl group may be,e.g., 6 to 14-membered or 7 to 10-membered. According to the number of membered rings, fused cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloal- kyl. In some embodiments, the fused cycloalkyl is a bicyclic or tricyclic fused cycloalkyl. In some embodiments, the fused cycloalkyl is a 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:

[0256] “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 have no completely conjugated pi-electron system. In some embodiments, a bridged cycloalkyl is 6 to 14-membered, e.g., 7 to 10-membered. Ac- cording to the number of membered rings, bridged cycloalkyl may be divided into bicyclic, tri- cyclic, tetracyclic, or polycyclic bridged cycloalkyl. Representative examples of bridged cyclo- alkyls include, but are not limited to, the following:

[0257] The term “heterocyclyl” or “heterocycloalkyl” refers to a 3 to 20-membered satu- rated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more (e.g., one to five or one to three) carbon ring atoms replaced with heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is 0, l, or 2) as ring atoms, but ex- cluding -O-O-,-O-S-, or -S-S- in the ring. The remaining ring atoms are C. In some embodi- ments, the heterocyclyl is a 3 to 12-membered ring having 1 to 4 heteroatoms; optionally a 3 to10-membered ring having 1 to 3 heteroatoms; further optionally a 4 to 8-membered ring having l to 3 heteroatoms or a 5 to 6-membered ring having l to 2 heteroatoms. In some embodiments, heterocycloalkyl / heterocyclyl is monocyclic heterocycloalkyl / heterocyclyl. Representative ex- amples of monocyclic heterocyclyls or heterocycloalkyl include, but are not limited to, oxeta- nyl, azabutyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl,sulfo-morpholinyl, homopiperazi- nyl, and so on. In some embodiments, heterocycloalkyl / heterocyclyl is polycyclic heterocyclo- alkyl / heterocyclyl (for example bicyclic heterocycloalkyl / heterocyclyl). In some embodiments, heterocycloalkyl / heterocyclyl is a spiro heterocycloalkyl / heterocyclyl, a fused heterocycloal- kyl / heterocyclyl or a bridged heterocycloalkyl / heterocyclyl. Polycyclic heterocyclyl or hetero- cycloalkyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring. Representa- tive examples of such heterocyclyl groups areWhen the heterocyclyl has substituents, the substituents may be attached to any atom in the ring, provided that a stable chemical structure results.

[0258] The term “heterocycloalkylene” refers to a di-radical (i.e., divalent) heterocycloal- kyl group that is conceptually formed by removing two hydrogen atoms from the same or dif- ferent carbon atom(s) of the parent heterocycloalkyl.

[0259] “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 (e.g., one to five or one to three) heteroatoms selected from the group con- sisting of N, O, and S(O)m (wherein m is 0,1 or 2) as ring atoms. The remaining ring atoms are 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. In some embodiments, a spiro heterocyclyl is 6 to 14-membered, optionally 7 to 10-membered. According to the number of common spiroatoms, spiro heterocyclyl may be divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly- spiro heterocyclyl (e.g., 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:

[0260] “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 another ring. One or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system. The rings may have have one or more (e.g., one to five or 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 are C. In some embodiments, a fused heterocyclyl is 6 to 14-membered, optionally 7 to 10-membered. According to the number of membered rings, fused heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl (e.g., 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heter- ocyclyl). Representative examples of fused heterocyclyl include, but are not limited to, the fol- lowing:

[0261] The ring of the heterocyclyl may be fused to the ring of an aryl, heteroaryl, or cy- cloalkyl, wherein the ring bound to the parent structure is heterocyclyl. Representative exam- ples include, but are not limited to, the following:

[0262] The heterocyclyl may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five or 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, heterocylic alkoxyl, cycloalkylthio, and heterocylic alkylthio.

[0263] “Bridged Heterocyclyl” refers to a 5 to l4-membered polycyclic heterocyclic alkyl group, wherein every two rings in the system share two disconnected atoms. The rings may have one or more double bonds, but may not have a completely conjugated pi-electron system. The rings may 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 are C. In some embod- iments, a bridged heterocyclyl is 6 to 14-membered, optionally 7 to 10-membered. According to the number of membered rings, bridged heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following:

[0264] The term “C1-6haloalkoxyl” refers to an alkoxyl group in which one or more hydro- gen atoms are replaced by a halogen, for example, -OCF3.

[0265] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, for example, -CF3.

[0266] The term “C1-6alkoxyC1-6alkyl” refers to a C1- 6alkyl group in which one or more hydrogen atoms are replaced by C1-6alkoxy or a C1-6alkoxy group in which one or more hydro- gen atoms are replaced by C1-6alkyl.

[0267] The term “alkoxy” refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, C1-6alkoxy refers to a straight or branched alkoxy group containing at least 1, and at most 6 carbon atoms. Examples of “alkoxy” include, but not limited to, methoxy, ethoxy, prop-1-oxy, pro-2-oxy, pentoxy, hexyloxy, and the like.

[0268] The term “alkylamino” refers to an amino group substituted by one or more alkyl groups such as NH(C1-6alkyl) and N(C1-6alkyl)2. Examples of alkylamino include, but are not limited to, -NH(CH3) and -N(CH3)2.

[0269] The term “aminoalkyl” refers to an alkyl moiety substituted by one or more amino or alkylamino moieties (e.g., NH(CH3) and N(CH3)2). Examples of aminoalkyl include, but are not limited to, -CH2(NH2) and -C(CH3)2N(CH3)2.

[0270] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0271] The term “oxo” refers to =O, i.e., an oxygen atom replaces two hydrogens on the same carbon atom, that is, carbonyl groups replace methylene groups.

[0272] The term “bond” refers to a covalent bond using a sign of “ ”. In some embodi-ments, represents a double bond or single bond.

[0273] The term “linker” refers to a divalent organic moiety connecting a first moiety (e.g., one portion of a macrocycle) to a second moiety (e.g., a second portion ofthe samemacrocycle). In some embodiments, the linker results in a compound capable of achieving an IC50of 1µM or less in the Ras-RAF disruption assay.

[0274] Without being bound by theory, the inventors postulate that non-covalent interac- tions of “Q” and the chaperone protein (e.g., cyclophilin A) may contribute to the inhibition of Ras activity. For example, van der Waals, hydrophobic, hydrophilic and hydrogen bond inter- actions, and combinations thereof, may contribute to the ability of the compounds of the pre- sent invention to form complexes andact as Ras inhibitors. The inventors also postulate that “Q” also imparts structural rigidity to the compounds, which may optimize these non-covalent interactions, thereby contributing to the inhibition of Ras activity.

[0275] In some embodiments, the linker comprises 20 or fewer linear atoms, optionally 15 or fewer linear atoms or 10 or fewer linear atoms. In some embodiments, the linker has a mo- lecular weight of under 500 g / mol, optionally under 400 g / mol, under 300 g / mol, under 200 g / mol, under 100 g / mol, or under 50 g / mol.

[0276] The compounds of the present invention may 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. Furthermore, and unless explicitly otherwise stated, all reactions,reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.

[0277] 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, in- cluding 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 im- provements 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 pro- tection of the present invention.

[0278] Unless otherwise defined, all technical and scientific terms in the present invention have the same meanings as generally understood by a person skilled in the art to which the in- vention belongs. In accordance with the general technical knowledge and customary means in the art, under the premise of not departing from the above-mentioned basic technical ideas of the present invention, other forms of modification, replacement or change can also be made.

[0279] Unless otherwise stated, the raw materials and reagents used in the following em- bodiments are commercially available or may be prepared by known methods. EXAMPLES Example 1. Preparation of compounds of formula (IIIa) and formula (IIIb)

[0280] General synthetic procedure for preparing compounds of formula (IIIa) and formula (IIIb) is shown in Scheme 1 below: Scheme 1

[0281] Scheme 1 illustrates the preparation of a compound of formula (IIIa) or formula (IIIb). The synthetic sequence commenced with the Suzuki coupling of a compound of for- mula (1) with a compound of formula (2) using Pd(dppf)Cl₂ and K₂CO₃ to provide a compound of formula (3). Subsequently, the compound of formula (3) was converted to a compound of formula (4) under standard Yamanaka-Sonogashira indole synthesis conditions [Pd(PPh₃)₂Cl₂, CuI]. This was followed by a Friedel-Crafts acylation of the compound of formula (4), employ- ing BCl₃-AlCl₃ as a Lewis acid, to furnish a compound of formula (5). Deprotonation of (5) with an organolithium base such as LDA yielded a compound of formula (6), which was then reduced via a triethylsilane-mediated conversion of the carbonyl group to a methylene group, affording a compound of formula (7). Reduction of (7) with a reducing agent (e.g., LiBH₄) gave a compound of formula (8). A subsequent Suzuki coupling of (8) [Pd(PPh₃)₂Cl₂, KOAc] provided a compound of formula (9), which was then coupled with a compound of for- mula (10) under similar Suzuki conditions [Pd(dppf)Cl₂, KOAc] to give a compound of for- mula (11). Deprotection of the ester in (11), for example via hydrolysis with Me₃SnOH, yielded a compound of formula (12). Condensation of (12) using a coupling reagent such as HATU provided a compound of formula (13), which underwent acid-mediated deprotection (e.g., with TFA) to give a compound of formula (14). Finally, a routine coupling between thecompound of formula (14) and acid (15), using a coupling reagent (e.g., HATU) and an organic base (e.g., DIPEA), provided a compound of formula (16). Deprotection and cyclization of (16) then furnished the final compound of formula (17). Example 2. Synthesis of Intermediate 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)a mino)propanoate

[0282] 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 ºC and stirred for 2 h, then the reaction was cooled to rt. Transfer the liquid to another 500 mL three-necked round-bottomed flask and purged with N2, and a solution of Pd(PPh3)Cl2(2.1 g, 3.04 mmol) and 2,4-dibromothiazole 2 (17.7 g, 72.95 mmol) in DMF (100 mL) was added dropwise over a period of 10 min. The reaction was stirred at 50 ºC for 16 h under N2atmosphere, 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 Na2SO4and concentrated to give the crude product. The crude product was purified by silica gel column chromatography purified by silica gel column eluting with EtOAc / PE from 0% to 25% to af- ford methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (10 g, 45.2%) as a yellow solid.

[0283] LCMS (ESI) calcd. for C12H17BrN2O4S [M+H]+m / z 365.01, found: 367.3. Example 3. Synthesis of Intermediate C: (S)-4-(methoxycarbonyl)-2,3-diazabicy- clo[3.1.1]heptan-2-ium 2,2,2-trifluoroacetateStep 1. Preparation of 3-oxocyclobutane-1-carbonyl chloride

[0284] To a stirred solution of 3-oxocyclobutane-1-carboxylic acid (50 g, 438.60 mmol) in DCM (500 mL) and DMF (321 mg, 4.39 mmol) was added (COCl)2(83.51 g, 657.89 mmol), the resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated under re- duced pressure to give the crude product. The crude product was used to next step without pu- rification.

[0285] LCMS (ESI) calcd. for C5H5ClO2[M+H]+m / z 133.00, found: 133.4. Step 2. Preparation of 3-(2-diazoacetyl)cyclobutan-1-one

[0286] To a stirred solution of crude 3-oxocyclobutane-1-carbonyl chloride in THF (250 mL) and CH3CN (250 mL) was added TMSCHN2(2M in hexanes, 285 mL, 570.18 mmol) dropwisely at 0 ºC. The resulting mixture was stirred at rt for 18 h. After completion, the reac- tion solution was concentrated under reduced pressure to give the residual, the residual was pu- rified by silica gel column (eluting with EtOAc / PE from 0% to 50%) to afford 3-(2-diazoace- tyl)cyclobutan-1-one (60.2 g, 99.5%) as a yellow oil.

[0287] LCMS (ESI) calcd. for C6H6N2O2[M+H]+m / z 139.04, found: 139.4. Step 3. Preparation of 2-(3-oxocyclobutyl)acetic acid

[0288] 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 ºC, the reaction mixturewas stirred at rt for 18 h. After completion, the reaction solution was concentrated under re- duced pressure to give the residual, the residual was diluted with H2O and acidified with HCl (2N) to pH 2. The resuliting mixture was extracted with EtOAc (5*300 mL). The organic lay- ers were combined and dried over Na2SO4, following with concentration under reduced pres- sure to afford crude 2-(3-oxocyclobutyl)acetic acid (55.8g, 99.9%) as a brown oil.

[0289] 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

[0290] To a stirred solution of 2-(3-oxocyclobutyl)acetic acid (52.0 g, 406.3 mmol), (S)-4- benzyloxazolidin-2-one (71.9 g, 406.3 mmol), 4-Dimethylaminopyridine (5.0 g, 40.6 mmol) and triethylamine (141.2 mL, 1015.6 mmol) in DCM (1 L) was added 2-Chloro-1-methylpyri- dinium iodide (135.0 g, 528.1 mmol) in portions at 0 ºC. 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 (S)-4-benzyl-3-(2-(3-oxocyclobutyl)ace- tyl)oxazolidin-2-one (68 g, 58.3%) as a yellow oil.

[0291] LCMS (ESI) calcd. for C16H17NO4[M+H]+m / z 288.1, found: 288.5. Step 5. Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one

[0292] To a stirred solution of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (45.0 g, 156.8 mmol) in THF (500 mL) was added AcOH (17.9 mL, 313.6 mmol) and NaBH4 (6.5 g, 172.5 mmol) in portions at 0 ºC. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was diluted with H2O then concentrated under reduced pres- sure to remove THF. The residual was extracted with EtOAc, the combined organic phase was dried over Na2SO4, following with concentration under reduced pressure to obtain (S)-4-ben- zyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (45 g, 99.3%) as a light yellow oil.

[0293] 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

[0294] To a stirred solution of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin- 2-one (48.0 g, 156.8 mmol) and DIEA (43.3 g, 249.1 mmol) in DCM (500 mL) was added 4- Dimethylaminopyridine (16.2 g, 132.9 mmol) and Tosyl chloride (34.8 g, 182.7 mmol) at 0 ºC. The reaction mixture was stirred at r.t. for 14 h. After completion, the reaction solution was di- luted with H2O and extracted with DCM, the combined organic phase was washed with H2Odried over Na2SO4, following with concentration under reduced pressure to obtain crude prod- uct which was purified by silica gel column (eluting with EA / PE from 0% to 30%) to give (S)- 3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, 84.3%) as a yellow oil.

[0295] 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

[0296] To a stirred solution of (S)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclo- butyl 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 ºC for 13 h. The reaction was monitored by LCMS. After completion, the reaction solution was di- luted with H2O and extracted with EtOAc, the combined organic phase was washed with NaCl (aq.) dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (42 g, 85.3%) as a light yellow oil.

[0297] LCMS (ESI) calcd. for C16H18BrNO3[M+H]+m / z 352.0, found: 352.5. Step 8. Preparation of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]hepta ne-4-carboxylic acid

[0298] To a stirred solution of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2- one (30.0 g, 85.5 mmol) in THF (300 mL) was added LDA (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 ºC for 30 mins, then a solution of di-tert-butyl azodicarboxylate (23.6 g, 102.6 mmol) in DCM (50 mL) was added rapidly. The reaction mixture was stirred at -78 ºC for 30 mins, then 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (310 mL, 2565.0 mmol) was added dropwise at -78 ºC. The reaction mixture was stirred at r.t. for 14 h. After comple- tion, the reaction solution was quenched with water (200 mL), then LiOH·H2O (10.8 g, 256.5 mmol) was added and the reaction solution was stirred at r.t. for 2 h. After completion, the re- action solution was diluted with brine (200 mL) and washed with tert-butyl methyl ether 2 times, the aqueous phase was acidified to pH 3-4 with 2 N HCl. The resulting mixture was ex- tracted with EtOAc, washed with water and brine, then dried over Na2SO4, following with con- centration under reduced pressure to obtain crude product (S)-2,3-bis(tert-butoxycarbonyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylic acid, which was used directly for the next step.

[0299] LCMS (ESI) calcd. for C16H26N2O6[M+H]+m / z 343.39, found: 343.5.Step 9. Preparation of 2,3-di-tert-butyl 4-methyl (S)-2,3-diazabicyclo[3.1.1]heptane -2,3,4-tricarboxylate

[0300] To a stirred solution of crude product (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabi- cyclo[3.1.1]heptane-4-carboxylic acid (27.0 g, 78.9 mmol) in DMF (300 mL) was added K2CO3(27.3 g, 197.4 mmol) and iodomethane (10 mL, 157.8 mmol) at r.t.. The reaction mix- ture was stirred at r.t. for 2 h. After completion, the reaction solution was concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 23%) to give 2,3-di-tert-butyl 4-methyl (S)-2,3-diazabicyclo[3.1.1]heptane- 2,3,4-tricarboxylate (5.6 g, 18.45% in two-steps) as a light yellow oil.

[0301] 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-iu m 2,2,2-trifluoroacetate

[0302] To a stirred solution of 2,3-di-tert-butyl 4-methyl (S)-2,3-diazabicyclo[3.1.1]hep- tane-2,3,4-tricarboxylate (7.3 g, 0.18 mmol) in DCM (100 mL) was added TFA (40 mL), the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product (S)-4-(methoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptan-2-ium 2,2,2-trifluoro- acetate (7.2 g) as a yellow solid.

[0303] LCMS (ESI) calcd. for C15H23BO4[M+H]+m / z 157.09, found: 157.4. Example 4. Synthesis of Intermediate E: (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyri- dineStep 1. Preparation of (S)-1-(3-bromopyridin-2-yl)ethan-1-ol

[0304] To a stirred solution of TEA (151.76 g, 1.50 mol) was added FA (13.81 g, 299.96 mmol) at 0 ºC. Then (S,S)-N-(p-Toluenesulfonyl)-1,2-diphenylethanediamine(chloro)(p-cy- mene)ruthenium(II) (800 mg, 1.25 mmol) was added into the reaction mixture, the resulting mixture was stirred at 40 ºC under N2for 0.5 h.1-(3-bromopyridin-2-yl)ethan-1-one (25.00 g, 124.98 mmol) was added into the reaction mixture, the resulitng mixture was stirred at 40 ºCunder N2for 1 h. The reaction was monitored by LCMS. After completion, the reaction mix- ture was diluted with EtOAc (500 mL), washed with saturated NH4Cl (300 x 3 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 25%) to give (S)- 1-(3-bromopyridin-2-yl)ethan-1-ol (28.80 g, 95.0%) as a yellow oil.

[0305] LCMS (ESI) calcd. for C7H6BrNO [M+H]+m / z 200.98, found: 202.1. Step 2. Preparation of (S)-3-bromo-2-(1-methoxyethyl)pyridine

[0306] To a stirred solution of (S)-1-(3-bromopyridin-2-yl)ethan-1-ol (23.80 g, 117.82 mmol) in THF (240 mL) was added NaH (60% in oil, 7.07 g, 176.73 mmol) portion wisely at 0 ºC, the resulting mixture was stirred at 0 ºC for 1 h. CH3I (33.45 g, 235.64 mmol) was added into the reaction mixture at 0 ºC, the resulting mixture was stirred at rt for 15 h. The reaction mixture was quenched with H2O (50 mL) at 0 ºC and extracted with EtOAc (2*200 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 25%) to give (S)-3-bromo-2-(1-methoxyethyl)pyridine (23.39 g, 91.9%) as a light yellow oil.

[0307] LCMS (ESI) calcd. for C8H10BrNO [M+H]+m / z 214.99, found: 216.3. Step 3. Preparation of (S)-3-bromo-2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine

[0308] To a stirred solution of (S)-3-bromo-2-(1-methoxyethyl)pyridine (12.00 g, 55.56 mmol) B2Pin2(15.53 g, 61.11 mmol) in THF (180 mL) was added [Ir(COD)(OMe)]2(737 mg, 1.11 mmol) and dtbpy (895 mg, 3.33 mmol) at rt, the resulting mixture was stirred at 75 ºC un- der N2for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give crude (S)-3-bromo-2-(1-methoxyethyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (20.9 g) as an orange oil.

[0309] LCMS (ESI) calcd. for C14H21BBrNO3[M+H]+m / z 341.08, found: 342.4. Step 4. Preparation of (S)-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0310] To a stirred solution of crude (S)-3-bromo-2-(1-methoxyethyl)-5-(4,4,5,5-tetrame- thyl-1,3,2-dioxaborolan-2-yl)pyridine (16.20 g, 47.51 mmol) in THF (150 mL) and H2O (150 mL) were added NH4OAc (14.60 g, 190.03 mmol ) and NaIO4 (40.60 g, 190.03 mmol) at 0 ºC, the resulting mixture was stirred at rt for 3h. The reaction was monitored by LCMS. After completion, the reaction mixture was extracted with EtOAc (2*300 mL). The organic layerswere 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-(1-methoxyethyl)pyridin-3-yl)boronic acid (10.98 g, 89.2%) as a yellow solid.

[0311] LCMS (ESI) calcd. for C8H11BBrNO3[M+H]+m / z 259.00, found: 260.3. Step 5. Preparation of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine

[0312] To a stirred solution of (S)-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (3.00 g, 11.58 mmol) in CH3CN (45 mL) was added NIS (3.13 g, 13.90 mmol) at rt, the result- ing mixture was stirred at 75 ºC for 20h. The reaction was monitored by LCMS. After comple- tion, the reaction mixture was quenched with sat. aq. Na2SO3 and concentrated to give the resi- due. 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 crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 20%) to give (S)-3- bromo-5-iodo-2-(1-methoxyethyl)pyridine (2.65 g, 67.1%) as a brown solid.

[0313] LCMS (ESI) calcd. for C8H9BrINO3[M+H]+m / z 340.89, found: 342.3. Example 5. Synthesis of Intermediate F: tert-butyl ((63S,4S)-25-(benzyloxy)-12-iodo- 10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyri- dazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamateStep 1. Preparation of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5 -yl)-5-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0314] To a stirred solution of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate (10.3 g, 31.8 mmol) and methyl (S)-3-(3-(benzyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (19.5 g, 38.1 mmol) in pre-mixtured sol- vents dioxane / H2O (240 mL, 4:1, V:V) was added Pd(dppf)Cl2(2.3 g, 3.2 mmol ) and K2CO3(11.0 g, 79.5 mmol) to the reaction mixture. The reaction was stirred at 80 ºC for 4 h under N2atmosphere, the reaction was monitored by LCMS. After completion, the reaction solution was concentrated under reduced pressure to remove dioxane, the residual was extracted with EtOAc (50 mL x 4), the combined organic phase was washed with saturated NaCl (20 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 EtOAc / PE from 0% to 50% to afford me- thyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5-(benzyloxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoate (14.0 g, 70%) as a light yellow solid.

[0315] LCMS (ESI) calcd. for C37H44N2O7[M-H]- m / z 627.31, found: 627.7. Step 2. Preparation of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H- indol-5-yl)-5-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0316] To a stirred solution of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-in- dol-5-yl)-5-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (14.13 g, 22.5 mmol) and NaHCO3 (2.25 g, 27.0 mmol) in THF (180 mL) under ice-water bath was added AgSO3CF3(6.94 g, 27.0 mmol) in THF (65 mL) and I2 (5.71 g, 22.5 mmol) in THF (80 mL) by dropwise to the reaction mixture. The reaction was stirred at 0 ºC for 2h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the reaction quenched with saturated Na2SO3(50 mL) and stirred for 30 mins, then filtered, the filtration was extracted with EtOAc (50 mL x 4), the combined organic phase was washed with saturated NaCl (25 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 EtOAc / PE gradient from 0% to 40% to afford methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)-5-(ben- zyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (14.0 g, 94%) as a light yellow solid.

[0317] LCMS (ESI) calcd. for C37H43IN2O7 [M+H]+ m / z 755.21, found: 655.7. Step 3. Preparation of (S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dimethylpropyl)-2- iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid

[0318] To a stirred solution of methyl (S)-3-(3-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo- 1H-indol-5-yl)-5-(benzyloxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (14.0 g, 18.5 mmol) in mixtured solvents THF / MeOH / H2O (180 mL, V:V:V = 1:1:1) was added LiOH (3.04 g, 74.1 mmol) by one portion at 0 ºC. The reaction mixture was stirred at room temperature un- til the reaction was completed, the reaction was monitored by LCMS. After completion, the re- action solution adjust to pH 5-7 with 1M HCl and generated a large mount of precipitation, fil- trated and the filter cake was washed with H2O (20 mL x 2). The mixture was dried under re- duced pressure to obtain crude (S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dimethylpropyl)-2- iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarb- onyl)amino)propanoic acid (9.56 g, 73%) as an light yellow solid. Which was directly used for the next step without further purification.

[0319] LCMS (ESI) calcd. for C37H43IN2O7[M-H]- m / z 697.57, found: 697.4. Step 4. Preparation of methyl (S)-1-((S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dime- thylpropyl)-2-iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahy- dropyridazine-3-carboxylate

[0320] To a solution of crude (S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dimethylpropyl)- 2-iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarb- onyl)amino)propanoic acid (9.56 g, 13.7 mmol), DIEA (6.36 g, 49.3 mmol) and HATU (6.25 g, 16.4 mmol) in dry DMF (100 ml), the mixture was stirred for 5 mins under ice-water bath, then methyl (S)-hexahydropyridazine-3- carboxylate bis(2,2,2-trifluoroacetate) (7.64 g, 20.54 mmol) in dry DMF (44 ml) was added by dropwise. The reaction temperature was gradually improved to room temperature and stirred for 2h, the reaction was monitored by LCMS. After completion, the reaction was diluted with saturated NaCl (250 mL) and was extracted with EtOAc (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 col- umn eluting with MeOH / DCM from 0% to 5% to afford methyl (S)-1-((S)-3-(3-(benzyloxy)-5- (3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)phenyl) -2-((tert-butoxycar- bonyl)amino)propanoyl)hexahydropyridazine-3-carboxylate (9.0 g, 79%) as a light yellow solid.

[0321] LCMS (ESI) calcd. for C40H49IN4O7 [M+H]+ m / z 825.27, found: 725.15. Step 5. Preparation of (S)-1-((S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dimethylpropyl)- 2-iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine- 3-carboxylic acid

[0322] To a solution ofmethyl (S)-1-((S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dime- thylpropyl)-2-iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahy- dropyridazine-3-carboxylate (8.5 g, 10.31 mmol) in mixtured solvents THF / MeOH / H2O (225 ml, V:V:V = 1:1:1) was added LiOH (1.06 g, 25.78 mmol) at room temperature. The reaction solution was stirred at room temperature for 2h, the reaction was monitored by LCMS. After completion, the reaction solution adjust to pH 5-7 with 1M HCl under ice-water bath, the reac- tion solution was extracted with EtOAc (250 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 (S)-1-((S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dimethylpro- pyl)-2-iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydro- pyridazine-3-carboxylic acid (7.9 g, quant) as a white solid.

[0323] LCMS (ESI) calcd. for C39H47IN4O7[M+H]+ m / z 811.25, found: 711.16 Step 6. Preparation of tert-butyl ((63S,4S)-25-(benzyloxy)-12-iodo-10,10-dimethyl-5,7 -dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenac ycloundecaphane-4-yl)carbamate

[0324] To a solution of crude (S)-1-((S)-3-(3-(benzyloxy)-5-(3-(3-hydroxy-2,2-dime- thylpropyl)-2-iodo-1H-indol-5-yl)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahy- dropyridazine-3-carboxylic acid (5.9 g, 7.28 mmol) and DIEA (2.82 g, 21.83 mmol) in dry DCM (1190 mL) under ice-water bath was added EDCI (4.19 g, 21.83 mmol) and HOBt (1.97 g, 14.55 mmol) by one portion. The reaction was gradually improved temperature to room tem- perature and stirred for 4h, the reaction was monitored by LCMS. After completion, the reac- tion was washed with H2O (100 mL x 3), then dried over with Na2SO4, following with concen- tration under reduced pressure to obtain crude one which was purified by silica gel column eluting with MeOH / DCM from 0% to 50% to afford tert-butyl ((63S,4S)-25-(benzyloxy)-12- iodo-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (4.6 g, 91%) as a white solid, which was directly used for the next step without further purification.

[0325] LCMS (ESI) calcd. for C39H45IN4O6[M+H]+ m / z 793.24, found: 693.5. Step 7. Preparation of tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo- 12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate

[0326] To a stirred solution of tert-butyl ((63S,4S)-25-(benzyloxy)-12-iodo-10,10-dimethyl- 5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (790 mg, 1.12 mmol), Pd2(dba)3(154 mg, 0.17 mmol), SPhos (154 mg, 0.17 mmol) and AcOK (495 mg, 5.04 mmol) in toluene was added B2Pin2(1.08 g, 8.40 mmol) at 0 ºC under N2atmosphere. The reaction mixture was stirred at 60 ºC under N2for 3h. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 60%) to give crude tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl- 5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8- oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (810 mg) as a pale yellow solid.

[0327] LCMS (ESI) calcd. for C45H57BN4O8 [M+H]+m / z 793.4, found: 793.6. Example 6. Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2-methylbut-3- yn-2-olStep 1. Preparation of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-o l

[0328] A mixture of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (200 mg, 0.59 mmol), 2-methylbut-3-yn-2-ol (99 mg, 1.17 mmol), K2CO3(243 mg, 1.76 mmol), Pd(PPh3)2Cl2(41 mg, 0.059 mmol) and CuI (11 mg, 0.059 mmol) in THF (4.5 mL) was stirred at 65 ºC under N2for 23 h. The reaction was monitored by LCMS. After completion, the reac- tion mixture was concentrated to give the crude product which was purified by silica gel col- umn (eluting with EtOAc / PE from 0% to 40%) to give (S)-4-(5-bromo-6-(1-methoxyethyl)pyr- idin-3-yl)-2-methylbut-3-yn-2-ol (160 mg, 91.3%) as a brown solid.

[0329] LCMS (ESI) calcd. for C13H16BrNO2[M+H]+m / z 297.04, found: 298.4. Example 7. Synthesis of tert-butyl (S)-3-((5-bromo-6-((S)-1-methoxyethyl)pyridin-3- yl)ethynyl)pyrrolidine-1-carboxylateStep 1. Preparation of tert-butyl (S)-3-ethynylpyrrolidine-1-carboxylate

[0330] To a stirred solution of tert-butyl (R)-3-formylpyrrolidine-1-carboxylate (1 g, 5.0 mmol) and K2CO3(1.4 g, 10.0 mmol) in MeOH (15 mL) was added dimethyl (1-diazo-2-ox- opropyl)phosphonate (1.2 g, 6.0 mmol) at RT. The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (30 mL), then dried over Na2SO4, following with concentration under reduced pressure to ob- tain crude product tert-butyl (S)-3-ethynylpyrrolidine-1-carboxylate (980 mg) as a yellow oil.

[0331] LCMS (ESI) calcd. for C11H17NO2[M+H-56]+m / z 140.1, found: 140.4. Step 2. Preparation of tert-butyl (S)-3-((5-bromo-6-((S)-1-methoxyethyl)pyridin-3- yl)ethynyl)pyrrolidine-1-carboxylate

[0332] A mixture of tert-butyl (S)-3-ethynylpyrrolidine-1-carboxylate (980 mg, 5.0 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (1.7 g, 5.0 mmol), CuI (96 mg, 0.5 mmol) TEA (1.0 g, 10.0 mmol) and Pd(PPh3)2Cl2(352 mg, 0.5 mmol) in THF (20 mL) was stirred at 50 ºC under N2for 2 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 25%) to give tert-butyl (S)-3-((5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-1- carboxylate (1.8 g, 90% in 2 steps) as a brown oil.

[0333] LCMS (ESI) calcd. for C19H25BrN2O3[M+H]+m / z 409.1, found: 409.6. Example 8. Synthesis of Exemplary Intermediates Containing Alkynyl Group

[0334] The following intermediates in Table 2 were prepared using the method described above in step for the preparation of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2-methyl- but-3-yn-2-ol or tert-butyl (S)-3-((5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)ethynyl)pyrrol- idine-1-carboxylate and utilizing the appropriate starting materials and modifications. Table 2. Exemplary Intermediates Containing Alkynyl GroupExample 9. Synthesis of (S)-4-(3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1- yl)morpholineStep 1. Preparation of 3-bromo-2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2 -yl)oxy)prop-1-yn-1-yl)pyridine

[0335] A mixture of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (10 g, 29.24 mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (4.92 g, 35.09 mmol), CuI (0.45 g, 2.34 mmol), TEA (8.88 g, 8.73 mmol) and Pd(PPh3)2Cl2 (1.64 g, 2.34 mmol) in THF (120 mL) was stirred at 50 ºC for 4h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 3% in 20 min) to obtain 3- bromo-2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (10.10 g, yield: 97.5%) as a yellow oil.

[0336] LCMS (ESI) calcd. for C16H20BrNO3[M+H]+m / z 354.1, found 354.5. Step 2. Preparation of (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-ol

[0337] To a solution of 3-bromo-2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2- yl)oxy)prop-1-yn-1-yl)pyridine (10.10 g, 28.51 mmol) in MeOH (100 mL) was added TsOH (19.64 g, 114.05 mmol) at 0 ºC, the mixture was stirred at room temperature for 5 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was dilutedwith DCM (50 mL) and H2O (150 mL) and extracted with DCM (50 mL x 3), the combined layers were washed with saturated NaCl (150 mL), dried over Na2SO4, concentrated to obtain (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-ol (7.10 g, yield: 92.2%) as a yel- low oil.

[0338] LCMS (ESI) calcd. for C11H12BrNO2[M+H]+m / z 270.0, found 270.3. Step 3. Preparation of (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl 4-methylbenzenesulfonate

[0339] To a solution of (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-ol (7.10 g, 26.28 mmol) in THF (100 mL) were added TsCl (10.02 g, 52.57 mmol) and KOH (2.95 g, 52.57 mmol) at 0 ºC, the mixture was stirred at 0 ºC for 2 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with EtOAc (50 mL) and water (100 mL), then extracted with EA (50 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4and concentrated under reduced pressure. The residual was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 30% in 30 min) to obtain (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1- yl 4-methylbenzenesulfonate (10.50 g, yield: 94.2%) as a brown solid.

[0340] LCMS (ESI) calcd. for C18H18BrNO4S [M+H]+m / z 424.0, found 424.8. Step 4. Preparation of (S)-4-(3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1 -yl)morpholine

[0341] To a solution of morpholine (358 mg, 4.11 mmol) in DCM (10 mL) were added DIEA (1.21 g, 9.34 mmol) and a solution of (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3- yl)prop-2-yn-1-yl 4-methylbenzenesulfonate (1.58 g, 3.74 mmol) in DCM (10 mL) at rt, the re- sulting mixture was stirred at rt for 16 h. The reaction was monitored by LCMS. After comple- tion, the mixture was concentrated under reduced pressureto give the residual which was puri- fied by silica gel column chromatography (eluting with EtOAc / PE from 0% to 40%) to obtain (S)-4-(3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)morpholine (980 mg, yield: 77.5%) as a brown oil.

[0342] LCMS (ESI) calcd. for C15H19BrNO2[M+H]+m / z 339.1, found 339.6. Example 10. Synthesis of Exemplary Intermediates Containing Alkynyl Group

[0343] The following intermediates in Table 3 were prepared using the method described above in step for the preparation of (S)-4-(3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2- yn-1-yl)morpholine and utilizing the appropriate starting materials and modifications. Table 3. Exemplary Intermediates Containing Alkynyl GroupExample 11. Synthesis of N-(dimethylcarbamoyl)-N-methyl-L-valineStep 1. Preparation of benzyl N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3- carbonyl)-N-methyl-L-valinate

[0344] A mixture of benzyl (2S)-3-methy1-2-(methylamino)butanoate (500 mg, 2.26 mmol) and ((2S,3S)-1-acetyl-3-(chlorocarbonyl)pyrrolidin-2-yl)methyl 4-methylbenzenesul- fonate (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 ºC for 12 h under nitrogen atmosphere, then quenched with water (100 ml) and was extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford benzyl N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyr- rolidine-3-carbonyl)-N-methyl-L-valinate (400 mg, 58.3% yield) as a colorless oil.

[0345] LCMS (ESI) calcd. for C16H25N2O3 [M+H]+m / z 545.2, found: 545.4. Step 2. Preparation of N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbony l)-N-methyl-L-valine

[0346] A mixture of benzyl N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-car- bonyl)-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 reac- tion mixture was filtered and the filter cake was washed with MeOH (100 mL x 3). The filtrate was concentrated under reduced pressure to afford N-((2S,3S)-1-acetyl-2-((tosyloxy)me- thyl)pyrrolidine-3-carbonyl)-N-methyl-L-valine (200 mg, crude) as a colorless oil.

[0347] LCMS (ESI) calcd. for C9H19N2O3[M+H]+m / z 455.2, found: 455.4. Example 12. Synthesis of Exemplary Peptide Intermediates

[0348] The following compounds in Table 4 were prepared according to the representative procedure described above for the synthesis of N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrol- idine-3-carbonyl)-N-methyl-L-valine and utilizing the appropriate starting materials and modi- fications. Table 4. Exemplary Peptide IntermediatesExample 13. Synthesis of Compound 11: ((2S,3S)-1-acetyl-3-(((2S)-1-(((63S,4S)-25-hy- droxy-12-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-di- methyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina- 2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)car- bamoyl)pyrrolidin-2-yl)methyl 4-methylbenzenesulfonateStep 1: Preparation of tert-butyl ((63S,4S)-25-(benzyloxy)-12-(2-((S)-1-methoxyethyl) -5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexah ydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carba mate

[0349] A mixture of (S)-4-(3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1- yl)morpholine (253 mg, 0.74 mmol), tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7- dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa- 1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (525 mg, 0.74 mmol), K2CO3(309 mg, 2.24 mmol) and Pd(dppf)Cl2(55 mg, 0.075 mmol) in dioxane (8 mL) and H2O (2 mL) was stirred at 85 ºC under N2for 19 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 100%) to give tert-butyl ((63S,4S)-25-(benzyloxy)-12- (2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-di- oxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzena- cycloundecaphane-4-yl)carbamate (323 mg, 52.1%) as a yellow solid.

[0350] LCMS (ESI) calcd. for C54H64N6O8[M+H]+m / z 925.5, found: 925.6. Step 2: Preparation of tert-butyl ((63S,4S)-25-(benzyloxy)-11-ethyl-12-(2-((S)-1-meth oxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65, 66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-y l)carbamate

[0351] To a stirred solution of tert-butyl ((63S,4S)-25-(benzyloxy)-12-(2-((S)-1-methoxy- ethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloun- decaphane-4-yl)carbamate (323 mg, 0.39 mmol) in DMF (4.5 mL) were added Cs2CO3(251 mg, 0.77 mmol) and Iodoethane (120 mg, 0.77 mmol) at 0 ºC, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture wasdiluted with EtOAc (100 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O (0.1% NH4HCO3) from 20% to 80%) to give tert-butyl ((63S,4S)-25-(benzyloxy)-11-ethyl-12-(2-((S)-1-methoxyethyl)- 5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexa- hydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carba- mate as atropisomer 1 (100 mg) and atropisomer 2 (140 mg) as white solids.

[0352] LCMS (ESI) calcd. for C56H68N6O8[M+H]+m / z 953.5, found: 953.6. Step 3: Preparation of tert-butyl ((63S,4S)-11-ethyl-25-hydroxy-12-(2-((S)-1-methoxye thyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-h exahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)ca rbamate

[0353] To a solution of tert-butyl ((63S,4S)-25-(benzyloxy)-11-ethyl-12-(2-((S)-1-methoxy- ethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloun- decaphane-4-yl)carbamate (100 mg (unpure), 1 mmol) in AcOH (2 mL) was added ZnCl2 (20 mg, 2 eq.) and Ac2O (20 mg, 2 eq.), the reaction was stirred under N2 atmosphere (balloon) for 4h. the reaction was monitored by LCMS. After completion, the reaction solution was concen- trated and diluted with DCM (10 mL), then filtered, the filtration was concentrated to obtain crude mixture, which was further purified by silica gel chromatography eluting with MeOH / DCM (from 0% to 5%) to obtain tert-butyl ((63S,4S)-11-ethyl-25-hydroxy-12-(2-((S)-1- methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloun- decaphane-4-yl)carbamate (3 mg, 38%) as a brown solid.

[0354] LCMS (ESI) calcd. for C49H62N6O8 [M+H]+m / z 863.5, found: 863.6. Step 4: Preparation of (63S,4S)-4-amino-11-ethyl-25-hydroxy-12-(2-((S)-1-methoxyeth yl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-5,7-dione

[0355] To a stirred solution of tert-butyl ((63S,4S)-11-ethyl-25-hydroxy-12-(2-((S)-1-meth- oxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloun- decaphane-4-yl)carbamate as atropisomer 1 (100 mg, 0.12 mmol) in dichloromethane (4 mL) was added TFA (1 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The re- action mixture was concentrated and lyophilized to give (63S,4S)-4-amino-11-ethyl-25-hy- droxy-12-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dime- thyl-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzena- cycloundecaphane-5,7-dione (110 mg) of its TFA salt as a yellow solid.

[0356] LCMS (ESI) calcd. for C44H54N6O6 [M+H]+m / z 763.4, found: 763.6. Step 5: Preparation of ((2S,3S)-1-acetyl-3-(((2S)-1-(((63S,4S)-25-hydroxy-12-(2-((S)-1 -methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,6 3,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaph ane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidin-2-yl)methyl 4-methy lbenzenesulfonate

[0357] To a stirred solution of (63S,4S)-4-amino-11-ethyl-25-hydroxy-12-(2-((S)-1-methox- yethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexahy- dro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-5,7-dione (125 mg, 0.16 mmol) and N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N- methyl-L-valine (19 mg, 0.16 mmol) and 2,6-lutidine (88 mg, 0.82 mmol) in ACN (5 mL) was added COMU (105 mg, 0.24 mmol) at rt, the resulting mixture was stirred at rt for 2 h. The re- action mixture was concentrated to give the crude product. The crude product was purified bypre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 95% in 30 min) to give ((2S,3S)-1-ace- tyl-3-(((2S)-1-(((63S,4S)-25-hydroxy-12-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1- yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-in- dola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2- yl)(methyl)carbamoyl)pyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (85 mg, 61.7%) as a white solid.

[0358] LCMS (ESI) calcd. for C63H78N8O12S [M+H]+m / z 1171.6, found: 1171.6. Step 6: Preparation of ((2S,3S)-1-acetyl-3-(((2S)-1-(((63S,4S)-25-hydroxy-12-(2-((S)- 1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,6 3,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaph ane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidin-2-yl)methyl 4-methyl benzenesulfonate

[0359] To a stirred solution of ((2S,3S)-1-acetyl-3-(((2S)-1-(((63S,4S)-25-hydroxy-12-(2- ((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- 61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloun- decaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (7.26 g, 5.77 mmol) in DMF (700 mL) were added K2CO3 (7.97 g, 57.7 mmol) and KI (0.96 g, 5.77 mmol) portion-wise at 0 ºC under an atmosphere of N2. The resulting mixture was stirred for additional 3h at 80 ºC. The reaction was quenched with H2O at 0oC. The resulting mixture was then extracted with EtOAc (3 x 300 mL), treated with brine (3 x 600 mL),dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue waspurified by reversed-phase flash column chromatography to give ((2S,3S)-1- acetyl-3-(((2S)-1-(((63S,4S)-25-hydroxy-12-(2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1- yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan- 2-yl)(methyl)carbamoyl)pyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (4.95 g, 79% yield) as a yellow oil.

[0360] LCMS (ESI) calcd. for C58H74N8O9[M+H]+m / z 1027.6, found: 1027.8.

[0361] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 12.1 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.13 (tt, J = 2.2, 0.9 Hz, 1H), 7.07 (t, J = 2.2 Hz, 1H), 6.64 (tt, J = 2.2, 1.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.69 (td, J = 13.5, 12.0 Hz, 1H), 4.33 (td, J = 7.3, 6.5 Hz, 1H), 4.22 (d, J = 6.8 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.76 – 3.54 (m, 11H), 3.33 (s, 3H), 3.16 – 3.09 (m, 3H), 3.06 (s, 1H), 3.02 (dd, J = 11.5, 9.0 Hz, 1H), 2.96 – 2.86 (m, 6H), 2.75 – 2.69 (m, 4H), 2.23 (dhept, J = 8.1, 5.1 Hz, 1H), 2.09 – 1.98 (m, 7H), 1.98 – 1.93 (m, 1H), 1.90 – 1.83 (m, 2H), 1.83 – 1.78 (m, 1H), 1.76 – 1.70 (m, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.92 (d, J = 5.0 Hz, 3H), 0.87 (d, J = 5.1 Hz, 3H). Example 14. Synthesis of Compound 34: (6S,9S,15S)-1-acryloyl-22-ethyl-6-isopropyl-21- (2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl- 3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H-11,15-epimino-23,25-etheno- 9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]dioxa[6,9,12]triazacy- clotriacontine-4,7,10,16(2H,13H)-tetraoneStep 1: Synthesis of (S)-2-(1-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine

[0362] To a stirred solution of (S)-3-bromo-2-(1-methoxyethyl)pyridine (80.1 g, 370.83 mmol) and B2Pin2(113.1 g, 445 mmol) in 1,4-dioxane (1000 mL) were added Pd(dppf)Cl2(23.1 g, 31.52 mmol) and KOAc (109.2 g, 1.11 mol). The reaction was stirred at 100 ºC for 18 h under N2 atmosphere. The reaction was monitored by LCMS. After completion, the reaction solution was concentrated under reduced pressure to give the residual which was purified by neutral Al2O3 column (eluting with EtOAc / PE from 0% to 100%) to afford (S)-2-(1-methoxy- ethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (130.8 g) as a brown oil.

[0363] LCMS (ESI) calcd. for C14H22BNO3[M+H]+m / z 264.2, found: 264.5. Step 2: Synthesis of (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)- 2,2-dimethylpropyl acetate

[0364] To a stirred solution of 3-(5-bromo-2-iodo-1H-indol-3-yl)-2,2-dimethylpropyl ace- tate (12.2 g, 27.17 mmol), (S)-2-(1-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (11.4 g, 43.47 mmol) and K2CO3(11.3 g, 81.51 mmol) in 1,4-dioxane (180 mL) and H2O (45 mL) was added Pd(dppf)Cl2(2.0 g, 2.72 mmol) at rt. The reaction mixture was stirred at 90 ºC under N2for 18 h. After completion, the reaction solution was concentrated un- der reduced pressure to remove 1,4-dioxane to give the residual which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to afford (S)-3-(5-bromo-2-(2-(1-meth- oxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (10.5 g, 84.1%) as a yellow solid.

[0365] LCMS (ESI) calcd. for C23H27BrN2O3[M+H]+m / z 459.1, found: 459.5. Step 3: Synthesis of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-in- dol-3-yl)-2,2-dimethylpropyl acetate

[0366] To a stirred solution of (S)-3-(5-bromo-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-in- dol-3-yl)-2,2-dimethylpropyl acetate (12.4 g, 27.10 mmol) in DMF (120 mL) were added Cs2CO3 (17.6 g, 54.19 mmol) and Iodoethane (6.3 g, 40.64 mmol) at 0 ºC, the resulting mix- ture was stirred at rt for 18 h. The reaction was monitored by LCMS. After completion, the re- action mixture was diluted with EtOAc (200 mL), washed with water (1000 mL x 2) and satu- rated NaCl (1000 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 60%) to afford (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3- yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (10.4 g, 79.0%) as a brown solid.

[0367] LCMS (ESI) calcd. for C25H31BrN2O3[M+H]+m / z 487.2, found: 487.6. Step 4: Synthesis of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-in- dol-3-yl)-2,2-dimethylpropan-1-ol

[0368] To a solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-in- dol-3-yl)-2,2-dimethylpropyl acetate (10.4 g, 21.42 mmol) in THF (100 mL), MeOH (50 mL)and H2O (50 mL) was added LiOH (2.7 g, 64.26 mmol) at 0-10 ºC, the resulting mixture was stirred at 0-10 ºC 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 HCl. The resulting mixture was extracted with EtOAc (100 mL x 2), the combined organic phase was washed with saturated NaCl (100 mL), then dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to afford (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxy- ethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (5.0 g, 52.0%) as a yellow solid.

[0369] LCMS (ESI) calcd. for C23H29BrN2O2[M+H]+m / z 445.2, found: 445.6. Step 5: Synthesis of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-in- dol-3-yl)-2,2-dimethylpropyl acetate

[0370] To a stirred solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)- 1H-indol-3-yl)-2,2-dimethylpropan-1-ol (5.0 g, 11.15 mmol) in DCM (50 mL) were added DIEA (2.9 g, 22.30 mmol), DMAP (136 mg, 1.11 mmol) and Ac2O (1.20 g, 11.71 mmol) at rt, the resulting mixture was stirred at rt for 18 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concetrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 50%) to give (S)-3-(5-bromo-1-ethyl-2- (2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (5.1 g, 94.3%) as a pale yellow solid.

[0371] LCMS (ESI) calcd. for C25H31BrN2O3[M+H]+m / z 487.2, found: 487.6 Step 6: Synthesis of (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1-ethyl-1H-in- dol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0372] To a stirred solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)- 1H-indol-3-yl)-2,2-dimethylpropyl acetate (5.1 g, 10.51 mmol), B2Pin2(4.0 g, 15.77 mmol)in THF (100 mL) was added [Ir(COD)Cl]2(353 mg, 0.53 mmol) and dtbpy (423 mg, 1.58 mmol) at rt, the resulting mixture was stirred at 85 ºC under N2for 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-1-ethyl-2-(5-hydroxy-2-(1-methoxyethyl)pyridin-3- yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0373] To a stirred solution of crude (S)-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-5-bromo-1- ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)boronic acid (4.5 g, 8.40 mmol) in THF (300 mL) was added H2O2(4.8 g, 41.98 mmol) at r.t. The reaction mixture was stirred at r.t. for 2 h. After completion, reaction mixture was diluted with EtOAc (60 mL), washed with water (50 mL x 2) and saturated NaCl (50 mL), then dried over Na2SO4, following with concentra- tion under reduced pressure to obtain the crude (S)-3-(5-bromo-1-ethyl-2-(5-hydroxy-2-(1- methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (3.4 g, 80.9%) as a yel- low solid.

[0374] LCMS (ESI) calcd. for C25H31BrN2O4[M+H]+m / z 503.2, found: 503.7. Step 8: Synthesis of (S)-3-(2-(5-(benzyloxy)-2-(1-methoxyethyl)pyridin-3-yl)-5-bromo- 1-ethyl-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0375] To a stirred solution of crude (S)-3-(5-bromo-1-ethyl-2-(5-hydroxy-2-(1-methoxy- ethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (3.4 g, 6.79 mmol) in CH3CN (68 mL) were added K2CO3(2.8 g, 20.38 mmol) and BnBr (1.7 g, 10.19 mmol), the resulting mixture was stirred at 85 ºC for 16 h. The reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 30%) to give(S)-3-(2-(5-(benzyloxy)-2-(1-methoxyethyl)pyridin-3-yl)-5-bromo-1-ethyl-1H-indol-3-yl)-2,2- dimethylpropyl acetate (3.2 g, 79.4%) as a yellow foam.

[0376] LCMS (ESI) calcd. for C32H37BrN2O4[M+H]+m / z 593.2, found: 593.6 Step 9: Synthesis of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-in- dol-3-yl)-2,2-dimethylpropan-1-ol

[0377] To a solution of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H- indol-3-yl)-2,2-dimethylpropyl acetate (10.4 g, 21.42 mmol) in THF (100 mL), MeOH (50 mL) and H2O (50 mL) was added LiOH⋅H2O (2.7 g, 64.26 mmol) at 0-10 ºC, the resulting mixture was stirred at 0-10 ºC 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 HCl. The resulting mixture was extracted with EtOAc (100 mL x 2), the combined organic phase was washed with saturated NaCl (100 mL), then dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to afford (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxy- ethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (5.0 g, 52.0%) as a yellow solid.

[0378] LCMS (ESI) calcd. for C23H29BrN2O2[M+H]+m / z 445.2, found: 445.6. Step 10: Synthesis of methyl (S)-3-(3-(2-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyridin- 3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phe- nyl)-2-((tert-butoxycarbonyl)amino)propanoate

[0379] To a stirred solution of (S)-3-(2-(5-(benzyloxy)-2-(1-methoxyethyl)pyridin-3-yl)-5- bromo-1-ethyl-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (6.9 g, 12.51 mmol), methyl (S)-2- ((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-((triisopropylsilyl)oxy)phenyl)propanoate (9.4 g, 16.26 mmol) and K2CO3(5.2 g, 37.54 mmol) in 1,4-dioxane / H2O (180 mL, V:V = 5:1) was added Pd(dppf)Cl2(915 mg, 1.25 mmol) at rt. The reaction mixture was stirred at 90 ºC under N2for 18 h. After completion, the reaction so- lution was concentrated under reduced pressure to remove 1,4-dioxane, the residual was diluted with H2O (200 mL) and extracted with EtOAc (200 mL x 2), the combined organic phase was washed with saturated NaCl (200 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (elut- ing with EtOAc / PE from 0% to 70%) to afford methyl (S)-3-(3-(2-(5-(benzyloxy)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5- ((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoate (7.5 g, 65.0%) as a yellow foam.

[0380] LCMS (ESI) calcd. for C54H75N3O8Si [M+H]+m / z 922.5, found: 923.6. Step 11: Synthesis of (S)-2-((S)-3-(4-(2-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyridin-3- yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycar- bonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid

[0381] To a solution of methyl (S)-3-(3-(2-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyridin- 3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phe- nyl)-2-((tert-butoxycarbonyl)amino)propanoate (7.9 g, 18.66 mmol) in THF (80 mL), and H2O (40 mL) was added LiOH⋅H2O (3.9 g, 17.20 mmol) at 0-10 ºC, the resulting mixture was stirred at rt for 17 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the residue. The residue was diluted with H2O and acidified to pH = 4-5 with 2 N HCl. The resulting mixture was extracted with EtOAc (100 mL x 2), the combined organic phase was washed with saturated NaCl (200 mL), then dried over Na2SO4 and concentrated to give crude (S)-2-((S)-3-(4-(2-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyri- din-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (8.2 g) as a yellow foam.

[0382] LCMS (ESI) calcd. for C53H73N3O8Si [M+H]+m / z 908.5, found: 910.0.Step 12: Synthesis of methyl (S)-2-((S)-3-(3-(2-(5-(benzyloxy)-2-((S)-1-methoxy- ethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsi- lyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4- carboxylate

[0383] To a solution of crude (S)-2-((S)-3-(4-(2-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyr- idin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)-2-((tert- butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (8.1 g, 8.92 mmol), methyl (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate hydrogen chloride (1.9 g, 9.87 mmol) and DIEA (5.8 g, 44.87 mmol) in DMF (90 mL) under ice-water bath was added HATU (5.1 g, 13.41 mmol) in batches at rt. The reaction was gradually warmed to room tem- perature and stirred for 2 h, the reaction was monitored by LCMS. After completion, the reac- tion was diluted with H2O (500 mL) and extracted with EtOAc (2*100 mL). The organic layers were combined, washed with brine (300 mL), dried over anhydrous Na2SO4 following with concentration under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to afford methyl (S)-2-((S)-3-(3-(2-(5-(ben- zyloxy)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H- indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3- diazabicyclo[3.1.1]heptane-4-carboxylate (4.9 g, 51.9%) as a yellow foam.

[0384] LCMS (ESI) calcd. for C60H83N5O9Si [M+H]+m / z 1046.6, found: 1048.1. Step 13: Synthesis of (S)-2-((S)-3-(3-(2-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyridin-3- yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)- 2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid

[0385] To a solution of methyl (S)-2-((S)-3-(3-(2-(5-(benzyloxy)-2-((S)-1-methoxy- ethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triiso- propylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicy- clo[3.1.1]heptane-4-carboxylate (4.9 g, 4.64 mmol) in THF (50 mL), and H2O (25 mL) was added LiOH⋅H2O (389 mg, 9.28 mmol) at 0-10 ºC, the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with H2O and acidified to pH = 4-5 with 2 N HCl. The resulting mixture was extracted with EtOAc (100 mL x 2), the combined organic phase was washed with saturated NaCl (200 mL), then dried over Na2SO4 and concentrated to give crude (S)-2-((S)-3-(3-(2-(5-(benzyloxy)-2- ((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)- 5-((triisopropylsilyl)oxy)phenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)-2,3-diazabicy- clo[3.1.1]heptane-4-carboxylic acid (4.7 g) as a yellow foam.

[0386] LCMS (ESI) calcd. for C59H81N5O9Si [M+H]+m / z 1032.6, found: 1034.1 Step 14: Synthesis of tert-butyl ((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyri- din-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza- 1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate

[0387] To a solution of TCFH (5.1 g, 18.19 mmol) in CH3CN ( 230 mL) was added a solu- tion of crude (S)-2-((S)-3-(3-(2-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3- (3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)-5-((triisopropylsilyl)oxy)phenyl)-2-((tert- butoxycarbonyl)amino)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (4.7 g, 4.56 mmol) and NMI (3.0 g, 36.49 mmol) in CH3CN (240 mL) dropwisely at rt. The resulting mixture was stirred at rt for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 70%) to afford tert-butyl ((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7- dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza-1(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (2.7 g, 57.8%) as a white foam.

[0388] LCMS (ESI) calcd. for C59H79N5O8Si [M+H]+m / z 1014.6, found: 1016.1 Step 15: Synthesis of (64S,4S)-4-amino-12-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyri- din-3-yl)-11-ethyl-10,10-dimethyl-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza-1(5,3)-in- dola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-5,7-dione

[0389] To a solution of tert-butyl ((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyri- din-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza- 1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate (2.0 g, 1.97 mmol) in DCM (20 mL) were added TFA (6 mL) at rt. The resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (30 mL) and basified with sat. aq. NaHCO3to pH 7-8. The organic layer was separated, dried over anhydrous Na2SO4and concentrated to give crude (64S,4S)-4-amino-12-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyri- din-3-yl)-11-ethyl-10,10-dimethyl-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza-1(5,3)-in- dola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-5,7-dione (1.7 g mg, 95.1%) as a pale orange foam.

[0390] LCMS (ESI) calcd. for C54H71N5O6Si [M+H]+m / z 914.5, found: 915.8 Step 16: Synthesis of tert-butyl 3-(((2S)-1-(((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methox- yethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4- yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1- carboxylate

[0391] To a solution of crude (64S,4S)-4-amino-12-(5-(benzyloxy)-2-((S)-1-methoxy- ethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-5,7-dione (330 mg, 0.36 mmol), N-(1-(tert-butoxycarbonyl)-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N- methyl-L-valine (203 mg, 0.40 mmol) and NMI (148 mg, 1.81 mmol) in CH3CN (3 mL) and DCM (3 mL) was added TCFH (152 mg, 0.54 mmol) at rt. The resulting mixture was stirred at 0-10 ºC for 1 h. After completion, the reaction mixture was concentrated under reduced pres- sure to obtain the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 60%) to afford tert-butyl 3-(((2S)-1-(((64S,4S)-12-(5-(benzyloxy)-2- ((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsi- lyl)oxy)-11H-8-oxa-62,63-diaza-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzena- cycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((to- syloxy)methyl)pyrrolidine-1-carboxylate (256 mg, 50.5%) as a yellow oil. Step 17: Synthesis of tert-butyl 3-(((2S)-1-(((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methox- yethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa- 62,63-diaza-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4- yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1- carboxylate

[0392] To a solution of tert-butyl 3-(((2S)-1-(((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methox- yethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa- 62,63-diaza-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4- yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1- carboxylate (256 mg, 8.71 mmol) in THF (2.5 mL) was added TBAF (101 mg, 0.36 mmol) in THF (2.5 mL) at rt. The resulting mixture was stirred at rt for 2 h. After completion, the reac- tion mixture was concentrated under reduced pressure to obtain crude product which was puri- fied by silica gel column eluting with (MeOH / DCM from 0% to 10%) to afford tert-butyl 3- (((2S)-1-(((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11-ethyl-10,10-di- methyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa-62,63-diaza-1(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4-yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1-carboxylate (215 mg, 95.5%) as a pale yellow foam.

[0393] LCMS (ESI) calcd. for C69H85N7O13S [M+H]+m / z 1252.6, found: 892.2 Step 18: Synthesis of tert-butyl (6S,9S,15S)-21-(5-(benzyloxy)-2-((S)-1-methoxy- ethyl)pyridin-3-yl)-22-ethyl-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate

[0394] A mixture of tert-butyl 3-(((2S)-1-(((64S,4S)-12-(5-(benzyloxy)-2-((S)-1-methoxy- ethyl)pyridin-3-yl)-11-ethyl-10,10-dimethyl-5,7-dioxo-25-((triisopropylsilyl)oxy)-11H-8-oxa- 62,63-diaza-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4- yl)amino)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)-2-((tosyloxy)methyl)pyrrolidine-1- carboxylate (215 mg, 0.17 mmol), K2CO3 (237 mg, 1.72 mmol) and KI (29 mg, 0.17 mmol) in DMF (20 mL) was stirred at 80 ºC for 19 h. After completion, the reaction was diluted with H2O (200 mL) and extracted with EtOAc (2*30 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous Na2SO4 following with concentration under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to afford tert-butyl (6S,9S,15S)-21-(5-(benzyloxy)-2-((S)-1- methoxyethyl)pyridin-3-yl)-22-ethyl-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate (109 mg, 59.4%) as a white foam.

[0395] LCMS (ESI) calcd. for C62H77N7O10[M+H]+m / z 1080.6, found: 1081.1 Step 19: Synthesis of tert-butyl (6S,9S,15S)-22-ethyl-21-(5-hydroxy-2-((S)-1-methoxy- ethyl)pyridin-3-yl)-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate

[0396] To a stirred solution of tert-butyl (6S,9S,15S)-21-(5-(benzyloxy)-2-((S)-1-methoxy- ethyl)pyridin-3-yl)-22-ethyl-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate (109 mg, 0.10 mmol) in MeOH (10 mL) was added Pd / C (10%, 20 mg) at rt, the resulting mixture was stirred at 50 ºC for 15 h. The reaction was monitored by LCMS. After completion, the reaction mixture was filtered, and the filtrate was concentrated to give crude tert-butyl (6S,9S,15S)-22-ethyl-21-(5-hydroxy-2-((S)-1-meth- oxyethyl)pyridin-3-yl)-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate (94 mg, 69.7%) as a grey foam.

[0397] LCMS (ESI) calcd. for C55H71N7O10[M+H]+m / z 990.5, found: 991.0. Step 20: Synthesis of tert-butyl (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2-((S)-1-methoxy- ethyl)-5-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate

[0398] To a solution of crude tert-butyl (6S,9S,15S)-22-ethyl-21-(5-hydroxy-2-((S)-1- methoxyethyl)pyridin-3-yl)-6-isopropyl-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate (94 mg, 0.095 mmol) in DCM (2 mL) were added DIEA (25 mg, 0.19 mmol) and PhN(Tf)2(34 mg, 0.095 mmol) at 0-10 ºC. The resultingmixture 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 reverse phase column chromatography (eluting with CH3CN / H2O(0.5%NH4HCO3) from 10% to 90%) to afford tert-butyl (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2-((S)-1-methoxy- ethyl)-5-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate (20 mg, 18.8%) as a white solid.

[0399] LCMS (ESI) calcd. for C56H70F3N7O12S [M+H]+m / z 1122.5, found: 1124.0. Step 21: Synthesis of tert-butyl (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2-((S)-1-methoxy- ethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate

[0400] A mixture of tert-butyl (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2-((S)-1-methoxy- ethyl)-5-(((trifluoromethyl)sulfonyl)oxy)pyridin-3-yl)-5,19,19-trimethyl-4,7,10,16-tetraoxo- 2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino- 23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate (20 mg, 0.018 mmol), 4-(prop-2-yn-1-yl)mor- pholine (4mg, 0.027 mmol), CuI (1 mg, 0.0054 mmol), TEA (6 mg, 0.054 mmol) and Pd(PPh3)2Cl2(3mg, 0.0027 mmol) in DMF (1 mL) was stirred at 100 ºC for 1 h under N2at- mosphere, the reaction was monitored by LCMS. After completion, the reaction was diluted with H2O (20 mL) and extracted with EtOAc (2*20 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4following with concentration under reduced pressure to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 10%) to afford tert-butyl (6S,9S,15S)-22-ethyl-6-isopropyl-21- (2-((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl- 4,7,10,16-tetraoxo-2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15-epimino-23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'- v][1,18]dioxa[6,9,12]triazacyclotriacontine-1-carboxylate (22 mg) as a brown foam.

[0401] LCMS (ESI) calcd. for C62H80N8O10[M+H]+m / z 1097.6, found: 1099.0 Step 22: Synthesis of (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2-((S)-1-methoxyethyl)-5-(3- morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl- 3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H-11,15-epimino-23,25-etheno- 9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]dioxa[6,9,12]triazacy- clotriacontine-4,7,10,16(2H,13H)-tetraone

[0402] To a stirred solution of tert-butyl (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2-((S)-1- methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl-4,7,10,16- tetraoxo-2,3,3a,4,5,6,7,8,9,10,13,14,15,16,18,19,20,22,32,32a-icosahydro-1H,12H-11,15- epimino-23,25-etheno-9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]di- oxa[6,9,12]triazacyclotriacontine-1-carboxylate (120 mg, 0.14 mmol) in dichloromethane (1 mL) was added TFA (0.3 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give crude (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2- ((S)-1-methoxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl- 3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H-11,15-epimino-23,25-etheno- 9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]dioxa[6,9,12]triazacyclot- riacontine-4,7,10,16(2H,13H)-tetraone which was used to next step without purification.

[0403] LCMS (ESI) calcd. for C57H72N8O8[M+H]+m / z 997.6, found: 998.7. Step 23: Synthesis of (6S,9S,15S)-1-acryloyl-22-ethyl-6-isopropyl-21-(2-((S)-1-methox- yethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl- 3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H-11,15-epimino-23,25-etheno- 9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]dioxa[6,9,12]triazacy- clotriacontine-4,7,10,16(2H,13H)-tetraone

[0404] To a stirred solution of crude (6S,9S,15S)-22-ethyl-6-isopropyl-21-(2-((S)-1-meth- oxyethyl)-5-(3-morpholinoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl- 3,3a,5,6,8,9,14,15,18,19,20,22,32,32a-tetradecahydro-1H,12H-11,15-epimino-23,25-etheno- 9,28:12,14-dimethano-26,30-(metheno)dipyrrolo[2,3-c:3',4'-v][1,18]dioxa[6,9,12]triazacyclot- riacontine-4,7,10,16(2H,13H)-tetraone in DCM (1.5 mL) were added DIEA (26 mg, 0.20 mmol) and acryloyl chloride (2 mg, 0.020 mmol) at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (eluting with CH3CN / H2O (0.1% NH4HCO3) from 20% to 80%) to give (6S,9S,15S)-1-acryloyl-22-ethyl-6-isopropyl-21-(2-((S)-1-methoxyethyl)-5-(3-morpho- linoprop-1-yn-1-yl)pyridin-3-yl)-5,19,19-trimethyl-3,3a,5,6,8,9,14,15,18,19,20,22,32,32a- tetradecahydro-1H,12H-11,15-epimino-23,25-etheno-9,28:12,14-dimethano-26,30-(me- theno)dipyrrolo[2,3-c:3',4'-v][1,18]dioxa[6,9,12]triazacyclotriacontine-4,7,10,16(2H,13H)- tetraone (4.3 mg) as white solids.

[0405] LCMS (ESI) calcd. for C60H74N8O9[M+H]+m / z 1051.6, found: 1052.0.

[0406] 1H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.59 (s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.58 (d, J = 9.3 Hz, 1H), 7.23 – 7.08 (m, 2H), 6.62 (dd, J = 16.2, 10.5 Hz, 1H), 6.36 (s, 1H), 6.18 (d, J = 15.5 Hz, 1H), 5.80 – 5.62 (m, 1H), 5.30 (s, 1H), 5.01 (s, 1H), 4.63 (d, J = 11.0 Hz, 1H), 4.53 (s, 2H), 4.19 (s, 2H), 4.09 – 3.83 (m, 3H), 3.70 – 3.44 (m, 5H), 3.32 (s, 2H), 3.15 (d, J = 5.2 Hz, 1H), 3.02 (d, J = 10.4 Hz, 2H), 2.75 (s, 2H), 2.51 (s, 2H), 2.29 (d, J = 10.0 Hz, 2H), 2.18 – 1.90 (m, 2H), 1.76 (s, 1H), 1.55 (s, 1H), 1.37 (d, J = 6.2 Hz, 2H), 1.21 (s, 3H), 1.03 (d, J = 16.0 Hz, 3H), 0.83 (d, J = 6.0 Hz, 2H), 0.63 (d, J = 10.8 Hz, 2H), 0.54 (s, 2H).

[0407] Each of the compounds set forth was prepared following one of the procedures set forth above. Example 15. Synthesis of Compound 1

[0408] Substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N- methyl-L-valine with (1S,2S,3R)-2-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3-methyl- cyclopropane-1-carboxylic acid in the Step 5 of Example 13 and substituting tert-butyl((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaboro- lan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-ben- zenacycloundecaphane-4-yl)carbamate with tert-butyl ((63S,4S,Z)-10,10-dimethyl-5,7-dioxo- 12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25-vinyl-15,16,61,62,63,64,65,66-octahydro- 14H-8-oxa-2(2,4)-thiazola-1(8,1)-pyrrolo[3,2,1-ij]quinolina-6(1,3)-pyridazinacycloundeca- phane-4-yl)carbamate in the Step 1 of Example 13, the title compound was prepared by the same procedures as described for Compound 11.

[0409] LCMS (ESI): 750.3 [M+1]+.

[0410] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.43 – 7.37 (m, 2H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.80 (q, J = 13.3 Hz, 1H), 4.07 – 3.99 (m, 2H), 3.99 – 3.90 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.63 – 3.54 (m, 7H), 3.45 (d, J = 7.3 Hz, 2H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 3.05 – 2.99 (m, 1H), 2.99 – 2.92 (m, 2H), 2.88 (dd, J = 11.7, 9.0 Hz, 1H), 2.81 (t, J = 11.4 Hz, 2H), 2.75 – 2.69 (m, 4H), 2.62 (dd, J = 8.8, 7.9 Hz, 1H), 2.16 – 1.97 (m, 5H), 1.95 – 1.86 (m, 1H), 1.85 – 1.78 (m, 2H), 1.76 – 1.70 (m, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (d, J = 4.9 Hz, 3H). Example 16. Synthesis of Compound 2

[0411] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25- vinyl-15,16-dihydro-14H-8-oxa-62,63-diaza-2(2,4)-thiazola-1(8,1)-pyrrolo[3,2,1-ij]quinolina- 6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate in the Step 1 of Example 13 and Substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl- L-valine with (1S,2S,3R)-2-((allyloxy)methyl)-3-methylcyclopropane-1-carboxylic acid in the Step 5 of Example 13, the title compound was prepared by the same procedures as described for Compound 1.

[0412] LCMS (ESI): 807.4 [M+1]+.

[0413] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.50 (d, J = 13.6 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.92 – 4.80 (m, 2H), 4.08 – 3.99 (m, 2H), 3.99 – 3.90 (m, 4H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.64 – 3.54 (m, 4H), 3.45 (d, J = 7.3 Hz, 2H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 3.07 – 2.99 (m, 2H), 2.96 (dd, J = 11.6, 9.0 Hz, 1H), 2.88 (dd, J = 11.7, 9.0 Hz, 1H), 2.81 (t, J = 11.4 Hz, 2H), 2.77 – 2.66 (m, 5H), 2.62 (dd, J = 8.8, 7.9 Hz, 1H), 2.16 – 1.97 (m, 9H), 1.90 (ddt, J = 9.7, 9.0, 7.4 Hz, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (d, J = 4.9 Hz, 3H). Example 17. Synthesis of Compound 3

[0414] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with tert-butyl ((63S,4S,Z)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-25- vinyl-15,16,61,62,63,64,65,66-octahydro-14H-8-oxa-2(2,4)-thiazola-1(8,1)-pyrrolo[3,2,1- ij]quinolina-6(1,3)-pyridazinacycloundecaphane-4-yl)carbamate in the Step 1 of Example 13 and Substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl- L-valine with (R)-2-((allyloxy)methyl)-3-methylbutanoic acid in the Step 5 of Example 13, the title compound was prepared by the same procedures as described for Compound 11.

[0415] LCMS (ESI): 807.4 [M+1]+.

[0416] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.10 (d, J = 13.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.77 (q, J = 13.2 Hz, 1H), 4.07 – 3.99 (m, 2H), 3.99 – 3.90 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.47 (m, 11H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 3.07 – 2.96 (m, 2H), 2.95 (dd, J = 9.3, 2.3 Hz, 1H), 2.92 – 2.84 (m, 1H), 2.81 (t, J = 11.4 Hz, 2H), 2.76 – 2.67 (m, 5H), 2.14 – 1.97 (m, 5H), 1.90 – 1.86 (m, 1H), 1.86 – 1.78 (m, 2H), 1.76 – 1.67 (m, 3H), 1.66 (s, 1H), 1.15 (s, 3H), 1.10 (s, 3H), 1.01 (d, J = 4.9 Hz, 3H), 0.96 (d, J = 5.0 Hz, 3H). Example 18. Synthesis of Compound 4

[0417] Substituting (R)-2-((allyloxy)methyl)-3-methylbutanoic acid with N-(but-3-enoyl)- N-methyl-L-valine in the Step 5 of Example 17, the title compound was prepared by the same procedures as described for Compound 3.

[0418] LCMS (ESI): 846.4 [M+1]+.

[0419] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 7.32 (d, J = 13.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.96 (d, J = 8.1 Hz, 1H), 4.80 (q, J = 13.2 Hz, 1H), 4.07 – 3.99 (m, 2H), 3.99 – 3.90 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.54 (m, 7H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 3.06 – 2.98 (m, 2H), 2.98 – 2.91 (m, 1H), 2.91 – 2.80 (m, 6H), 2.75 – 2.69 (m, 4H), 2.52 (t, J = 10.5 Hz, 2H), 2.25 (dhept, J = 8.0, 5.0 Hz, 1H), 2.08 – 1.94 (m, 4H), 1.90 – 1.86 (m, 1H), 1.86 – 1.78 (m, 2H), 1.76 – 1.70 (m, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.91 (d, J = 5.1 Hz, 3H), 0.85 (d, J = 5.1 Hz, 3H). Example 19. Synthesis of Compound 5

[0420] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with di-tert-butyl ((63S,4S)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 15,16,61,62,63,64,65,66-octahydro-14H-8-oxa-1(8,1)-pyrrolo[3,2,1-ij]quinolina-6(1,3)-pyri- dazina-2(1,3)-benzenacycloundecaphane-25,4-diyl)dicarbamate in the Step 1 of Example 13 and substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl-L- valine with (1S,2S,3R)-2-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3-methylcyclopro- pane-1-carboxylic acid in the Step 5 of Example 13, the title compound was prepared by the same procedures as described for Compound 11.

[0421] LCMS (ESI): 846.4 [M+1]+.

[0422] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.19 (d, J = 12.3 Hz, 1H), 7.13 (tt, J = 2.0, 0.9 Hz, 1H), 6.70 (t, J = 2.2 Hz, 1H), 6.47 (tt, J = 2.2, 1.1 Hz, 1H), 5.96 (t, J = 5.9 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.70 (td, J = 13.4, 12.4 Hz, 1H), 4.07 – 3.99 (m, 2H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.54 (m, 9H), 3.50 (d, J = 7.3 Hz, 2H), 3.48 – 3.45 (m, 1H), 3.45 – 3.37 (m, 2H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 2.94 – 2.82 (m, 4H), 2.75 – 2.64 (m, 5H), 2.11 (ddq, J = 9.7, 7.9, 4.9 Hz, 1H), 2.02 (dtd, J = 11.7, 9.2, 6.7 Hz, 2H), 1.95 – 1.86 (m, 2H), 1.86 – 1.78 (m, 3H), 1.76 – 1.67 (m, 3H), 1.66 (s, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (d, J = 4.9 Hz, 3H). Example 20. Synthesis of Compound 6

[0423] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaboro- lan-2-yl)-15,16,61,62,63,64,65,66-octahydro-14H-8-oxa-1(8,1)-pyrrolo[3,2,1-ij]quinolina- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate in the Step 1 of Example 13 and Substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-me- thyl-L-valine with (1S,2S,3R)-2-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3-methylcy- clopropane-1-carboxylic acid in the Step 5 of Example 13, the title compound was prepared by the same procedures as described for Compound 11.

[0424] LCMS (ESI): 829.4 [M+1]+.

[0425] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.22 – 7.16 (m, 2H), 7.12 (tt, J = 2.2, 1.1 Hz, 1H), 7.03 (t, J = 2.1 Hz, 1H), 6.63 (tt, J = 2.2, 1.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.73 (td, J = 13.5, 12.4 Hz, 1H), 4.21 (td, J = 7.1, 0.9 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.77 – 3.70 (m, 4H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.63 – 3.50 (m, 7H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 2.96 – 2.84 (m, 4H), 2.75 – 2.69 (m, 4H), 2.62 (dd,J = 8.8, 7.9 Hz, 1H), 2.13 – 1.97 (m, 3H), 1.95 – 1.89 (m, 1H), 1.89 – 1.78 (m, 3H), 1.76 – 1.67 (m, 3H), 1.66 (s, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (d, J = 4.9 Hz, 3H). Example 21. Synthesis of Compound 7

[0426] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaboro- lan-2-yl)-15,16,61,62,63,64,65,66-octahydro-14H-8-oxa-1(8,1)-pyrrolo[3,2,1-ij]quinolina- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate in the Step 1 of Example 13 and substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-me- thyl-L-valine with (R)-2-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3-methylbutanoic acid in the Step 5 of Example 13, the title compound was prepared by the same procedures as described for Compound 11.

[0427] LCMS (ESI): 827.4 [M+1]+.

[0428] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.14 – 7.05 (m, 2H), 7.03 (t, J = 2.1 Hz, 1H), 6.63 (tt, J = 2.2, 1.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.71 (td, J = 13.5, 12.0 Hz, 1H), 4.28 – 4.16 (m, 2H), 4.07 – 3.99 (m, 2H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.81 – 3.71 (m, 4H), 3.69 – 3.54 (m, 9H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 3.07 – 2.99 (m, 1H), 2.96 – 2.86 (m, 3H), 2.76 – 2.67 (m, 5H), 2.12 – 1.97 (m, 3H), 1.90 – 1.78 (m, 3H), 1.76 – 1.67 (m, 3H), 1.66 (s, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.01 (d, J = 4.9 Hz, 3H), 0.96 (d, J = 5.0 Hz, 3H). Example 22. Synthesis of Compound 8

[0429] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with di-tert-butyl ((63S,4S)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 15,16,61,62,63,64,65,66-octahydro-14H-8-oxa-1(8,1)-pyrrolo[3,2,1-ij]quinolina-6(1,3)-pyri- dazina-2(1,3)-benzenacycloundecaphane-25,4-diyl)dicarbamate in the Step 1 of Example 13 and Substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl- L-valine with (R)-2-((2-((tert-butyldimethylsilyl)oxy)ethoxy)methyl)-3-methylbutanoic acid in the Step 5 of Example 13, the title compound was prepared by the same procedures as de- scribed for Compound 11.

[0430] LCMS (ESI): 882.3 [M+1]+.

[0431] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.13 (tt, J = 2.0, 0.9 Hz, 1H), 7.03 (d, J = 11.9 Hz, 1H), 6.70 (t, J = 2.2 Hz, 1H), 6.47 (tt, J = 2.2, 1.1 Hz, 1H), 6.00 (t, J = 6.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.72 (td, J = 13.4, 11.9 Hz, 1H), 4.07 – 3.99 (m, 2H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.54 (m, 11H), 3.49 – 3.39 (m, 2H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 3.02 (dd, J = 11.6, 9.0 Hz, 1H), 2.95 – 2.87 (m, 2H), 2.87 (t, J = 1.0 Hz, 1H), 2.76 – 2.67 (m, 5H), 2.12 – 1.97 (m, 3H), 1.89 – 1.83 (m, 2H), 1.83 – 1.78 (m, 1H), 1.76 – 1.67 (m, 3H), 1.66 (s, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 1.01 (d, J = 4.9 Hz, 3H), 0.96 (d, J = 5.0 Hz, 3H). Example 23. Synthesis of Compound 9

[0432] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)- indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaboro- lan-2-yl)-15,16,61,62,63,64,65,66-octahydro-14H-8-oxa-1(8,1)-pyrrolo[3,2,1-ij]quinolina- 6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate in the Step 1 of Example 13 and substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl-L-valine with N-(3-((tert-butyldimethylsilyl)oxy)propanoyl)-N-methyl-L-valine in the Step 5 of Example 13, the title compound was prepared by the same procedures as described for Compound 11.

[0433] LCMS (ESI): 866.4 [M+1]+.

[0434] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 12.1 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.12 (tt, J = 2.2, 1.1 Hz, 1H), 7.03 (t, J = 2.1 Hz, 1H), 6.63 (tt, J = 2.0, 0.9 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.1 Hz, 1H), 4.69 (td, J = 13.5, 12.0 Hz, 1H), 4.22 (t, J = 8.3 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.54 (m, 7H), 3.33 (s, 3H), 3.09 (d, J = 2.6 Hz, 2H), 3.02 (dd, J = 11.6, 9.0 Hz, 1H), 2.94 (td, J = 1.9, 1.0 Hz, 1H), 2.91 (s, 4H), 2.75 – 2.68 (m, 6H), 2.25 (dhept, J = 8.0, 5.1 Hz, 1H), 2.02 (dtd, J = 11.7, 9.2, 6.7 Hz, 2H), 1.90 – 1.83 (m, 2H), 1.83 – 1.78 (m, 1H), 1.76 – 1.70 (m, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.91 (d, J = 5.1 Hz, 3H), 0.85 (d, J = 5.1 Hz, 3H). Example 24. Synthesis of Compound 10

[0435] Substituting N-(3-((tert-butyldimethylsilyl)oxy)propanoyl)-N-methyl-L-valine with N-(N-(aziridine-2-carbonyl)-O-(tert-butyldimethylsilyl)-L-homoseryl)-N-methyl-L-valine in the Step 5 of Example 23, the title compound was prepared by the same procedures as de- scribed for Compound 9.

[0436] LCMS (ESI): 820.4 [M+1]+.

[0437] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 11.2 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 11.9 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.13 (tt, J = 2.0, 0.9 Hz, 1H), 7.04 (t, J = 2.1 Hz, 1H), 6.63 (tt, J = 2.0, 0.9 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.88 (d, J = 8.1 Hz, 1H), 4.68 (td, J = 13.5, 12.0 Hz, 1H), 4.45 (dt, J = 11.2, 10.5 Hz, 1H), 4.13 – 4.06 (m, 2H), 4.06 – 3.99 (m, 2H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.76 – 3.54 (m, 10H), 3.33 (s, 3H), 3.21 (dddd, J = 13.2, 7.1, 6.1, 2.0 Hz, 2H), 3.09 (d, J = 2.6 Hz, 2H), 3.02 (dd, J = 11.6, 9.0 Hz, 1H), 2.96 – 2.86 (m, 6H), 2.75 – 2.69 (m, 4H), 2.57 (dt, J = 8.4, 7.1 Hz, 1H), 2.23 (dhept, J = 8.1, 5.1 Hz, 1H), 2.11– 1.97 (m, 4H), 1.90 – 1.83 (m, 2H), 1.83 – 1.78 (m, 1H), 1.76 – 1.67 (m, 3H), 1.66 (s, 2H), 1.15 (s, 3H), 1.10 (s, 3H), 0.90 (d, J = 5.0 Hz, 3H), 0.85 (d, J = 5.1 Hz, 3H). Example 25. Synthesis of Compound 12

[0438] Substituting N-(N-(aziridine-2-carbonyl)-O-(tert-butyldimethylsilyl)-L-homoseryl)- N-methyl-L-valine with N-((3S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(oxazol-5-yl)pyr- rolidine-3-carbonyl)-N-methyl-L-valine in the Step 5 of Example 24, the title compound was prepared by the same procedures as described for Compound 10.

[0439] LCMS (ESI): 860.5 [M+1]+.

[0440] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 12.1 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.13 (tt, J = 2.2, 0.9 Hz, 1H), 7.07 (t, J = 2.2 Hz, 1H), 6.64 (dt, J = 3.7, 1.3 Hz, 2H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.69 (td, J = 13.5, 12.0 Hz, 1H), 4.42 (dt, J = 7.9, 7.0 Hz, 1H), 4.11 (dd, J = 7.0, 0.9 Hz, 2H), 4.07 – 3.99 (m, 2H), 3.97 – 3.90 (m, 2H), 3.90 – 3.85 (m, 1H), 3.85 – 3.81 (m, 1H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.54 (m, 7H), 3.33 (s, 3H), 3.14 – 3.06 (m, 2H), 3.06 – 2.99 (m, 2H), 2.96 – 2.86 (m, 6H), 2.75 – 2.69 (m, 4H), 2.23 (dhept, J = 8.1, 5.1 Hz, 1H), 2.02 (dtd, J = 11.7, 9.2, 6.7 Hz, 2H), 1.91 (td, J = 7.3, 6.2 Hz, 1H), 1.89 – 1.81 (m, 4H), 1.76 – 1.70 (m, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.92 (d, J = 5.0 Hz, 3H), 0.87 (d, J = 5.1 Hz, 3H). Example 26. Synthesis of Compound 13: (1r,2R,3S)-N-((64S,4S,Z)-11-ethyl-12-(2-((S)-1- methoxyethyl)-5-(3-(4-methylpiperazin-1-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl- 5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cycloundecaphane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0441] Substituting (3S)-3-((2S)-2-(aziridine-2-carboxamido)-4-((tert-butyldimethylsi- lyl)oxy)-N-methylbutanamido)-4-methyl-2-oxopentanoic acid with N-((3S)-2-(((tert-butyldimethylsilyl)oxy)methyl)-1-(2-fluoro-2-methylpropanoyl)pyrrolidine-3-carbonyl)-N-me- thyl-L-valine in the Step 5 of Example 24, the title compound was prepared by the same pro- cedures as described for Compound 10.

[0442] LCMS (ESI): 875.5 [M+1]+.

[0443] 1H NMR (400 MHz, DMSO) δ 8.78 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 11.7 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 5.86 (d, J = 11.1 Hz, 1H), 5.29 (t, J = 7.9 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 3.99 – 3.72 (m, 4H), 3.60 – 3.47 (m, 4H), 3.27 – 2.98 (m, 8H), 2.60 (dd, J = 27.9, 22.1 Hz, 5H), 2.41 – 2.22 (m, 6H), 2.17 – 2.09 (m, 4H), 1.59 (t, J = 9.2 Hz, 1H), 1.29 – 1.02 (m, 16H), 0.89 (s, 3H), 0.45 (s, 3H). Example 27. Synthesis of Compound 14

[0444] Substituting (3S)-3-((2S)-2-(aziridine-2-carboxamido)-4-((tert-butyldimethylsi- lyl)oxy)-N-methylbutanamido)-4-methyl-2-oxopentanoic acid with N-((3S)-2-(((tert-butyl- dimethylsilyl)oxy)methyl)-1-(3-methyloxetane-3-carbonyl)pyrrolidine-3-carbonyl)-N-methyl- L-valine in the Step 5 of Example 24, the title compound was prepared by the same procedures as described for Compound 10.

[0445] LCMS (ESI): 903.5 [M+1]+.

[0446] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 12.1 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.13 (tt, J = 2.2, 0.9 Hz, 1H), 7.07 (t, J = 2.2 Hz, 1H), 6.64 (tt, J = 2.2, 1.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.69 (td, J = 13.5, 12.0 Hz, 1H), 4.38 (q, J = 6.6 Hz, 1H), 4.23 (d, J = 6.6 Hz, 2H), 4.07 – 3.99 (m, 6H), 3.94 (ddd, J = 9.6, 6.9, 2.7 Hz, 2H), 3.76 – 3.54 (m, 11H), 3.33 (s, 3H), 3.21 – 3.12 (m, 1H), 3.09 (d, J = 2.6 Hz, 2H), 3.07 – 2.99 (m, 1H), 2.96 – 2.86 (m, 6H), 2.75 – 2.69 (m, 4H), 2.23 (dhept, J = 8.1, 5.1 Hz, 1H), 2.10 – 1.95 (m, 4H), 1.90 – 1.78 (m, 3H), 1.76 – 1.70 (m, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.27 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.92 (d, J = 5.0 Hz, 3H), 0.87 (d, J = 5.1 Hz, 3H). Example 28. Synthesis of Compound 15

[0447] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-15,16,61,62,63,64,65,66-octahydro-14H-8-oxa- 1(8,1)-pyrrolo[3,2,1-ij]quinolina-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)car- bamate with tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-15-(4,4,5,5-tetra- methyl-1,3,2-dioxaborolan-2-yl)-12,13,61,62,63,64,65,66-octahydro-8-oxa-1(8,6)-[1,4]oxa- zino[2,3,4-hi]indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate in the Step 1 of Example 24 and Substituting (3S)-3-((2S)-2-(aziridine-2-carboxamido)-4-((tert-bu- tyldimethylsilyl)oxy)-N-methylbutanamido)-4-methyl-2-oxopentanoic acid with (S)-3-((S)-4- ((tert-butyldimethylsilyl)oxy)-2-(2-fluoro-N,2-dimethylpropanamido)-N-methylbutanamido)- 4-methyl-2-oxopentanoic acid in the Step 5 of Example 24, the title compound was prepared by the same procedures as described for Compound 10.

[0448] LCMS (ESI): 848.4 [M+1]+.

[0449] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.26 (d, J = 11.9 Hz, 1H), 7.15 (tt, J = 2.2, 1.0 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.63 (tt, J = 2.0, 0.9 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.88 (d, J = 8.1 Hz, 1H), 4.68 (td, J = 13.5, 12.0 Hz, 1H), 4.49 (t, J = 9.4 Hz, 1H), 4.26 (dt, J = 7.5, 4.5 Hz, 2H), 4.16 (td, J = 8.2, 2.1 Hz, 2H), 4.10 – 3.99 (m, 4H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.54 (m, 7H), 3.33 (s, 3H), 3.11 (d, J = 0.7 Hz, 2H), 2.99 – 2.87 (m, 8H), 2.75 – 2.69 (m, 4H), 2.23 (dhept, J = 8.1, 5.0 Hz, 1H), 2.12 (dt, J = 9.5, 8.1 Hz, 2H), 1.96 (s, 3H), 1.91 (s, 3H), 1.90 – 1.84 (m, 2H), 1.84 – 1.78 (m, 1H), 1.76 – 1.67 (m, 3H), 1.66 (s, 2H), 1.14 (s, 3H), 1.09 (s, 3H), 0.90 (d, J = 5.0 Hz, 3H), 0.85 (d, J = 5.1 Hz, 3H). Example 29. Synthesis of Compound 16

[0450] Substituting tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-12- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indola-6(1,3)-pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate with tert-butyl ((63S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-15-(4,4,5,5-tetramethyl-1,3,2-dioxaboro- lan-2-yl)-12,13,61,62,63,64,65,66-octahydro-8-oxa-1(8,6)-[1,4]oxazino[2,3,4-hi]indola-6(1,3)- pyridazina-2(1,3)-benzenacycloundecaphane-4-yl)carbamate in the Step 1 of Example 13 and substituting N-((2S,3S)-1-acetyl-2-((tosyloxy)methyl)pyrrolidine-3-carbonyl)-N-methyl-L-va- line with N-(3-((tert-butyldimethylsilyl)oxy)propanoyl)-N-methyl-L-valine in the Step 5 of Ex- ample 13, the title compound was prepared by the same procedures as described for Com- pound 11.

[0451] LCMS (ESI): 896.4 [M+1]+.

[0452] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 12.1 Hz, 1H), 7.15 (tt, J = 2.2, 1.0 Hz, 1H), 7.01 (t, J = 2.2 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.63 (tt, J = 2.0, 0.9 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.1 Hz, 1H), 4.68 (td, J = 13.5, 12.0 Hz, 1H), 4.29 – 4.19 (m, 4H), 4.10 – 3.99 (m, 4H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.69 – 3.54 (m, 7H), 3.33 (s, 3H), 3.11 (d, J = 0.7 Hz, 2H), 2.96 – 2.89 (m, 5H), 2.75 – 2.68 (m, 6H), 2.25 (dhept, J = 8.0, 5.1 Hz, 1H), 1.90 – 1.83 (m, 2H), 1.83 – 1.78 (m, 1H), 1.76 – 1.70 (m, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 0.91 (d, J = 5.1 Hz, 3H), 0.85 (d, J = 5.1 Hz, 3H). Example 30. Synthesis of Compound 17

[0453] Substituting (S)-3-((S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-fluoro-N,2-dime- thylpropanamido)-N-methylbutanamido)-4-methyl-2-oxopentanoic acid with N-((3S)-2-(((tert- butyldimethylsilyl)oxy)methyl)-1-(2-fluoro-2-methylpropanoyl)pyrrolidine-3-carbonyl)-N-me- thyl-L-valine in the Step 5 of Example 28, the title compound was prepared by the same pro- cedures as described for Compound 15.

[0454] LCMS (ESI): 910.4 [M+1]+.

[0455] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 12.1 Hz, 1H), 7.15 (tt, J = 2.2, 1.1 Hz, 1H), 7.04 (t, J = 2.2 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.64 (tt, J = 2.2, 1.0 Hz, 1H), 5.32 (d, J = 9.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.68 (td, J = 13.5, 12.0 Hz, 1H), 4.39 (q, J =6.6 Hz, 1H), 4.29 – 4.20 (m, 4H), 4.10 – 3.99 (m, 4H), 3.76 – 3.54 (m, 11H), 3.33 (s, 3H), 3.16 (ddd, J = 8.8, 7.9, 6.6 Hz, 1H), 3.11 (d, J = 0.7 Hz, 2H), 2.96 – 2.86 (m, 5H), 2.75 – 2.69 (m, 4H), 2.23 (dhept, J = 8.1, 5.1 Hz, 1H), 2.08 – 2.00 (m, 1H), 2.00 – 1.94 (m, 4H), 1.92 (s, 3H), 1.90 – 1.78 (m, 3H), 1.76 – 1.67 (m, 3H), 1.66 (s, 2H), 1.14 (s, 3H), 1.09 (s, 3H), 0.92 (d, J = 5.0 Hz, 3H), 0.87 (d, J = 5.1 Hz, 3H). Example 31. Synthesis of Compound 18

[0456] Substituting (S)-3-((S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-fluoro-N,2-dime- thylpropanamido)-N-methylbutanamido)-4-methyl-2-oxopentanoic acid with tert-butyl ((64S,4S)-25-(benzyloxy)-10,10-dimethyl-5,7-dioxo-15-(4,4,5,5-tetramethyl-1,3,2-dioxaboro- lan-2-yl)-12,13-dihydro-8-oxa-62,63-diaza-1(8,6)-[1,4]oxazino[2,3,4-hi]indola-6(2,4)-bicy- clo[3.1.1]heptana-2(1,3)-benzenacycloundecaphane-4-yl)carbamate in the Step 1 of Example 28, the title compound was prepared by the same procedures as described for Compound 15.

[0457] LCMS (ESI): 892.4 [M+1]+.

[0458] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.27 (d, J = 11.9 Hz, 1H), 7.15 (tt, J = 2.2, 1.0 Hz, 1H), 7.01 (t, J = 2.1 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.63 (tt, J = 2.0, 0.9 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.93 – 4.86 (m, 2H), 4.71 (td, J = 13.5, 12.0 Hz, 1H), 4.49 (t, J = 9.4 Hz, 1H), 4.26 (dt, J = 7.5, 4.5 Hz, 2H), 4.16 (td, J = 8.2, 2.1 Hz, 2H), 4.10 – 3.99 (m, 4H), 3.98 – 3.89 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.58 (d, J = 2.6 Hz, 2H), 3.33 (s, 3H), 3.11 (d, J = 0.7 Hz, 2H), 2.99 – 2.90 (m, 5H), 2.89 (s, 3H), 2.78 – 2.66 (m, 5H), 2.23 (dhept, J = 8.1, 5.1 Hz, 1H), 2.17 – 1.98 (m, 6H), 1.96 (s, 3H), 1.91 (s, 3H), 1.67 (d, J = 5.3 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 0.90 (d, J = 5.0 Hz, 3H), 0.85 (d, J = 5.1 Hz, 3H). Example 32. Synthesis of Compound 19

[0459] Substituting (S)-3-((S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-fluoro-N,2-dime- thylpropanamido)-N-methylbutanamido)-4-methyl-2-oxopentanoic acid with N-(3-((tert-butyl- dimethylsilyl)oxy)propanoyl)-N-methyl-L-valine in the Step 5 of Example 31, the title com- pound was prepared by the same procedures as described for Compound 18.

[0460] LCMS (ESI): 892.4 [M+1]+.

[0461] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.29 (d, J = 11.9 Hz, 1H), 7.15 (tt, J = 2.2, 1.0 Hz, 1H), 7.01 (t, J = 2.2 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.63 (tt, J = 2.0, 0.9 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.94 – 4.87 (m, 2H), 4.72 (td, J = 13.4, 12.0 Hz, 1H), 4.29 – 4.19 (m, 4H), 4.10 – 3.99 (m, 4H), 3.98 – 3.89 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.58 (d, J = 2.6 Hz, 2H), 3.33 (s, 3H), 3.11 (d, J = 0.7 Hz, 2H), 2.97 – 2.90 (m, 5H), 2.78 – 2.66 (m, 7H), 2.25 (dhept, J = 8.0, 5.1 Hz, 1H), 2.13 – 1.97 (m, 4H), 1.67 (d, J = 5.3 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 0.91 (d, J = 5.1 Hz, 3H), 0.85 (d, J = 5.1 Hz, 3H). Example 33. Synthesis of Compound 20

[0462] Substituting (S)-3-((S)-4-((tert-butyldimethylsilyl)oxy)-2-(2-fluoro-N,2-dime- thylpropanamido)-N-methylbutanamido)-4-methyl-2-oxopentanoic acid with N-((3S)-2-(((tert- butyldimethylsilyl)oxy)methyl)-1-(2-fluoro-2-methylpropanoyl)pyrrolidine-3-carbonyl)-N-me- thyl-L-valine in the Step 5 of Example 31, the title compound was prepared by the same pro- cedures as described for Compound 18.

[0463] LCMS (ESI): 892.4 [M+1]+.

[0464] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.31 (d, J = 11.9 Hz, 1H), 7.15 (tt, J = 2.2, 1.0 Hz, 1H), 7.04 (t, J = 2.2 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.64 (tt, J = 2.2, 1.0 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.6 Hz, 1H), 4.85 (d, J = 8.2 Hz, 1H), 4.72 (td, J = 13.4, 12.0 Hz, 1H), 4.39 (q, J = 6.6 Hz, 1H), 4.29 – 4.20 (m, 4H), 4.10 – 3.99 (m, 4H), 3.98 – 3.89 (m, 2H), 3.76 – 3.68 (m, 3H), 3.68 – 3.62 (m, 3H), 3.58 (d, J = 2.6 Hz, 2H), 3.33 (s, 3H), 3.16 (ddd, J = 8.8, 7.9, 6.6 Hz, 1H), 3.11 (d, J = 0.7 Hz, 2H), 2.93 (ddt, J = 13.4, 2.0, 1.1 Hz, 2H), 2.89 (s, 3H), 2.78 – 2.66(m, 5H), 2.23 (dhept, J = 8.1, 5.0 Hz, 1H), 2.13 – 1.94 (m, 9H), 1.92 (s, 3H), 1.67 (d, J = 5.3 Hz, 3H), 1.14 (s, 3H), 1.09 (s, 3H), 0.92 (d, J = 5.0 Hz, 3H), 0.87 (d, J = 5.1 Hz, 3H). Example 34. Synthesis of Exemplary Compounds

[0465] The following exemplary compounds were synthesized from different starting ma- terials according to the method described above (such as methods for Compounds 1-20). Table 5. Exemplary Compounds Prepared by Methods of the Present InventionExample 35. Biological activity results

[0466] The following compound was used as the reference compound.Cell viability assay

[0467] Selective screening using RAS-driven and RAS-non-driven cells: (1) RAS-driven cells, including cells with persistent RAS activation due to RAS mutations and upstream EGFR activation. Cells that are continuously activated due to RAS mutations, such as KRAS G12D (AsPC-1, HPAC, AGS, etc.) mutant cells, KRAS G12C (NCI-H358, MIAPaCa-2, etc.) KRAS G13D (LOVO, HCT15, etc.) mutant cells, etc. Cells with continuous activation of RAS due to EGFR mutations, such as EGFREx19del (PC-9, etc.) mutant cells, EGFRT790M / L858R (NCI- H1975, etc.) mutant cells, etc.; (2) Non-RAS driven cells, including BRAFV600E (A375, SK,) -MEL-3, etc.) mutant cells, RASWT (BxPC-3, etc.) cells, etc.

[0468] Specific experimental methods: The above cells were seeded in a 96-well plate at a density of 1000-10000 per well. Drugs were diluted in DMSO to make a 10 mM stock solu- tion. Subsequently, the drug was diluted in a 3-fold gradient to a final concentration of 1000 nM. The cells were treated with the drug for 5 days. Cell viability was then detected by the MTS method. Representative compound results

[0469] The reference compound (Ref.1) and the representative Compound A significantly inhibited the cell viability of KRAS mutant cells: MIA PACA-2(KRAS G12C), NCI-H358 (KRAS G12C), NCI-H2122 (KRAS G12C) HPAF II (KRAS G12D), AGS (KRAS G12D), ASPC-1(KRAS G12D), HPAC (KRAS G12D), LS174T (KRAS G12D), SW480 (KRAS G12V), SW620 (KRAS G12V), CAL-62 (KRAS G12R), LOVO (KRAS G13D) Calu6 (KRAS Q61K) and HCC827 (EGFR). The inhibitory IC50 of the compounds of the examples of the present invention was shown in Table 6.

Claims

CLAIMS 1. A compound of formula (I), or a stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof:wherein, is 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 cyclo- alkylene, or optionally substituted 4 to 11-membered bicyclic heterocycloalkylene; G is optionally substituted C1-6alkylene; between U and T is a bond or null; when between U and T is a bond, U and T are absent, or they are each inde- pendently O, S, -NR3or optionally substituted C1-6alkylene; when between U and T is null, T is absent, and U is optionally substituted C1-6al- kyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6heteroalkyl, optionally substituted C3-10cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, option- ally substituted C2-6alkenyl, or optionally substituted C2-6alkynyl; W and Q are each independently a linker; R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or op- tionally substituted C1-3alkyl; or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6cycloalkyl or a carbonyl; R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or op- tionally substituted C1-3alkyl; or R10and R11combine with the atoms to which they are at- tached to form an optionally substituted C3-6cycloalkyl or a carbonyl; R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionallysubstituted C1-3alkyl, -O(optionally substituted C1-6alkyl), -S(optionally substituted C1-6alkyl) or -N(optionally substituted C1-6alkyl)(optionally substituted C1-6alkyl); RAis optionally substituted C3-6cycloalkyl, optionally substituted 3 to 6-membered heter- ocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-mem- bered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; RBis hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, optionally substi- tuted C3-6cycloalkyl, 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 attached to form a 3 to 6-membered ring, wherein the ring may be optionally substituted with halogen, hy- droxy, or C1-3alkyl; 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, C1-3alkyl, C1-3alkoxyl, C1-3haloalkyl, C1-3haloalkoxyl, C3-6cycloalkyl, or 3 to 6-membered heterocycloalkyl; R3is hydrogen, C1-3alkyl, C3-6cycloalkyl, C1-3haloalkyl, C3-6halocycloalkyl, -C(O)C1-3alkyl, -S(O2), or -S(O2)C1-3alkyl; E is absent, a bond, , optionally substituted C3-10cycloalkylene, optionally substi-tuted C3-10cycloalkenylene, optionally substituted 4 to 12-membered heterocycloalkylene, op- tionally substituted 6 to 10-membered arylene, or optionally substituted 5 to 10-membered het- eroarylene; wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-3alkyl, optionally substituted C1-3alkoxyl, C1-3aminoalkyl, or C1-3hydroxyalkyl; R4is a bond, optionally substituted C1-6alkylene, optionally substituted C1-6heteroal- kylene, optionally substituted C1-6haloalkylene, optionally substituted C2-6alkenylene, option- ally substituted C2-6haloalkenylene, optionally substituted C3-10cycloalkylene, optionally sub- stituted C3-10cycloalkenylene, optionally substituted C3-10heterocycloalkylene (or 4 to 12- membered heterocycloalkylene, optionally substituted 6 to 10-membered arylene, optionally substituted 5 to 10-membered heteroarylene, orR5is hydrogen, C1-6alkyl or C3-6cycloalkyl; wherein the C1-6alkyl or C3-6cycloalkyl may be further optionally substituted;or E, R4and R5combine together to form a group of -Rr2- or -Rr1-Rr2-; wherein Rr1is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, or C1-2alkylene-N(C1-3al- kyl); Rr2is a ring selected from optionally substituted 3 to 10-membered cycloalkylene, option- ally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, and option- ally substituted 4 to 11-membered bicyclic heterocycloalkylene; wherein L4is N(R6) or C(R6)2; L is absent, O, -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rgis optionally substituted C1-6alkyl; R6is each independently hydrogen, or optionally substituted C1-6alkyl; R7is a bond, -R72- or -R71-R72-; wherein R71is C1-3alkylene; R72is optionally substituted C1-6alkylene, optionally substituted C1-6heteroalkylene, optionally substituted C3-10cycloal- kylene, optionally substituted 3 to 10-membered heterocycloalkylene, optionally substituted 6 to 10-membered arylene, or optionally substituted 5 to 10-membered heteroarylene; or L, N, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkylene, optionally substi- tuted 3 to 10-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloal- kenylene, optionally substituted 4 to 11-membered bicyclic cycloalkylene, or optionally substi- tuted 4 to 11-membered bicyclic heterocycloalkylene.

2. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II):wherein A, B, G, U, T, E, Q, X1, X2, X3, X4, X5, X6, RB, R3, R8, R9, R10, R11, R12, R13and n are de- fined as in claim 1;Y is CH or N; R1ais hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxy- alkyl, C1-6aminoalkyl, optionally substituted C2-4alkynyl, optionally substituted C3-6cycloal- kyl, 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 C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, or C1-6hydrox- yalkyl may be further optionally substituted; R2is optionally substituted C1-6alkoxy or optionally substituted C1-6alkyl; RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, C1-6al- kyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted 3 to 6-membered heterocycloalkyl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, and C1-6hydroxyalkyl may be further optionally substituted; R4and R5are defined as in claim 1; and optionally, E, R4and R5combine together to form a group of -Rr2- or -Rr1-Rr2-; wherein Rr1is O, NH, N(C1-3alkyl), C1-3alkylene, C1-2alkylene-O, C1-2alkylene-NH, C1-2al- kylene-N(C1-3alkyl); Rr2is a ring selected from optionally substituted 3 to 10-membered cyclo- alkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6- membered cycloalkenyl, optionally substituted 4 to 11-membered bicyclic cycloalkyl, or op- tionally substituted 4 to 11-membered bicyclic heterocycloalkyl.

3. The compound of claim 1 or 2, or the stereoisomer, pharmaceutically acceptable salt, me- tabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IIIa) or formula (IIIb):wherein A, G, U, T, R3, X6, Q and E are defined as in claim 1; Y, R2, R4and R5are defined as in claim 1 or 2;R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6heterocyclo- alkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered het- eroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2alkylene-C3-6cycloalkyl, optionally substituted -C1-2alkylene-C3-6heterocycloalkyl, optionally substituted -C1-2alkylene- 5 to 8-membered aryl, optionally substituted -C1-2alkylene-5 to 8-membered heteroaryl, option- ally substituted -C1-2alkylene-8 to 10-membered fused bicyclic aryl, or optionally substituted - C1-2alkylene-8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl may be further optionally substituted; and Raand Rbare each independently hydrogen, halogen, cyano, C1-3alkyl, C1-3alkoxyl, C1-3haloalkyl, C1-3haloalkoxyl, C3-6cycloalkyl, or 3 to 6-membered heterocycloalkyl.

4. The compound of any one of claims 1-3, or the stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (IVaa), (IVab), (IVba), or (IVbb):wherein A, G, U, T, R3, X6, Q and E are defined as in claim 1; Y, R2, R4and R5are defined as in claim 1 or 2; andR1, Raand Rbare defined as in claim 3.

5. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein B is optionally substitutedor optionally substituted andwherein R1is hydrogen, C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6heterocyclo- alkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered het- eroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -C1-2alkylene-C3-6cycloalkyl, optionally substituted -C1-2alkylene-C3-6heterocycloalkyl, optionally substituted -C1-2alkylene- 5 to 8-membered aryl, optionally substituted -C1-2alkylene-5 to 8-membered heteroaryl, op- tionally substituted -C1-2alkylene-8 to 10-membered fused bicyclic aryl, or optionally substi- tuted -C1-2alkylene-8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl may be further optionally substi- tuted; in R1, when the C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, or C1-6hydroxy- alkyl is further substituted, the substituent is selected from the group consisting of C1-6alkyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, optionally substituted C3-6heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, and optionally substituted 8 to 10-membered fused bicy- clic heteroaryl; optionally, the substituent is selected from the group consisting of optionally substituted C3-6cycloalkyl, optionally substituted C3-6heterocycloalkyl, 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 C3-6heterocycloalkyl; Y is -CH- or N; R2is optionally substituted C1-6alkoxy or optionally substituted C1-6alkyl; optionally R2is optionally substituted C1-6alkyl; andRMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, C1-6al- kyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl, C1-6aminoalkyl, optionally substituted C3-6cycloalkyl, or optionally substituted C3-6heterocycloalkyl; wherein the C1-6al- kyl, C1-6alkoxyl, C1-6haloalkyl, C1-6haloalkoxyl, C1-6hydroxyalkyl may be further optionally substituted; optionally wherein RMand RNare each independently hydrogen or C1-6alkyl.

6. The compound of claim 5, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein R1is optionally substituted -C1-2alkylene-3 to 6-membered heterocycloalkyl; optionally wherein the 3 to 6-membered heterocycloalkyl has a structure ofwherein n1and n2are each independently 1, 2 or 3, optionally n1and n2are both 2, and ZRAis O, S or NH; optionally, C1-2alkylene is -CH2- or –CH(CH3)-; wherein 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, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and C1-C4 deuterated alkyl; optionally with one or more (such as 1, 2, 3, or 4) substituent(s) being D or C1-6alkyl; or, R1is substituted C1-6alkyl, and optionally, the C1-6alkyl is substituted with one substit- uent of -CONRiRiiand 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, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, and C1-C4 deuterated alkyl.

7. The compound of claim 5, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein R1is8. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein E, 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 substi- tuted 3 to 10-membered heterocycloalkyl; wherein optionally, 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 ring atom, optionally wherein the heteratom is S; wherein optionally substituted means unsubtituted or substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of D, halogen, -CN, C1-6alkyl, - C2-6alkenyl, C2-6alkynyl, C3-10cycloalkyl, 3 to 10-membered heterocycloalkenyl, C6-10 aryl, 5 to 10-membered heteroaryl, -C1-4alkylene-C3-10cycloalkyl, -C1-4alkylene-C3-10cycloalkenyl, - C1-4alkylene-3 to 10-membered heterocycloalkyl, -C1-4alkylene-3 to 10-membered heterocy- cloalkenyl, -C1-4alkylene-C6-10 aryl, and -C1-4alkylene-5 to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is unsubtituted or substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of D, halogen, and C1-6alkyl; optionally wherein, 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 C1-6alkyl, C6-10aryl, and 5 to 10-membered heteroaryl; wherein the aryl and heteroaryl is unsubtituted or substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consist- ing of D, halogen, and C1-6alkyl.

9. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein10. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 6-membered heteroarylene, the heteroatom is inde- pendently selected from one or two of N, O and S, and the number of heteroatoms is inde- pendently 1 to 3. optionally, A is further optionally, A is11. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein when between U and T is null, T is absent, and U is optionally substituted C1-6al- kyl, optionally substituted C1-6haloalkyl, optionally substituted C1-6heteroalkyl, optionally substituted C1-6cycloalkyl, or optionally substituted C1-6heterocycloalkyl; optionally, U is12. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or solvate thereof, or the 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-.

13. The compound of claim 1, or the stereoisomer, pharmaceutically acceptable salt, metabo- lite, prodrug, or 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.

14. The compound of any one of claims 1-13, or the stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein, the compound is:

15. A pharmaceutical composition comprising the compound of any one of claims 1 to 14, or the stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A use of a compound of any one of claims 1 to 14, or the stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15, in the prepa- ration of a medicament used for the treatment of cancer.

17. The use of claim 16, wherein the cancer is small cell lung cancer (SCLC), colorectalcancer (CRC), pancreatic cancer, and cholangiocarcinoma, pancreatic cancer, appendiceal can- cer, small bowel cancer, colorectal cancer, ampullary cancer, non-small cell lung cancer, cervi- cal cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroen- docrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovar- ian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma, or combinations thereof.

18. The use of claim 16, wherein the cancer is non-small cell lung cancer, small cell lung can- cer, colorectal cancer, pancreatic cancer, or cholangiocarcinoma.

19. The compound of any one of claims 1 to 14, or the stereoisomer, pharmaceutically ac- ceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically ac- ceptable salt thereof, or the pharmaceutical composition of claim 15, for use in treating cancer.

20. A method for treating cancer in a subject in need thereof, the method comprising adminis- tering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 14, or the stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15.

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