Macrocyclic compound, synthesis method therefor and use thereof

Abstract

The present invention relates to a macrocyclic compound and a therapeutic use thereof. Disclosed in the present invention is a compound of formula (I), a pharmaceutically acceptable salt of said compound, a solvate of said compound, or a solvate of said pharmaceutically acceptable salt, and a use thereof in the preparation of a drug for treating cancer.

Description

Macrocyclic compounds, their synthesis methods and applications Technical Field

[0001] This invention belongs to the field of drug synthesis, specifically, it relates to macrocyclic compounds and their therapeutic uses. Background Technology

[0002] RAS proteins (including KRAS4A, KRAS4B, HRAS, and NRAS) are small membrane-bound guanine nucleotide-binding proteins that act as molecular switches by cycling between an active GTP-binding state and an inactive GDP-binding state. When RAS binds to GEF family proteins (such as SOS1), its conformation changes, reducing its affinity for GDP and causing it to dissociate from GDP and bind to GTP at high concentrations in the environment, thus becoming active. In normal cells, activation of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) promotes the exchange of GDP and GTP in RAS, activating RAS. RAS plays a crucial role in regulating cell survival, proliferation, and differentiation through multiple cascade reactions, including the PI3K-AKT-mTOR, RAF-MEK-ERK, and RALGDS-RAL pathways. Mutations in RAS are often a driver of oncogenesis and tumor development because they disrupt the guanine exchange cycle and lock RAS into an activated state, continuously activating downstream signaling pathways and leading to tumor development.

[0003] RAS mutations occur in approximately 19% of cancers and play a crucial role in tumorigenesis and development. KRAS is the most common mutation subtype, followed by NRAS and HRAS. KRAS mutations are frequently found in pancreatic ductal adenocarcinoma, lung adenocarcinoma, and colorectal adenocarcinoma, while NRAS mutations are relatively common in hematologic malignancies such as chronic myeloid leukemia and acute myeloid leukemia, as well as malignant melanoma, thyroid cancer, and laryngeal cancer. HRAS mutations are less common in human cancers, but have a relatively high mutation rate in head and neck squamous cell carcinoma, bladder cancer, salivary gland cancer, and oral cancer.

[0004] RAS molecular glue can simultaneously bind highly activated RAS (RAS-ON) proteins and commonly expressed proteins in cells to form a three-complex, occupying the binding sites of RAS-interacting proteins such as SOS1 and RAF1, thus locking the RAS proteins alone and preventing them from activating downstream signaling pathways, thereby blocking the transmission of RAS signaling pathways and inhibiting tumor growth.

[0005] Therefore, there is an urgent need in this field for an inhibitor of RAS molecular glue type with good activity and high drugability to meet clinical needs. Summary of the Invention

[0006] The RAS inhibitors provided herein are molecular glues. The methods described herein require the formation of a high-affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions: the target protein (e.g., RAS) and a widely expressed cytosolic chaperone (e.g., CYPA). More specifically, in some embodiments, the RAS molecular glues described herein induce new binding pockets in RAS by forming a high-affinity three-component complex between the RAS protein and the cytosolic chaperone CYPA. Without being bound by theory, the inventors believe that one way the compounds of the present invention and the three-component complexes formed therefrom inhibit RAS is through spatial occlusion of the interaction sites between RAS and downstream effector molecules (e.g., RAF and PI3K), which is necessary for the propagation of oncogenic signals.

[0007] In a first aspect of the invention, a compound of formula (I), or an isotopic derivative thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a metabolite thereof, a prodrug thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof is provided.

[0008] in

[0009] n is 0, 1, 2, or 3;

[0010] A is selected from optionally substituted 5-6 membered heterocyclic alkylene, optionally substituted 5-6 membered arylene, optionally substituted 5-6 membered heterocyclic arylene;

[0011] Cycle B is selected from optionally substituted 3-6 membered heterocyclic alkylene groups, 5-6 membered heterocyclic alkenylene groups, and optionally substituted 4-11 membered heterocyclic alkylene groups (including bridged rings, spiro rings, and fused rings);

[0012] The ring C is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl;

[0013] G is selected from C, which can be substituted arbitrarily. 1-6 Alkylene;

[0014] X 1 It is N or C;

[0015] X 2 Is it N or -CR a -;

[0016] X 3 Is it N or -CR b -;

[0017] X 4 Is it N or -CR c -;

[0018] X 5It is N or C;

[0019] X 6 It is S, O, N, or C;

[0020] R B Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl; or, if n is greater than 1, R B Any two atoms bonded to them can combine to form a 3-6 membered ring, wherein the ring may optionally be made of halogen, hydroxyl, or C. 1-3 Alkyl substitution;

[0021] R a R b and R c Each can be independently represented by hydrogen, halogen, cyano, or C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups;

[0022] R M and R Z Each is independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl; furthermore, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl groups may be further optionally substituted;

[0023] R 1 Selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted or R p Replacement C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Heterocyclic alkyl, optionally substituted 4-6-membered heterocyclic alkyl with 4-5-membered heteroaryl, optionally substituted benzo5-7-membered heterocyclic, optionally substituted 5-8-membered aryl, optionally substituted 5-8-membered heteroaryl, optionally substituted 8-10-membered aryl or optionally substituted 8-10-membered heteroaryl; in addition, ynyl, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 The hydroxyalkyl and benzo5-7-membered heterocyclic groups can be further optionally substituted;

[0024] R p Selected from the following groups: hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, optionally substituted 5-7 membered heterocyclic groups, -NR 15 R 16 or -OR 17 -SR 17 -C(O)-NR 15 R 16 C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, optional substituted C 3-6 Cycloalkyloxy;

[0025] Or, R1 is Where m is 0, 1, 2 or 3;

[0026] P does not exist, or is selected from S, O, Se, -NR 8 -、-CR 9 R 10 -、

[0027] Q does not exist, or is selected from the arbitrarily substituted C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted 5-10-membered aryl, optionally substituted 5-10-membered heteroaryl, -NR 15 R 16 or -OR 17 ;

[0028] R 8 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl groups;

[0029] R 9 R 10 and R 14 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 9 and R 10 A carbonyl group or a 3-6 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0030] R 11 R 12 and R 13 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 11 R 12 and R 13 Any two phosphorus atoms in the ring form a phosphorus-oxygen double bond or a 3-6 membered ring through the phosphorus atoms they are connected to. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0031] R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; or R t and R sA carbonyl group or a 3-8 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4.

[0032] R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, straight-chain or branched C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, the ring may contain heteroatoms, the heteroatoms being independently selected from one or more of N, O and S, the number of heteroatoms being independently 0-3; and the ring is optionally substituted.

[0033] R 17 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl groups;

[0034] R 2 Selected from optional replacement C 1-6 Oxyalkyl, optionally substituted C 1-6 Alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(3-8 heterocyclic alkyl), and optionally, the above groups may be substituted with 0, 1, or 2 or fewer substituents: -OR 51 -SR 51 Or -NR 51 R 52 ;

[0035] R 51 R 52 Each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; or R 51 and R 52Together with the N atom it is attached to, a 3-8 membered heterocycle is formed, wherein the 3-8 membered heterocycle optionally contains 0, 1, 2 or 3 heteroatoms selected from N, O or S; furthermore, the C3-C8 cycloalkyl, C3-C8 heterocycloalkyl and 3-8 membered heterocycle may be further optionally substituted or deuterated;

[0036] R 3 It does not exist, or is selected from hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; provided that X 6 When it is O or S, R 3 It does not exist;

[0037] E is selected from N or from -CR d -, where R d Selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl or -NR e R f Among them, R e and R f Selected independently from hydrogen, or optionally substituted with C 1-6 alkyl;

[0038] R 4 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted 3-12 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 aryl, or

[0039] R 5 Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl, in addition, C 1-6 Alkyl or C 3-6 Cycloalkyl groups can also be optionally substituted;

[0040] Or R 4 and R 5 The atoms bonded to them form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Monocyclic cycloalkyl, optionally substituted 3-10 membered monocyclic heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11Polycyclic cycloalkyl groups (including fused, bridged, and spirocyclic groups), and optionally substituted 4-11 membered polycyclic heterocyclic alkyl groups (including fused, bridged, and spirocyclic groups);

[0041] in

[0042] L does not exist, or is selected from -CH2-, -C(O)-, -CHR g -or-C(R) g )2-, where R g Optional replacement of C 1-6 alkyl;

[0043] R 6 Selected from hydrogen, or optionally substituted with C 1-6 alkyl;

[0044] R 7 Selected from -NR 15 R 16 Optional replacement of C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted with 5-10 heteroaryl groups;

[0045] or L, R 6 and R 7 They bond with the atoms to form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11 Bicyclic (including spirocyclic, fused, and bridged) cycloalkyl groups, and optionally substituted 4-11 member (including spirocyclic, fused, and bridged) heterocyclic alkyl groups;

[0046] Unless otherwise defined, “optional substitution” means that the group is substituted by one or more (e.g., 2, 3, 4, or 5) groups selected from the group consisting of: deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), -S(O)2-(C 1-4 Alkyl), -C(O)-(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2、-C(O)O-(C 1-4 Alkyl), -C(O)-(C 3-6 cycloalkyl), -C(O)-3-6 heterocyclic alkyl, -C(O)-(C 2-6 alkenyl), -C(O)-(C 2-6 ynyl group), -C(O)-(C 2-6ynyl)-3-6-membered heterocyclic alkyl, -C(O)-(C 2-6 ynyl)-N(C 1-3 Alkyl)2、-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2、-NH-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2, C 1-4 Alkyl-substituted or unsubstituted -C(O)-(C 2-6 ynyl)N(C 1-4 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, oxo C 2-4 alkenyl, C 2- C4 ynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, Or phenyl.

[0047] In another preferred embodiment, "optional substitution" means that the group is substituted by one or more (e.g., 2, 3, 4, or 5) groups selected from the group consisting of: deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), -S(O)2-(C 1-4 Alkyl), -C(O)-(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2、-C(O)O-(C 1-4 Alkyl), -C(O)-(C 3-6 cycloalkyl), -C(O)-(C 2-6 alkenyl), -C(O)-(C 2-6 ynyl group), -C(O)-(C 2-6 ynyl)-3-6-membered heterocyclic alkyl, -C(O)-(C 2-6 ynyl)-N(C 1-3 Alkyl)2、-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2、-NH-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2, C 1-4 Alkyl-substituted or unsubstituted -C(O)-(C 2-6 ynyl)N(C 1-4 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, oxo C 2-4 alkenyl, C 2- C4 ynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, Or phenyl.

[0048] In another preferred embodiment, "optional substitution" means that the group is substituted by one or more (e.g., 2, 3, 4, or 5) groups selected from the group consisting of: deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), -S(O)2-(C 1-4 Alkyl), -C(O)-(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2、-C(O)O-(C 1- 4-alkyl), -C(O)-(C 3-6 cycloalkyl), -C(O)-(C 2-6 alkenyl), -C(O)-(C 2-6 alkynyl group), C 1-4 Alkyl-substituted or unsubstituted -C(O)-(C 2-6 ynyl)N(C 1-4 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1- 3-alkoxy group, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, oxo C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, Or phenyl.

[0049] In another preferred embodiment, R 1 Selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted or R p Replacement C 2- 8-acetylinyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-6Heterocyclic alkyl, optionally substituted 4-5-membered heterocyclic alkyl with 4-5-membered heteroaryl, optionally substituted benzo5-7-membered heterocyclic, optionally substituted 5-8-membered aryl, optionally substituted 5-8-membered heteroaryl, optionally substituted 8-10-membered aryl or optionally substituted 8-10-membered heteroaryl; in addition, ynyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 The hydroxyalkyl and benzo5-7-membered heterocyclic groups can be further optionally substituted.

[0050] In another preferred embodiment, R 2 Selected from optional replacement C 1-6 Oxyalkyl, or optionally substituted C 1-6 alkyl.

[0051] In another preferred embodiment, R p Selected from the following groups: hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-6 Alkoxy, C 1- 3-Haloalkoxy, optionally substituted 5-7 membered heterocyclic groups, -NR 15 R 16 or -OR 17 C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, optional substituted C 3-6 Cycloalkyloxy;

[0052] R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, and the ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0053] In another preferred embodiment, unless otherwise specified, the heterocyclic alkyl and heteroaryl groups in the present invention each independently contain 1-3 (preferably 1-2) heteroatoms independently selected from N, O and S.

[0054] In another preferred embodiment, R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, the ring may contain heteroatoms selected independently from one or more of N, O and S, the number of heteroatoms being 0-3; and the ring is optionally substituted.

[0055] In some embodiments of this disclosure, the cyclic C is selected from C6 aryl or 6-membered heteroaryl; preferably pyridyl.

[0056] In another preferred example, X 1 C. In another preferred example, X 2 For -CR a - In another preferred example, X 3 For -CR b - In another preferred example, X 4 It is -CH-.

[0057] In some embodiments of this disclosure, X 1 X 2 X 3 X 4 and X 5 The ring C is selected from 6-membered aryl or heteroaryl, and R is... 1 Compounds of formula (I) are compounds of formula (II), selected from optionally substituted alkynyl groups:

[0058] Or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof.

[0059] in

[0060] m and n are each independently selected from 0, 1, 2 or 3;

[0061] A is selected from optionally substituted 5-6 membered heterocyclic alkylene, optionally substituted 5-6 membered arylene, optionally substituted 5-6 membered heterocyclic arylene;

[0062] Cycle B is selected from optionally substituted 3-6 membered heterocyclic alkylene groups, 5-6 membered heterocyclic alkenyl groups, and optionally substituted 4-11 membered heterocyclic alkylene groups (including bridged rings, spiro rings, and fused rings);

[0063] G is selected as an optional replacement for C. 1-6 Alkylene;

[0064] P does not exist, or is selected from S, O, Se, -NR 8 -、-CR 9 R 10 -、

[0065] Q does not exist, or is selected from the arbitrarily substituted C. 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3- 10 Heterocyclic alkyl, optionally substituted 5-10 aryl, optionally substituted 5-10 heteroaryl, -NR 15 R 16 or -OR 17 ;

[0066] R 8 and R 17 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups;

[0067] R 9 R 10 and R 14 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 9 and R 10 A carbonyl group or a 3-6 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0068] R 11 R 12 and R 13 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C3-6 Heterocyclic alkyl; or R 11 R 12 and R 13 Any two atoms in the ring form a phosphorus-oxygen double bond or a 3-6 membered ring through the phosphorus atoms they are connected to. The ring may also contain other heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0069] R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, straight-chain or branched C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 9 and R 10 A 3-6 membered ring is formed by the nitrogen atom attached thereto, and the ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0070] Y is selected from -CH- or N;

[0071] X 6 Selected from S, O, N or -CH-;

[0072] R B Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl; or, if n is greater than 1, R B Any two atoms bonded to them can combine to form a 3-6 membered ring, wherein the ring may optionally be made of halogen, hydroxyl, or C. 1-3 Alkyl substitution;

[0073] R a and R b Each is independently selected from hydrogen, halogen, cyano, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups;

[0074] R M and RZ Each group is independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1- 6-Hydroalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl; furthermore, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl groups may be further optionally substituted;

[0075] R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl; or R t and R s A carbonyl group or a 3-8 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4.

[0076] R 2 Selected from optional replacement C 1-6 Alkoxy, optional substituted C 1-6 Alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(3-8 heterocyclic alkyl), and optionally, the above groups may be substituted with 0, 1, or 2 or fewer substituents: -OR 51 -SR 51 Or -NR 51 R 52 ;

[0077] R 51 R 52 Each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; or R 51 and R 52Together with the N atom it is attached to, a 3-8 membered heterocycle is formed, wherein the 3-8 membered heterocycle optionally contains 0, 1, 2 or 3 heteroatoms selected from N, O or S; furthermore, the C3-C8 cycloalkyl, C3-C8 heterocycloalkyl and 3-8 membered heterocycle may be further optionally substituted or deuterated;

[0078] R 3 It does not exist, or is selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, provided that X 6 When it is O or S, R 3 It does not exist;

[0079] E is selected from N, or from -CR d -, where R d Selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl or -NR e R f Among them, R e and R f Selected independently from hydrogen, or optionally substituted with C 1-6 alkyl;

[0080] R 4 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted C 3-10 Heterocyclic alkyl, optionally substituted 6-10 aryl, optionally substituted 5-10 heteroaryl, or

[0081] R 5 Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl, in addition, C 1-6 Alkyl or C 3-6 The cycloalkyl group can also be optionally substituted;

[0082] Or R 4 and R 5 The atoms bonded to them form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Monocyclic cycloalkyl, optionally substituted 3-10 membered monocyclic heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11Polycyclic cycloalkyl groups (including fused, bridged, and spirocyclic groups), and optionally substituted 4-11 membered heterocyclic alkyl groups (including fused, bridged, and spirocyclic groups);

[0083] in,

[0084] L does not exist, or is selected from -CH2-, -C(O)-, -CHR g -or-C(R) g )2-, where R g Optional replacement of C 1-6 alkyl;

[0085] R 6 Selected from hydrogen, or optionally substituted C 1-6 alkyl;

[0086] R 7 Selected from -NR 15 R 16 Optional replacement of C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3- 10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 aryl,

[0087] or L, R 6 and R 7 They bond with the atoms to form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11 Cycloalkyl, optionally substituted 4-11 membered heterocyclic alkyl.

[0088] In addition, in 5-6 membered heterocyclic alkyl groups, 5-6 membered heteroaryl groups, C 3-5 Heterocyclic alkyl, C 3-6 Heterocyclic alkyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C 1-6 Heteroalkyl, C 3-10 In heterocyclic alkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl or 4-11-membered heterocyclic alkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1-4.

[0089] In some embodiments of this disclosure, X 6 Selected from N or -CH-.

[0090] In some embodiments of this disclosure, R B Selected from hydrogen, C 1-6Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy; or, if n is greater than 1, R B Any two atoms bonded to them can combine to form a 3-6 membered ring, wherein the ring may optionally be made of halogen, hydroxyl, or C. 1-3 Alkyl substitution.

[0091] In some embodiments of this disclosure, P is absent, or is selected from S, O, Se, -NR. 8 -、-CR 9 R 10 -、

[0092] In some embodiments of this disclosure, n is 0, 1, or 2; preferably, n is 0 or 1.

[0093] In some embodiments of this disclosure, ring B is selected from tetrahydropyridazine group, R M and R Z Compounds of formula (II) that are independently selected from hydrogen are compounds of formula (IIa):

[0094] Or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof.

[0095] in

[0096] m is selected from 0, 1, 2, or 3;

[0097] A is selected from optionally substituted 5-6 membered heterocyclic alkylene, optionally substituted 5-6 membered arylene, optionally substituted 5-6 membered heterocyclic arylene;

[0098] G is selected as an optional replacement for C. 1-6 Alkylene;

[0099] P does not exist, or is selected from S, O, Se,

[0100] Q does not exist, or is selected from the arbitrarily substituted C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted 5-10-membered aryl, optionally substituted 5-10-membered heteroaryl, -NR 15 R 16 or -OR 17 ;

[0101] R 11 R 12 and R 13Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 11 R 12 and R 13 Any two phosphorus atoms in the ring form a phosphorus-oxygen double bond or a 3-6 membered ring through the phosphorus atoms they are connected to. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0102] R 14 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups;

[0103] R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, and the ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0104] R 17 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl;

[0105] Y is selected from -CH- or N;

[0106] X 6 Selected from S, O, N or -CH-;

[0107] R a and R b Each is independently selected from hydrogen, halogen, cyano, and C.1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl;

[0108] R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; or R t and R s A carbonyl group or a 3-8 membered ring is formed through the carbon atom attached thereto, the ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4; R 2 Selected from optional replacement C 1-6 Alkoxy, optional substituted C 1-6 Alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(3-8 heterocyclic alkyl), and optionally, the above groups may be substituted with 0, 1, or 2 or fewer substituents: -OR 51 -SR 51 Or -NR 51 R 52 ;

[0109] R 51 R 52 Each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; or R 51 and R 52 Together with the N atom it is attached to, a 3-8 membered heterocycle is formed, wherein the 3-8 membered heterocycle optionally contains 0, 1, 2 or 3 heteroatoms selected from N, O or S; furthermore, the C3-C8 cycloalkyl, C3-C8 heterocycloalkyl and 3-8 membered heterocycle may be further optionally substituted or deuterated;

[0110] R 3 It does not exist, or is selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, provided that X 6 When it is O or S, R 3 It does not exist;

[0111] E is selected from N, or from -CR d -, where R dSelected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl or -NR e R f Among them, R e and R f Selected independently from hydrogen, or optionally substituted with C 1-6 alkyl;

[0112] R 4 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 aryl, or

[0113] R 5 Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl, in addition, C 1-6 Alkyl or C 3-6 The cycloalkyl group can also be optionally substituted;

[0114] Or R 4 and R 5 The atoms bonded to them form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Monocyclic cycloalkyl, optionally substituted 3-10 membered monocyclic heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11 Cycloalkyl, optionally substituted 4-11 membered heterocyclic alkyl.

[0115] in

[0116] L does not exist, or is selected from -CH2-, -C(O)-, -CHR g -or-C(R) g )2-, where R g Optional replacement of C 1-6 alkyl;

[0117] R 6 Selected from hydrogen, or optionally substituted C 1-6 alkyl;

[0118] R 7 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C1-6 Heteroalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Heterocyclic alkyl, optionally substituted C 6-10 Aryl groups, and optionally substituted 5-10 heteroaryl groups;

[0119] or L, R 6 and R 7 They bond with the atoms to form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Monocyclic cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4-11 Bicyclic (including spirocyclic, fused, and bridged) cycloalkyl groups, and optionally substituted 4-11 membered heterocyclic alkyl groups.

[0120] In addition, in 5-6 membered heterocyclic alkyl groups, 5-6 membered heteroaryl groups, C 3-5 Heterocyclic alkyl, 3-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C 1-6 In heteroalkyl, 3-10-membered heterocyclic alkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl or 4-11-membered heterocyclic alkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1-4.

[0121] In some embodiments of this disclosure, ring B is selected from 2,3-diazabicyclo[3.1.1]heptyl, R M and R Z Compounds of formula (II) that are independently selected from hydrogen are compounds of formula (IIb):

[0122] Or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof.

[0123] in

[0124] m is selected from 0, 1, 2, or 3;

[0125] A is selected from optionally substituted 5-6 membered heterocyclic alkylene, optionally substituted 5-6 membered arylene, optionally substituted 5-6 membered heterocyclic arylene;

[0126] G is selected as an optional replacement for C. 1-6 Alkylene;

[0127] P does not exist, or is selected from S, O, Se, -NR 8 -、-CR 9 R 10 -、

[0128] Q does not exist, or is selected from the arbitrarily substituted C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted 5-10-membered aryl, optionally substituted 5-10-membered heteroaryl, -NR 15 R 16 or -OR 17 ;

[0129] R 8 and R 17 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl;

[0130] R 9 R 10 and R 14 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 9 and R 10 A carbonyl group or a 3-6 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0131] R 11 R 12 and R 13 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 11 R 12 and R 13 Any two phosphorus atoms in the ring form a phosphorus-oxygen double bond or a 3-6 membered ring through the phosphorus atoms they are connected to. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0132] R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C.1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, the ring may contain heteroatoms, the heteroatoms being independently selected from one or more of N, O and S, and the number of heteroatoms being independently 0-3; Y is selected from -CH- or N;

[0133] X 6 Selected from S, O, N or -CH-;

[0134] R a and R b Each is independently selected from hydrogen, halogen, cyano, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl;

[0135] R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; or R t and R s A carbonyl group or a 3-8 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4.

[0136] R 2 Selected from optional replacement C 1-6 Alkoxy, optional substituted C 1-6 Alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(3-8 heterocyclic alkyl), and optionally, the above groups may be substituted with 0, 1, or 2 or fewer substituents: -OR 51 -SR 51 Or -NR 51 R 52 ;

[0137] R 51 R 52Each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; or R 51 and R 52 Together with the N atom it is attached to, a 3-8 membered heterocycle is formed, wherein the 3-8 membered heterocycle optionally contains 0, 1, 2 or 3 heteroatoms selected from N, O or S; furthermore, the C3-C8 cycloalkyl, C3-C8 heterocycloalkyl and 3-8 membered heterocycle may be further optionally substituted or deuterated;

[0138] R 3 It does not exist, or is selected from hydrogen, C 1-6 Alkyl or C 1-6 Haloalkyl, provided that X 6 When it is O or S, R 3 It does not exist;

[0139] E is selected from N, or from -CR d -, where R d Selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl or -NR e R f Among them, R e and R f Selected independently from hydrogen, or optionally substituted with C 1-6 alkyl;

[0140] R 4 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 aryl, or

[0141] R 5 Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl, in addition, C 1-6 Alkyl or C 3-6 The cycloalkyl group can also be optionally substituted;

[0142] Or R 4 and R 5 The atoms bonded to them form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10Monocyclic cycloalkyl, optionally substituted 3-10 membered monocyclic heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11 4-11 member polycyclic heterocyclic alkyl groups, with optional substitution.

[0143] in

[0144] L does not exist, or is selected from -CH2-, -C(O)-, -CHR g -or-C(R) g )2-, where R g Optional replacement of C 1-6 alkyl;

[0145] R 6 Selected from hydrogen, or optionally substituted C 1-6 alkyl;

[0146] R 7 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 heteroaryl groups;

[0147] or L, R 6 and R 7 They bond with the atoms to form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Monocyclic cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4-11 Bicyclic cycloalkyl, optionally substituted 4-11 membered heterocyclic alkyl;

[0148] In addition, in 5-6 membered heterocyclic alkyl groups, 5-6 membered heteroaryl groups, C 3-5 Heterocyclic alkyl, C 3-6 Heterocyclic alkyl, 5-6 membered heteroaryl, 8-10 membered heteroaryl, C 1-6 Heteroalkyl, C 3-10 In heterocyclic alkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl or 4-11-membered heterocyclic alkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1-4.

[0149] In some embodiments of this disclosure, R a R b and R c Each is independently selected from hydrogen, halogen, cyano, C 1- 3-alkyl, C 1-3Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups; preferably, R a R b and R c Each is independently selected from hydrogen.

[0150] In some embodiments of this disclosure, A is selected from optionally substituted 5-6 membered heterocyclic alkyl groups, wherein the heteroatom in the heterocyclic alkyl group is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1-2.

[0151] In some implementation schemes, A is Preferably, A is

[0152] In some embodiments of this disclosure, A is selected from optionally substituted 5-6 aryl groups. In some embodiments, A is...

[0153] In some embodiments of this disclosure, A is selected from optionally substituted 5-6-membered heteroaryl groups (preferably optionally substituted 5-membered heteroaryl groups), wherein the heteroatom in the heteroaryl group is independently selected from one or two of N, O and S, and the number of the heteroatom is independently 1-3.

[0154] In some implementation schemes, A is Preferably, A is

[0155] In some embodiments of this disclosure, ring B is selected from optionally substituted 3-6 membered heterocyclic alkylene groups, 5-6 membered heterocyclic alkenyl groups, and optionally substituted 4-11 membered heterocyclic alkylene groups.

[0156] In some implementation schemes, ring B is Preferably, ring B is

[0157] In some embodiments of this disclosure, G is selected from C, which can be arbitrarily replaced. 1-6 Alkylene; in some embodiments of this disclosure, G is selected from optionally substituted C. 1-3 Alkylene; in some embodiments, G is

[0158] In some embodiments of this disclosure, Y is N.

[0159] In some embodiments of this disclosure, X6 It is N.

[0160] In another preferred embodiment, R 1 for

[0161] m can be 0, 1, 2, or 3;

[0162] P does not exist, or is selected from S, O, Se, -NR 8 -、-CR 9 R 10 -、

[0163] Q does not exist, or is selected from the arbitrarily substituted C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted 5-10-membered aryl, optionally substituted 5-10-membered heteroaryl, -NR 15 R 16 or -OR 17 ;

[0164] R 8 and R 17 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl groups;

[0165] R 9 R 10 and R 14 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 9 and R 10 A carbonyl group or a 3-6 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0166] R 11 R 12 and R 13 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 11 R 12 and R 13 Any two phosphorus atoms in the ring form a phosphorus-oxygen double bond or a 3-6 membered ring through the phosphorus atoms they are connected to. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0167] R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl; or R t and R s A carbonyl group or a 3-8 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4.

[0168] R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, straight-chain or branched C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, and the ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0169] In another preferred example, P is -C(=O)-.

[0170] In some embodiments of this disclosure, P is absent, or is selected from -C(=O)-, S, O, -NR. 8 -or-CR 9 R 10 -; preferably S, O, -NR 8 -or-CR 9 R 10In some embodiments, P is preferably -C(=O)-, -CH2-, S or O; more preferably -CH2-, S or O.

[0171] In some embodiments of this disclosure, Q is absent, or is selected from alternatively chosen C. 1-6 Alkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-10 Heterocyclic alkyl, optionally substituted 5-10 aryl, optionally substituted 5-10 heteroaryl;

[0172] In some implementations, Q is preferably... More preferably, Q is

[0173] In some implementations, Q is selected from -NR 15 R 16 or -OR 17 .

[0174] In some implementations, Q is preferably... More preferably, Q is

[0175] In some embodiments of this disclosure, R 8 Selected from hydrogen, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups.

[0176] In some implementation schemes, R 8 Preferably hydrogen or C 1-3 alkyl.

[0177] In some embodiments of this disclosure, R 9 and R 10 Each element is independently selected from hydrogen, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 9 and R 10A carbonyl group or a 3-6 membered ring is formed by the carbon atom attached to it. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3.

[0178] In some implementation schemes, R 9 and R 10 Preferably hydrogen, or

[0179] In some embodiments of this disclosure, R M and R Z Each group is independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and C. 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl; furthermore, the C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkyl, C 1-6 The hydroxyalkyl group may be further optionally substituted.

[0180] In some implementation schemes, R M and R Z Hydrogen is preferred.

[0181] In some embodiments of this disclosure, R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1- 6-alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl; or R t and R s A carbonyl group or a 3-8 membered ring is formed by the carbon atom attached to it. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4.

[0182] In some implementation schemes, R t and R s Preferably, they are hydrogen, hydroxyl, or C. 1-6 alkyl.

[0183] In some implementations, m is 0 or 1.

[0184] In some embodiments of this disclosure, R1 is and Selected from the following group:

[0185] Preferred, Selected from

[0186] In some embodiments of this disclosure, R 1 Selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1- 6-Hydroalkoxy, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-6 Cycloalkyl, or optionally substituted 3-6 membered heterocyclic alkyl.

[0187] In some implementation schemes, R 1 yes

[0188] In some embodiments of this disclosure, R 1 It is selected from optionally substituted 4-6-membered heterocyclic alkyl and 4-5-membered heteroaryl, optionally substituted benzo5-6-membered heterocyclic alkyl; preferably, it is optionally substituted 4-5-membered heterocyclic alkyl and 4-5-membered heteroaryl.

[0189] In some implementations, R1 is

[0190] In some embodiments of this disclosure, R 1 The heteroatom is selected from optionally substituted 5-8 aryl, optionally substituted 5-8 heteroaryl, optionally substituted 8-10 aryl or optionally substituted 8-10 heteroaryl, wherein the heteroatom is independently selected from one or two of N, O and S, and the number of heteroatoms is independently 1-4.

[0191] In some implementation schemes, R 1 yes

[0192] In some embodiments of this disclosure, R 2 Selected from optional substituted straight or branched C 1-6 Alkyl group; preferably C 1-6 Alkyl group. In some embodiments, R 2 yes Preferred

[0193] In some embodiments of this disclosure, R 2 Selected from -(C0-C6 alkylene)-(3-8 membered heterocyclic alkyl). In some embodiments, R 2 yes Preferred

[0194] In some embodiments of this disclosure, R 3 Selected from halogenated C 1-6 Alkyl, C 1-6 Alkyl; preferably C 1-6 Alkyl group. In some embodiments, R 3 yes

[0195] In some embodiments of this disclosure, R 3 Selected from C 1-6 Halogenated alkyl groups. In some embodiments, R 3 yes

[0196] In some embodiments of this disclosure, E is selected from N or -CR d -, where R d Selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl or -NR e R f ;where R e and R f Selected independently from hydrogen, or optionally substituted with C 1-6 Alkyl; preferably, E is selected from N or -CR d -, where R d Selected from hydrogen, halogen, hydroxyl or C 1-6 alkyl.

[0197] In some embodiments of this disclosure, R d Selected from halogens. In some embodiments, R d It is -F, -Cl, -Br or -I; preferably -F.

[0198] In some embodiments of this disclosure, R d Selected from C 1-6 Alkyl; in some embodiments, R d yes

[0199] In some embodiments of this disclosure, R d Selected from C 1-6 Halogenated alkyl groups. In some embodiments, R d It is -CF3.

[0200] In some embodiments of this disclosure, R d Selected from C 1-6 Alkoxy; in some embodiments, R d for

[0201] In some embodiments of this disclosure, R d Selected from C 1-6 Aminoalkyl; in some embodiments, R d yes

[0202] In some embodiments of this disclosure, R e Or R f Selected from C 1-6 Alkyl; in some embodiments, R e Or R f Selected independently

[0203] In some embodiments of this disclosure, R 4 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1- 6 heteroalkyl groups, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 heteroaryl, optionally substituted 5-10 heteroaryl, or Where R 6 Selected from hydrogen, or optionally substituted C 1-6 Alkyl; R 7 Optional substitution of C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Heterocyclic alkyl, optionally substituted 6-10 aryl, optionally substituted 5-10 heteroaryl.

[0204] Preferably, R 4 Selected from hydrogen, C 1-6 Alkyl, 3-6 membered heterocyclic alkyl, 3-6 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl or Where R 6 Selected from hydrogen, or C 1-6Alkyl; R 7 C 1-6 Alkyl, 3-10 membered heterocyclic alkyl; optionally C 1-6 Alkyl, -N(C1-4 alkyl)2, 6-10 aryl, -C(O)OC 3-6 cycloalkyl or -C(O)OC 1-6 Alkyl-substituted 3-10-membered heterocyclic alkyl groups; wherein the 3-6-membered cycloalkyl group is optionally substituted with a hydroxyl group, a cyano group, a halogen, or a C-type group. -1-6 Alkyl substitution; in 3-10 membered heterocyclic alkyl groups, the heteroatoms are independently selected from one or more of N, O, and S, and the number of heteroatoms is independently 1-3; more preferably, R 4 For hydrogen, C 1-6 alkyl, or Where R 6 Selected from hydrogen, C 1-6 Alkyl; R 7 It is C 1-6 Alkyl, 3 to 10-membered heterocyclic alkyl.

[0205] In some embodiments of this disclosure, R 4 Selected from C (optional substitution) 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted C 3-10 Heterocyclic alkyl groups, with heteroatoms of N, O, or S, and the number of heteroatoms is independently 1-2. In some embodiments, R 4 yes

[0206] In some embodiments of this disclosure, R 4 Selected from optionally substituted 6-10 aryl groups, optionally substituted 5-10 heteroaryl groups; in some embodiments, R 4 yes

[0207] In some embodiments of this disclosure, R 5 Selected from C (optional substitution) 1-6 Alkyl group. In some embodiments, R 5 yes

[0208] In some embodiments of this disclosure, R 5 Selected as an alternative to C 3-6 Cycloalkyl. In some embodiments, R 5 yes

[0209] In some embodiments of this disclosure, R 4 and R5 The atoms bonded to them form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 4-11 Cycloalkyl, optionally substituted 4-11 membered heterocycloalkyl, wherein the heteroatom is N, O or S, and the number of heteroatoms is independently 1-3; preferably R. 4 and R 5 The atoms bonded to them form a ring, wherein the ring is selected from optionally substituted C3-6 cycloalkyl groups or optionally substituted 3-7 membered heterocyclic alkyl groups, wherein the heteroatom in the heterocyclic alkyl group is independently N, O, or S, and the number of heteroatoms is independently 1-3; preferably...

[0210] In some embodiments of this disclosure, R 6 Selected from C that can be arbitrarily replaced 1-6 Alkyl; in some embodiments, R 6 yes

[0211] In some embodiments of this disclosure, L is -C(O)-.

[0212] In some implementation schemes, R 7 Selected from C that can be arbitrarily replaced 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl; preferably, the 3-10 membered heterocyclic alkyl is optionally C 1-6 Alkyl, C 6-10 Aryl, -C(O)OC 3-6 cycloalkyl or -C(O)OC 1-6 Alkyl substitution; the C 3-10 The cycloalkyl group may be optionally replaced by a hydroxyl group, a cyano group, a halogen group, or a C group. 1-6 Alkyl substitution; in 3-10 membered heterocyclic alkyl groups, the heteroatoms are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1-3.

[0213] In some implementation schemes, R 7 Selected from optionally substituted 5-6 membered heteroaryls, wherein the heteroaryl contains 1-3 independent heteroatoms selected from N, O and S.

[0214] In some embodiments of this disclosure, R 7 Selected from C 1-6 Alkyl; in some embodiments, R 7 yes

[0215] In some embodiments of this disclosure, R 7Selected from 3-6 membered heterocyclic alkyl groups, preferably, the heteroatom is N, O, or S, and the number of heteroatoms is independently 1-2; in some embodiments, R 7 yes The better location is

[0216] In some embodiments of this disclosure, R 7 Selected from C 3-6 Cycloalkyl. In some embodiments, R 7 yes

[0217] In some embodiments of this disclosure, R 7 Selected from C 6-10 Aryl. In some implementations, R 7 yes

[0218] In some embodiments of this disclosure, R 7 Selected from C 1-6 Alkyl or 3-6 membered heterocyclic alkyl; the 3-6 membered heterocyclic alkyl is optionally C 6-10 Aryl or -C(O)OC 1-6 Alkyl substitution; in 3-6 membered heterocyclic alkyl groups, the heteroatoms are independently selected from one or both of N and O, and the number of heteroatoms is independently 1-2.

[0219] In some embodiments of this disclosure, R 7 Selected from 5-6-membered heteroaryl groups; the above groups are optionally replaced by deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), -S(O)2-(C 1-4 Alkyl), -C(O)-(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2、-C(O)O-(C 1-4 Alkyl), -C(O)-(C 3-6 cycloalkyl), -C(O)-3-6 heterocyclic alkyl, -C(O)-(C 2-6 alkenyl), -C(O)-(C 2-6 ynyl group), -C(O)-(C 2-6 ynyl)-3-6-membered heterocyclic alkyl, -C(O)-(C 2-6 ynyl)-N(C 1-3 Alkyl)2、-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2、-NH-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2, C 1-4Alkyl-substituted or unsubstituted -C(O)-(C 2-6 ynyl)N(C 1-4 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, oxo C 2-4 alkenyl, C 2- C4 ynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, Or phenyl substitution.

[0220] In some embodiments of this disclosure, R 7 Selected from phenyl, C 1-6 Alkyl or 3-6 membered heterocyclic alkyl; the above groups are optionally replaced by deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), -S(O)2-(C 1-4 Alkyl), -C(O)-(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2、-C(O)O-(C 1-4 Alkyl), -C(O)-(C 3-6 cycloalkyl), -C(O)-(C 2-6 alkenyl), -C(O)-3-6 membered heterocyclic alkyl, -C(O)-(C 2-6 ynyl group), -C(O)-(C 2-6 ynyl)-3-6-membered heterocyclic alkyl, -C(O)-(C 2-6 ynyl)-N(C 1-3 Alkyl)2、-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2、-NH-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2, C 1-4 Alkyl-substituted or unsubstituted -C(O)-(C 2-6 ynyl)N(C 1-4 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, oxo C 2-4 alkenyl, C 2- C4 ynyl group, C 3-6Cycloalkyl, 3-6 membered heterocyclic alkyl, Or phenyl substitution.

[0221] In some implementation schemes, R 7 yes

[0222] In some embodiments of this disclosure, R 4 It has the structure of formula (IV): Among them, L and R 6 and R 7 As defined above;

[0223] Preferably, L, R 6 and R 7 They bond with the atoms to form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4-11 Cycloalkyl, optionally substituted 4-11 membered heterocyclic alkyl.

[0224] In some implementations... yes

[0225] In some embodiments of this disclosure, yes

[0226] Preferred, Selected from

[0227] More preferably, Selected from

[0228] In some embodiments of this disclosure, the "halogen" is selected from F, Cl, Br or I; preferably F.

[0229] Furthermore, the present invention provides a compound having the structure of formula (IIa) or (IIb) as described above, or an isotopic derivative thereof, its stereoisomer, its pharmaceutically acceptable salt, its metabolite, its prodrug, its solvate, or a solvate of its pharmaceutically acceptable salt, wherein the compound of formula (IIa) or (IIb) has the structure of formula (IIIa) or (IIIb), respectively:

[0230] Other variables are as defined in this invention as described above.

[0231] This invention provides compound A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, wherein compound A is selected from any of the following compounds in Table 1:

[0232] Table 1. Certain compounds of the present invention

[0233] A second aspect of the invention provides a pharmaceutical composition comprising a compound, wherein a pharmaceutically acceptable salt, a solvation thereof, or a solvation of a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, the compound being a compound of formula I as defined above.

[0234] A third aspect of the invention provides the use of a compound, wherein a pharmaceutically acceptable salt, a solvation thereof, or a solvation of a pharmaceutically acceptable salt, or as described above, is used to prepare a pharmaceutical composition for treating a disease or condition characterized by abnormal RAS activity caused by a RAS mutant, wherein the compound is compound A as defined above.

[0235] In some embodiments disclosed in this invention, the cancer is a RAS-driven cancer.

[0236] In some embodiments disclosed in this invention, the cancer includes RAS mutations.

[0237] In some embodiments disclosed in this invention, the RAS protein is wild-type (RAS). WT The compounds of this invention are used to treat patients with RAS-containing diseases. WT (e.g. K-RAS) WT H-RAS WT or N-RAS WT (This refers to a method for treating cancer patients.)

[0238] In some embodiments disclosed in this invention, the RAS protein is a RAS amplification (e.g., K-RAS). amp The compounds of this invention are used to treat patients with RAS-containing diseases. amp (K-RAS amp H-RAS amp or N-RAS amp (This refers to a method for treating cancer patients.)

[0239] In some embodiments disclosed in this invention, the cancer comprises a RAS mutation, as described herein. The mutation is selected from: (a) the following K-RAS mutants: G12D, G12V, G12C, G13D, G12R, G12A, Q61H, G12S, A146T, G13C, Q61L, Q61R, K117N, A146V, G12F, Q61K, L19F, Q22K, V14I, A59T, A146P, G13R, G12L, or G13V, and combinations thereof; (b) the following H-RAS mutants: Q61R, G13R, Q61K, G12S, Q61L, G12D, G13V, G13D, G12C, K117N, A59T, G12V, G13C, Q61H. (c) The following N-RAS mutants: Q61R, Q61K, G12D, Q61L, Q61H, G13R, G13D, G12S, G12C, G12V, G12A, G13V, G12R, P185S, G13C, A146T, G60E, Q61P, A59D, E132K, E49K, T50I, A146V or A59T, and combinations thereof; or any combination of the aforementioned KRAS mutations, HRAS mutations and NRAS mutations.

[0240] In some embodiments disclosed in this invention, the cancer includes RAS mutations and EGFR, PI3K, MEK, ERK, and STK11. LOF KEAP1, EPHA5, or NF1 mutations, or any combination of the aforementioned mutations.

[0241] In some embodiments disclosed in this invention, the cancer includes RAS inhibitor-resistant cancer, wherein the RAS inhibitors include various KRAS mutation inhibitors such as KRAS G12C inhibitors, KRAS G12D inhibitors, KRAS G12V inhibitors, etc.; HRAS mutation inhibitors and NRAS inhibitors; and also include RAS signaling pathway inhibitors such as ERK inhibitors, PI3K inhibitors, MEK inhibitors, etc.

[0242] In some embodiments disclosed in this invention, the cancer includes, but is not limited to, tumor types such as: astrocytoma, breast, cervix, colon and rectum, endometrium, esophagus, stomach, head and neck, hepatocytes, larynx, lungs, oral cavity, ovary, prostate, and thyroid carcinoma and sarcoma. Other cancers include, for example: the heart, such as sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; the lungs, such as bronchogenic carcinomas (squamous cell lung cancer, non-small cell lung cancer, small cell lung cancer, undifferentiated small cell lung cancer, undifferentiated large cell lung cancer, lung adenocarcinoma), alveolar (bronchiolar) carcinomas, bronchial adenomas, sarcomas, lymphomas, chondromatous hamartomas, and mesotheliomas; the gastrointestinal tract, such as the esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), the stomach (carcinoma, lymphoma, leiomyosarcoma), the pancreas (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), and the small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma). Sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas; colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyomas); urogenital tract, such as: kidney (adenocarcinoma, Wilms' tumor). Tumors (nephroblastoma, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminomatous tumor, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver, such as hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct, such as gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; bone, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma. Sarcoma), malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrogenic osteoma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma and giant cell tumor; nervous system, such as: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma;Gynecological conditions, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer); hematopoietic system conditions, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodyplasia syndrome), Hodgkin's disease). Diseases such as non-Hodgkin's lymphoma (malignant lymphoma); skin conditions such as malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, and psoriasis; and adrenal gland conditions such as neuroblastoma.

[0243] In some embodiments disclosed in this invention, the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0244] In some embodiments disclosed in this invention, the RAS protein is KRAS.

[0245] The present invention also provides a method for treating cancer in a subject who requires it, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutically acceptable salt, a solvation thereof, or a pharmaceutically acceptable salt or solvation of a pharmaceutical composition, wherein the compound is compound A as defined above.

[0246] In some embodiments disclosed in this invention, the cancer is a RAS-driven cancer.

[0247] In some embodiments disclosed in this invention, the cancer includes RAS mutations.

[0248] In some embodiments disclosed in this invention, the RAS mutation is at position 12, 13 or 61.

[0249] In some embodiments disclosed in this invention, the RAS mutation is located at position 12.

[0250] In some embodiments disclosed in this invention, the RAS mutation is located at a position selected from the group or combination of G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R and Q61L.

[0251] In some embodiments disclosed in this invention, the RAS mutation is a position selected from the group consisting of G12D, G12V, and G12R, or a combination thereof.

[0252] In some embodiments disclosed in this invention, the cancer is pancreatic cancer, appendix cancer, small bowel cancer, colorectal cancer, ampullary cancer, non-small cell lung cancer, cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, endometrioid uterine cancer, esophageal cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid adenocarcinoma, myelodysplastic syndrome, or squamous cell lung cancer.

[0253] In some embodiments disclosed in this invention, the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0254] In some embodiments disclosed in this invention, the RAS protein is KRAS.

[0255] In some implementations, methods are provided for treating RAS protein-related diseases in subjects who require it.

[0256] The methods of this invention may include the use of the compounds of this invention alone or in combination with one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents). The compounds of this invention may be administered before, after, or simultaneously with one or more of the additional therapies. When combined, the dose of the compounds of this invention and the dose of the one or more additional therapies (e.g., non-pharmacological treatments or therapeutic agents) provide a therapeutic effect (e.g., synergistic or additive therapeutic effect). The compounds of this invention and additional therapies, such as anticancer agents, may be administered together, such as in the form of a single pharmaceutical composition, or separately, and when administered separately, the administration may occur simultaneously or sequentially. Such sequential administration may be proximate or staggered in time.

[0257] In some embodiments disclosed in this invention, the additional therapy is the administration of a side effect limiter (e.g., an agent intended to reduce the occurrence or severity of treatment side effects). For example, in some embodiments, the compounds of this invention may also be used in combination with a therapeutic agent for treating nausea. Examples of agents that can be used to treat nausea include: drocannabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or pharmaceutically acceptable salts thereof.

[0258] In some embodiments disclosed in this invention, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy).

[0259] In some embodiments disclosed in this invention, the one or more additional therapies include therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors).

[0260] In some embodiments disclosed in this invention, the one or more additional therapies include non-pharmacological treatments (e.g., surgery or radiation therapy) and therapeutic agents (e.g., compounds or biological agents that are anti-angiogenic agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors, or autophagy inhibitors).

[0261] In some embodiments disclosed in this invention, the one or more additional therapies comprise two therapeutic agents. In other embodiments, the one or more additional therapies comprise three therapeutic agents.

[0262] In some embodiments disclosed in this invention, the one or more additional therapies comprise four or more therapeutic agents.

[0263] Therapeutic agents can be compounds used to treat cancer or its related symptoms. For example, a therapeutic agent can be a steroid; a therapeutic agent can be a biological agent (e.g., cytokines such as interferon or interleukins, such as IL-2) used to treat cancer or its related symptoms.

[0264] In some embodiments disclosed in this invention, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that activates a target to stimulate an anticancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included. The therapeutic agent may be a T-cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, such as a monoclonal antibody). The antibody may be, for example, a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, such as an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is a pharmaceutical agent that interacts with a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a pharmaceutical agent that interacts with a ligand of a checkpoint protein, such as an antibody. In some embodiments, the checkpoint inhibitor is a CTLA-4 inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) (e.g., an anti-CTLA-4 antibody or a fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PDL-2 inhibitor or antagonist (e.g., an inhibitory antibody or an Fc fusion compound or a small molecule inhibitor) (e.g., a PDL-2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or combinations thereof (e.g., an inhibitory antibody or a small molecule inhibitor).

[0265] The therapeutic agent can be an agent for treating cancer or related symptoms (e.g., cytotoxic agents, non-peptide small molecules, or other compounds that can be used to treat cancer or related symptoms, collectively referred to as "anticancer agents"). Anticancer agents can be, for example, chemotherapeutic agents or targeted therapeutic agents. In some embodiments, the anticancer agent is an inhibitor of a downstream member of a receptor tyrosine kinase (RTK) / growth factor receptor (e.g., SHP2 inhibitors (e.g., SHP099, TNO155, RMC-4550, RMC-4630, JAB-3068, RLY-1971), an SOS1 inhibitor (e.g., BI-1701963, BI-3406), a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, or an mTOR inhibitor (e.g., an mTORC1 inhibitor or an mTORC2 inhibitor). In some embodiments, the anticancer agent is JAB-3312. In some embodiments, the anticancer agent is an additional RAS inhibitor (e.g., AMG). 510, MRTX1257, MRTX849, ARS-853, ARS-1620, ARS-3248 (or JNJ-74699157, LY3499446) or RAS vaccines or other treatments designed to directly or indirectly reduce the carcinogenic activity of RAS. In some embodiments, therapeutic agents that can be combined with the compounds of the present invention are MAP kinase (MAPK) pathway inhibitors (or "MAPK inhibitors"). In some embodiments, the anticancer agent is a disruptor or an inhibitor of the RAS-RAF-ERK or PI3K-AKT-TOR or PI3K-AKT signaling pathway. In some embodiments, additional therapeutic agents include ALK inhibitors, HER2 inhibitors, EGFR inhibitors, IGF-1R inhibitors, MEK inhibitors, PI3K inhibitors, AKT inhibitors, TOR inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, proteasome inhibitors, and immunotherapy. In some embodiments, the therapeutic agent may be a pan-RTK inhibitor.

[0266] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Attached Figure Description

[0267] Figure 1 shows the injection of NSCLC tumor (LU99) into the tumor. G12C Data on tumor volume changes in mice after administration of the compounds of this invention and the reference compounds over 24 days. Detailed Implementation

[0268] the term

[0269] In this invention, unless otherwise specified, the terms used have the general meanings known to those skilled in the art.

[0270] As used herein, the term “comprising” or its variations such as “including” or “comprises” are to be understood as including the stated elements or components without excluding other elements or other components.

[0271] As used in this article, the term "halogen" or "halogen" refers to a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.

[0272] As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid. When the compounds of the present invention are acidic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. When the compounds of the present invention are basic, their corresponding salts can be readily prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.

[0273] As used in this article, the term "solvent" refers to a solvent addition form containing stoichiometric or non-stoichiometric amounts of solvent.

[0274] Excipients used to prepare pharmaceutical compositions that are generally safe, non-toxic, and have neither biological significance nor other adverse value, and include carriers acceptable for veterinary and human pharmaceutical use.

[0275] As used herein, "pharmaceuticalally acceptable carrier" includes one or more such carriers. The term "pharmaceuticalally acceptable carrier" also includes "pharmaceuticalally acceptable excipients" and "pharmaceuticalally acceptable diluents." The specific carrier used in the pharmaceutical compositions of this disclosure will depend on the means and purpose of applying the compounds of this disclosure.

[0276] When a substituent is described using a conventional chemical formula written from left to right, it also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0277] "Alkyl (alone or as part of other groups)" refers to a monovalent, straight-chain or branched saturated hydrocarbon group consisting of 1 to 12 carbon atoms, consisting only of carbon and hydrogen atoms. Alkyl groups are preferably C1-C6 alkyl groups (i.e., containing 1, 2, 3, 4, 5, or 6 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, etc. In this application, alkyl is also intended to include substituted alkyl groups, i.e., one or more positions of an alkyl group are substituted, particularly 1-4 substituents, which may be substituted at any position. "Haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms are replaced by the same or different halogens. Examples of haloalkyl groups include -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3), etc.

[0278] The term "alkenyl" refers to a straight-chain or branched carbon chain group having at least one carbon-carbon double bond. Alkenyl groups can be substituted or unsubstituted. When an alkenyl group is preceded by a carbon number qualifier (e.g., C...), it is considered a substituted group. 2-8 When ), it refers to the alkenyl group containing 2-8 carbon atoms. For example, C 2-8 Alkenyl refers to an alkenyl group containing 2-8 carbon atoms, including vinyl, propenyl, 1,2-butenyl, 2,3-butenyl, butadienyl, or similar groups.

[0279] The term "alkynyl" refers to an aliphatic hydrocarbon group having at least one carbon-carbon triple bond. The alkynyl group can be straight-chain or branched, or a combination thereof. When the alkynyl group is preceded by a carbon number definiteness (e.g., C2-8 alkynyl), it indicates that the alkynyl group contains 2-8 carbon atoms, preferably 2-6 carbon atoms. For example, the term "C2-8 alkynyl" refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, including ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, sec-butynyl, tert-butynyl, or similar groups. "Alkylene" refers to a divalent alkyl group, such as -CH2-, -CH2CH2-, and -CH2CH2CH2-.

[0280] "Alkoxy group (alone or as part of other groups)" refers to an alkyl group having an oxygen group attached thereto, having an alkyl O- structure, wherein the alkyl group has the definition as described above. Preferably, the alkoxy group is a C1-C6 alkoxy group. Alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, etc. "Haloalkoxy group" refers to a group of formula -OR, where R is a haloalkyl group as defined herein. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, etc.

[0281] "Heteroalkyl" refers to a substituted alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges may be given; for example, C1-C6 heteroalkyl refers to the number of carbon atoms in the chain, ranging from 1 to 6 carbon atoms. For example, the -CH2OCH2CH3 group is called a "C3" heteroalkyl. Connection to the rest of the molecule can be via heteroatoms or carbon atoms in the heteroalkyl chain. "Heteroalkylene" refers to an optionally substituted divalent alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof.

[0282] "Cycloalkyl" refers to a monovalent saturated carbocyclic group composed of a monocyclic, bicyclic, or polycyclic ring, having 3-12, preferably 3-10, and more preferably 3-8 ring atoms. The cycloalkyl group may optionally be substituted by one or more substituents, wherein each substituent is independently a hydroxyl, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. It can be a monocyclic, or multiple fused, spirocyclic, or bridged rings. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0283] The term "cycloalkylene" is a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "cycloalkylene".

[0284] "Aryl (alone or as part of other groups)" refers to a monovalent group in an aromatic ring system. Representative aryl groups include phalloaromatic systems such as phenyl, naphthyl, and anthracene; and ring systems in which an aromatic carbon ring is fused with one or more non-aromatic carbon rings, such as indanyl, phthalimide, naphthylimide, or tetrahydronaphthyl, etc. In this invention, the aryl group is preferably a C6-C12 aryl group. In this invention, the aryl group is also intended to include substituted aryl groups.

[0285] The term "aryl" is a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "aryl".

[0286] In this invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaryl group containing one or more heteroatoms. Heteroatoms referred to herein include oxygen, sulfur, and nitrogen. Examples include furanyl, thiophene, pyridinyl, pyrazolyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclic, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted.

[0287] The term "alkylene" is a divalent group that is connected to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "alkyl".

[0288] "Heteroaryl" refers to a monocyclic (e.g., 5- or 6-membered), bicyclic (e.g., 8- or 10-membered), or tricyclic group with 5 to 12 ring atoms, containing at least one aromatic ring with 1, 2, or 3 ring heteroatoms selected from N, O, or S, and the remaining ring atoms being C. It should be clear that the connection point of the heteroaryl group should be located on the aromatic ring. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indoleyl, isindoleyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazole, and azazolyl. basalt, diazoxide Compounds such as acridine and aryl. Heteroaryl refers to a heteroaryl group having two linkage sites.

[0289] The term "hybrid aryl" is a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term "heteroaryl".

[0290] "Heterocyclic group" refers to a monovalent group in a heterocyclic system, usually a stable monocyclic (e.g., 3-8 ternary, i.e., 3, 4, 5, 6, 7 or 8 ternary), bicyclic (e.g., 5-12 ternary, i.e., 5, 6, 7, 8, 9, 10, 11 or 12 ternary), or polycyclic (e.g., 7-14 ternary, i.e., 7, 8, 9, 10, 11, 12, 13 or 14 ternary), including fused rings, spirocyclic and / or bridged ring structures, which are saturated or partially unsaturated, and contain a carbon atom and one, two, three or four heteroatoms independently selected from N, O and S. Representative heterocyclic groups include the following ring systems, wherein (1) each ring is non-aromatic and at least one ring contains a heteroatom, for example, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolylalkyl, pyrrolidoneyl, piperidinyl, pyrrololinyl, decahydroquinolinyl, oxazolylalkyl, piperazineyl, dioxalyl, dioxopentyl, diachexenyl, oxachexenyl, thiaachexenyl, morpholinyl, and quininecycloyl; (2) at least one ring is Non-aromatic compounds containing heteroatoms and at least one other ring being an aromatic carbocyclic ring, such as 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; and (3) at least one ring being non-aromatic and containing heteroatoms and at least one other ring being aromatic and containing heteroatoms, such as 3,4-dihydro-1H-pyrano[4,3-c]pyridine and 1,2,3,4-tetrahydro-2,6-diazanaphthalene. A heterocyclic group refers to a heterocyclic group having two connecting sites. In this invention, the heterocyclic group is preferably a bicyclic group, one ring being a heteroaryl group and connected to the other parts of the general formula via the heteroaryl group. In this invention, the heterocyclic group is preferably a 5-6 member monocyclic heterocyclic group or an 8-10 member bicyclic heterocyclic group. Examples of such heterocyclic groups include... When a heterocyclic group has substituents, the substituents can be attached to any atom in the ring, provided that a stable chemical structure is produced.

[0291] The term “heterocyclic alkyl” is a divalent group that is attached to the rest of the molecule by two single bonds, and the rest of the definition is the same as that of the term “heterocyclic alkyl”.

[0292] As used herein, the term "alkylamino" refers to an alkyl moiety substituted with one or more amino groups.

[0293] As used in this article, the term "C" 1-6 "Haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen, such as -OCF3.

[0294] As used in this article, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, such as -CF3.

[0295] The term "C" used in this article 1-6 Alkoxy C1-6 "alkyl" refers to C 1-6 Alkyl groups, wherein one or more hydrogen atoms are C 1-6 Alkoxy substitution, or C 1-6 Alkoxy groups, in which one or more hydrogen atoms are bonded by C 1-6 Alkyl substitution.

[0296] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0297] The term "oxo" refers to the =O group, where an oxygen atom replaces two hydrogen atoms on the same carbon atom, i.e., a carbonyl group replaces a methylene group.

[0298] The term "double ring" refers to a spiral ring, a parallel ring, or a bridge ring.

[0299] As used herein, the term "spirocycle" refers to two rings that share a single ring atom (e.g., carbon).

[0300] As used in this article, the term "ring-linked ring" refers to two rings that share two adjacent ring atoms.

[0301] As used in this article, the term "bridged ring" refers to two rings that share three adjacent ring atoms.

[0302] As used in this article, the term "optional substitution" means that an atom may or may not be substituted, unless otherwise specified.

[0303] "Cyano" refers to the -CN group.

[0304] "Nitro" refers to -NO2.

[0305] "Hydroxy group" refers to -OH.

[0306] "Amino" refers to -NH2 or RNH-, where R is a ketone carbonyl group, sulfonyl group, sulfonamide group, or R a -C(=O)-、R a R b NC(=O)- etc., where R a and R b It can be alkyl, cycloalkyl, aryl, or heteroaryl, etc.

[0307] In this invention, the term "multiple" independently refers to 2, 3, 4, or 5.

[0308] In this invention, the term "substitution" refers to the replacement of one or more hydrogen atoms on a specific group by a specific substituent. The specific substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substituted site of that group, and the substituents may be the same or different at each position. Cyclic substituents, such as heterocyclic alkyl groups, may be attached to another ring, such as a cycloalkyl group, thereby forming a spirobicyclic system, for example, where the two rings share a common carbon atom. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0309] Preparation method

[0310] The following schemes and examples describe methods for preparing compounds of formula I. Starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps in performing the reaction scheme may be altered to promote the reaction or avoid unwanted byproducts.

[0311] The preparation method of the compound of Formula I of the present invention is described in more detail below, but these specific methods do not constitute any limitation on the present invention. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations can be easily performed by those skilled in the art.

[0312] Active ingredients

[0313] As used herein, the terms “compound of the invention” or “active ingredient of the invention” are used interchangeably to refer to a compound of formula (I), its isotopic derivatives, its stereoisomers, its pharmaceutically acceptable salts, its metabolites, its prodrugs, its solvates, or solvates of its pharmaceutically acceptable salts. The term also includes racemic mixtures and optical isomers.

[0314] The compound of formula I has the following structure:

[0315] The definitions of each group are as described above.

[0316] Salts that may form from the compounds of this invention are also within the scope of this invention. Unless otherwise stated, compounds of this invention are understood to include their salts. The term "salt" as used herein refers to a salt formed from an inorganic or organic acid and a base in an acidic or basic form. Furthermore, when a compound of this invention contains a basic segment, it includes, but is not limited to, pyridine or imidazole; when it contains an acidic segment, it includes, but is not limited to, carboxylic acids; and any zwitterions ("internal salts") that may form are included within the scope of the term "salt." Pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable) salts are preferred, although other salts are also useful, for example, for separation or purification steps in the preparation process. Compounds of this invention may form salts, for example, by reacting compound I with a certain amount, such as an equimolar amount, of an acid or base, precipitating it in a medium, or by freeze-drying it in an aqueous solution.

[0317] The compounds of this invention contain basic fragments, including but not limited to amines, pyridines, or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (such as acetic acid or trihaloacetic acids, such as trifluoroacetic acid), adipates, alginates, ascorbic acid salts, aspartate salts, benzoates, benzenesulfonates, hydrogen sulfates, borates, butyrates, citrates, camphor salts, camphor sulfonates, cyclopentanepropionate, diethylene glycol salts, dodecyl sulfates, ethanesulfonates, fumarates, glucono-2-phosphates, glycerol phosphates, hemisulfates, heptarates, hexanoates, hydrochlorides, hydrobromide, and hydroiodide. Salts, hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonate), lactates, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonate), nicotinates, nitrates, oxalates, pectates, persulfates, phenylpropionates (e.g., 3-phenylpropionates), phosphates, picrates, neopentanoates, propionates, salicylates, succinates, sulfates (e.g., those formed with sulfuric acid), sulfonates, tartrates, thiocyanates, toluenesulfonates such as p-toluenesulfonate, dodecanoates, etc.

[0318] Some compounds of this invention may contain acidic fragments, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-formed salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (such as organic amines), such as benzylamine, dicyclohexylamine, hepatopanylamine (a salt formed with N,N-di(dehydroabietic)ethylenediamine), N-methyl-D-glucosamine, N-methyl-D-glucosamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, etc. Basic nitrogen-containing groups can react with quaternary ammonium halides, such as small alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, dodecyl, tetradecyl, and tetradecyl halides), aralkyl halides (e.g., benzyl and phenyl bromides), etc.

[0319] The prodrugs and solvates (or solvents) of the compounds in this invention are also within the scope of this invention.

[0320] The term "prodrug" here refers to a compound that, in the course of treating a related disease, undergoes a metabolic or chemical transformation to produce the compounds, salts, or solvates of this invention. The compounds of this invention include solvates, such as hydrates.

[0321] The compounds, salts, or solvates of this invention may exist in tautomer forms (e.g., amides and imine ethers). All such tautomers are part of this invention.

[0322] All stereoisomers of compounds (e.g., those with asymmetric carbon atoms due to various substitutions), including their enantiomers and diastereomeric forms, are within the scope of this invention. The independent stereoisomers of the compounds in this invention may not coexist with other isomers (e.g., possessing special activity as a pure or substantially pure optical isomer), or may be mixtures, such as racemates, or mixtures formed with all other stereoisomers or a portion thereof. The chiral center of this invention has two configurations, S or R, as defined by the International Union of Theoretical and Applied Chemistry (IUPAC) in 1974. Racemic forms can be resolved by physical methods, such as stepwise crystallization, or by derivatization into diastereomers followed by crystallization, or by chiral column chromatography. Individual optical isomers can be obtained from racemates by suitable methods, including but not limited to conventional methods, such as recrystallization after salting with an optically active acid.

[0323] The compounds of this invention, obtained sequentially through preparation, separation, and purification, have a weight content equal to or greater than 90%, for example, equal to or greater than 95%, or equal to or greater than 99% (“very pure” compounds), as listed in the text description. Such “very pure” compounds of this invention are also included as part of this invention.

[0324] All configurational isomers of the compounds of this invention are included within the scope of this invention, whether in mixtures, pure or very pure forms. The definition of the compounds of this invention includes two olefin isomers, cis (Z) and trans (I), as well as cis and trans isomers of carbocyclic and heterocyclic compounds.

[0325] Pharmaceutical compositions containing active ingredients

[0326] Because the compounds of the present invention have excellent RAS (especially KRAS protein) inhibitory activity, the compounds of the present invention and their various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compounds of the present invention as the main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) diseases or conditions related to RAS (especially KRAS protein) mutations, such as tumors, preferably lung cancer, pancreatic cancer, kidney cancer, head and neck cancer, breast cancer, lymphoma, skin cancer, urothelial carcinoma, gastric cancer, hepatocellular carcinoma and colorectal cancer, etc.

[0327] The pharmaceutical compositions of the present invention comprise the compound of the present invention within a safe and effective range and a pharmaceutically acceptable excipient or carrier. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 0.01-99.99% by weight of the compound of the present invention per dose, more preferably, 0.1-99.9% by weight of the compound of the present invention per dose. Preferably, "one dose" is a capsule or tablet.

[0328] "Pharmaceutically acceptable carriers" refer to one or more compatible solid or liquid fillers or gelling substances that are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with and with the compounds of the present invention without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0329] There are no particular limitations on the administration of the compounds or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous, intramuscular, or subcutaneous).

[0330] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0331] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0332] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0333] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0334] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0335] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or excipients include water, ethanol, polyols, and suitable mixtures thereof.

[0336] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).

[0337] When administered in combination, the pharmaceutical composition further comprises one or more (two, three, four, or more) other pharmaceutically acceptable compounds. One or more (two, three, four, or more) of these other pharmaceutically acceptable compounds may be used simultaneously, separately, or sequentially with the compounds of the present invention for the prevention and / or treatment of diseases or conditions associated with RAS mutations.

[0338] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is the pharmaceutically considered effective dose. Of course, the specific dose should also take into account factors such as the route of administration and the patient's health condition, which are all within the scope of the skill of a skilled physician.

[0339] It should be understood that the above description of the two preferred embodiments is intended to purely illustrate the principles of the invention, rather than to describe them exhaustively, and variations and modifications will be apparent to those skilled in the art. The invention is not intended to be limited except as expressly stated in the following claims.

[0340] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions as described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0341] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of this invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0342] Synthesis method

[0343] The compounds of this invention can be prepared by any conventional method. Suitable methods for synthesizing these compounds and their starting materials are provided in the following schemes and examples. Unless otherwise stated, all substituents are as described above. Furthermore, unless explicitly stated otherwise, all reactions, reaction conditions, abbreviations, and symbols have meanings well known to those skilled in the art of organic chemistry.

[0344] The general synthetic procedure for preparing compounds of formula (IIa) or (IIb) is shown in Scheme 1:

[0345] Option 1

[0346] Scheme 1 illustrates a method for preparing the compound of formula (II). First, the compound of formula (I) can be coupled under standard Suzuki coupling conditions (e.g., Pd(dppf)Cl2 and K2CO3) to provide the compound of formula (2). The compound of formula (2) is coupled with the compound of formula (3) under Suzuki coupling conditions (e.g., Pd(dppf)Cl2 and K2CO3) to obtain the compound of formula (4), which is then converted to the compound of formula (5) in the presence of an iodine reagent (e.g., I2 or NIS). The compound of formula (5) is deprotected to provide the compound of formula (6), such as by hydrolyzing the ester with LiOH·OH or by deprotecting the silanizing protecting group of the hydroxyl group with TBAF. The compound of formula (8) is obtained by conventional coupling conditions in the presence of an organic base (such as Et3N, DIPEA, or pyridine) with a compound of formula (6) and an amine of formula (7) or (7'), or a coupling agent (such as HATU, EDCI / HOBt, or PyBOP). This coupling agent is hydrolyzed under alkaline conditions to provide an acid of formula (9), such as LiOH·OH. Intramolecular coupling of the compound of formula (9) with a coupling agent (such as EDCI / HOBt and HATU) yields the compound of formula (10). The compound of formula (10) can then be coupled under standard Suzuki coupling conditions (e.g., Pd(dppf)Cl2 and K2CO3) to provide the compound of formula (11). Under Suzuki coupling conditions, the compound of formula (11) is coupled with a compound of formula (12) (e.g., Pd(dppf)Cl2 and K2CO3) to give the compound of formula (13), which is then converted to the compound of formula (14) in the presence of an inorganic base (e.g., Cs2CO3) using an alkylating agent (e.g., iodomethane or iodoethane). Deprotection of compound (14) allows the compound of formula (15) to be obtained in the presence of an acid (e.g., TFA). The compound of formula (II) can be obtained by coupling the acid of formula (16) and the compound of formula (15) with a coupling agent (e.g., HATU, EDCI / HOBy, PyBOP, or COMU) in the presence of a base (e.g., TEA, DIPEA, pyridine, or 2,6-didiamine).

[0347] Preparation of intermediates

[0348] Intermediate A: 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0349] Step 1: Preparation of (5-bromo-1H-indol-3-yl)methanol

[0350] 100.0 g (0.45 mol) of 5-bromo-1H-indole-3-carboxaldehyde was added to a premixed solution of THF / MeOH (1 L, V:V = 4:1) and stirred at 0 °C for 5 min. Then, 20.0 g (0.53 mol) of NaBH4 was added to the above solution at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was quenched dropwise with H2O (300 mL), diluted with ethyl acetate (100 mL), and then extracted with ethyl acetate (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to give crude product (5-bromo-1H-indole-3-yl)methanol (107.5 g, 98%) as a white solid. The crude product was used directly in the next reaction without purification.

[0351] LCMS (ESI) calculation of C9H8BrNO[MH]+ m / z is 224.07, yielding: 224.10

[0352] Step 2: Preparation of methyl 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropionate

[0353] Under a nitrogen atmosphere, (1-methoxy-2-methyl-1-prop-1-en-1-yl)oxy)trimethylsilane (157.3 g, 0.90 mol) was added to anhydrous THF (150 mL). The reaction mixture was stirred at -40 °C for 5 minutes. Then, under a nitrogen atmosphere, (5-bromo-1H-indol-3-yl)methanol (107.5 g, 0.48 mol) dissolved in anhydrous THF (50 mL) was added dropwise. After 10 minutes, TMSOTf (90.0 g, 0.40 mol) dissolved in anhydrous THF (50 mL) was added dropwise to the above solution under a nitrogen atmosphere. The reaction mixture was stirred at this temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was brought to room temperature and diluted with NaHCO3 solution (100 mL), and then the mixture was extracted with EtOAc (100 mL x 4). The organic layer was separated, dried with anhydrous Na2SO4 and concentrated to obtain a crude product. The crude product was further purified by silica gel chromatography with petroleum ether / ethyl acetate (0%-20%) to obtain methyl 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropionate (98g, 70%) as a yellow solid.

[0354] LCMS (ESI) calculates C 14 H 16 The m / z ratio of BrNO2[M+H]+ is 310.19, therefore we get: 310.20.

[0355] Step 3: Preparation of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethyl-1-propanol

[0356] Methyl 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropionate (98 g, 0.32 mol) and LiBH4 (40 g, 1.82 mol) were added to anhydrous THF (300 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 12 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was cooled to room temperature, quenched with NH4Cl solution (150 mL), diluted with ethyl acetate (100 mL), and then extracted with ethyl acetate (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated to give crude product 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylprop-1-ol (91.3 g, 99%) as a pale yellow solid. The crude product was used directly in the next reaction without purification.

[0357] LCMS (ESI) calculates C 13 H 16 BrNO[M+H]+m / z is 282.18, therefore we get: 282.40

[0358] Step 4: Preparation of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate

[0359] 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylprop-1-ol (91.3 g, 0.31 mol) was added to anhydrous DCM (150 mL) solution at room temperature and under a N2 atmosphere. Then, DIPEA (62.7 g, 0.49 mol), DMAP (4.0 g, 0.03 mol), and AC2O (24.0 g, 0.31 mol) were added to the above solution under a N2 atmosphere. The reaction mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with NaHCO3 solution (100 mL), and the mixture was extracted with DCM (100 mL x 4). The combined organic phases were washed with saturated NaCl (50 mL), dried with Na2SO4, and then concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column chromatography with petroleum ether / ethyl acetate (from 0% to 20%) to give 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate (82.0 g, 79%) as a white solid.

[0360] LCMS (ESI) calculates C 15 H 18 The m / z of BrNO2[M+H]+ is 324.22, so we get: 324.60

[0361] Intermediate B: (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)methyl propionate

[0362] Step 1: Preparation of methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionate

[0363] A solution of activated Zn powder (22 g, 334 mmol) and DMF (100 mL) was added to a 250 mL three-necked round-bottom 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 at room temperature for 10 min, and then a solution of (R)-2-((tert-butyloxycarbonyl)amino)-3-iodopropionate methyl ester (20 g, 60.79 mmol) in DMF (200 mL) was added dropwise over 10 min. The mixture was heated at 35 °C and stirred for 2 h, and then the reaction was cooled to room temperature. The liquid was transferred to another 500 mL three-necked round-bottom flask and purged with N2. A solution of Pd(PPh3)Cl2 (2.1 g, 3.04 mmol) and 2,4-dibromothiazole (17.7 g, 72.95 mmol) in DMF (100 mL) was added dropwise over 10 min. The reaction was stirred for 16 h under a nitrogen atmosphere and at 50 °C, and the reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with brine and extracted with ethyl acetate (2 × 500 mL). The organic layers were combined, washed with saturated NaCl (2 × 500 mL), dried over anhydrous Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography, eluting the silica gel column with ethyl acetate / petroleum ether from 0% to 25%, to give methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionate (10 g, 45.2%) as a yellow solid.

[0364] LCMS (ESI) calculates C 12 H 17 The m / z of BrN₂O₄S[M+H]+ is 365.01, therefore we get 367.3.

[0365] Intermediate C: ((6) 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)carbamate

[0366] Step 1: Preparation of propyl 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indol-3-yl)acetate

[0367] Pd(dppf)Cl₂ (2.2 g, 3.10 mmol) and KOAc (18.4 g, 185.76 mmol) were added to a solution of 3-(5-bromo-1H-indol-3-yl)-2,2-dimethylpropyl acetate (20 g, 61.92 mmol) in 1,4-dioxane (400 mL) and stirred. The reaction was carried out under N₂ atmosphere and at 90 °C for 16 h with stirring, and the reaction was monitored by LCMS. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane. The residue was diluted with H2O, extracted with ethyl acetate (500 mL × 3), and the combined organic phases were washed with saturated NaCl (500 mL). The mixture was then dried with Na2SO4 and concentrated under reduced pressure to obtain a crude product. The crude product was purified from 0% to 27% by silica gel column chromatography with ethyl acetate / petroleum ether to give 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoborheptacyclopentan-2-yl)-1H-indol-3-yl)propyl acetate (18.7 g, 81.4%) as a pale yellow solid.

[0368] LCMS (ESI) calculates C 21 H 30 The value of BNO4[M+H]+m / z is 372.23, therefore we get: 372.5.

[0369] Step 2: Preparation of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionate

[0370] To a stirred solution of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indol-3-yl)propyl acetate (18.7 g, 50.40 mmol), a mixed solution of (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionate (27.5 g, 75.61 mmol) and K3PO4 (26.7 g, 126.01 mmol) in toluene / 1,4-dioxane / H2O (300 mL, V:V:V = 4:1:1) was added, and Pd(dppf)Cl2 (1.6 g, 2.52 mmol) was added at room temperature. The reaction mixture was stirred at 70 °C under N2 for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane and toluene. The residue was diluted with H2O, extracted with ethyl acetate (500 mL × 3), washed with saturated NaCl (500 mL), and the combined organic phases were dried with Na2SO4. The crude product was then concentrated under reduced pressure and purified from 0% to 36% by silica gel column elution with ethyl acetate / petroleum ether to give methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionate (20.7 g, 77.6%) as a pale yellow solid.

[0371] LCMS (ESI) calculates C 27 H 35 The N3O6S[M+H]+m / z value is 530.22, therefore: 530.6

[0372] Step 3: Preparation of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionate

[0373] Under ice-water bath conditions, a THF solution of (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionate (12.3 g, 23.25 mmol) and NaHCO3 (2.3 g, 27.90 mmol) in 150 mL of THF was added dropwise to a reaction mixture. The reaction mixture was stirred at -20 °C for 1 h, and the reaction was monitored by LC-MS. After completion, the reaction was quenched with saturated Na2S2O3 (200 mL), extracted with ethyl acetate (500 mL x 2), washed with saturated NaCl (500 mL), and the combined organic phases were dried with Na2SO4. The crude product was then concentrated under reduced pressure and purified from 0% to 40% by silica gel column elution with ethyl acetate / petroleum ether to give methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)-2-((tert-butoxycarbonyl)amino)propionate (12.0 g, 78.8%) as a pale yellow solid.

[0374] LCMS (ESI) calculates C 27 H 34 The value of IN3O6S[M+H]+m / z is 656.12, therefore we get: 656.5

[0375] Step 4: Preparation of (S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)propionic acid

[0376] LiOH·H2O (4.6 g, 190.84 mmol) was added to a mixed solution of (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazo-2-yl)-2-((tert-butoxycarbonyl)amino)propionate (25 g, 38.17 mmol) in THF (500 mL) and H2O (100 mL) at 0–10 °C. The resulting mixture was stirred at 0–10 °C for 16 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was acidified to pH 3–4 with 2N HCl. The mixture was extracted with ethyl acetate (300 mL x 2), the combined organic phases were washed with saturated NaCl (500 mL), dried with Na2SO4 and concentrated to give (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)propionic acid (22.8 g, 100%) as a pale yellow solid.

[0377] LCMS (ESI) calculates C 24 H 30 The value of IN3O5S[M+H]+m / z is 599.10, resulting in 600.6.

[0378] Step 5: Preparation of methyl (S)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid

[0379] HATU (19.0 g, 49.92 mmol) and DIEA (26.7 mL, 153.60 mmol) were added to a DMF (300 mL) solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl-2-yl)propionic acid (23.0 g, 38.40 mmol) at 0–10 °C. The resulting mixture was stirred at 0–10 °C for 10 min. Then, methyl (S)-hexahydropyridazine-3-carboxylate (11.5 g, 40.08 mmol) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 20 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with brine and extracted with ethyl acetate (2 × 400 mL). The combined organic phases were washed with saturated NaCl (500 mL), dried over Na2SO4, and then concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel column elution with EtOAc / PE from 0% to 57% to give (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (17.8 g, 63.9%) as a pale yellow solid.

[0380] LCMS (ESI) calculates C 30 H 40 The value of IN5O6S[M+H]+m / z is 726.17, therefore we get: 727.4.

[0381] Step 6: Preparation of (S)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid

[0382] LiOH·H₂O (708 mg, 29.44 mmol) was added to a solution of (S)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (17.8 g, 24.53 mmol) in THF (400 mL) and H₂O (100 mL). The resulting mixture was stirred at 0–10 °C for 3 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH 3–4 with 2N HCl. The mixture was extracted with ethyl acetate (300 mL x 2), the combined organic phases were washed with saturated NaCl (500 mL), dried with Na2SO4 and concentrated to give (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid (17.5 g, 100%) as a pale yellow solid.

[0383] LCMS (ESI) calculates C 29 H 38 The value of IN5O6S[M+H]+m / z is 712.16, therefore we get: 713.0

[0384] Step 7: (6) 3 S,4S,Z)-1 2 -Iodo-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)tert-butyl carbamate

[0385] Under ice-water bath conditions, EDCI (61.2 g, 318.99 mmol) was added in portions to anhydrous DCM (1000 mL) containing (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-1H-indol-5-yl)thiazolyl)propionyl)hexahydropyridazine-3-carboxylic acid (8.1 g, 11.39 mmol), HOBt (7.7 g, 56.96 mmol), and DIEA (59.4 mL, 341.77 mmol). The reaction was gradually brought to room temperature and stirred for 20 h, with the reaction monitored by LC-MS. After completion, the reaction was washed with H2O (700 mL x 3) and NH4Cl (aqueous solution) (700 mL x 3), then dried with Na2SO4, and subsequently concentrated under reduced pressure to obtain a crude product. This crude product was purified from 0% to 63% by silica gel column elution with EtOAc / PE to give tert-butyl(((6)) 3 S,4S,Z)-1 2 -Iodo-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl) tert-butyl carbamate (6.26 g, 79.3%) is a pale yellow solid.

[0386] LCMS (ESI) calculates C 29 H 36 The value of IN5O5S[M+H]+m / z is 694.15, thus yielding 694.9.

[0387] Step 8: (6) 3 (S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Preparation of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)tert-butyl carbamate

[0388] Under N2 atmosphere and 0℃ conditions, tert-butyl((6)3 S, 4S, Z)-1 2 -Iodo-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 B2Pin2 (830 mg, 6.49 mmol) was added to a toluene solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-doldol-6(1,3)-pyridazinecyclodecaalkyl-4-yl)carbamate (600 mg, 0.87 mmol), Pd2(dba)3 (80 mg, 0.087 mmol), SPhos (89 mg, 0.22 mmol), and AcOK (255 mg, 2.60 mmol). The reaction mixture was stirred at 60 °C under N2 for 3 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluting with EtOAc / PE from 0% to 60%) to give crude tert-butyl((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxoborheptan-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecaalkyl-4-yl) tert-butyl carbamate (618 mg) is a brown solid.

[0389] LCMS (ESI) calculates C 35 H 48 BN5O7S[M+H] + The m / z value is 693.34, therefore we get 695.0.

[0390] Intermediate D: (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine

[0391] Step 1: Preparation of (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol

[0392] FA (13.81 g, 299.96 mmol) was added to a stirred TEA solution (151.76 g, 1.50 mol) at 0 °C. Then, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine(chloro)(p-cyanobenzene)ruthenium(II) (800 mg, 1.25 mmol) was added to the reaction mixture, and the resulting mixture was stirred at 40 °C under N2 for 0.5 h. 1-(3-bromopyridin-2-yl)ethyl-1-one (25.00 g, 124.98 mmol) was added to the reaction mixture, and the reaction mixture was stirred at 40 °C under N2 for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with ethyl acetate (500 mL), washed with saturated NH4Cl (300 x 3 mL), dried with Na2SO4, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 25%) to give (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol (28.80 g, 95.0%) as a yellow oil.

[0393] LCMS (ESI) calculation of C7H6BrNO[M+H] + With m / z = 200.98, we get: 202.1

[0394] Step 2: Preparation of (S)-3-bromo-2-(1-methoxyethyl)pyridine

[0395] In a stirred solution of (S)-1-(3-bromopyridin-2-yl)ethanol-1-ol (23.80 g, 117.82 mol) in 240 mL of THF, NaH (60% oil solution, 7.07 g, 176.73 mmol) was added in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour. Then, CH3I (33.45 g, 235.64 mmol) was added to the reaction mixture at 0 °C, and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was quenched with H2O (50 mL) at 0 °C and extracted with ethyl acetate (2 x 200 mL). The organic layers were combined and washed with brine, dried with Na2SO4 and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 25%) to give (S)-3-bromo-2-(1-methoxyethyl)pyridine (23.39 g, 91.9%) as a pale yellow oil.

[0396] LCMS (ESI) calculation of C8H 10 BrNO[M+H] + With m / z = 214.99, we get: 216.3

[0397] Step 3: Preparation of (S)-3-bromo-2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecylpentane-2-yl)pyridine

[0398] At room temperature, [Ir(COD)(OMe)]2 (737 mg, 1.11 mmol) and dtbpy (895 mg, 3.33 mmol) were added to a THF (180 mL) stirred solution of (S)-3-bromo-2-(1-methoxyethyl)pyridine (12.00 g, 55.56 mmol) and B2Pin2 (15.53 g, 61.11 mmol). The resulting mixture was stirred at 75 °C under N2 for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 80%) to give crude (S)-3-bromo-2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (20.9 g) as an orange oil.

[0399] LCMS (ESI) calculates C 14 H 21 BBrNO3[M+H] + m / z 341.08, resulting in: 342.4

[0400] Step 4: Preparation of (S)-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0401] To a stirred solution of crude (S)-3-bromo-2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine (16.20 g, 47.51 mmol) in THF (150 mL) and H₂O (150 mL), NH₄OAc (14.60 g, 190.03 mmol) and NaIO₄ (40.60 g, 190.03 mmol) were added at 0 °C, and the resulting mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was extracted with ethyl acetate (2 x 300 mL). The organic layers were combined, washed with brine, dried with Na2SO4 and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether 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.

[0402] LCMS (ESI) calculation of C8H 11 BBrNO3[M+H] + m / z 259.00, resulting in: 260.3

[0403] Step 5: Preparation of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine

[0404] 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), NIS (3.13 g, 13.90 mmol) was added at room temperature, and the resulting mixture was stirred at 75 °C for 20 h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with Na2SO3 solution and concentrated to obtain a residue. The residue was extracted with ethyl acetate (2 x 30 mL). The organic layers were combined and washed with brine, then dried over Na2SO4 and concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting 0% to 20% with ethyl acetate / petroleum ether) to give (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (2.65 g, 67.1%) as a brown solid.

[0405] LCMS (ESI) calculation of C8H9BrINO3[M+H] + m / z 340.89, resulting in: 342.3

[0406] Intermediate E: tert-butyl ((6) 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxa-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptanecycloundecane-4-yl)carbamate

[0407] Intermediate E was prepared using the method described in step C of intermediate C, with appropriate starting materials and modifications. In step 5 of intermediate C, the trifluoroacetate of (S)-hexahydropyridazine-3-carboxylic acid methyl ester was replaced with the trifluoroacetate of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester, and the title compound was prepared by the same steps.

[0408] LCMS (ESI) calculates C 36 H 48 BN5O7S[M+H] + m / z 706.3, resulting in: 707.0

[0409] Intermediate F: trifluoroacetate of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester

[0410] Step 1: Preparation of 3-oxocyclobutane-1-carbonyl chloride

[0411] (COCl)₂ (83.51 g, 657.89 mmol) was added 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), and the resulting mixture was stirred at rt for 3 hours. The reaction mixture was concentrated under reduced pressure to give a crude product. The unpurified crude product was used in the next step.

[0412] LCMS (ESI) calculation of C5H5ClO2[M+H] + m / z 133.00, resulting in: 133.4

[0413] Step 2: Preparation of 3-(2-diazoacetyl)cyclobutane-1-one

[0414] TMSCHN2 (2M in hexane, 285 mL, 570.18 mmol) was added dropwise to a stirred solution of crude 3-oxocyclobutane-1-carbonyl chloride in THF (250 mL) and CH3CN (250 mL). The resulting mixture was stirred at room temperature for 18 hours. After completion, the reaction solution was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluting with EtOAc / PE from 0% to 50%) to give 60.2 g (yield: 99.5%) of 3-(2-diazoacetyl)cyclobutanone-1-one as a yellow oil.

[0415] LCMS (ESI) calculation of C6H6N2O2[M+H] + m / z 139.04, resulting in: 139.4

[0416] Step 3: Preparation of 2-(3-oxocyclobutyl)acetic acid

[0417] A CF3COOAg stirred solution (4.82 g, 21.81 mmol) was added to tetrahydrofuran (300 mL), water (30 mL), and triethylamine (181.91 mL, 1.31 mmol). A 3-(2-diazoacetyl)cyclobutane-1-one solution (60.20 g, 436.23 mmol) was added to tetrahydrofuran (300 mL) and water at 0 °C (30 mL). The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction solution was concentrated under reduced pressure to obtain a residue, which was diluted with water and acidified with hydrochloric acid (2N) to pH 2. The resulting mixture was extracted with EtOAc (5 x 300 mL). The organic layers were combined and dried over Na2SO4, followed by concentration under reduced pressure to give crude 2-(3-oxocyclobutyl)acetic acid (8 g, yield: 99.9%) as a brown oil.

[0418] LCMS (ESI) calculation of C6H8O3[M+H] + m / z 129.13, resulting in: 129.4

[0419] Step 4: Preparation of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one

[0420] 2-(3-oxocyclobutyl)acetic acid (52.0 g, 406.3 mmol), (S)-4-benzylazolidine-2-one (71.9 g, 406.3 mmol), 4-dimethylaminopyridine (5.0 g, 40.6 mmol), and triethylamine (141.2 mL, 1015.6 mmol) were added to a stirred solution in a 1 L DCM container, followed by the addition of 2-chloro-1-methylpyridine ammonium iodide (135.0 g, 528.1 mmol). After the reaction was complete, the reaction solution was diluted with water, extracted with DCM, dried over Na2SO4, washed with water, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (EA / PE elution 0%–20%) to give a yellow oily (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidine-2-one (68 g, yield: 58.3%).

[0421] LCMS (ESI) calculates C 16 H 17 NO4[M+H] + m / z 288.1, resulting in: 288.5

[0422] Step 5: Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one

[0423] At 0 °C, AcOH (17.9 mL, 313.6 mmol) and NaBH4 (6.5 g, 172.5 mmol) were added in portions to a stirred solution of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (45.0 g, 156.8 mmol) dissolved in THF (500 mL). The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction solution was diluted with H2O and then concentrated under reduced pressure to remove THF. The residue was extracted with EtOAc, the combined organic phase was dried over Na2SO4, and then concentrated under reduced pressure to give a pale yellow oil (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (45 g, yield: 99.3%).

[0424] LCMS (ESI) calculates C 16 H 19 NO4[M+H] + m / z 290.1, resulting in: 290.5

[0425] Step 6: Preparation of (S)-3-(2-(4-benzyl-2-oxazolidine-3-yl)-2-oxoethyl)cyclobutyl-4-methylbenzenesulfonate

[0426] At 0 °C, 4-dimethylaminopyridine (16.2 g, 132.9 mmol) and toluenesulfonyl chloride (34.8 g, 182.7 mmol) were added 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) dissolved in DCM (500 mL). The reaction mixture was stirred for 14 hours. After completion, the reaction solution was diluted and extracted with DCM and water. The combined organic phase was flushed with water and dried over Na2SO4. The mixture was then concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluting with EA / PE from 0% to 30%) to give (S)-3-(2-(4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, yield: 84.3%), which was a yellow oil.

[0427] LCMS (ESI) calculates C 23 H 25 NO6S[M+H] + m / z 444.1, resulting in: 444.6

[0428] Step 7: Preparation of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one

[0429] Lithium bromide (24.3 g, 279.6 mmol) was added to a stirred solution of (S)-3-(2-(4-benzyl-2-oxooxazolidine-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, 139.8 mmol) in N-methyl-2-pyrrolidone (650 mL). The resulting mixture was stirred at 65 °C for 13 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with water, extracted with EtOAc, the bound organic phase was washed with NaCl, dried over Na2SO4, concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (EA / PE elution 0%–20%) to give a pale yellow oil (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidine-2-one (42 g, yield: 85.3%).

[0430] LCMS (ESI) calculates C 16 H 18 BrNO3[M+H] + m / z 352.0, resulting in: 352.5

[0431] Step 8: Preparation of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid

[0432] LDA (2M in THF, 111.0 mmol) was added dropwise over 15 minutes to a stirred solution of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (30.0 g, 85.5 mmol) dissolved in THF (300 mL). The reaction mixture was stirred at -78 °C for 30 minutes, and then a solution of di-tert-butyl azodicarboxylate (23.6 g, 102.6 mmol) in DCM (50 mL) was rapidly added. The reaction mixture was stirred at -78 °C for 30 minutes, and then 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (310 mL, 2565.0 mmol) was added dropwise at -78 °C. The reaction mixture was stirred at room temperature for 14 hours. After the reaction was complete, the reaction solution was quenched with water (200 mL), and then LiOH·H2O (10.8 g, 256.5 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was diluted with brine (200 mL), washed twice with tert-butyl methyl ether, and the aqueous phase was acidified with 2N HCl to pH 3-4. The resulting mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid, which was used directly in the next step.

[0433] LCMS (ESI) calculates C 16 H 26 N₂O₆[M+H] + m / z 343.39, resulting in: 343.5

[0434] Step 9: Preparation of 2,3-di-tert-butyl-4-methyl(S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylate

[0435] At room temperature, K₂CO₃ (27.3 g, 197.4 mmol) and iodomethane (10 mL, 157.8 mmol) were added to a stirred solution of DMF (300 mL) containing the crude product (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]n-alkane-4-carboxylic acid (27.0 g, 78.9 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the crude product was concentrated under reduced pressure and purified by silica gel column chromatography (EA / PE elution 0%–23%) to give a pale yellow oily product of 2,3-di-tert-butyl-4-methyl(S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylic acid (5.6 g, two-step elution yield: 18.45%).

[0436] LCMS (ESI) calculates C 17 H 28 N2O6[MH] - m / z 357.2, resulting in: 357.6

[0437] Step 10: Preparation of trifluoroacetate of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester

[0438] TFA (40 mL) was added to a stirred solution of DCM (100 mL) containing 7.3 g, 0.18 mmol of 2,3-di-tert-butyl-4-methyl(S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylic acid (2,3-di-tert-butyl-4-methyl(S)-2,3-diazabicyclo[3.1.1]heptane-2-ethylene-2,2,2-trifluoroacetate (7.2 g) as a yellow solid.

[0439] LCMS (ESI) calculates C 15 H 23 BO4[M+H] + m / z 157.09, resulting in: 157.4

[0440] Example 3: Synthesis of intermediate (S)-3-bromo-5-(3-(cyclopentoxy)propynyl)-2-(1-methoxyethyl)pyridine

[0441] Step 1: Synthesis of (propynoxy)cyclopentane

[0442] In a stirred solution of cyclopentanol (200 mg, 2.32 mmol) added to tetrahydrofuran (4 mL), NaH (60% mineral oil, 112 mg, 2.79 mmol) was added at 0–10 °C, and the resulting mixture was stirred at room temperature for 30 min. Then, 3-bromopropyne (331 mg, 2.79 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for another 15 h. The reaction mixture was used directly for the next reaction without purification.

[0443] Step 2: Synthesis of (S)-3-bromo-5-(3-(cyclopentoxy)propynyl)-2-(1-methoxyethyl)pyridine

[0444] Under a nitrogen atmosphere, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (527 mg, 1.55 mmol), cyclopentanepropynyl ether (230 mg, 1.85 mmol), TEA (469 mg, 4.64 mmol), Pd(PPh)3Cl2 (108 mg, 0.15 mmol), and CuI (30 mg, 0.15 mmol) were mixed in THF (5 mL) and stirred at 50 °C for 1 hour. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate from 0% to 60%) to give (S)-3-bromo-5-(3-(cyclopentoxy)propynyl)-2-(1-methoxyethyl)pyridine (89 mg, 17.0%) as a yellow oil.

[0445] LCMS (ESI) calculated value: C 16 H 20 BrNO2[M+H]+ m / z 337.1, measured value: 338.5

[0446] Example 4, 62 Intermediate: Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-yneamide

[0447] Step 1: Synthesis of N,N,2,2-Tetramethylbut-3-yneamide

[0448] In THF (6 mL), CDI (357 mg, 2.20 mmol) was added to a stirred solution of 2,2-dimethylbut-3-ynthetic acid (190 mg, 1.69 mmol), and the mixture was stirred at room temperature for 30 min. Then, TEA (686 mg, 6.78 mmol) and dimethylamine hydrochloride (207 mg, 2.54 mmol) were added, and the mixture was stirred at room temperature for another 3 h. After the reaction was complete, the unpurified mixture was used directly for the next reaction.

[0449] Step 2: Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-yneamide

[0450] (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (384 mg, 1.13 mmol), N,N,2,2-tetramethylbut-3-yneamide (188 mg, 1.35 mmol), TEA (228 mg, 2.25 mmol), Pd(PPh)3Cl2 (79 mg, 0.11 mmol), and CuI (22 mg, 0.11 mmol) were stirred in THF (6 mL) at 50 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate from 0% to 60%) to give (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-yneamide (350 mg) as a yellow oil.

[0451] LCMS (ESI) calculated value: C 16 H 21 BrN₂O₂[M+H]+ m / z 352.1, measured value: 353.5

[0452] Example 5 Intermediate: Synthesis of 4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)but-3-yn-2-ol

[0453] Step 1: Synthesis of 4-(propynyl-1-oxy)tetrahydro-2H-pyran

[0454] In a THF (10 mL) solution of tetrahydro-2H-pyran-4-ol (300 mg, 2.94 mmol), 60% NaH (235 mg, 5.88 mmol) was added at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 hours, followed by the addition of 3-bromopropyne (350 mg, 2.94 mmol). The mixture was stirred at room temperature for 8 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. This crude product was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 25%) to give 4-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (214 mg, 52.0%) as a colorless oil.

[0455] Step 2: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-4-yloxy)propyn-1-yl)pyridine

[0456] In 1,4-dioxane (15 mL), TEA (0.71 mL, 5.09 mmol) was added to a stirred solution containing 4-(propynyloxy)tetrahydro-2H-pyran (214 mg, 1.53 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (434 mg, 1.27 mmol), Pd(PPh3)2Cl2 (89 mg, 0.13 mmol), and CuI (48 mg, 0.25 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane. The residue was diluted with H2O and extracted with EtOAc. The combined organic phases were dried with Na2SO4 and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluting from 0% to 40% using EA / PE) to give (S)-3-bromo-2-(1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)propynyl)pyridine (372 mg, 82.8%) as a pale yellow solid.

[0457] LCMS (ESI) calculated value: C 16 H 20 BrNO3[M+H] + m / z 354.1, measured value: 354.4

[0458] Example 6: Synthesis of intermediate 4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)but-3-yn-2-ol

[0459] Step 1: Synthesis of 2-(tetrahydro-2H-pyran-4-yl)but-3-yne-2-ol

[0460] In a stirred solution of 1-(tetrahydro-2H-pyran-4-yl)acetone (500 mg, 3.9 mmol), acetylenyl magnesium bromide (9.5 mL, 0.5 M in THF, 4.7 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate (30 mL), washed with water-saturated brine (20 mL), dried over Na₂SO₄, and finally concentrated under reduced pressure to give crude 2-(tetrahydro-2H-pyran-4-yl)but-3-yn-2-ol (550 mg, crude product), which was an orange oil.

[0461] LCMS (ESI) calculated value: C9H 14 O2[M+H]+m / z 367.6, measured value: 368.1

[0462] Step 2: Synthesis of 4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)but-3-yn-2-ol

[0463] The following were added: 2-(tetrahydro-2H-pyran-4-yl)but-3-yn-2-ol (200 mg, 1.3 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (444 mg, 1.3 mmol), CuI (50 mg, 0.26 mmol), TEA (1 mL), and Pd(PPh) 3 182 mg of 2Cl2 (0.26 mmol) was mixed in 5 mL of THF and stirred overnight at 70 °C under a N2 atmosphere. After the reaction was complete, the reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting with EA / PE from 0% to 33%) to give 4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)but-3-yn-2-ol (477 mg, 92% yield in two steps) as an orange oil.

[0464] LCMS (ESI) calculated value: C 17 H 22 BrNO3[M+H]+ m / z 368.08, measured value: 368.6

[0465] Example 9: Synthesis of intermediate (S)-3-bromo-5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-(1-methoxyethyl)pyridine

[0466] Step 1: Synthesis of 4-(propynyl-1-oxy)tetrahydro-2H-pyran

[0467] Cyclopentylthiol (300 mg, 2.94 mmol) was added to 10 mL of THF solution, followed by K₂CO₃ (811 mg, 5.88 mmol) and 3-bromopropyne (350 mg, 2.94 mmol) at room temperature. The mixture was stirred at room temperature for 8 hours. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 5%) to give 4-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (273 mg, 66.3%) as a colorless oil.

[0468] Step 2: Synthesis of (S)-3-bromo-5-(3-(cyclopentylthio)propynyl)-2-(1-methoxyethyl)pyridine

[0469] TEA (0.66 mL, 4.76 mmol) was added to a stirred solution of cyclopentyl(prop-2-yn-1-yl)thione (200 mg, 1.43 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (406 mg, 1.19 mmol), Pd(PPh3)2Cl2 (84 mg, 0.12 mmol), and CuI (45 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent EA / PE, from 0% to 30%) to give (S)-3-bromo-5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-(1-methoxyethyl)pyridine (390 mg, 92.8%) as a yellow oil.

[0470] LCMS (ESI) calculated value: C 16 H 20 BrNOS[M+H]+m / z 354.0, measured value: 354.4

[0471] Example 10: Synthesis of intermediate (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2,2-dimethyl-1-morpholinobut-3-yn-1-one

[0472] Step 1: Synthesis of 2,2-dimethyl-1-morpholinobut-3-yn-1-one

[0473] In 3 mL of THF, CDI (174 mg, 1.07 mmol) was added to a stirred solution of 2,2-dimethylbut-3-ynetic acid (100 mg, 0.89 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, TEA (226 mg, 2.23 mmol) and morpholine (94 mg, 1.07 mmol) were added, and the mixture was stirred for another 2 hours at room temperature. After the reaction was complete, the unpurified solution was used directly for the next reaction.

[0474] Step 2: Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2,2-dimethyl-1-morpholinobut-3-yn-1-one

[0475] (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (228 mg, 0.67 mmol), N,N,2,2-tetramethylbut-3-yneamide (145 mg, 0.80 mmol), TEA (203 mg, 2.01 mmol), Pd(PPh)3Cl2 (47 mg, 0.067 mmol), and CuI (13 mg, 0.067 mmol) were mixed in THF (3 mL) and stirred at 50 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting with petroleum ether / ethyl acetate from 0% to 50%) to give (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2,2-dimethyl-1-morpholinobut-3-yne-1-one (250 mg, 94.7%) as a yellow solid.

[0476] LCMS (ESI) calculated value: C 16 H 21 BrN₂O₂[M+H]+ m / z 394.1, measured value: 395.5

[0477] Example 63 Intermediate: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridine

[0478] Step 1: Synthesis of 4-(2-methylbut-3-yn-2-yloxy)tetrahydro-2H-pyran

[0479] 3-Chloro-3-methylbut-1-yne (1.00 g, 9.75 mmol) and tetrahydro-2H-pyran-4-ol (4.98 g, 48.75 mmol) were mixed and 50% KOH (0.60 g, 10.73 mmol) was added at 0 °C. The mixture was stirred at 50 °C for 16 h under a nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was complete, the mixture was diluted with H2O (10.00 mL) and extracted with MTBE (10.00 mL × 3). The organic phases were combined, dried over water-saturated Na2SO4, and concentrated under reduced pressure. The residue was purified by FCC (eluting with EtOAc / PE, from 0% to 20%, within 20 min) to give a yellow oily 4-(2-methylbut-3-yne-2-yloxy)tetrahydro-2H-pyran (200 mg, 1.19 mmol, yield: 12.2%).

[0480] LCMS (ESI) calculated value: C 10 H 16 O2[M+H]+m / z 169.1, measured value: 169.3

[0481] Step 2: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridine

[0482] 4-((2-methylbut-3-yn-2-yl)oxy)tetrahydro-2H-pyran (200 mg, 1.19 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (407 mg, 1.19 mmol), CuI (23 mg, 0.12 mmol) and Pd(PPh3)2Cl2 (83 mg, 0.12 mmol) were stirred in TEA (1.00 mL) and THF (5.00 mL) at 50 °C under a nitrogen atmosphere for 16 hours. After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by FCC (eluting with EtOAc / PE, from 0% to 10% over 20 minutes) to give (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridine (270 mg, 0.71 mmol, yield: 59.5%) as a yellow oil.

[0483] LCMS (ESI) calculated value: C 18 H 24 BrNO3[M+H]+ m / z 382.1, measured value: 382.5

[0484] Example 65 Intermediate: Synthesis of (S)-3-bromo-5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-(1-methoxyethyl)pyridine

[0485] Step 1: Synthesis of 3-isopropoxy-3-methylbutyne

[0486] At room temperature, an aqueous solution (3 mL) of KOH (3.00 g, 53.63 mmol) was added to a stirred solution containing 5.00 g (48.75 mmol) and propanol. The mixture was stirred at room temperature for 18 hours. After the reaction was complete, the reaction mixture was diluted with TBME (50 mL) and water (50 mL). The organic layer was separated and concentrated to give a crude product. The crude product was purified by silica gel column chromatography (eluting with PE / EtOAc from 0% to 10%) to give crude 3-isopropoxy-3-methylbutyne (1.83 g, 29.8%) as a brown oil.

[0487] Step 2: Synthesis of (S)-3-bromo-5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-(1-methoxyethyl)pyridine

[0488] (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (1.83 g, 5.37 mmol), crude 3-isopropoxy-3-methylbut-1-yne (1.16 mg, 6.44 mmol), TEA (1.63 g, 16.10 mmol), Pd(PPh)3Cl2 (376 mg, 0.54 mmol), and CuI (102 mg, 0.54 mmol) were stirred in THF (25 mL) at 50 °C for 1 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting with PE / EtOAc from 0% to 15%) to give (S)-3-bromo-5-(3-isopropoxy-3-methylbut-1-yne-1-yl)-2-(1-methoxyethyl)pyridine (70 mg) as a wine-colored solid.

[0489] LCMS (ESI) calculated value: C 16 H 22 BrNO2[M+H]+ m / z 339.1, measured value: 340.5

[0490] Example 66: Synthesis of intermediate 3-bromo-2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridine

[0491] Step 1: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-ol

[0492] A THF solution of acetylenol magnesium bromide (13 mL, 6.5 mmol, 0.5 M) in 10 mL of tetrahydro-2H-pyran-4-carboxaldehyde (500 mg, 4.39 mmol) was added, and the temperature was 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. The reaction solution was quenched with H₂O and extracted with EtOAc. The combined organic phases were washed with water and dried over anhydrous Na₂SO₄. The mixture was then concentrated under reduced pressure to give crude 1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-ol (600 mg, 98%) as a pale yellow oil.

[0493] 1 H NMR (400MHz, CDCl3) δ4.18-4.16(m,1H),4.04-4.09(m,2H),3.42-3.34(m,2H),2.49-2.48(m,1H),1.85-1.71(m,3H),1.57-1.44(m,2H).

[0494] Step 2: Synthesis of 3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-ol

[0495] In 10 mL of THF, (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (500 mg, 1.46 mmol), CuI (28 mg, 0.146 mmol), TEA (442 mg, 4.38 mmol) and Pd(PPh3)2Cl2 (103 mg, 0.146 mmol) were added to a stirred solution of (1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-ol (287 mg, 2.05 mmol). The mixture was stirred at 70°C for 5 hours under a nitrogen atmosphere, and the reaction progress was monitored by LCMS. After the reaction was completed, 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 30%, within 20 minutes) to give 3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-ol (950 mg, yield: 90%) as a yellow oil.

[0496] LCMS (ESI) calculated value: C 16 H 20 BrNO3[M+H]+ m / z 353.1, measured value: 354.4

[0497] Step 3: Synthesis of 3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-yl methanesulfonate

[0498] In 30 mL of dichloromethane, triethylamine (457 mg, 4.52 mmol) and methanesulfonyl chloride (336 mg, 2.94 mmol) were added to a stirred solution of 3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-ol (800 mg, 2.26 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 23%) to give 3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-yl methanesulfonate (970 mg, 99% yield) as a pale yellow oil.

[0499] LCMS (ESI) calculated value: C 17 H 22 BrNO5S[MH]+ m / z 431.0, measured value: 432.5

[0500] Step 4: Synthesis of S-(3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-yl)ethyl thioester

[0501] In 100 mL of DMF, potassium ethyl sulfide (385 mg, 3.37 mmol) was added to a stirred solution of 3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-yl methanesulfonate (970 mg, 2.25 mmol), and the resulting mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The combined organic phases were washed with water and dried with anhydrous sodium sulfate. The crude product was then concentrated under reduced pressure and purified by silica gel column chromatography (eluting with ethyl acetate and petroleum ether from 0% to 12%) to give S-(3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-yl) ethyl sulfide (570 mg, 960%) as a pale yellow oil.

[0502] LCMS (ESI) calculated value: C 18 H 22 BrNO3S[M+H]+m / z 411.1, measured value: 412.4

[0503] Step 5: Synthesis of 3-bromo-2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridine

[0504] In methanol (10 mL), potassium carbonate (131 mg, 0.95 mmol) was added to a stirred solution of S-(3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)prop-2-yn-1-yl)ethane thioester (400 mg, 0.950 mmol). The mixture was stirred at room temperature for 15 minutes. Then, iodomethane (284 mg, 2.00 mmol) was added to the mixture, and the mixture was stirred at room temperature for another 15 minutes. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 25%) to give 3-bromo-2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)prop-1-yn-1-yl)pyridine (360 mg, 98%) as a pale yellow oil.

[0505] LCMS (ESI) calculated value: C 17 H 22 BrNO2S[M+H]+m / z 383.1, measured value: 384.4

[0506] Example 68: Synthesis of intermediate (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridine

[0507] Step 1: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)butyn-1-yl)pyridine

[0508] (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (212 mg, 0.68 mmol), 3-methyl-3-(methanesulfonyl)but-1-yne (100 mg, 0.68 mmol), TEA (189 mg, 1.87 mmol), Pd(PPh)3Cl2 (44 mg, 0.062 mmol), and CuI (12 mg, 0.062 mmol) were mixed in THF (4 mL) and stirred at 50 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting from 0% to 8% with DCM / CH3OH) to give (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yne-1-yl)pyridine (260 mg) as a yellow oil.

[0509] LCMS (ESI) calculated value: C 14 H 18 BrNO3S[M+H]+ m / z 359.0, measured value: 360.4

[0510] Example 69 Intermediate: Synthesis of (tert-butyl(S)-4-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0511] Step 1: Preparation of tert-butyl-4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate

[0512] NaH (80 mg, 2 mmol) was added to a THF (5 mL) solution of tert-butyl-4-hydroxypiperidine-1-carboxylate (200 mg, 1 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. Then 3-bromoprop-1-yne (119 mg, 1 mmol) was added. The mixture was stirred at 0 °C for another 2 h. After completion, the mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL * 3). The bound organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by FCC with EtOAc / PE = 0-30% to give tert-butyl-4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (130 mg, yield: 54%) as a pale yellow oil.

[0513] LCMS (ESI) calculates C 13 H 21 NO3[M+H] + m / z 240.30, resulting in: 240.4

[0514] Step 2: Preparation of tert-butyl(S)-4-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0515] A mixture of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (168 mg, 0.49 mmol), tert-butyl-4-(prop-2-yn-1-yloxy)piperidine-1-carboxylate (130 mg, 0.54 mmol), CuI (19 mg, 0.1 mmol), TEA (202 mg, 2 mmol), and Pd(PPh3)2Cl2 (35 mg, 0.05 mmol) in dioxane (5 mL) was stirred at 45 °C for 4 hours under N2. After completion, the mixture was concentrated, and the residue was purified with FCC of EA / PE = 0-30% to give tert-butyl(S)-4-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (196 mg, yield: 88%) as a yellow oil.

[0516] LCMS (ESI) calculates C 21 H 29 BrN2O4[M+H] + m / z 454.40, resulting in: 454.6

[0517] Example 70 Intermediate: Synthesis of (tert-butyl(S)-4-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0518] Step 1: Synthesis of tert-butyl(S)-3-(propyn-1-oxy)pyrrolidine-1-carboxylic acid ester

[0519] In 10 mL of THF, 60% NaH (85 mg, 2.13 mmol) was added to a stirred solution of tert-butyl(S)-3-hydroxypyrrolidine-1-carboxylic acid ester (200 mg, 1.06 mmol). After stirring at 0°C for 0.5 hours, 3-bromopropyne (126 mg, 1.06 mmol) was added. The mixture was stirred for another 2 hours at room temperature. The reaction was monitored by LCMS. After the reaction was complete, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 20%) to give 4-(prop-2-yn-1-oxy)tetrahydro-2H-pyran (160 mg, 67.1%) as a colorless oil.

[0520] Step 2: Synthesis of tert-butyl(S)-3-((3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)propyn-1-yl)oxy)pyrrolidine-1-carboxylic acid ester

[0521] TEA (0.36 mL, 2.59 mmol) was added to a stirred solution of tert-butyl(S)-3-(prop-2-yn-1-oxy)pyrrolidine-1-carboxylic acid ester (160 mg, 0.71 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (220 mg, 0.65 mmol), Pd(PPh3)2Cl2 (45 mg, 0.07 mmol), and CuI (25 mg, 0.13 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane. The residue was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent EA / PE from 0% to 35%) to give tert-butyl(S)-3-((3-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-oxy)pyrrolidine-1-carboxylic acid ester (160 mg, 82.8%) as a yellow oil.

[0522] LCMS (ESI) calculated value: C 20 H 27 BrN₂O₄[M+H]+ m / z 439.1, measured value: 439.6

[0523] The following intermediates in Table 2 were prepared using the method described in step 1 above, for the preparation of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol, with the use of appropriate starting materials and modifications.

[0524] Table 2. Certain alkynyl-containing intermediates of the present invention

[0525] Synthesis of intermediate G: Synthesis of N-(dimethylcarbamoyl)-N-methyl-L-valine

[0526] Step 1: Preparation of N-(dimethylcarbamoyl)-N-methyl-L-valine benzyl ester

[0527] A mixture of THA (2.286 g, 22.59 mmol) and DMAP (276.02 mg, 2.26 mmol) in THF (5 mL) and dimethylcarbamoyl chloride (1.215 g, 11.3 mmol) was added in portions under a nitrogen atmosphere. The reaction mixture was stirred at 65 °C under a nitrogen atmosphere for 12 hours, then quenched with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography to give N-(dimethylcarbamoyl)-N-methyl-L-valine benzyl ester (400 mg, 58.3% yield) as a colorless oil.

[0528] LCMS (ESI) calculates C 16 H 25 N₂O₃[M+H] + m / z 293.2, resulting in: 293.4

[0529] Step 2: Preparation of N-(dimethylcarbamoyl)-N-methyl-L-valine

[0530] A mixture of N-(dimethylcarbamoyl)-N-methyl-L-valine benzyl ester (400 mg, 1.37 mmol) and palladium hydroxide on carbon (400 mg, 2.85 mmol) in MeOH (10 mL) was stirred for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filter cake was washed with MeOH (100 mL x 3). The filtrate was concentrated under reduced pressure to give N-(dimethylcarbamoyl)-N-methyl-L-valine (200 mg, crude oil) as a colorless oil.

[0531] LCMS (ESI) calculation of C9H 19 N₂O₃[M+H] + m / z 203.1, resulting in: 203.1

[0532] The following compounds in Table 3 were prepared according to the above representative procedure for the synthesis of N-methyl-N-((2R,3R)-3-phenyltetrahydrofuran-2-carbonyl)-L-valine, using appropriate starting materials and modifications.

[0533] Table 3. Certain peptides used in the present invention

[0534] Specific Examples: Synthesis and Preparation

[0535] Example 3

[0536] (1S,2S)-N-((6 3 S,4S,Z)-1 1-Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0537] Step 1: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazaza-undecadecyltetradecene-4-yl)carbamate

[0538] (S)-3-bromo-5-(3-(cyclopentoxy)propynyl)-2-(1-methoxyethyl)pyridine (85 mg, 0.25 mmol), tert-butyl ((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3192 mg, 0.28 mmol) of diaza-2(4,2)-thiazo[1(5,3)]indolo[6(2,4)]bicyclo[3.1.1]heptane-1,1-undecane-4-yl)carbamate (192 mg, 0.28 mmol), K2CO3 (104 mg, 0.76 mmol) and Pd(dppf)Cl2 (19 mg, 0.025 mmol) were stirred in dioxane (4 mL) and water (1 mL) and heated to 85 °C under N2 atmosphere for 21 hours. After the reaction was complete, the reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting from 0% to 60% with PE / EtOAc) to give tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentoxy)propynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecane-4-yl)carbamate (33 mg, yield 16.0%), is a brown solid.

[0539] LCMS (ESI) calculated value: C 45 H 56 N6O7S[M+H]+m / z 824.4, measured value: 826.5

[0540] Step 2: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecanonaphth-4-yl)carbamate

[0541] In 1 ml of DMF, tert-butyl((6) 3 S,4S,Z)-1 2-(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Cesium carbonate (26 mg, 0.08 mmol) and iodoethane (13 mg, 0.08 mmol) were added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (33 mg, 0.040 mmol) and the reaction was carried out at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL × 3) and saturated NaCl (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, purified by silica gel column chromatography (eluting from 0% to 50% with petroleum ether / ethyl acetate) to give tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (28 mg, 82.1%) is a brown solid.

[0542] LCMS (ESI) calculated value: C 47 H 60 N6O7S[M+H]+m / z 852.4, measured value: 854.6

[0543] Step 3: Synthesis (6) 3 (S,4S,Z)-4-amino-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 36 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecanonaphthyl-5,7-dione

[0544] In 1 ml of dichloromethane, tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 In a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (28 mg, 0.033 mmol), 0.3 mL of TFA was added dropwise, and the mixture was stirred at room temperature for 1 hour. After concentration, the reaction mixture yielded (6 3 (S,4S,Z)-4-amino-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione (33 mg) is a brown oily TFA salt.

[0545] LCMS (ESI) calculated value: C 42 H 52 N6O5S[M+H]+m / z 752.4, measured value: 753.9

[0546] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-11 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0547] In 1 mL of ACN, COMU (25 mg, 0.23 mmol) was added to a stirred solution containing TFA salt (33 mg, 0.038 mmol), (1S,2S)-2-methylcyclopropanecarboxylic acid (4 mg, 0.038 mmol), and 2,6-dimethylpyridine (25 mg, 0.057 mmol), and stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 100%, within 30 minutes) to give a white solid (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(cyclopentoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropanecarboxamide (3.5 mg).

[0548] LCMS (ESI) calculated value: C 47 H 58 N6O6S[M+H]+m / z 834.4, measured value: 836.6

[0549] 1H NMR (400MHz, DMSO-d6) δ8.80(d,J=1.9Hz,1H),8.49(d,J=10.7Hz,2H),7.85(d,J=2.0Hz,1H),7.78(s,1H),7.73(d,J=9.3Hz,1H),7.56(d,J=8.8Hz,1 H),5.54(t,J=9.4Hz,1H),5.05(d,J=12.1Hz,1H),4.33(d,J=10.9Hz,2H), 4.32–4.13(m,3H),4.07(dt,J=14.9,10.2Hz,2H),3.55(s,2H),3.29–3.27 (m,1H),3.23(s,2H),3.16–3.05(m,1H),2.93(d,J=14.0Hz,1H),2.73(s,1 H),2.36(d,J=14.2Hz,1H),2.05(d,J=10.4Hz,1H),1.76(s,2H),1.64(dd, J=25.3,8.0Hz,4H),1.47(s,3H),1.33(d,J=6.0Hz,3H),1.21(s,2H),1.04 (s,3H),0.86(dd,J=14.8,7.9Hz,5H),0.51(d,J=5.8Hz,1H),0.31(s,3H).

[0550] Example 4

[0551] (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridinoundecyltetradecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0552] Step 1: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2-(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate

[0553] (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-ynylamine (100 mg, 0.28 mmol), tert-butyl((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1(5,3)]indolo[6(2,4)]bicyclo[3.1.1]undecane-4-yl)carbamate (217 mg, 0.31 mmol), K2CO3 (118 mg, 0.85 mmol) and Pd(dppf)Cl2 (21 mg, 0.028 mmol) were stirred in dioxane (4 mL) and water (1 mL) and heated to 85 °C under nitrogen atmosphere for 5 hours. After the reaction was complete, the reaction mixture was concentrated to give crude product, which was purified by silica gel column chromatography (eluting from 0% to 80% with petroleum ether / ethyl acetate) to give tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecane-4-yl)carbamate (190 mg, 80.8%) is a brown solid.

[0554] LCMS (ESI) calculated value: C 45 H 57 N7O7S[M+H]+m / z 839.4, measured value: 841.6

[0555] Step 2: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate

[0556] In 3 ml of DMF, tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Cesium carbonate (147 mg, 0.45 mmol) and iodoethane (71 mg, 0.45 mmol) were added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridinocycloundecane-4-yl)carbamide (190 mg, 0.23 mmol) and the reaction was carried out at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (30 mL × 3) and saturated NaCl (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, purified by silica gel column chromatography (eluting from 0% to 100% with PE / ethyl acetate) to give tert-butyl((6 3 S,4S,Z)-1 2-(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (184 mg, 92.2%) is a brown solid.

[0557] LCMS (ESI) calculated value: C 47 H 61 N7O7S[M+H]+m / z 867.4, measured value: 869.6

[0558] Step 3: Synthesize 4-(5-((6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-1 2 -(S)-6-((S)-1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-yneamide

[0559] In dichloromethane (2 ml), tert-butyl ((6 3 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1In a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamide (180 mg, 0.21 mmol), TFA (0.6 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After concentration, the reaction mixture yielded 4-(5-((6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-1 2 TFA salt of (217 mg)-6-((S)-1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-yneamide, as a brown solid.

[0560] LCMS (ESI) calculated value: C 42 H 52 N6O5S[M+H]+m / z 767.4, measured value: 769.4

[0561] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0562] In 3 mL of ACN, 4-(5-((6) in the form of TFA salt were added. 3 (S,4S,Z)-4-amino-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 63 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyltetradecane-1 2 (1S,2S)-N-((S)-1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-yneamide (100 mg, 0.11 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (14 mg, 0.14 mmol), and 2,6-dimethylpyridine (73 mg, 0.17 mmol) were stirred in a stirred solution with COMU (73 mg, 0.68 mmol) added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 85% within 30 minutes) to give (1S,2S)-N-((6-yl)-((2S)- ... 3 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyltetradecane-4-yl)-2-methylcyclopropane-1-carboxamide (14 mg) is a white solid.

[0563] LCMS (ESI) calculated value: C 47 H 58 N6O6S[M+H]+m / z 849.4, measured value: 851.7

[0564] 1H NMR (400MHz, DMSO-d6) δ8.77(d,J=2.0Hz,1H),8.49(d,J=9.4Hz,2H),7.84–7.76(m,2H),7.73(d,J=8.7Hz,1H),7.55(d,J=8.7Hz,1H ),5.54(t,J=9.2Hz,1H),5.05(d,J=12.1Hz,1H),4.38–4.10(m,4H),4.04(dd,J=14.7,7.2Hz,1H),3.55(s,2H),3.32(s,2H),3.22(s ,3H),3.18–3.05(m,2H),2.94(d,J=14.5Hz,1H),2.85(s,2H),2.74(s,1H),2.35(d,J=14.5Hz,1H),2.05(d,J=10.5Hz,1H),1.76(s, 2H), 1.48 (s, 6H), 1.33 (d, J = 6.0Hz, 3H), 1.21 (s, 1H), 1.04 (s, 3H), 0.86 (dd, J = 15.1, 8.0Hz, 6H), 0.51 (d, J = 5.3Hz, 1H), 0.32 (s, 3H).

[0565] Example 5

[0566] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -[2-[(S)-1-methoxyethyl]-5-[3-[(tetrahydro-2H-pyran-4-yl)oxy]propyn-1-yl]pyridin-3-yl]-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridinoundecyltetradecene-4-yl)-2-methylcyclopropane-1-carboxamide

[0567] Step 1: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 26 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)carbamate

[0568] In 1,4-dioxane / water (7 mL, volume ratio 6:1), tert-butyl ((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Pd(dppf)Cl2 (41 mg, 0.06 mmol) was added to a stirred solution of H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecane-4-yl)carbamate (412 mg, 0.59 mmol), (S)-3-bromo-2-(1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-4-yloxy)propyn-1-yl)pyridine (200 mg, 0.57 mmol) and K2CO3 (273 mg, 1.98 mmol). The reaction mixture was stirred at 85 °C for 4 hours at room temperature under a N2 atmosphere. After the reaction was complete, the crude product was obtained under reduced pressure and purified by silica gel column chromatography (eluting from 0% to 5% with MeOH / DCM) to give tert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-4-yloxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecane-4-yl)carbamate (205 mg, 43.2%) is a pale yellow solid.

[0569] LCMS (ESI) calculated value: C 44H 48 N8O6S[M+H] + m / z 841.4, measured value: 842.5

[0570] Step 2: Synthesize tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)carbamate

[0571] Add 205 mg (0.244 mmol) of tert-butyl(6) to 5 mL of DMF solution. 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate was added, followed by the addition of 238 mg (0.731 mmol) Cs₂CO₃ and 76 mg (0.488 mmol) EtI at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with 11 mL of DCM / MeOH (v / v 10:1), washed with water (10 mL × 3) and saturated NaCl (10 mL × 2), dried over Na₂SO₄, concentrated under reduced pressure to obtain the crude product, and then purified by silica gel column chromatography (eluting with MeOH / DCM from 0% to 5%) to give 195 mg (92.1%) of tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate is a pale yellow solid.

[0572] LCMS (ESI) calculated value: C 47 H 60 N6O8S[M+H] + m / z 869.4, measured value: 869.8

[0573] Step 3: Synthesis (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-5,7-dione

[0574] In dichloromethane (5 ml), tert-butyl (6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1TFA (1 mL) was slowly added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecylphosphono-4-yl)carbamate (195 mg, 0.22 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product (6... 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecylphosphine-5,7-dione (176 mg, crude) is a pale yellow solid.

[0575] LCMS (ESI) calculated value: C 42 H 53 N6O6S[M+H] + m / z 769.3, measured value: 769.8

[0576] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0577] In ACN / DMF (volume ratio 10:1, total 5.5 mL), (63S,4S,Z)-4-amino-11-ethyl-12-[2-[(S)-1-methoxyethyl]-5-[3-[(tetrahydro-2H-pyran-4-yl)oxy]propyn-1-yl]pyridin-3-yl]-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 The mixture of H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyltetradecene-5,7-dione (170 mg, 0.22 mmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (33 mg, 0.33 mmol) and 2,6-dimethylpyridine (142 mg, 1.33 mmol) was stirred with COMU (142 mg, 0.33 mmol) for 3 hours at room temperature. The reaction mixture was concentrated to give the crude product. The crude product was purified by HPLC (ACN / H2O (containing 0.5% NH4HCO3) from 40% to 95% within 30 minutes) to give (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -[2-[(S)-1-methoxyethyl]-5-[3-[(tetrahydro-2H-pyran-4-yl)oxy]propyn-1-yl]pyridin-3-yl]-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridinoundecyltetradecene-4-yl)-2-methylcyclopropane-1-carboxamide (50 mg, 26.7%) is a white solid.

[0578] LCMS (ESI) calculated value: C 47 H 58 N6O7S[M+H] + m / z 851.4, measured value: 852.6

[0579] 1H NMR (400MHz, DMSO-d6) δ8.83(d,J=2.0Hz,1H),8.51(d,J=9.4Hz,2H),7.88(d,J=2. 0Hz,1H),7.81(s,1H),7.75(d,J=8.6Hz,1H),7.58(d,J=8.7Hz,1H),5.56(t,J=9.1H z,1H),5.08(d,J=12.1Hz,1H),4.48(s,2H),4.39–4.15(m,4H),4.08(dd,J=14.6,7 .2Hz,1H),3.81(dt,J=11.4,4.2Hz,2H),3.72(ddd,J=13.3,8.9,4.0Hz,1H),3.57(s ,2H),3.40–3.34(m,2H),3.30(s,1H),3.25(s,3H),3.14(dd,J=14.9,9.4Hz,1H),2 .96(d,J=14.2Hz,1H),2.75(s,1H),2.38(d,J=14.4Hz,1H),2.08(d,J=10.9Hz,1H), 1.90(d,J=9.2Hz,2H),1.77(d,J=11.9Hz,2H),1.56–1.40(m,4H),1.35(d,J=6.0Hz, 3H), 1.06 (s, 4H), 0.88 (dd, J = 14.2, 7.2Hz, 6H), 0.54 (d, J = 5.4Hz, 1H), 0.33 (s, 3H).

[0580] Example 6

[0581] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0582] Step 1: Synthesize tert-butyl((6) 3S,4S,Z)-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)carbamate

[0583] (1r,2R,3S)-N-((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1(5,3)]indolo[6(2,4)]bicyclo[3.1.1]undecylheptane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (898 mg, 1.3 mmol), 4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)but-3-yn-2-ol (477 mg, 1.3 mmol), K2CO3 (447 mg, 3.2 mmol) and Pd(dppf)Cl2 (190 mg, 0.26 mmol) were stirred at 90 °C for 19 h in dioxane (10 mL) and H2O (2 mL) under N2 atmosphere. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting from 0% to 100% with EA / PE) to give tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecane-4-yl)carbamate (1.1 g, 99%), is a brown oil.

[0584] LCMS (ESI) calculated value: C 46 H 58 N6O8S[M+H]+m / z 855.4, measured value: 856.1

[0585] Step 2: Synthesize tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)carbamate

[0586] In 20 ml of DMF, tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1Cesium carbonate (840 mg, 2.6 mmol) and iodoethane (402 mg, 2.6 mmol) were added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (1.1 g, 1.3 mmol) and the reaction was carried out at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL × 3) and saturated NaCl (100 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to give crude product, purified by silica gel column chromatography (eluting from 0% to 100% with EA / PE) to give tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (1 g, 88%) is a yellow oil.

[0587] LCMS (ESI) calculated value: C 48 H 62 N6O8S[M+H]+m / z 883.4, measured value: 883.9

[0588] Step 3: Synthesis (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridododecane-5,7-dione

[0589] In dichloromethane (3 ml), tert-butyl ((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 In a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecylphosphono-4-yl)carbamate (500 mg, 0.6 mmol), trifluoroacetic acid (1 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with saturated NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and then concentrated under reduced pressure to give the crude product (6... 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecylphosphine-5,7-dione (230 mg, crude) is a yellow solid.

[0590] LCMS (ESI) calculated value: C 47 H 57 N7O5S[M+H]+m / z 783.4, measured value: 783.9

[0591] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0592] In 4 ml of ACN, to (6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -[5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl]-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 COMU (189 mg, 0.4 mmol) was added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione (230 mg, 0.3 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (35 mg, 0.4 mmol), and 2,6-dimethylpyridine (157 mg, 1.5 mmol), and stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 95%, within 30 minutes) to give (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -[5-(3-hydroxy-3-(tetrahydro-2H-pyran-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl]-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (43 mg, 16.9%) is a white solid.

[0593] LCMS (ESI) calculated value: C 48 H 60 N6O7S[M+H]+m / z 865.4, measured value: 865.9

[0594] 1 H NMR (400MHz, DMSO-d6) δ8.74(m,1H),8.50-8.48(m,2H),7.82–7.69(m,2H),7.61-7.54(m,2H),5.53(t,J=9.4Hz,1 H),5.47(s,1H),5.05(d,J=12.3Hz,1H),4.38–3.96(m,5H),3.88(d,J=10.5Hz,2H),3.55(s,3H),3.24-3.12(m,5H ),3.10-3.08(m,2H),2.95(d,J=14.4Hz,1H),2.80–2.58(m,2H),2.37–2.28(m,1H),2.18–1.94(m,2H),1.85–1.60 (m,4H),1.46-1.42(m,8H),1.26-1.20(m,2H),1.04(s,4H),0.96–0.77(m,6H),0.53(t,J=8.2Hz,1H),0.32(s,3H).

[0595] Example 9

[0596] (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodeca-4-yl)-2-methylcyclopropane-1-carboxamide

[0597] Step 1: Preparation of tert-butyl((6) 3 S,4S,Z)-1 2-(5-(3-(cyclopentathio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecaalkyl-4-yl)carbamate

[0598] (S)-3-bromo-5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-(1-methoxyethyl)pyridine (106 mg, 0.37 mmol), tert-butyl ((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 A mixture of H-8-oxa-2(4,2)-thiazo-1(5,3)-indole-6(1,3)-pyridazinecyclodecaalkyl-4-yl)carbamate (307 mg, 0.44 mmol), K2CO3 (127 mg, 0.92 mmol), and Pd(dppf)Cl2 (27 mg, 0.037 mmol) was added to a mixed solution of toluene (4 mL) / dioxane (2 mL) / H2O (2 mL) and stirred at 75 °C under a N2 atmosphere for 22 hours. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting with methanol / dichloromethane from 0% to 100%) to give tert-butyl((6) 3 S,4S,Z)-12-(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinylcyclodecaalkyl-4-yl)carbamate (159 mg, 54.8%) is a brown solid.

[0599] LCMS (ESI) calculates C 45 H 57 N6O6S2[M+H] + m / z 842.1, resulting in: 842.4

[0600] Step 2: Preparation of tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecaalkyl-4-yl)carbamate

[0601] At 0℃, tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-(((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecaalkyl-4-yl)carbamate (240 mg, 0.31 mmol) was added to a stirred solution of Cs₂CO₃ (200 mg, 0.61 mmol) and iodoethane (96 mg, 0.61 mmol) in DMF (3.5 mL). The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (100 mL x 3) and saturated NaCl (100 x 2 mL), dried over Na₂SO₄, and concentrated under reduced pressure to give crude product. The crude product was purified by silica gel column chromatography (eluting with methanol / dichloromethane from 0% to 5%) to give tert-butyl((6) 3 S,4S,Z)-1 2-(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecaalkyl-4-yl)carbamate (190 g, 75.5%) is a brown solid.

[0602] LCMS (ESI) calculates C 47 H 61 N6O6S2[M+H] + m / z 870.2, resulting in: 770.2

[0603] Step 3: Preparation (6 3 (S,4S,Z)-4-amino-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecadecane-5,7-dione

[0604] To the stirred tert-butyl ((6) 3 S,4S,Z)-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1In a solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinylcyclodecaalkyl-4-yl)carbamate (190 mg, 0.23 mmol) in dichloromethane (4 mL), TFA (1 mL) was added dropwise at room temperature, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give the residue. The residue was purified by reversed-phase chromatography (eluting with acetonitrile / water (0.5% NH4HCO3) from 0% to 60%) to give (6 3 (S,4S,Z)-4-amino-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecadecane-5,7-dione (140 mg, 93.6%), yellow solid.

[0605] LCMS (ESI) calculates C 42 H 53 N6O4S2[M+H]+m / z 770.34, yielding: 770.2

[0606] Step 4: Preparation of (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecayl-4-yl)-2-methylcyclopropane-1-carboxamide

[0607] At room temperature, to (6 3 (S,4S,Z)-4-amino-1 2-(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 COMU (126 mg, 0.29 mmol) was added to an acetonitrile solution (8 mL) of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodecadecane-5,7-dione (140 mg, 0.20 mmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (24 mg, 0.24 mmol) and 2,6-dimethylpyridine (106 mg, 0.99 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated to give a crude product. The crude product was purified by HPLC (acetonitrile / water (0.5% NH4HCO3) from 20% to 95% in 30 min) to give (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3-(cyclopentylthio)prop-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecyclodeca-4-yl)-2-methylcyclopropane-1-carboxamide (40 mg).

[0608] LCMS (ESI) calculates C 47 H 59 N6O5S2[M+H] + m / z 852.38, resulting in: 852.4

[0609] 1H NMR (400MHz, CDCl3) δ8.39(d,J=2.0Hz,1H),8.07(d,J=12.6Hz,1H),8.02(d,J=2.0Hz,1H),7.77(d,J=2.3Hz,1H),7.69(dd,J=7.7,2.4Hz, 1H),7.59(s,1H),7.48(d,J=7.7Hz,1H),5.32(d,J=9.7Hz,1H),5.24(q,J=5.4Hz,1H),4.58(q,J=12.5Hz,1H),4.15(q,J=4.4Hz,2H),4.07– 3.99(m,2H),3.67–3.55(m,3H),3.45(s,2H),3.33(s,3H),3.30–3.17(m,2H),3.15(p,J=5.7Hz,1H),3.06(d,J=2.6Hz,2H),1.98–1.89(m,1 H),1.89–1.78(m,7H),1.76–1.67(m,2H),1.67–1.50(m,8H),1.37(t,J=4.4Hz,3H),1.15(s,3H),1.15–1.05(m,4H),0.91(d,J=5.0Hz,3H).

[0610] Example 10

[0611] (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0612] Step 1: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-butyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 16 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate

[0613] (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2,2-dimethyl-1-morpholinobut-3-yn-1-one (250 mg, 0.63 mmol), tert-butyl((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1,3]-indole[6,2]-bicyclo[3.1.1]heptane-1, ... 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1,3]-indol[6,2]-pyridoundecane-4-yl)carbamate (460 mg, 82.9%) is a pale yellow solid.

[0614] LCMS (ESI) calculated value: C 47 H 59 N7O8S[M+H]+m / z 881.4, measured value: 882.8

[0615] Step 2: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate

[0616] Add 460 mg (0.52 mmol) tert-butyl(6) to 5 mL of DMF solution. 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate was added at 0 °C, followed by the addition of Cs₂CO₃ (340 mg, 1.04 mmol) and iodoethane (163 mg, 1.04 mmol). The mixture was stirred at room temperature for 3 hours. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (50 mL × 3) and saturated NaCl (30 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (eluting from 0% to 100% with PE / EtOAc) to give 490 mg (92.2%) of yellow solid tert-butyl((6) 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 63 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate.

[0617] LCMS (ESI) calculated value: C 49 H 63 N7O8S[M+H]+m / z 909.5, measured value: 911.5

[0618] Step 3: Synthesis (6) 3 (S,4S,Z)-4-amino-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-butyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecanonaphthyl-5,7-dione

[0619] In dichloromethane (5 ml), tert-butyl (6 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 In a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (490 mg, 0.51 mmol), TFA (2 mL) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to give a yellow solid (6... 3 (S,4S,Z)-4-amino-1 2-(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 TFA salt of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione (629 mg).

[0620] LCMS (ESI) calculated value: C 42 H 52 N6O5S[M+H]+m / z 809.4, measured value: 811.5

[0621] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0622] In 4 mL of ACN, to a solution containing TFA salt (200 mg, 0.19 mmol) (6 3 (S,4S,Z)-4-amino-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1The mixture of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (23 mg, 0.23 mmol) and 2,6-dimethylpyridine (124 mg, 1.16 mmol) was stirred with COMU (124 mg, 0.29 mmol) for 2 hours at room temperature. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 85% within 30 minutes) to give a white solid (1S,2S)-N-((6 3 S,4S,Z)-1 2 -(5-(3,3-dimethyl-4-morpholin-4-one-but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (31 mg).

[0623] LCMS (ESI) calculated value: C 49 H 61 N7O7S[M+H]+m / z 891.4, measured value: 892.9

[0624] 1H NMR (400MHz, DMSO-d6) δ8.76(d,J=2.0Hz,1H),8.47(d,J=9.4Hz,2H),7.85(d,J=2.0Hz,1H),7.77(s,1H),7.72(d,J=8.6Hz,1H),7 .55(d,J=8.6Hz,1H),5.54(t,J=9.3Hz,1H),5.03(d,J=12.2Hz,1H),4.35–4.10(m,4H),4.05(dd,J=14.4,7.2Hz,1H),3.55(s,5H), 3.50–3.37(m,1H),3.32(s,1H),3.23(s,3H),3.17–2.85(m,4H),2.85–2.66(m,2H),2.37(d,J=14.4Hz,2H),2.05(d,J=10.9Hz,1H ),1.76(s,2H),1.48(s,7H),1.33(d,J=6.1Hz,3H),1.04(s,4H),0.86(dd,J=13.3,6.2Hz,6H),0.51(d,J=5.3Hz,1H),0.31(s,3H).

[0625] Example 39

[0626] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0627] Step 1: Synthesis of tert-butyl(S)-6-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester

[0628] tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester (200 mg, 0.56 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (191 mg, 0.56 mmol), K2CO3 (193 mg, 1.40 mmol), and Pd(dppf)Cl2 (41 mg, 0.06 mmol) were stirred at 50 °C for 3 hours under a nitrogen atmosphere in dioxane (4.00 mL) and water (1.00 mL). After the reaction was complete, the mixture was diluted with water (15.00 mL) and extracted with ethyl acetate (3 × 10.00 mL). The combined organic phases were washed with water (20.00 mL), dried, and concentrated. The residue was purified by FCC (eluting with ethyl acetate / petroleum ether from 0% to 18%, 20 min) to give (S)-6-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (110 mg, 0.25 mmol, yield: 44.2%) as a colorless oil.

[0629] LCMS (ESI) calculated value: C 22 H 27 BrN₂O₃[M+H]+ m / z 447.1, measured value: 447.5

[0630] Step 2: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0631] (6) 4 S,4S,Z)-4-amino-10,10-dimethyl-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3-diaza-2(4,2)-thiazo[1(5,3)]indolo[6(2,4)]bicyclo[3.1.1]heptanododecyl-5,7-dione (650 mg, 1.07 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (123 mg, 1.07 mmol) and NMI (220 mg, 2.68 mmol) in a mixture of ACN (3.00 mL) and DCM (3.00 mL) were added to TCFH (452 ​​mg, 1.61 mmol) at room temperature and stirred under a nitrogen atmosphere for 2 hours. After the reaction was complete, the mixture was concentrated and the residue was purified by FCC (eluting with EtOAc / PE, from 5% to 40%, within 20 min) to give (1S,2S)-N-((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridinoundecyldodecene-4-yl)-2-methylcyclopropane-1-carboxamide (150 mg, 0.22 mmol, yield: 87.7%) is a pale yellow solid.

[0632] LCMS (ESI) calculated value: C 37 H 48 BN5O6S[M+H]+m / z 702.3, measured value: 702.7

[0633] Step 3: Synthesize tert-butyl6-(5-(((6) 4 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamide)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-1-heptadecane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester

[0634] (1r,2R,3S)-N-((6 4S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1(5,3)-indolo[6(2,4)-bicyclo[3.1.1]heptane-undecadodecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (173 mg, 0.25 mmol), tert-butyl(S)-6-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester (110 mg, 0.25 mmol), K2CO3 (85 mg, 0.61 mmol) and Pd(dppf)Cl2 (18 mg, 0.02 mmol) were stirred in dioxane (2.00 mL) and water (0.50 mL) and reacted at 85 °C for 4 h under a nitrogen atmosphere. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was diluted with water (15.00 mL) and extracted with ethyl acetate (3 × 10.00 mL). The combined organic phases were washed with water (20.00 mL), dried, and concentrated. The residue was purified by FCC (eluting with MeOH / DCM, from 0% to 4% within 15 min) to give tert-butyl6-(5-(6-) 4 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamide)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1(5,3)-indolo[6(2,4)-bicyclo[3.1.1]heptane-undecacyclododecane-1 2 3-(S)-1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester (180 mg, 0.07 mmol, yield: 77.6%), is a yellow solid.

[0635] LCMS (ESI) calculated value: C 53 H 63 N7O7S[M+H]+m / z 942.5, measured value: 942.9

[0636] Step 4: Synthesize tert-butyl6-(5-(6) 4 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamide)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-11 H-8-Oza-6 2 6 3 -diazol-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptadecylcycloundecane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester

[0637] tert-butyl 6-(5-((6) 4 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamide)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-1 2 180 mg (0.19 mmol) of tert-butyl 6-(5-(6-)-(1H)-(1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester (180 mg, 0.19 mmol), iodoethane (60 mg, 0.38 mmol), and Cs₂CO₃ (125 mg, 0.38 mmol) were stirred in DMF (3.00 mL) at room temperature under nitrogen atmosphere for 16 h, and the reaction was monitored by LCMS. After the reaction was complete, the mixture was diluted with water (10.00 mL) and extracted with ethyl acetate (3 × 10.00 mL). The combined organic phases were washed with water-saturated brine (2 × 20.00 mL), dried, and concentrated. The residue was purified by preparative HPLC to give tert-butyl 6-(5-(6-)-(1H ... 4 S,4S,Z)-4-((1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxamide)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptadecyl-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid ester (23 mg, 0.02 mmol, yield: 12.4%), is a white solid.

[0638] LCMS (ESI) calculated value: C 55 H 67 N7O7S[M+H]+m / z 970.5, measured value: 970.8

[0639] Step 5: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0640] 13 mg (0.01 mmol) of tert-butyl 4-(4-(5-((6) 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecane-1 2 (1r,2R,3S)-N-((6-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester was reacted with 2M hydrochloric acid in dioxane (1.50 mL) under stirring at room temperature for 3 hours. The mixture was then concentrated to give (1r,2R,3S)-N-((6-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester. 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -Diazo-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptadecylundecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (12 mg, 0.01 mmol, yield: 100%), as a pale yellow solid.

[0641] LCMS (ESI) calculated value: C 50 H59 N7O5S[M+H]+m / z 870.4, measured value: 870.9

[0642] Step 6: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0643] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecacyclo-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (12 mg, 0.01 mmol) was dissolved in DCM (2.00 mL), 37% formaldehyde (5 mg, 0.07 mmol) and acetic acid (2 drops) were added, and the mixture was stirred at room temperature for 2 hours. Then, NaBH3CN (1 mg, 0.01 mmol) was added, and the mixture was stirred at room temperature for another 16 hours. The reaction was monitored by LCMS. After the reaction was complete, the mixture was concentrated, and the residue was purified by preparative HPLC to give (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3-diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undeca-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (5 mg, 0.01 mmol, yield: 41.7%), is a white solid.

[0644] LCMS (ESI) calculated value: C 51 H 61 N7O5S[M+H]+m / z 884.5, measured value: 884.9

[0645] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.48-8.46(m,2H),8.27(s,1H),7.78 (s,1H),7.75-7.72(m,2H),7.55(d,J=8.9Hz,1H),5.54(t,J=8.8Hz,1H),5. 04(d,J=12.3Hz,1H),4.33-4.13(m,5H),4.05(dd,J=15.1,7.7Hz,1H),3.56 (s,2H),3.32(s,1H),3.28(s,1H),3.23(s,3H),3.13(dd,J=14.7,9.5Hz,2H ),2.95(d,J=14.1Hz,2H),2.91-2.84(m,2H),2.76-2.69(m,1H),2.35(d,J =14.3Hz,1H),2.18(m,3H),2.06(d,J=13.1Hz,1H),1.96-1.84(m,3H),1.80 -1.70(m,3H),1.51-1.46(m,3H),1.41(s,3H),1.33(d,J=6.0Hz,3H),1.04( s,3H),0.89(s,3H),0.86(t,J=6.9Hz,3H),0.54-0.50(m,1H),0.33(s,3H).

[0646] Example 46

[0647] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 46 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0648] Step 1: Synthesis of (S)-5-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

[0649] (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (203 mg, 0.59 mmol), 4,5,6,7-tetrahydro-2-methyl-2H-pyrazolo[4,3-c]pyridine dihydrochloride (150 mg, 0.71 mmol), Cs2CO3 (581 mg, 1.79 mmol), Pd2(dba)3 (55 mg, 0.060 mmol), and Xantphos (69 mg, 0.12 mmol) were stirred in dioxane (7 mL) and heated to 110 °C under N2 atmosphere for 22 hours. After the reaction was completed, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting from 0% to 100% with PE / EtOAc) to give (S)-5-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (96 mg, 46.5%) as a yellow solid.

[0650] LCMS (ESI) calculated value: C 15 H 19 BrN4O[M+H]+ m / z 350.1, measured value: 351.5

[0651] Step 2: Synthesize tert-butyltert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]undecyltetradecane-4-yl)carbamate

[0652] (S)-5-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (95 mg, 0.27 mmol), tert-butyl((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1,3]-indolo[6,2]-bicyclo[3.1.1]heptano[1,3]-undecano[6,2]-bicyclo[3.1.1]heptano[1,3]-undecano[6,2]-bicyclo[3.1.1]heptano[1,3]-undecano[6,2]-bicyclo[3.1.1]-undec ...6,2]-bicyclo[3.1.1]-undecano[6,2]-bicyclo[3.1.1]-undecano[6,2]-bicyclo[3.1.1]-undecano[6,2]-bicyclo[3.1.1]-undecano[6,2 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1,3]-indolo[6,2]-pyridoundecane-4-yl)carbamate (200 mg, 88.5%) is a brown solid.

[0653] LCMS (ESI) calculated value: C 44 H 55 N9O6S[M+H]+m / z 838.4, measured value: 839.4

[0654] Step 3: Synthesize tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate

[0655] Add 200 mg (0.24 mmol) of tert-butyl-tert-butyl (6-) to 3 mL of DMF solution. 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate was added at 0 °C, followed by the addition of Cs₂CO₃ (155 mg, 0.48 mmol) and iodoethane (75 mg, 0.48 mmol). The mixture was stirred at room temperature for 4 hours. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (50 mL × 3) and saturated NaCl (50 mL), dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (eluting from 0% to 10% with MeOH / DCM) to give 200 mg (96.2%) of tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6-hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate, is a brown solid.

[0656] LCMS (ESI) calculated value: C 46 H 59 N9O6S[M+H]+m / z 866.4, measured value: 867.7

[0657] Step 4: Synthesis (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -[2-[(S)-1-methoxyethyl]-5-[2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]pyridin-3-yl]-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridododecane-5,7-dione

[0658] In 3 ml of dichloromethane, tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 1 mL of TFA was added dropwise to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (200 mg, 0.23 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated to obtain (6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione (295 mg) is a brown oily substance in its TFA salt form.

[0659] LCMS (ESI) calculated value: C 41 H 51 N9O4S[M+H]+m / z 766.4, measured value: 767.0

[0660] Step 5: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0661] In ACN (5 ml), to (6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1The TFA salt of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione (295 mg, 0.33 mmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (34 mg, 0.33 mmol) and 2,6-dimethylpyridine (215 mg, 0.50 mmol) were mixed with COMU (215 mg, 2.01 mmol) and stirred at room temperature for 3 hours. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 85% in 30 min) to give (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (16.5 mg) is a white solid.

[0662] LCMS (ESI) calculated value: C 46 H 57 N9O5S[M+H]+m / z 848.4, measured value: 849.9

[0663] 1H NMR (400MHz, DMSO-d6) δ8.51–8.36(m,3H),7.76(s,1H),7.69(d,J=8.5Hz,1H),7.52(d,J=8.6Hz,1H),7.44(s,1H),7.23(d,J=2.7H z,1H),5.53(t,J=9.3Hz,1H),5.05(d,J=12.2Hz,1H),4.41–4.05(m,7H),3.83–3.60(m,5H),3.52(s,2H),3.30(d,J=14.7Hz,3H),3 .21–3.06(m,4H),2.87(d,J=14.4Hz,1H),2.73(s,1H),2.64(t,J=5.8Hz,2H),2.32(d,J=14.0Hz,1H),2.05(d,J=10.5Hz,1H),1.76 (s,2H),1.55–1.41(m,2H),1.29(d,J=6.1Hz,3H),1.21(s,1H),1.04(s,4H),0.90–0.77(m,6H),0.51(d,J=5.5Hz,1H),0.26(s,3H).

[0664] Example 48

[0665] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -[2-[(S)-1-methoxyethyl]-5-[5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl]pyridin-3-yl]-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridinoundecyltetradecene-4-yl)-2-methylcyclopropane-1-carboxamide

[0666] Step 1: Synthesis of tert-butyl(S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-6,7-dihydrothiazo[5,4-c]pyridine-5(4H)-carboxylic acid ester

[0667] In a stirred solution of (S)-3-bromo-2-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine (400 mg, 1.17 mmol), tert-butyl-2-bromo-6,7-dihydrothiazo[5,4-c]pyridine-5(4H)-carboxylic acid ester (373 mg, 1.17 mmol), and K₂CO₃ (485 mg, 3.52 mmol), Pd(dppf)Cl₂ (86 mg, 0.12 mmol) was added. The reaction mixture was stirred at 80 °C for 14 hours at room temperature under a nitrogen atmosphere. After the reaction was completed, the crude product was obtained under reduced pressure and purified by silica gel column chromatography (eluting with ethyl acetate / petroleum ether from 0% to 37%) to give tert-butyl(S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-6,7-dihydrothiazo[5,4-c]pyridine-5(4H)-carboxylic acid ester (360 mg, 67.8%), as a pale yellow oil.

[0668] LCMS (ESI) calculated value: C 19 H 24 BrN3O3S[M+H] + m / z 454.1, measured value: 454.5

[0669] Step 2: Synthesis of (S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine

[0670] In dichloromethane (3 mL), TFA (0.5 mL) was slowly added to a stirred solution of (S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-6,7-dihydrothiazo[5,4-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (360 mg, 1.43 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crude (S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (360 mg, crude), which was a yellow oil.

[0671] LCMS (ESI) calculated value: C 19 H 24 BrN3O3S[M+H] + m / z 354.3, measured value: 354.5

[0672] Step 3: Synthesis of (S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine

[0673] In a stirred solution of (S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (270 mg, 0.76 mmol), formaldehyde (247 mg, 37% aqueous solution, 3.05 mmol) and acetic acid (0.2 mL) were added to DCl / MeOH (12 mL, v / v) and the reaction mixture was reacted at room temperature. After stirring the reaction mixture at room temperature for 5 hours, sodium cyanoborohydride (72 mg, 1.14 mmol) was added. The reaction mixture was then stirred at room temperature for another 2 hours. After the reaction was complete, the reaction solution was diluted with water and extracted with dichloromethane. The organic phases were combined, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent EA / PE, from 0% to 55%) to give (S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (260 mg, 93.0%) as a pale yellow oil.

[0674] LCMS (ESI) calculated value: C 15 H 18 BrN3OS[M+H] + m / z 368.0, measured value: 368.5

[0675] Step 4: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecyltetradecene-4-yl)carbamate

[0676] In 1,4-dioxane / water (12 mL, volume ratio 5:1), tert-butyl ((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 65 6 6 -hexahydro-1 1 Pd(dppf)Cl2 (30 mg, 0.04 mmol) was added to a stirred solution of H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridinodecane-4-yl)carbamate (296 mg, 0.43 mmol), (S)-2-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridine (150 mg, 0.41 mmol) and K2CO3 (113 mg, 0.82 mmol). The mixture was stirred at 85 °C for 8 hours at room temperature under a nitrogen atmosphere. After the reaction was complete, the crude product was obtained under reduced pressure and purified by silica gel column chromatography (eluting from 0% to 5% with MeOH / DCM) to give tert-butyl((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecane-4-yl)carbamate (216 mg, 58.9%, yellow solid).

[0677] LCMS (ESI) calculated value: C 44 H 54 N8O6S2[M+H] + m / z 855.4, measured value: 855.8

[0678] Step 5: Synthesize tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate

[0679] In 3 ml of DMF, tert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Cs₂CO₃ (156 mg, 0.76 mmol) and EtI (118 mg, 0.76 mmol) were added to a stirred solution of H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecyltetradecane-4-yl)carbamate (216 mg, 0.25 mmol) at 0 °C. The mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with DCM / MeOH (11 mL, v / v 10:1), washed with water (10 mL × 3) and saturated NaCl (10 mL × 2), dried over Na₂SO₄, concentrated under reduced pressure to give crude product, purified by silica gel column chromatography (eluting with MeOH / DCM from 0% to 5%) to give tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecyltetradecane-4-yl)carbamate (190 mg, 86.2%), is a yellow solid.

[0680] LCMS (ESI) calculated value: C 46 H 58 N8O6S2[M+H] +m / z 883.4, measured value: 883.9

[0681] Step 6: Synthesis (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecyltetradecene-5,7-dione

[0682] In dichloromethane (3 ml), tert-butyl ((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 TFA (0.5 mL) was slowly added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (190 mg, 0.22 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give the crude product (6... 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione (130 mg, crude product) is a pale yellow solid.

[0683] Step 7: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0684] Add (6) to 3.5 mL of ACN / DMF (6:1 v / v) solution. 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -[2-[(S)-1-methoxyethyl]-5-[3-[(tetrahydro-2H-pyran-4-yl)oxy]propyn-1-yl]pyridin-3-yl]-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyltetradecene-5,7-dione (130 mg, 0.17 mmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (25 mg, 0.25 mmol) and 2,6-dimethylpyridine (89 mg, 0.83 mmol) were added, followed by the addition of COMU (106 mg, 0.25 mmol) at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified by HPLC (ACN / H2O (0.5% NH4HCO3) from 40% to 95% within 30 minutes) to give (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-[2-[(S)-1-methoxyethyl]-5-[5-methyl-4,5,6,7-tetrahydrothiazo[5,4-c]pyridin-2-yl]pyridin-3-yl]-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridinoundecyltetradecene-4-yl)-2-methylcyclopropane-1-carboxamide (21 mg, 8.5%) is a white solid.

[0685] LCMS (ESI) calculated value: C 46 H 56 N8O5S2[M+H] + m / z 865.4, measured value: 865.8

[0686] 1 H NMR (400MHz, DMSO-d6) δ9.21(d,J=2.1Hz,1H),8.51(d,J=5.4Hz,2H),8.14(d,J=2.1Hz,1H),7.81(s,1H),7.76(d,J=7.7Hz,1H),7.60(d ,J=8.6Hz,1H),5.57(t,J=9.2Hz,1H),5.07(d,J=12.2Hz,1H),4.41–4.30(m,2H),4.28–4.07(m,3H),3.67(s,2H),3.58(s,2H),3.28(s,3 H),3.14(dd,J=14.6,9.4Hz,1H),3.00(d,J=14.1Hz,1H),2.85(s,2H),2.76(d,J=5.1Hz,3H),2.41(d,J=14.7Hz,4H),2.08(d,J=11.0Hz ,1H),1.78(s,2H),1.50(s,2H),1.39(d,J=6.0Hz,3H),1.23(s,2H),1.07(s,4H),0.93–0.81(m,6H),0.54(d,J=5.4Hz,1H),0.37(s,3H).

[0687] Example 62

[0688] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2-(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0689] Step 1: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0690] (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)-N,N,2,2-tetramethylbut-3-acetylenol (75 mg, 0.21 mmol), (1r,2R,3S)-N-((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1(5,3)-indolo[6(2,4)-bicyclo[3.1.1]heptane-undecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (150 mg, 0.21 mmol), K2CO3 (88 mg, 0.64 mmol) and Pd(dppf)Cl2 (24 mg, 0.032 mmol) were stirred at 85 °C for 5 h under a nitrogen atmosphere in dioxane (2 mL) and water (0.5 mL). After the reaction was complete, the reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting from 0% to 8% with DCM / MeOH) to give (1r,2R,3S)-N-((64 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1(5,3)-indolo[6(2,4)-bicyclo[3.1.1]heptane-undecadecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (128 mg, 72.0%, yellow solid).

[0691] LCMS (ESI) calculated value: C 47 H 57 N7O6S[M+H]+m / z 847.4, measured value: 848.8

[0692] Step 2: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecyltetradecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0693] In 1.5 mL of DMF, (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3-diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecaenocyclo-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (125 mg, 0.15 mmol) was added to a stirred solution of Cs2CO3 (96 mg, 0.30 mmol) and iodoethane (46 mg, 0.30 mmol) and carried out at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with 20 mL of EtOAc, washed with water (20 mL × 3) and saturated NaCl (20 mL), dried over Na2SO4, concentrated under reduced pressure to give crude product, purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 90% in 30 min) to give (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(4-(dimethylamino)-3,3-dimethyl-4-oxobut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -Diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undeca-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (30 mg), is a white solid.

[0694] LCMS (ESI) calculated value: C 49 H 61 N7O6S[M+H]+m / z 875.4, measured value: 876.8

[0695] 1H NMR (400MHz, DMSO-d6) δ8.77(d,J=1.9Hz,1H),8.40(d,J=5.8Hz,2H),7.85(d ,J=1.7Hz,1H),7.81(s,1H),7.73(d,J=8.8Hz,1H),7.56(d,J=8.5Hz,1H),5. 92(d,J=11.1Hz,1H),5.35(s,1H),4.64(d,J=10.6Hz,1H),4.47(d,J=4.7Hz, 1H),4.35–4.20(m,2H),4.04(dd,J=14.7,7.0Hz,1H),3.54(dd,J=20.0,10.7H z,2H),3.24(d,J=21.7Hz,4H),3.12(dd,J=14.7,7.3Hz,1H),2.97–2.78(m,3 H),2.61(d,J=5.8Hz,1H),2.46–2.35(m,2H),2.30(d,J=5.3Hz,1H),2.18–2.0 8(m,1H),1.60–1.51(m,1H),1.48(s,5H),1.34(d,J=6.0Hz,3H),1.18(d,J=2 4.1Hz, 3H), 1.06 (dd, J=10.3, 5.7Hz, 5H), 0.85 (d, J=7.5Hz, 5H), 0.31 (s, 3H).

[0696] Example 63

[0697] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecyltetradecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0698] Step 1: (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2-(2-((S)-1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0699] (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridine (75 mg, 0.20 mmol), (1r,2R,3S)-N-((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 1,3-Dimethylcyclopropane-1-carboxamide (137 mg, 0.20 mmol), K₂CO₃ (81 mg, 0.59 mmol), and Pd(dppf)Cl₂ (21 mg, 0.03 mmol) were stirred in dioxane (4.00 mL) and water (1.00 mL) and reacted at 85 °C for 6 h under a nitrogen atmosphere. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was diluted with water (20.00 mL) and extracted with ethyl acetate (15.00 mL × 3). The organic phases were combined, washed with brine (25.00 mL), dried, passed through Na₂SO₄, and concentrated under reduced pressure. The residue was purified by FCC (eluting with ethyl acetate / petroleum ether, from 0% to 7%, within 15 minutes) to give (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 32-Diaza-2(4,2)-thiazo[1(5,3)-indolo[6(2,4)-bicyclo[3.1.1]heptane-undecadodecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (130 mg, 0.15 mmol, yield: 76.0%), is a yellow solid.

[0700] LCMS (ESI) calculated value: C 49 H 60 N6O7S[M+H]+m / z 877.4, measured value: 877.9

[0701] Step 2: (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0702] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecacyclo-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (130 mg, 0.15 mmol), iodoethane (46 mg, 0.30 mmol), and Cs2CO3 (97 mg, 0.30 mmol) were stirred in DMF (2.00 mL) at room temperature for 3 hours under N2 atmosphere, and the reaction progress was monitored by LCMS. After the reaction was completed, the mixture was diluted with water (15.00 mL) and extracted with ethyl acetate (3 × 10.00 mL). The combined organic phases were washed with brine (2 × 20.00 mL), dried, concentrated, and the residue was purified by preparative HPLC to give isomer 1:(1r,2R,3S)-N-((64 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (40 mg, 0.04 mmol, yield: 29.9%) and isomer 2 (Example 63): (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecyltetradecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (35 mg, 0.04 mmol, yield: 26.1%), all as white solids.

[0703] Isomer 1: LCMS (ESI) calculated value: C 51 H 64 N6O7S[M+H]+m / z 905.5, measured value: 906.4

[0704] Isomer 1: 1H NMR (400MHz, DMSO-d6) δ8.78(d,J=1.9Hz,1H),8.43(t,J=4.4Hz,2H),7.97(d,J=1.9Hz,1H),7.83(s,1H),7.74(dd,J=8.7,0.6Hz,1H),7.55(d,J=8.7Hz, 1H),5.90(d,J=11.2Hz,1H),5.31(t,J=8.4Hz,1H),4.73(d,J=11.2Hz,1H), 4.49(dd,J=10.0,5.1Hz,1H),4.02-3.89(m,3H),3.85-3.73(m,3H),3.56(dd ,J=38.3,10.8Hz,2H),3.39(d,J=10.9Hz,3H),3.25(d,J=14.5Hz,1H),3.16 (d,J=7.0Hz,1H),3.14-3.00(m,4H),2.66(dd,J=11.3,5.0Hz,1H),2.34(dd, J=15.0,9.5Hz,2H),2.19-2.10(m,1H),1.83(d,J=12.7Hz,2H),1.62(t,J=9 .4Hz,1H),1.56-1.41(m,7H),1.30-1.05(m,14H),0.92(s,3H),0.47(s,3H).

[0705] Isomer 2 (Example 63): LCMS (ESI) calculated value: C 51 H 64 N6O7S[M+H]+m / z 905.2, measured value: 905.9

[0706] Isomer 2 (Example 63): 1H NMR (400MHz, DMSO-d6) δ8.77(d,J=2.0Hz,1H),8.45(d,J=8.1Hz,1H),8.42(s,1H ),7.84-7.83(m,2H),7.75(dd,J=8.7,0.9Hz,1H),7.58(d,J=8.7Hz,1H),5.94(d, J=11.1Hz,1H),5.40-5.32(m,1H),4.66(d,J=11.3Hz,1H),4.48(dd,J=9.4,5.1H z,1H),4.34-4.34(m,2H),4.13-3.93(m,3H),3.81-3.72(m,2H),3.55(dd,J=18.4 ,10.8Hz,2H),3.40(d,J=10.7Hz,2H),3.29-3.10(m,5H),2.92(d,J=15.0Hz,1H) ,2.63(dd,J=11.5,5.9Hz,1H),2.46-2.36(m,2H),2.31(dd,J=9.1,3.4Hz,1H),2. 19-2.10(m,1H),1.87-1.78(m,2H),1.60-1.40(m,8H),1.35(d,J=6.1Hz,3H),1.2 5-1.15(m,4H),1.07(dd,J=10.5,5.9Hz,5H),0.88(d,J=9.2Hz,5H),0.32(s,3H).

[0707] Example 64

[0708] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methanesulfonyl)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0709] Step 1: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-11 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methanesulfonyl)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0710] In 2 mL of dichloromethane, (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 To a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (40 mg, 0.045 mmol), m-chloroperbenzoic acid (23 mg, 0.11 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 95%, 30 min) to give (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methanesulfonyl)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (5 mg, 12%) is a white solid.

[0711] LCMS (ESI) calculated value: C 48 H 60 N6O8S2[M+H]+m / z 912.4, measured value: 913.9

[0712] Example 65

[0713] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0714] Step 1: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3 -diazol-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0715] (S)-3-bromo-5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-(1-methoxyethyl)pyridine (70 mg, 0.21 mmol), (1r,2R,3S)-N-((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 63 -diaza-2(4,2)-thiazo[1(5,3)-indolo[6(2,4)-bicyclo[3.1.1]heptane-undecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (145 mg, 0.21 mmol), K2CO3 (86 mg, 0.62 mmol) and Pd(dppf)Cl2 (23 mg, 0.031 mmol) were stirred at 85 °C under a nitrogen atmosphere for 3 hours in dioxane (2 mL) and water (0.5 mL). After the reaction was complete, the reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting from 0% to 60% with PE / EtOAc) to give (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -Diaza-2(4,2)-thiazo[1(5,3)-indolo[6(2,4)-bicyclo[3.1.1]heptane-undecadecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (95 mg, 54.2%), as a light brown foam.

[0716] LCMS (ESI) calculated value: C 47 H 58 N6O6S[M+H]+m / z 834.4, measured value: 836.0

[0717] Step 2: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diazol-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0718] In 2 ml of DMF, (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2-(5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (93 mg, 0.11 mmol) was added to a stirred solution of Cs2CO3 (73 mg, 0.22 mmol) and iodoethane (35 mg, 0.22 mmol) and the reaction was carried out at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS. After the reaction was completed, the reaction mixture was diluted with 20 mL of EtOAc, washed with water (20 mL × 3) and saturated NaCl (20 mL), dried over Na2SO4, concentrated under reduced pressure to give crude product, purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 90%, 30 min) to give (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-isopropoxy-3-methylbut-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -Diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (17 mg), is a white solid.

[0719] LCMS (ESI) calculated value: C 52 H 61 N7O7S[M+H]+m / z 862.5, measured value: 864.0

[0720] 1H NMR (400MHz, DMSO-d6) δ8.75(d,J=2.0Hz,1H),8.45–8.32(m,2H),7.80(d,J=3.6Hz,1H),7.73(d,J=8.6Hz,1H),7.56(d,J=8.6Hz,1H),5.91(d,J=11 .0Hz,1H),5.36(s,1H),4.63(d,J=11.1Hz,1H),4.47(d,J=4.7Hz,1H),4. 27(dt,J=12.1,6.5Hz,2H),4.12–3.97(m,2H),3.54(dd,J=21.3,10.7Hz,2 H),3.23(d,J=21.5Hz,3H),3.12(dd,J=14.8,7.4Hz,1H),2.91(d,J=14.7 Hz,1H),2.61(d,J=5.6Hz,1H),2.46–2.36(m,2H),2.34–2.25(m,1H),2.17 –2.07(m,1H),1.59–1.42(m,5H),1.34(d,J=6.1Hz,2H),1.13(dd,J=11.1, 5.3Hz, 5H), 1.06 (dd, J=10.2, 5.8Hz, 4H), 0.92–0.77 (m, 4H), 0.32 (s, 2H).

[0721] Example 66

[0722] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0723] Step 1: Synthesize tert-butyl((6) 3 S,4S,Z)-1 2-(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)carbamate

[0724] In a stirred solution of 200 mg (0.520 mmol) of 3-bromo-2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridine, tert-butyl ((6-methylthio)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridine was added) 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyl-4-yl)carbamate (360 mg, 0.520 mmol) and K2CO3 (215 mg, 1.56 mmol) were used in a solvent of 1,4-dioxane / water (8 mL / 2 mL). Pd(dppf)Cl2·CH2Cl2 (42 mg, 0.052 mmol) was added at room temperature. The reaction mixture was stirred at 85 °C for 5 hours under a nitrogen atmosphere. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, and the residue was diluted with H2O and extracted with EtOAc (10 mL × 3). The organic phases were combined, washed with 500 mL of water-saturated NaCl, dried over Na2SO4, and then concentrated under reduced pressure to obtain the crude product. The crude product was then subjected to silica gel column chromatography, eluting with EtOAc / PE from 0% to 30%, to give tert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 16 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyl-4-yl)carbamate (450 mg, 66%) is a white solid.

[0725] LCMS (ESI) calculated value: C 46 H 58 N6O7S2[M+H]+m / z 870.4, measured value: 871.8

[0726] Step 2: Synthesize tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)carbamate

[0727] In 3 ml of DMF, tert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1Cs₂CO₃ (225 mg, 0.69 mmol) and iodoethane (122 mg, 0.86 mmol) were added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (300 mg, 0.344 mmol). The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was poured into 20 mL of water. The mixture was filtered, the solid was collected and dried to give tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)carbamate (300 mg, 97%), is a yellow solid.

[0728] LCMS (ESI) calculated value: C 48 H 62 N6O7S2[M+H]+m / z 898.4, measured value: 900.0

[0729] Step 3: Synthesis (6) 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-5,7-dione

[0730] In dichloromethane (9 mL), tert-butyl (6 3 S,4S,Z)-1 1 -Ethyl-12 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 TFA (3 mL) was added dropwise to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecylphosphono-4-yl)carbamate (390 mg, 0.434 mmol), and the mixture was stirred at room temperature for 2 hours. After concentration of the reaction mixture, the residue was dissolved in ethyl acetate (30 mL), washed successively with water-saturated sodium bicarbonate solution (10 mL) and brine, dried and concentrated to give a yellow solid (6... 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecylphosphine-5,7-dione (340 mg, 98%).

[0731] LCMS (ESI) calculated value: C 43 H 54 N6O5S2[M+H]+m / z 798.4, measured value: 799.9

[0732] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 56 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0733] In 10 ml of ACN, (6 3 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 TCFH (163 mg, 0.579 mmol) was added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-5,7-dione (340 mg, 0.386 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (42 mg, 0.42 mmol), and NMI (95 mg, 1.16 mmol), and stirred at room temperature for 1 h. The reaction mixture was concentrated to give a crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 95%, 30 min) to give isomer 1:(1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (80 mg, 23%) is a white solid, and isomer 2 (Example 66): (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-12 -(2-((S)-1-methoxyethyl)-5-(3-(methylthio)-3-(tetrahydro-2H-pyran-4-yl)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (120 mg, 35%) is a white solid.

[0734] Isomer 1: LCMS (ESI) calculated value: C 48 H 60 N6O6S2[M+H]+m / z 880.4, measured value: 882.3

[0735] Isomer 1: 1 H NMR (400MHz, DMSO-d6) δ8.79(d,J=2Hz,1H),8.50-8.49(m,2H),7.98(d,J=2Hz,1H),7.78(s,1H),7.72(d,J=8.8Hz,1H),7.52(d, J=8.4Hz,1H),5.25(t,J=9.2Hz,1H),5.02(d,J=12.4Hz,1H),4.28-4.17(m,2H),3.94-3.79(m,6H),3.65–3.63(m,1H),3.54-3.5 1(m,1H),3.32–3.31(m,1H),3.29-3.26(m,1H),3.16-3.00(m,5H),2.79–2.70(m,1H),2.31-2.28(m,1H),2.20(s,2H),2.11-2.0 8(m,1H),1.86–1.77(m,5H),1.48-1.37(m,5H),1.20(d,J=6.4Hz,3H),1.10-1.05(m,6H),0.91-0.86(m,4H),0.53-0.47(m,4H).

[0736] Isomer 2 (Example 66): LCMS (ESI) calculated value: C 48 H 60 N6O6S2[M+H]+m / z 880.4, measured value: 882.2

[0737] Isomer 2 (Example 66):1 H NMR (400MHz, DMSO-d6) δ8.78(d,J=2Hz,1H),8.48-8.46(m,2H),7.84(d,J=2Hz,1H),7.78(s,1H),7.73(d,J=7.2Hz,1H),7.5 5(d,J=8.8Hz,1H),5.54(t,J=8.8Hz,1H),5.06-5.03(m,1H),4.33-4.02(m,6H),3.88-3.80(m,3H),3.56(s,2H),3.32-3.30 (m,1H),3.28–3.23(m,3H),3.15-3.08(m,1H),2.96-32.93(m,1H),2.77–2.70(m,1H),2.38-2.34(m,1H),2.21(d,J=2Hz,3H ),2.07-2.04(m,1H),1.88–1.75(m,5H),1.47-1.33(m,7H),1.04(s,4H),0.89-0.85(m,7H),0.52-0.51(m,1H),0.33(s,3H).

[0738] Example 67

[0739] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(3-(2-acetamidophenoxy)propynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0740] Step 1: Synthesis of (S)-N-(2-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)propyn-1-yl)oxy)phenyl)acetamide

[0741] (S)-3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)propyn-1-yl p-toluenesulfonic acid (200 mg, 0.47 mmol), N-(2-hydroxyphenyl)acetamide (86 mg, 0.57 mmol), and K₂CO₃ (130 mg, 0.95 mmol) were stirred in ACN (3 mL) and reacted at 50 °C for 17 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was concentrated to obtain a crude product, which was purified by silica gel column chromatography (eluting from 0% to 50% with PE / EtOAc) to give (S)-N-(2-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)propyn-1-yl)oxy)phenyl)acetamide (180 mg, 95.3%) as a yellow oil.

[0742] LCMS (ESI) calculated value: C 19 H 19 BrN₂O₃[M+H]+ m / z 402.1, measured value: 403.5

[0743] Step 2: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(3-(2-acetamidophenoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3 -diazol-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecylane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0744] (S)-N-(2-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)propyn-1-yl)oxy)phenyl)acetamide (87 mg, 0.22 mmol), (1r,2R,3S)-N-((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3-diaza-2(4,2)-thiazo[1(5,3)]indolo[6(2,4)]bicyclo[3.1.1]heptane-undecaeno-4-yl)-2,3-dimethylcyclopropane-1-carboxylic acid (152 mg, 0.22 mmol), K2CO3 (90 mg, 0.65 mmol), and Pd(dppf)Cl2 (24 mg, 0.032 mmol) were stirred in dioxane (2.4 mL) and water (0.6 mL) and heated to 85 °C under a nitrogen atmosphere for 5 hours. After the reaction was complete, the reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (eluting from 0% to 100% with petroleum ether / ethyl acetate) to give (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(3-(2-acetamidophenoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo[1(5,3)]indolo[6(2,4)]bicyclo[3.1.1]heptane-undecacyclo-4-yl)-2,3-dimethylcyclopropane-1-carboxylic acid (148 mg, 75.0%), is a yellow solid.

[0745] LCMS (ESI) calculated value: C 50 H 55 N7O7S[M+H]+m / z 897.4, measured value: 898.9

[0746] Step 3: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(3-(2-acetamidophenoxy)propyn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecyltetradecane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0747] In 1.5 mL of DMF, (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2-(5-(3-(2-acetamidophenoxy)propynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecacyclo-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (145 mg, 0.16 mmol) was added to a stirred solution of Cs2CO3 (105 mg, 0.32 mmol) and iodoethane (50 mg, 0.32 mmol) and carried out at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with 20 mL of EtOAc, washed with water (15 mL × 3) and saturated NaCl (15 mL), dried over Na2SO4, concentrated under reduced pressure to give crude product, purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 85% in 30 min) to give (1r,2R,3S)-N-((6 4 S,4S,Z)-1 2 -(5-(3-(2-acetamidophenoxy)propynyl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-1 1 -Ethyl-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -Diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undeca-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (35 mg), is a white solid.

[0748] LCMS (ESI) calculated value: C 52 H 61 N7O7S[M+H]+m / z 927.4, measured value: 927.7

[0749] 1H NMR(400MHz, DMSO-d6)δ8.78–8.68(m,1H),8.48–8.32(m,2H),7.88–7.66(m,4H),7.66–7.49(m,2H),7.18–6.97(m,3H),6.95–6.80(m,2H), 5.96–5.82(m,1H),5.35(s,1H),5.29(s,1H),4.74–4.61(m,1H),4.47(d,J=4.5Hz,1H),4.37–4.18(m,2H),4.13–3.81(m,3H),3.62–3.47(m ,2H),3.17–3.09(m,2H),3.08–2.88(m,2H),2.63(d,J=5.8Hz,1H),2.31(d,J=8.5Hz,2H),2.13(t,J=9.7Hz,1H),2.01–1.88(m,3H),1.55(d ,J=9.0Hz,2H),1.35(t,J=8.7Hz,3H),1.28–1.08(m,6H),1.11–1.00(m,6H),0.89(d,J=16.4Hz,3H),0.76(s,2H),0.47(s,1H),0.29(s,2H).

[0750] Example 68

[0751] (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3 Synthesis of diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecan-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0752] Step 1: Synthesize tert-butyl((6) 4 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)butyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3-diazol-2(4,2)-thiazol-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]undecylheptane)carbamide

[0753] (S)-3-bromo-2-(1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)butyn-1-yl)pyridine (135 mg, 0.38 mmol), tert-butyl ((6 4 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptadecylheptane-4-yl)carbamate (265 mg, 0.38 mmol), K2CO3 (156 mg, 1.13 mmol) and Pd(dppf)Cl2 (41 mg, 0.056 mmol) were stirred in dioxane (4 mL) and water (1 mL) and heated to 85 °C under N2 atmosphere for 10 hours. After the reaction was complete, the reaction mixture was concentrated to obtain the crude product, which was purified by silica gel column chromatography (eluting from 0% to 10% with DCM / MeOH) to give tert-butyl((6 4 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)butyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 2-diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptadecylheptane-4-yl)carbamate (184 mg, 56.4%), is a pale yellow solid.

[0754] LCMS (ESI) calculated value: C 44 H 54 N6O8S2[M+H]+m / z 858.3, measured value: 859.8

[0755] Step 2: Synthesize tert-butyl((6) 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)butyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-11 H-8-Oza-6 2 6 3 -diazol-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]undecylheptane-4-yl)carbamate

[0756] Add 180 mg (0.21 mmol) of tert-butyl(6) to 3 mL of DMF solution. 4 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3 2-Diazon-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecyl-4-yl)carbamate was added, followed by the addition of 136 mg (0.42 mmol) Cs2CO3 and 65 mg (0.42 mmol) iodoethane at 0 °C. The mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with 20 mL of ethyl acetate, washed with water (30 mL × 3) and saturated NaCl (30 mL), dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product, purified by silica gel column chromatography (eluting from 0% to 100% with DCM / MeOH) to obtain a yellow solid tert-butyl((6) 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3 2-(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undecayl-4-yl)carbamate, 145 mg, yield 77.9%.

[0757] LCMS (ESI) calculated value: C 46 H 58 N6O8S2[M+H]+m / z 886.4, measured value: 887.9

[0758] Step 3: Synthesis (6) 4 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)butyn-1-yl)pyridin-3-yl)-10,10-dimethyl-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecyltetradecylone

[0759] In dichloromethane (2 ml), tert-butyl ((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 In a stirred solution of diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecadecane-4-yl)carbamate (145 mg, 0.16 mmol), TFA (0.5 mL) was added dropwise at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated to obtain (6 4 (S,4S,Z)-4-amino-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-1 1 H-8-Oza-6 2 6 3 TFA salt of 269 mg diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]heptane-undecadecane-5,7-dione, as a yellow solid.

[0760] LCMS (ESI) calculated value: C 41 H 50 N6O6S2[M+H]+m / z 786.3, measured value: 787.8

[0761] Step 4: Synthesize (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)butyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazo-1(5,3)-indolo-6(2,4)-bicyclo[3.1.1]undecylheptane-4-yl)-2,3-dimethylcyclopropane-1-carboxamide

[0762] In 8 mL of ACN, TCFH (69 mg, 0.25 mmol) was added to a stirred solution of TFA salt (269 mg, 0.16 mmol), (1r,2R,3S)-2,3-dimethylcyclopropane-1-carboxylic acid (19 mg, 0.16 mmol), and NMI (67 mg, 0.82 mmol) and stirred at room temperature for 1 hour. The reaction mixture was concentrated to give a crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5% NH4HCO3) from 20% to 85%, within 30 minutes) to give a white solid (1r,2R,3S)-N-((6 4 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-methyl-3-(methanesulfonyl)but-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dione-1 1 H-8-Oza-6 2 6 3 -diaza-2(4,2)-thiazolyl-1(5,3)-indole-6(2,4)-bicyclo[3.1.1]heptane-undeca-4-yl)-2,3-dimethylcyclopropane-1-carboxamide (13.5 mg).

[0763] LCMS (ESI) calculated value: C 47 H 58 N6O7S2[M+H]+m / z 882.4, measured value: 883.8

[0764] 1H NMR (400MHz, DMSO-d6) δ9.95(s,1H),8.83(s,1H),8.43(s,1H),7.95(s,1H),7.85(s,1H),7.75(d,J=8.8Hz,1H),7.57(d,J=8.7Hz, 1H),6.16(d,J=10.9Hz,1H),5.34(s,1H),4.70(d,J=10.8Hz,1H),4.50(d,J=4.5Hz,1H),4.30(dd,J=22.9,6.7Hz,2H),4.03(dd,J=1 4.8,7.6Hz,1H),3.63–3.42(m,3H),3.36(s,1H),3.21(d,J=16.6Hz,4H),2.94(d,J=13.8Hz,1H),2.63(d,J=5.6Hz,1H),2.42(d,J= 7.3Hz,1H),2.38–2.27(m,1H),2.21–2.10(m,1H),1.65(s,4H),1.35(d,J=5.9Hz,2H),1.21(s,1H),0.97–0.77(m,5H),0.32(s,2H).

[0765] Example 69

[0766] (1S,2S)-N-((6 3 S,4S,E)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((1-methylpiperidin-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H,2 3 Synthesis of H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(5,2)-pyrrolidinecycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0767] Step 1: Preparation of tert-butyl-4-((3-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carbamate)-5,7-dioxo-6 1 6 2 6 3 64 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridylcyclododecane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0768] tert-Butyl(S)-4-((3-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (123.5 mg, 0.272 mmol), (1S,2S)-N-((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxoboron-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 A solution of H-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazonyl-4-yl)-2-methylcyclopropane-1-carboxamide (184 mg, 0.272 mmol), K2CO3 (122.7 mg, 0.82 mmol), and Pd(dppf)Cl2 (22 mg, 0.03 mmol) in dioxane (6 mL) and H2O (1.5 mL) was stirred at 85 °C under N2 for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC with MeOH / DCM = 0-7% to give tert-butyl 4-((3-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carbamate)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-1 2 1-(S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylic acid ester (150 mg, yield: 60%) is a yellow solid.

[0769] LCMS (ESI) calculates C 50 H 63 N7O8S[M+H]+m / z 922.4, yields: 922.9

[0770] Step 2: Preparation of tert-butyl-4-((3-(5-((6) 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrazine-cycloundecane-1 2 -yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate

[0771] 4-((3-(5-((6) 3 S,)4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-1 2 150 mg (0.16 mmol) of 1-(s)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidin-1-carboxylate was added to DMF (6 mL) along with Cs₂CO₃ (156.1 mg, 0.48 mmol) and iodoethane (74.9 mg, 0.48 mmol). The resulting mixture was stirred at room temperature for 0.5 h. After completion, the reaction mixture was diluted with EtOAc (20 mL) and H₂O (20 mL). The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by FCC with MeOH / DCM = 0-5% to give tert-butyl 4-((3-(5-(6) 3 S,4S,Z)-1 1-Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carbamate)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridazinecycloundecane-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxo)piperidine-1-carboxylate (110 mg, yield: 72%) is a yellow solid.

[0772] LCMS (ESI) calculates C 52 H 67 N7O8S[M+H]+m / z 950.5, yields: 951.0

[0773] Step 3: Preparation of (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(piperidin-4-yl)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazinecycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0774] tert-butyl-4-((3-(5-((6) 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine-1 2(1S,2S)-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)piperidine-1-carboxylate (110 mg, 0.116 mmol) was added to TFA (1 mL) in DCM (5 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-(S)-1-methoxyethyl)-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridazinecyclododecane-4-yl)-2-methylcyclopropane-1-carboxamide (150 mg), its TFA salt is a yellow solid.

[0775] LCMS (ESI) calculates C 47 H 59 N7O6S[M+H]+m / z 850.4, yields: 850.9

[0776] Step 4: Preparation of (1S,2S)-N-((6 3 S,4S,E)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((1-methylpiperidin-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H,2 3 H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(5,2)-pyrrolidinecycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0777] To (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazonyl-4-yl)-2-methylcyclopropane-1-carboxamide (100 mg, 0.117 mmol) was added to DCM (2 mL) and MeOH (0.5 mL) with CH2O (47 mg, 0.47 mmol, 37% in H2O) and AcOH (0.1 mL). The resulting mixture was stirred at room temperature for 16 h. Then NaBH3CN (11 mg, 0.175 mmol) was added. The reaction mixture was stirred for another 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residues were purified by pre-HPLC to give isomer 1:(1S,2S)-N-((6 3 S,4S,E)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((1-methylpiperidin-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H,2 3 H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(5,2)-pyrrolidinecycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (20 mg) and isomer 2 (Example 69): (1S,2S)-N-((6 3 S,4S,E)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((1-methylpiperidin-4-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H,2 3 H-8-oxa-1(5,3)-indole-6(1,3)-pyridazine-2(5,2)-pyrrolidinecycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (10 mg) are both white solids.

[0778] LCMS (ESI) calculates C 49 H 63 N7O6[M+H]+m / z 864.5, yielding: 864.9

[0779] Isomer 1: 1 H NMR (400MHz, DMSO-d6) δ8.84(d,J=1.8Hz,1H),8.53(t,J=4.3Hz,2H),8.02(d,J=1.9Hz,1H),7.81(s,1H),7.74(d,J=7.5Hz,1H),7.5 4(d,J=8.6Hz,1H),5.55(t,J=9.2Hz,1H),5.05(d,J=12.1Hz,1H),4.45(s,2H),4.22(t,J=12.4Hz,2H),4.02–3.90(m,2H),3.81(dd, J=14.4,7.4Hz,1H),3.67(d,J=10.8Hz,1H),3.58–3.46(m,2H),3.21–3.01(m,5H),2.83–2.54(m,4H),2.32(d,J=14.1Hz,1H),2.17– 1.66(m,11H),1.49(d,J=9.2Hz,4H),1.22(t,J=5.0Hz,4H),1.10(dd,J=15.5,8.3Hz,6H),0.91(d,J=20.5Hz,5H),0.60–0.42(m,4H).

[0780] Isomer 2 (Example 69): 1H NMR (400MHz, DMSO-d6) δ8.80(d,J=1.8Hz,1H),8.49(d,J=8.7Hz,2H),7.85(d,J=2.0Hz,1H),7.80–7.70(m,2H),7.56(d,J=8.6Hz,1H),5.54(t, J=9.1Hz,1H),5.05(d,J=12.1Hz,1H),4.42(s,2H),4.35–4.12(m,4H),4.05(dd,J=14.7,7.3Hz,1H),3.59–3.44(m,3H),3.23(s,3H),3.17–3.06 (m,2H),2.94(d,J=14.3Hz,1H),2.75(d,J=8.4Hz,2H),2.57(dd,J=8.2,6.7Hz,2H),2.37(d,J=14.4Hz,1H),2.13–1.95(m,6H),1.79(d,J=23.1H z,4H),1.46(d,J=8.1Hz,4H),1.33(d,J=6.0Hz,3H),1.22(d,J=9.8Hz,3H),1.04(s,3H),0.90–0.80(m,6H),0.52(d,J=5.5Hz,1H),0.31(s,3H).

[0781] Example 70

[0782] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(((S)-1-methylpyrrolidin-3-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide

[0783] Step 1: Synthesis of tert-butyl(3S)-3-((3-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 62 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-1 2 -6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)pyrrolidine-1-carboxylic acid ester

[0784] In 1,4-dioxane / water (7 mL, volume ratio 6:1), the (1S,2S)-N-((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Pd(dppf)Cl2 (30 mg, 0.04 mmol) was added to a stirred solution of H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridino-undecadodecene-4-yl)-2-methylcyclopropane-1-carboxamide (300 mg, 0.44 mmol), (S)-3-bromo-2-(1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-4-yloxy)propyn-1-yl)pyridine (176 mg, 0.40 mmol) and K2CO3 (139 mg, 1.01 mmol). The reaction mixture was stirred at 85 °C for 8 hours under a nitrogen atmosphere at room temperature. After the reaction was complete, the crude product was obtained under reduced pressure and purified by silica gel column chromatography (eluting with MeOH / DCM from 0% to 5%) to give tert-butyl(3S)-3-((3-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo-1(5,3)-indolo-6(1,3)-pyridoundecyldodecene-1 21-(S)-1-methoxyethyl)pyridin-3-yl)propyn-1-yl)oxy)pyrrolidine-1-carboxylic acid ester (89 mg, 24.5%), is a yellow solid.

[0785] Step 2: Synthesis of tert-butyl(3S)-3-((3-(5-((6) 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecyltetradecene-1 2 -6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)pyrrolidine-1-carboxylic acid ester

[0786] In 3 ml of DMF, tert-butyl(3S)-3-((3-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Cs₂CO₃ (96 mg, 0.29 mmol) and EtI (46 mg, 0.29 mmol) were added to a stirred solution of H-8-oxa-2(4,2)-thiazo-1(5,3)-indol-6(1,3)-pyridocycloundeciphagen-12-yl)-6-((S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)pyrrolidine-1-carboxylic acid ester (89 mg, 0.10 mmol) at 0 °C. The mixture was stirred at room temperature for 3 h. The reaction was monitored by LCMS. After the reaction was complete, the reaction mixture was diluted with DCM / MeOH (11 mL, v / v ratio 10:1), washed with water (10 mL × 3) and saturated NaCl (10 mL × 2), dried over Na₂SO₄, concentrated under reduced pressure to obtain the crude product, and purified by silica gel column chromatography (eluting with MeOH / DCM from 0% to 5%) to give tert-butyl(3S)-3-((3-(5-((6) 3 S,4S,Z)-1 1-Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocyclododecylphosphine-1 2 1-(S)-1-methoxyethyl)pyridin-3-yl)prop-2-yn-1-yl)oxy)pyrrolidine-1-carboxylic acid ester (90 mg, 96.2%), is a pale yellow solid.

[0787] LCMS (ESI) calculated value: C 51 H 65 N7O8S[M+H] + m / z 936.5, measured value: 936.9

[0788] Step 3: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(((S)-pyrrolidine-3-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0789] In dichloromethane (5 mL), tert-butyl(3S)-3-((3-(5-((6) 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocyclododecylphosphine-1 2 TFA (1 mL) was slowly added to a stirred solution of (1S,2S)-N-((6-)-( ... 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(((S)-pyrrolidine-3-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecylphosphine-4-yl)-2-methylcyclopropane-1-carboxamide (80 mg, crude) is a pale yellow solid.

[0790] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(((S)-1-methylpyrrolidin-3-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0791] (1S,2S)-N-((6) were stirred in DCl / MeOH (volume ratio 4:1, 2.5 mL). 3 S,4S,Z)-1 1 -Ethyl-1 2-(2-((S)-1-methoxyethyl)-5-(3-(((S)-pyrrolidine-3-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 In a solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (80 mg, 0.10 mmol), formaldehyde (11 mg, 37% aqueous solution, 0.38 mmol) and acetic acid (0.1 mL) were added, and the reaction was carried out at room temperature. After stirring the reaction mixture at room temperature for 5 hours, sodium cyanoborohydride (9 mg, 0.14 mmol) was added. The reaction mixture was stirred at room temperature for another 2 hours. The reaction mixture was concentrated to give a crude product. The crude product was purified by HPLC (ACN / H2O (0.5% NH4HCO3) from 40% to 95% within 30 minutes) to give (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(((S)-1-methylpyrrolidin-3-yl)oxy)propyn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (17 mg, 20.8%) is a white solid.

[0792] LCMS (ESI) calculated value: C 47 H 59 N7O6S[M+H] + m / z 850.4, measured value: 850.9

[0793] 1H NMR (400MHz, DMSO-d6) δ8.82(d,J=1.9Hz,1H),8.51(d,J=7.3Hz,2H),7.88(d,J =2.0Hz,1H),7.80(s,1H),7.75(d,J=8.7Hz,1H),7.58(d,J=8.7Hz,1H),5.56(t ,J=9.0Hz,1H),5.07(d,J=12.2Hz,1H),4.38(s,2H),4.35–4.26(m,2H),4.24–4 .18(m,2H),4.08(dd,J=14.6,7.1Hz,1H),3.57(s,2H),3.25(s,3H),3.20–3.12( m,1H),2.96(d,J=13.8Hz,1H),2.77(d,J=8.2Hz,2H),2.62(dd,J=10.1,6.1Hz, 1H),2.39(d,J=14.7Hz,1H),2.31(dd,J=14.3,8.0Hz,1H),2.21(s,3H),2.11–2 .00(m,2H),1.84–1.69(m,3H),1.49(s,2H),1.35(d,J=6.0Hz,3H),1.23(s,3H) ,1.06(s,4H),0.88(dd,J=14.2,7.2Hz,7H),0.54(d,J=5.2Hz,1H),0.33(s,3H).

[0794] Example 71

[0795] (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(1-methylpiperidin-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0796] Step 1: Synthesis of tert-butyl-4-(2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylate

[0797] At 0 °C, a solution of tert-butyl-4-acetylpiperidine-1-carboxylic acid ester (1.00 g, 4.40 mmol) in THF (3.00 mL) was added to a mixture of acetylenyl magnesium bromide (0.5 M in THF, 15.80 mL, 7.90 mmol). The mixture was stirred at room temperature for 3 h under a nitrogen atmosphere. The reaction was monitored by LCMS. After the reaction was complete, it was quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (eluting with MeCN / H2O, from 5% to 42%, 20 min) to give a yellow oil of tert-butyl-4-(2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester (800 mg, 3.16 mmol, yield: 72.1%).

[0798] LCMS (ESI) calculated value: C 14 H 23 NO3[M+H]+m / z 254.2, measured value: 254.5

[0799] Step 2: Synthesis of tert-butyl 4-(4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester

[0800] tert-butyl-4-(2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylate (800 mg, 3.16 mmol), (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (1080 mg, 3.16 mmol), CuI (122 mg, 0.63 mmol) and Pd(PPh3)2Cl2 (443 mg, 0.63 mmol) were stirred at 70 °C for 2 hours under nitrogen atmosphere in TEA (2.00 mL) and THF (10.00 mL). After the reaction was complete, the mixture was filtered, the filtrate was concentrated, and the residue was purified by FCC (eluting with EtOAc / PE, from 0% to 27%, 20 min) to give tert-butyl 4-(4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylate (1.20 g, 2.57 mmol, yield: 81.3%) as a yellow oil.

[0801] LCMS (ESI) calculated value: C 22 H 31 BrN₂O₄[M+H]+ m / z 467.2, measured value: 467.6

[0802] Step 3: Synthesis (6) 3 S,4S,Z)-4-amino-10,10-dimethyl-1 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyltetradecone

[0803] 200 mg (0.29 mmol) tert-butyl ((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyl-4-yl)carbamate was stirred in TFA (0.30 mL) and DCM (3.00 mL) and reacted at room temperature for 3 h. The reaction progress was monitored by LCMS. After the reaction was complete, the pH of the mixture was adjusted to 8 with saturated NaHCO3 solution and then extracted with DCM (10 mL × 3). The organic phases were combined, washed with water (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a white solid (6). 3 S,4S,Z)-4-amino-10,10-dimethyl-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyl-5,7-dione (150 mg, 0.25 mmol, yield: 87.7%).

[0804] LCMS (ESI) calculated value: C 30 H 40 BN5O5S[M+H]+m / z 593.3, measured value: 593.7

[0805] Step 4: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecyl-4-yl)-2-methylcyclopropane-1-carboxamide

[0806] (6) 3 S,4S,Z)-4-amino-10,10-dimethyl-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyltetradecene-5,7-dione (150 mg, 0.25 mmol), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (25 mg, 0.25 mmol) and 2,6-dimethylpyridine (105 mg, 1.01 mmol) were mixed in ACN (3 mL), COMU (141 mg, 0.33 mmol) was added at room temperature, and the mixture was stirred for 16 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was concentrated, and the residue was purified by reversed-phase column chromatography (eluting with MeCN / H2O, from 5% to 55%, within 20 minutes) to give (1S,2S)-N-((63S,4S,Z)-10,10-dimethyl-5,7-dioxo-12-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridino-undecadecyl-4-yl)-2-methylcyclopropane-1-carboxamide (150 mg, 0.22 mmol, yield: 87.7%) as a yellow solid.

[0807] LCMS (ESI) calculated value: C 35 H46 BN5O6S[M+H]+m / z 676.3, measured value: 676.7

[0808] Step 5: Synthesize tert-butyl 4-(4-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-1 2 -6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester

[0809] (1S,2S)-N-((6) 3 S,4S,Z)-10,10-dimethyl-5,7-dioxo-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborane-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridinoundecyltetradecene-4-yl)-2-methylcyclopropane-1-carboxamide (150 mg, 0.25 mmol), tert-butyl-4-(4-(5-bromo-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester (104 mg, 0.22 mmol), K₂CO₃ (77 mg, 0.56 mmol), and Pd(dppf)Cl₂ (16 mg, 0.02 mmol) were stirred in dioxane (4.00 mL) and water (1.00 mL) and reacted at 90 °C for 16 h under a nitrogen atmosphere. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was filtered, and the filtrate was purified by reverse-phase column chromatography (eluting with MeCN / H2O, from 5% to 55%, within 25 minutes) to give tert-butyl4-(4-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 62 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazo[1(5,3)]indolo[6(1,3)]pyridoundecyltetradecene-1 2 1-(S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester (70 mg, 0.07 mmol, yield: 33.7%), is a yellow solid.

[0810] LCMS (ESI) calculated value: C 51 H 65 N7O8S[M+H]+m / z 936.5, measured value: 937.1

[0811] Step 6: Synthesize tert-butyl 4-(4-(5-((6) 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocycloundecane-1 2 -6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester

[0812] tert-butyl 4-(4-(5-((6) 3 S,4S,Z)-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocyclododecylphosphine-1 270 mg (0.07 mmol) of tert-butyl(-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester, iodoethane (23 mg, 0.15 mmol), and Cs₂CO₃ (49 mg, 0.15 mmol) were stirred in DMF (1.00 mL) and reacted at room temperature under a nitrogen atmosphere for 16 h. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was diluted with water (10.00 mL) and extracted with ethyl acetate (3 × 10.00 mL). The organic phases were combined, washed with brine (2 × 20.00 mL), dried, concentrated, and the residue was purified by preparative HPLC to give tert-butyl-4-(4-(5-((6-)-)-(6 ... 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridocyclododecylphosphine-1 2 16 mg (16 mg, 0.02 mmol, yield: 22.2%)-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester, as a white solid.

[0813] LCMS (ESI) calculated value: C 53 H 69 N7O8S[M+H]+m / z 964.5, measured value: 965.2

[0814] Step 7: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(piperidin-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0815] tert-butyl 4-(4-(5-((6) 3 S,4S,Z)-1 1 -Ethyl-10,10-dimethyl-4-((1S,2S)-2-methylcyclopropane-1-carboxamide)-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridoundecyltetradecene-1 2 (1S,2S)-6-((S)-1-methoxyethyl)pyridin-3-yl)-2-hydroxybut-3-yn-2-yl)piperidine-1-carboxylic acid ester (16 mg, 0.02 mmol) was reacted with a TFA / DCM mixture (v / v = 1 / 4, 2.50 mL) and stirred at room temperature for 2 hours. After concentration, the reaction yielded (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(piperidin-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridoundecyltetradecene-4-yl)-2-methylcyclopropane-1-carboxamide (14 mg, 0.02 mmol, yield: 100%), is a yellow oil.

[0816] LCMS (ESI) calculated value: C48H61N7O6S[M+H]+m / z 864.4, measured value: 865.1

[0817] Step 8: Synthesize (1S,2S)-N-((6 3 S,4S,Z)-1 1 -Ethyl-1 2-(5-(3-hydroxy-3-(1-methylpiperidin-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyrido[1,2-a]dodecylheptane-4-yl)-2-methylcyclopropane-1-carboxamide

[0818] Add (1S,2S)-N-((6) to methanol (3.00 mL). 3 S, 4S, Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(piperidin-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (14 mg, 0.02 mmol) was added, followed by the addition of 30% formaldehyde (4 mg, 0.05 mmol) and acetic acid (2 drops) at room temperature. The mixture was stirred at room temperature for 16 hours, then NaBH(AcO)3 (17 mg, 0.08 mmol) was added, and stirring continued for 1 hour at room temperature. The reaction progress was monitored by LCMS. After the reaction was complete, the mixture was purified by reversed-phase column chromatography (eluting with methanol / water, from 5% to 40%, completed within 25 minutes) to give (1S,2S)-N-((6 3 S, 4S, Z)-1 1 -Ethyl-1 2 -(5-(3-hydroxy-3-(1-methylpiperidin-4-yl)but-1-yn-1-yl)-2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-11 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indol-6(1,3)-pyridocycloundecane-4-yl)-2-methylcyclopropane-1-carboxamide (8 mg, 0.01 mmol, yield: 57.1%) is a white solid.

[0819] LCMS (ESI) calculated value: C 49 H 63 N7O6S[M+H]+m / z 878.5, measured value: 878.9

[0820] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.48-8.46(m,2H),8.27(s,1H),7.78 (s,1H),7.75-7.72(m,2H),7.55(d,J=8.9Hz,1H),5.54(t,J=8.8Hz,1H),5. 04(d,J=12.3Hz,1H),4.33-4.13(m,5H),4.05(dd,J=15.1,7.7Hz,1H),3.56 (s,2H),3.32(s,1H),3.28(s,1H),3.23(s,3H),3.13(dd,J=14.7,9.5Hz,2H ),2.95(d,J=14.1Hz,2H),2.91-2.84(m,2H),2.76-2.69(m,1H),2.35(d,J =14.3Hz,1H),2.18(m,3H),2.06(d,J=13.1Hz,1H),1.96-1.84(m,3H),1.80 -1.70(m,3H),1.51-1.46(m,3H),1.41(s,3H),1.33(d,J=6.0Hz,3H),1.04( s,3H),0.89(s,3H),0.86(t,J=6.9Hz,3H),0.54-0.50(m,1H),0.33(s,3H).

[0821] Example 72

[0822] (1S,2S)-N-((6 3 S,4S,Z)-11-ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-4-yl)thio)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 56 6 -hexahydro-1 1 Synthesis of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine-4-yl)-2-methylcyclopropane-1-carboxamide

[0823] Step 1: Preparation of S-(tetrahydro-2H-pyran-4-yl)ethylthioester

[0824] Add 4-bromotetrahydro-2H-pyran (1 g, 6 mmol) and KSAc (1.4 g, 12 mmol) to a stirred solution of DMF (12 mL), and stir the resulting mixture at room temperature for 12 hours. Dilute the reactants with NaHCO3 (20 mL) using MTBE (10 mL) and saturated aqueous solution. Extract the mixture with MTBE (10 mL x 3). Wash the bound organic layer with brine (15 mL x 2), dry with anhydrous Na2SO4, and concentrate under reduced pressure to give crude S-(tetrahydro-2H-pyran-4-yl) ethioester (440 mg, 46%) as a yellow oil.

[0825] LCMS (ESI) calculation of C7H 12 O2S[M+H]+m / z 161.2, resulting in: 161.5

[0826] Step 2: Preparation of tetrahydro-2H-pyran-4-thiol

[0827] LiAlH4 (1.1 mL, 2.5 M THF) was added dropwise to a THF solution (5 mL) of S-(tetrahydro-2H-pyran-4-yl)ethane sulfate (440 mg, 2.7 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 hours. The reaction was quenched with saturated aqueous NH4Cl and 1 M HCl. The mixture was extracted with MTBE (10 mL x 3). The bound organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude tetrahydro-2H-pyran-4-thiol (440 mg, yield: 99%) as a yellow oil.

[0828] LCMS (ESI) calculation of C5H 10 Calculating OS[M+H]+m / z 119.2 yields: 119.4

[0829] Step 3: Preparation of 3-bromo-2-((S)-1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine

[0830] A mixture of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (200 mg, 0.59 mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (98 mg, 0.7 mmol), CuI (11.4 mg, 0.06 mmol), TEA (182 mg, 1.8 mmol), and Pd(PPh3)2Cl2 (42 mg, 0.06 mmol) in THF (3 mL) was stirred at 50 °C for 4 hours under N2. After completion, the mixture was filtered and the filtrate was concentrated. The residue was purified with FCC of EtOAc / PE = 0-20% to give 3-bromo-2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (208 mg, yield: 99%) as a yellow oil.

[0831] LCMS (ESI) calculates C 16 H 20 BrNO3[M+H]+m / z 354.1, resulting in: 354.5.

[0832] Step 4: Preparation of tert-butyl((6) 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine-4-yl)carbamate

[0833] 3-bromo-2-((S)-1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (208 mg, 0.58 mmol), tert-butyl ((6 3 S,4S,Z)-10,10-dimethyl-5,7-dioxa-1 2 -(4,4,5,5-Tetramethyl-1,3,2-dioxoboronic acid ester-2-yl)-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1A mixture of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine-1,4-undecane-4-yl)carbamate (400 mg, 0.58 mmol), K2CO3 (234.6 mg, 1.7 mmol), and Pd(dppf)Cl2 (44 mg, 0.06 mmol) in dioxane (10 mL) and H2O (2 mL) was stirred at 85 °C for 16 hours under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by FCC with EtOAc / PE = 0-70% to give tert-butyl((6) 3 S,4S,Z)-1 2 -(2-(S)-1-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazine cycloundecane-4-yl)carbamate (300 mg, yield: 62%) is a yellow solid.

[0834] LCMS (ESI) calculates C 45 H 56 N6O8S[M+H]+m / z 841.4, yields: 841.8

[0835] Step 5: Preparation of tert-butyl((6) 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridineazine-1 / 2-cycloundecane-4-yl)carbamate

[0836] 6 3 S,4S,Z)-1 2-(2-((S)-1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 6 2 6 3 6 4 6 5 6 6 -hexahydro-1 1 Cs₂CO₃ (348.6 mg, 1.07 mmol) and iodoethane (166.9 mg, 1.07 mmol) were added to a stirred solution of H-8-oxa-2(4,2)-thiazolyl-1(5,3)-indole-6(1,3)-pyridazol-6(1,3)-pyridazolcyclododecane-4-yl)carbamate (300 mg, 0.35 mmol). The resulting mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with EtOAc (5 mL) and H₂O (10 mL). The mixture was extracted with EtOAc (5 mL * 3). The bound organic layer was washed with brine (10 mL * 2), dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified with FCC of EtOAc / PE = 0-100% to give tert-butyl((6 3 S,4S,Z)-1 1 -Ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(3-(tetrahydro-2H-pyran-2-yl)oxy)...

Claims

1. A compound of formula (I), its isotopic derivatives, its stereoisomers, its pharmaceutically acceptable salts, its metabolites, its prodrugs, its solvates, or solvates of its pharmaceutically acceptable salts, in, Indicates a double bond or a single bond; n is 0, 1, 2, or 3; A is selected from optionally substituted 5-6 membered heterocyclic alkylene, optionally substituted 5-6 membered arylene, optionally substituted 5-6 membered heterocyclic arylene; Cycle B is selected from optionally substituted 3-6 membered heterocyclic alkylene groups, 5-6 membered heterocyclic alkenylene groups, and optionally substituted 4-11 membered heterocyclic alkylene groups (including bridged rings, spiro rings, and fused rings); The ring C is selected from 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 5-10 membered aryl, and 5-10 membered heteroaryl; G is selected from C, which can be substituted arbitrarily. 1-6 Alkylene; X 1 It is N or C; X 2 Is it N or -CR a -; X 3 Is it N or -CR b -; X 4 Is it N or -CR c -; X 5 It is N or C; X 6 It is S, O, N, or C; R B Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl; or, if n is greater than 1, R B Any two atoms bonded to them can combine to form a 3-6 membered ring, wherein the ring may optionally be made of halogen, hydroxyl, or C. 1-3 Alkyl substitution; R a R b and R c Each can be independently represented by hydrogen, halogen, cyano, or C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl groups; R M and R Z Each is independently selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Heteroalkyl, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl; furthermore, the C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1- 6-Hydroalkyl, C 1-6 Hydroxyalkyl groups may be further optionally substituted; R 1 Selected from hydrogen, halogen, cyano, hydroxyl, optionally substituted or R p Replacement C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 Hydroxyalkyl, C 1-6 Aminoalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Heterocyclic alkyl, optionally substituted 4-6-membered heterocyclic alkyl with 4-5-membered heteroaryl, optionally substituted benzo5-7-membered heterocyclic, optionally substituted 5-8-membered aryl, optionally substituted 5-8-membered heteroaryl, optionally substituted 8-10-membered aryl or optionally substituted 8-10-membered heteroaryl; in addition, ynyl, C 1-6 Alkyl, C 1- 6-alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 1-6 The hydroxyalkyl and benzo5-7-membered heterocyclic groups can be further optionally substituted; R p Selected from the following groups: hydrogen, deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-6 Alkoxy, C 1-3 Haloalkoxy groups, optionally substituted 5-7 membered heterocyclic groups, -NR 15 R 16 or -OR 17 -SR 17 -C(O)-NR 15 R 16 C 3-6 Cycloalkyl-substituted C 1-6 Alkoxy, optional substituted C 3-6 Cycloalkyloxy; Or, R1 is Where m is 0, 1, 2 or 3; P does not exist, or is selected from S, O, Se, -NR 8 -、-CR 9 R 10 -、 Q does not exist, or is selected from the arbitrarily substituted C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted 5-10-membered aryl, optionally substituted 5-10-membered heteroaryl, -NR 15 R 16 or -OR 17 ; R 8 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl groups; R 9 R 10 and R 14 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 9 and R 10 A carbonyl group or a 3-6 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3. R 11 R 12 and R 13 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 11 R 12 and R 13 Any two phosphorus atoms in the ring form a phosphorus-oxygen double bond or a 3-6 membered ring through the phosphorus atoms they are connected to. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3. R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl; or R t and R s A carbonyl group or a 3-8 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4. R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, straight-chain or branched C 1-6 Hydroxyalkyl, C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, the ring may contain heteroatoms, the heteroatoms being independently selected from one or more of N, O and S, the number of heteroatoms being independently 0-3; and the ring is optionally substituted. R 17 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 cycloalkyl, optionally substituted C 3-6 Heterocyclic alkyl groups; R 2 Selected from optional replacement C 1-6 Oxyalkyl, substituted C 1-6 Alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(3-8 heterocyclic alkyl), and optionally, the above groups may be substituted with 0, 1, or 2 or fewer substituents: -OR 51 -SR 51 Or -NR 51 R 52 ; R 51 R 52 Each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl; or R 51 and R 52 Together with the N atom it is attached to, a 3-8 membered heterocycle is formed, wherein the 3-8 membered heterocycle optionally contains 0, 1, 2 or 3 heteroatoms selected from N, O or S; furthermore, the C3-C8 cycloalkyl, C3-C8 heterocycloalkyl and 3-8 membered heterocycle may be further optionally substituted or deuterated; R 3 It does not exist, or is selected from hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl; provided that X 6 When it is O or S, R 3 It does not exist; E is selected from N or from -CR d -, where R d Selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, and optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Alkoxy, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl or -NR e R f Among them, R e and R f Selected independently from hydrogen, or optionally substituted with C 1-6 alkyl; R 4 Selected from hydrogen, or optionally substituted C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 cycloalkyl, optionally substituted C 3-10 Cycloalkenyl, optionally substituted 3-12 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted 5-10 aryl, or R 5 Selected from hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl, in addition, C 1-6 Alkyl or C 3-6 Cycloalkyl groups can also be optionally substituted; Or R 4 and R 5 The atoms bonded to them form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Monocyclic cycloalkyl, optionally substituted 3-10 membered monocyclic heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11 Polycyclic cycloalkyl groups (including fused, bridged, and spirocyclic groups), and optionally substituted 4-11 membered polycyclic heterocyclic alkyl groups (including fused, bridged, and spirocyclic groups); in, L does not exist, or is selected from -CH2-, -C(O)-, -CHR g -or-C(R) g )2-, where R g Optional replacement of C 1-6 alkyl; R 6 Selected from hydrogen, or optionally substituted with C 1-6 alkyl; R 7 Selected from -NR 15 R 16 Optional replacement of C 1-6 Alkyl, optionally substituted C 1-6 Heteroalkyl, optionally substituted C 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 6-10 Aryl, optionally substituted with 5-10 heteroaryl groups; or L, R 6 and R 7 They bond with the atoms to form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Monocyclic cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4-11 Bicyclic (including spirocyclic, fused, and bridged) cycloalkyl groups, and optionally substituted 4-11 member (including spirocyclic, fused, and bridged) heterocyclic alkyl groups; Unless otherwise defined, "optional substitution" means that the group is substituted by one or more (e.g., 2, 3, 4, or 5) groups selected from the group consisting of: deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=O), thio (=S), -S(O)2-(C 1-4 Alkyl), -C(O)-(C 1-4 Alkyl), -C(O)-N(C) 1-4 Alkyl)2、-C(O)O-(C 1-4 Alkyl), -C(O)-(C 3-6 cycloalkyl), -C(O)-3-6 heterocyclic alkyl, -C(O)-(C 2-6 alkenyl), -C(O)-(C 2-6 ynyl group), -C(O)-(C 2-6 ynyl)-3-6-membered heterocyclic alkyl, -C(O)-(C 2-6 ynyl)-N(C 1-3 Alkyl)2、-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2、-NH-C(O)-(C 2-6 alkenyl)-N(C 1-3 Alkyl)2, C 1-4 Alkyl-substituted or unsubstituted -C(O)-(C 2-6 ynyl)N(C 1-4 Alkyl)2, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy groups, C 2-4 alkenyl, oxo C 2-4 alkenyl, C 2- C4 ynyl group, C 3-6 Cycloalkyl, 3-6 membered heterocyclic alkyl, Or phenyl.

2. The compound according to claim 1, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, having the structure of formula (II): in A, B, G, n, X 6 R B R M R Z R a R b R 2 R 3 R 4 R 5 The definition of E is as described in claim 1; m is selected from 0, 1, 2, or 3; P does not exist, or is selected from S, O, Se, -NR 8 -、-CR 9 R 10 -、 Q does not exist, or is selected from the arbitrarily substituted C. 1-6 Alkyl, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-10-membered heterocycloalkyl, optionally substituted 5-10-membered aryl, optionally substituted 5-10-membered heteroaryl, -NR 15 R 16 or -OR 17 ; R 8 and R 17 Selected from hydrogen, deuterium, and C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, optionally substituted C 3-6 Cycloalkyl, optionally substituted 3-6 membered heterocyclic alkyl; R 9 R 10 and R 14 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 9 and R 10 A carbonyl group or a 3-6 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3. R 11 R 12 and R 13 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 11 R 12 and R 13 Any two phosphorus atoms in the ring form a phosphorus-oxygen double bond or a 3-6 membered ring through the phosphorus atoms they are connected to. The ring may also contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3. R 15 and R 16 Each element is independently selected from hydrogen, deuterium, halogen, hydroxyl, and C. 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, straight-chain or branched C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl; or R 15 and R 16 A 3-6 membered ring is formed by the nitrogen atom attached thereto, and the ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-3. Y is selected from -CH- or N: R t and R s Each element is independently selected from hydrogen, halogen, hydroxyl, cyano, and C. 1-6 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy groups, C 3-8 cycloalkyl, C 3-8 Heterocyclic alkyl; or R t and R s A carbonyl group or a 3-8 membered ring is formed by the carbon atom attached thereto. The ring may contain heteroatoms, which are independently selected from one or more of N, O and S, and the number of heteroatoms is independently 0-4. Preferably, R 4 and R 5 They combine with the atoms they are connected to to form rings, in which, The ring is selected from optionally substituted 3-10 membered cycloalkyl, optionally substituted 3-10 membered heterocycloalkyl, optionally substituted 3-6 membered alkenyl, optionally substituted 4-11 membered cycloalkyl, and optionally substituted 4-11 membered heterocycloalkyl.

3. The compound according to any one of claims 1-2, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, having the structure of formula (IIa): in A, G, X 6 R a R b R 2 R 3 R 4 R 5 The definition of E is as described in claim 1; m, Q, Y, R 8 R 9 R 10 R t and R s The definition is as described in claim 2; P does not exist, or is selected from S, O, Se, R 11 R 12 R 13 and R 14 The definition is also as described in claim 2; Preferably, the 5-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic alkyl, 3-6 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 1-6 In heteroalkyl, 3-10-membered heterocyclic alkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl or 4-11-membered heterocyclic alkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1-4.

4. The compound according to any one of claims 1-2, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, having the structure of formula (IIb): in A, G, X 6 R a R b R 2 R 3 R 4 R 5 The definition of E is as described in claim 1; m, P, Q, Y, R 8 R 9 R 10 R t and R s The definition is as described in claim 2; R 11 R 12 R 13 R 14 R 15 R 16 and R 17 The definition is as described in claim 2; Preferably, the 5-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 1- In the 6-membered heteroalkyl, 3-6-membered heterocyclic alkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl or 4-11-membered heterocyclic alkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1-4.

5. The compound according to any one of claims 1-4, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, having a structure of formula (IIIa) or (IIIb): in A, G, X 6 R a R b R 2 R 3 R 4 R 5 The definition of E is as described in claim 1; m, P, Q, Y, R 8 R 9 R 10 R t and R s The definition is as described in claims 2-4; Preferably, the 5-6 membered heterocyclic alkyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic alkyl, 5-10 membered heteroaryl, C 1- In the 6-membered heteroalkyl, 3-10-membered heterocyclic alkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl or 4-11-membered heterocyclic alkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of heteroatoms is independently 1-4.

6. The compound according to any one of claims 1-5, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, wherein... Choose from the following groups: Preferred, Selected from 7. The compound according to any one of claims 1-5, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, wherein R 4 It has the structure of formula (IV): L, R 6 and R 7 The definition is as described in claim 1; Preferably, L, R 6 and R 7 The atoms bonded to them form a ring, wherein the ring is selected from the optionally substituted C atoms. 3-10 Cycloalkyl, optionally substituted 3-10 membered heterocyclic alkyl, optionally substituted C 3-6 Cycloalkenyl, optionally substituted C 4- 11 Cycloalkyl, optionally substituted 4-11 membered heterocyclic alkyl; Preferably, in C 1-6 In heteroalkyl, 3-10-membered heterocyclic alkyl, 5-10-membered heteroaryl, 3-10-membered heterocyclic alkyl or 4-11-membered heterocyclic alkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1-4.

8. The compound according to any one of claims 1-5, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, wherein... Choose from the following groups: Preferred, Selected from More preferably, Selected from 9. The compound according to any one of claims 1-5, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, wherein... A is selected from an optional substituted 5-6 membered heteroaryl group, wherein the heteroatom is independently selected from one or two of N, O and S, and the number of the heteroatom is independently 1-3; Preferably, A is an optionally substituted 5-membered heteroaryl group, wherein the heteroatom is independently selected from N, O and S, and the number of heteroatoms is independently 1 to 2; preferably, one heteroatom is N and the other, if present, is O or S; Preferably, A is More preferably, A is 10. The compound of formula (I) according to any one of claims 1-5, or its isotopic derivatives, stereoisomers, pharmaceutically acceptable salts, metabolites, prodrugs, solvates, or solvates of pharmaceutically acceptable salts thereof, wherein, The compound of formula (I) is selected from any one of the following compounds:

11. A pharmaceutical composition comprising a compound, its isotopic derivative, its stereoisomer, its pharmaceutically acceptable salt, its metabolite, its prodrug, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein, The compound is a compound of formula (I) according to any one of claims 1-10.

12. A compound, its isotopic derivative, its stereoisomer, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 11, for preparing a medicament for treating cancers characterized by abnormal RAS activity caused by RAS mutants, wherein, The compound is the compound of formula (I) according to any one of claims 1-10.

13. The use according to claim 12, characterized in that, The compounds of this invention or their pharmaceutically acceptable salts, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a variety of cancers caused by RAS mutations, including tumors caused by RAS mutations such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc.; cancers caused by RAS mutations can be treated by the compounds of this invention or their salts, pharmaceutical compositions comprising such compounds or salts, and the methods thereof, including but not limited to the following tumor types: astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral cavity, ovarian, prostate, and thyroid cancers and sarcomas; other cancers include, for example, cardiac, and sarcomas (angiosarcoma, fibrosarcoma, etc.). Sarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung, such as: bronchogenic carcinoma (squamous cell lung cancer, non-small cell lung cancer, small cell lung cancer, undifferentiated small cell lung cancer, undifferentiated large cell lung cancer, lung adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract, such as: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, islet tumor, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma). Tumors, colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract, such as: kidney (adenocarcinoma, Wilms' tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminomatous sarcoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoma-like tumor, lipoma); liver, such as: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct, such as: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; bone, such as: osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma. Tumors, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondrogenic osteoma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma and giant cell tumors; nervous system, such as: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, neurofibromatosis type 1, meningioma, glioma, sarcoma);Gynecological conditions, such as: uterus (endometrial cancer, uterine cancer, endometrial cancer), cervix (cervical cancer, cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Celey's cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer). Hematopoietic system, such as: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodyplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin, such as: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; adrenal glands, such as: neuroblastoma.

14. The use according to claim 13, characterized in that, The compounds of the present invention or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein may be used to treat a variety of cancers caused by RAS mutations, wherein the cancers are selected from non-small cell lung cancer, small cell lung cancer, colorectal cancer, pancreatic cancer, and bile duct cancer.

15. A method for treating a subject with cancer requiring treatment, the method comprising administering to the subject an effective therapeutic amount of a compound according to any one of claims 1 to 10, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, or a metabolite thereof, or a prodrug thereof, or a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same ingredient.

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