Cyclic compound as well as preparation method and medical application thereof

Abstract

Compounds of Formula (I), Formula (II) or Formula (III), processes for their preparation, pharmaceutical compositions containing these compounds and medical uses for the treatment of diseases or conditions are disclosed. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the medical field and relates to a nitrogen-containing tetracyclic compound, a preparation method thereof, a pharmaceutical composition containing the compound and medical use thereof. Background Art

[0002] The most prominent members of the RAS subfamily are HRAS, KRAS, and NRAS, which are primarily involved in many types of cancer.

[0003] Kirsten rat sarcoma 2 viral oncogene homolog ("KRas") is a small GTPase and a member of the Ras oncogene family. KRas acts as a molecular switch, cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce upstream cellular signals received from a variety of tyrosine kinases to downstream effectors to regulate a variety of processes, including cell proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).

[0004] The role of activated KRas in malignancy was observed more than three decades ago. Abnormal expression of KRas accounts for up to 20% of all cancers, and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25-30% of lung adenocarcinomas (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12):928-942). Single nucleotide substitutions that lead to missense mutations in codons 12 and 13 of the KRas primary amino acid sequence account for approximately 40% of these KRas driver mutations in lung adenocarcinoma. KRAS G12D mutations are present in 25.0% of all pancreatic ductal adenocarcinoma patients, 13.3% of all colorectal cancer patients, 10.1% of all rectal cancer patients, 4.1% of all non-small cell lung cancer patients, and 1.7% of all small cell lung cancer patients (e.g., see The AACR Project GENIEConsortium, (2017) Cancer Discovery; 7(8):818-831. Database Version 4).

[0005] The well-known role of KRas in malignancies and the discovery of these frequent mutations in KRas in various tumor types make KRas an extremely attractive target for the pharmaceutical industry for cancer treatment. Despite 30 years of extensive discovery efforts, supported by patent WO 2021 / 041671, to develop KRas inhibitors for the treatment of cancer, KRas inhibitors have not yet been demonstrated to be sufficiently safe and / or effective to obtain regulatory approval.

[0006] Compounds that inhibit KRas activity remain highly desirable and are under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem Int Ed Engl. 51(25):6140-6143) and recent advances in covalently targeting the KRas G12C allosteric pocket (e.g., see Ostrem et al., (2013) Nature 503:548-551 and Fell et al., (2018) ACS Med. Chem. Lett. 9:1230-1234).

[0007] While progress has been made in this area, there remains a need in the art for improved compounds and methods for treating cancer, for example by inhibiting KRAS, HRAS or NRAS. The present invention satisfies this need and provides further related advantages. Summary of the invention

[0008] In one aspect, the present invention provides a compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt, solvate or prodrug thereof, including tautomers, cis or trans isomers, meso-isomers, racemates, enantiomers, diastereomers, or mixtures thereof:

[0009]

[0010] or a tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,

[0011] in,

[0012] Ring A and Ring B are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0013] R1 is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl,

[0014] wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, C 3-12 Cycloalkyl, C 3-12 One or more substituents in the heterocyclic group are substituted, wherein the C 3-12 The heterocyclyl group is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, heterocyclyl;

[0015] L and M are each independently selected from alkyl, alkoxy, alkyl-OC(O)-, alkoxy-OC(O)-, -alkyl-cycloalkyl-alkyl-OC(O)-;

[0016] R2, R3, R4, R5, R6, R7 and R8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, cycloalkyl and heterocyclyl;

[0017] Alternatively, R4 and R5 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group, wherein each of the cycloalkyl group or the heterocyclic group is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxyl, hydroxyalkyl, and haloalkyl;

[0018] n is 1, 2 or 3;

[0019] G is Among them, R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl;

[0020] Or, R a and R b Together with the carbon atoms to which they are attached, they form cycloalkyl, heterocyclyl, aryl and heteroaryl groups;

[0021] K is selected from vinyl ketone, vinyl sulfone, alkynyl ketone, alkynyl sulfone, -S(O)2 and alkyl, -C(O)-C(O)-alkyl;

[0022] J is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl and NR c R d ,

[0023] R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl;

[0024] Alternatively, J is absent, provided that K is selected from alkyl, -C(O)-C(O)-alkyl.

[0025] In some embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (Ia) or Formula (IIa), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0026]

[0027] in,

[0028] R 13 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, heteroaryl;

[0029] m is 1, 2 or 3.

[0030] In some embodiments, the compound of Formula (I) or Formula (II) is a compound of Formula (Ib) or Formula (IIb), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0031]

[0032] in,

[0033] X1 is absent, C or N;

[0034] X2 is C, O, or N;

[0035] R9, R 10 , R 11 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, cycloalkyl and heterocyclyl.

[0036] In some embodiments, Ring A and Ring B are each independently selected from C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C 3-12 The aryl group and the C 3-12 Heteroaryl.

[0037] In some embodiments, each Ring B is independently selected from C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C 3-12 The aryl group and the C 3-12 Heteroaryl.

[0038] In some embodiments, R1 is selected from C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C 3-12 The aryl group and the C3-12 Heteroaryl, wherein the C 3-12 Cycloalkyl, C 3-12 Heterocyclic group, C 3-12 Aryl and C 3-12 Each of the heteroaryl groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group, containing 1 to 3 heteroatoms independently selected from N, O or S 7-10 One or more substituents in the bridged heterocyclic group are substituted, wherein the C 3-6 Heterocyclic and C 7-10 Each of the bridged heterocyclic groups is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 3-5 The heterocyclic group is substituted with one or more substituents.

[0039] In some embodiments, L and M are each independently selected from a bond, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkyl-OC(O)-, C 1-8 Alkoxy-OC(O)-, -C 1-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Alkyl-OC(O)-.

[0040] In some embodiments, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group;

[0041] Alternatively, R4 and R5 together with the carbon atom to which they are attached form C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12Each of the heterocyclic groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 The haloalkyl group is substituted with one or more substituents.

[0042] In some embodiments, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group.

[0043] In some embodiments, wherein n is 1.

[0044] In some embodiments, G is Among them, R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl;

[0045] Or, R a and R b Together with the carbon atom to which they are attached, they form C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C 3-12 The aryl group and the C 3-12 Heteroaryl.

[0046] In some embodiments, K is selected from C 1-6 Vinyl ketone, C 1-6 Vinyl sulfone, C 1-6 Alkynone, C 1-6 Alkynyl sulfone, C 1-3 Alkyl and -C(O)-C(O)-C 1-3 alkyl.

[0047] In some embodiments, J is selected from C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C3-12 The aryl group and the C 3-12 Heteroaryl and NR c R d ;

[0048] R c and R d are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Alkenyl, C 1-3 Alkynyl, C 1-3 Alkoxy, hydroxyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl;

[0049] Or J does not exist, provided that K is C 1-3 alkyl;

[0050] In some embodiments, Ring A and Ring B are each independently selected from C 5-10 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 5-10 Heterocyclic group, C 5-10 The aryl group and the C 5-10 Heteroaryl, C 5-10 The aryl group and the C 5-10 Heteroaryl.

[0051] In some embodiments, each Ring B is independently selected from C 5-10 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 5-10 Heterocyclic group, C 5-10 The aryl group and the C 5-10 Heteroaryl.

[0052] R1 is selected from C 5-8 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 5-8 Heterocyclic group, C 5-8 The aryl group and the C 5-8 Heteroaryl, wherein the C 5-8 Cycloalkyl, C 5-8 Heterocyclic group, C 5-8 Aryl and C 5-8 Each of the heteroaryl groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C1-4 haloalkyl, C containing 1 to 2 heteroatoms independently selected from N 3-6 Heterocyclic group, containing 1 to 3 heteroatoms independently selected from N or O 7-10 One or more substituents in the bridged heterocyclic group are substituted, wherein the C 3-6 Heterocyclic and C 7-10 Each of the bridged heterocyclic groups is optionally selected from C 1-6 Alkyl, C containing a heteroatom selected from O 3-5 The heteroaryl group is substituted with one or more substituents.

[0053] In some embodiments, L is independently selected from a linear or branched C 3-6 Alkyl, linear or branched C 3-6 Alkoxy, linear or branched C 3-6 Alkyl-OC(O)-, linear or branched C 3-6 Alkoxy-OC(O)- and -C 1-3 Alkyl-C 3-6 Cycloalkyl-C 1-3 Alkyl-OC(O)-.

[0054] In some embodiments, M is independently selected from a bond, C 1-3 Alkyl, C 1-3 Alkoxy.

[0055] In some embodiments, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group;

[0056] Alternatively, R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group, wherein the C 3-6 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Each of the heterocyclic groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 One or two substituents in the haloalkyl group are substituted.

[0057] In some embodiments, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group.

[0058] In some embodiments, G is Among them, R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl;

[0059] Or, R a and R b Together with the carbon atom to which they are attached, they form C 3-8 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-8 The heterocyclic group and the C containing 1 to 2 heteroatoms independently selected from N, O or S 3-8 Heteroaryl.

[0060] In some embodiments, K is selected from C 3-6 Vinyl ketone, C 3-6 Vinyl sulfone, C 3-6 Alkynone, C 3-6 Alkynyl sulfone, -C(O)-C(O)-methyl, -C(O)-C(O)-ethyl, -C(O)-C(O)-propyl;

[0061] In some embodiments, J is selected from C 3-8 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-8 Heterocyclic group, C 3-8 The aryl group and the C 3-8 Heteroaryl and NR c R d ;

[0062] R c and R d are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Alkenyl, C1-3 Alkynyl, C 1-3 Alkoxy, hydroxyl, C 1-3 Hydroxyalkyl, C 1-3 Halogenated alkyl.

[0063] In some embodiments, Ring A and Ring B are each independently selected from:

[0064]

[0065] In some embodiments, R1 is selected from phenyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, wherein each of the phenyl, pyridinyl, pyrimidinyl, pyrazolyl and imidazolyl is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, One or two substituents are substituted.

[0066] In some embodiments, G is selected from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl.

[0067] In some embodiments, K is Among them, R 12 C 1-6 alkyl.

[0068] In some embodiments, R 12 C 1-3 alkyl.

[0069] In some embodiments, J is selected from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl.

[0070] In some embodiments, the compound of formula (I) is a compound of formula (Ic), a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0071]

[0072] in,

[0073] X2 is N, CH;

[0074] R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 One or more substituents in the alkyl group are substituted;

[0075] Preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S 8-12 fused heterocyclic group;

[0076] R 10 are independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl;

[0077] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl;

[0078] Or two R3 together with the atoms of ring B to which they are attached form C 3-8 bridged cycloalkyl;

[0079] r is 0, 1, 2, or 3;

[0080] s is 0, 1, 2, or 3.

[0081] In some embodiments, the compound of formula (III) is a compound of formula (IIIc) or (IIId), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0082]

[0083] in,

[0084] X3 is N, CH and S;

[0085] R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 One or more substituents in the alkyl group are substituted;

[0086] Preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S 8-12 fused heterocyclic group;

[0087] R 10 are independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl;

[0088] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl;

[0089] Or two R3 together with the ring B to which they are connected form C 3-8 bridged cycloalkyl;

[0090] r is 0, 1, 2, or 3;

[0091] s is 0, 1, 2, or 3.

[0092] In some embodiments, the compound is a compound of formula (IV), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0093]

[0094] R 14are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 alkyl and C containing 1, 2 or 3 heteroatoms selected from N 4-6 One or more substituents in the heterocyclic group are substituted;

[0095] u is 0, 1, 2, or 3;

[0096] R4, R5, R6, R 13 and m are as defined above.

[0097] In some embodiments, the compound is a compound of formula (V), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

[0098]

[0099] R 14 are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 alkyl and C containing 1, 2 or 3 heteroatoms selected from N 4-6 One or more substituents in the heterocyclic group are substituted;

[0100] u is 0, 1, 2, or 3;

[0101] R4, R5, R6, R7, R8, R 13 and m are as defined above.

[0102] In some embodiments, the compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is a compound of formula (Id)

[0103]

[0104] in,

[0105] X2 is N, CH;

[0106] X3 is N, CH and S;

[0107] R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 One or more substituents in the alkyl group are substituted;

[0108] Preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S 8-12 fused heterocyclic group;

[0109] R 10 are independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl;

[0110] R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl;

[0111] Or two R3 together with the ring B to which they are connected form C 3-8 bridged cycloalkyl;

[0112] r is 0, 1, 2 or 3.

[0113] In some embodiments, Ring B is selected from

[0114] Phenyl or

[0115] In some embodiments, Ring B is selected from

[0116] Phenyl or

[0117]

[0118] In some embodiments, R 11 Selected from straight chain or branched C 1-3 Alkoxy, C 2-4 haloalkenyl, C containing 1, 2 or 3 heteroatoms selected from N, O, S 5-8 A monocyclic group, a C group containing 1, 2 or 3 heteroatoms selected from N, O, S 5-12 The mono-heterocyclic group and the fused heterocyclic group are optionally selected from hydrogen, deuterium, halogen, C 1-3 The alkyl group is substituted with one or more substituents.

[0119] In a preferred embodiment, R 11 Selected from branched C 1-3 Alkoxy, C 2-4 Fluoro-alkenyl,

[0120] r is 1 or 2.

[0121] In some embodiments, R 13 selected from C containing 1, 2 or 3 heteroatoms selected from N, O or S 5-7 Heteroaryl.

[0122] In some embodiments, the compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is a compound of formula (VIII)

[0123]

[0124] in,

[0125] X2 is N, CH;

[0126] L is independently selected from linear or branched C3-6 Alkyl, linear or branched C 3-6 Alkoxy, linear or branched C 3-6 Alkyl-OC(O)-, linear or branched C 3-6 Alkoxy-OC(O)-, -C 1-3 Alkyl-C 3-6 Cycloalkyl-C 1-3 Alkyl-OC(O)-;

[0127] M is independently selected from a bond, C 1-3 Alkyl, branched or straight chain C 1-3 Alkoxy;

[0128] R6, R7 and R8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group;

[0129] R 10 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-8 Cycloalkyl and 4-8 membered heterocyclyl containing one or more heteroatoms independently selected from N, O or S;

[0130] R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 One or more substituents in the alkyl group are substituted; preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S8-12 fused heterocyclic group;

[0131] R 15 and R 16 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 2-4 Halogenated alkenyl, C 3-6 Cycloalkyl and 3-6 membered heterocyclyl containing 1 to 2 heteroatoms independently selected from N, O or S;

[0132] Ring B is a 7-12 membered fused heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0133] Ring C is selected from a 5-10 membered monoheterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, or a 7-12 membered biheterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0134] r is 0, 1, 2, or 3;

[0135] t is 0, 1, 2, or 3.

[0136] In some embodiments, Ring B is selected from

[0137] In a preferred embodiment, Ring B is selected from

[0138] In some embodiments, Ring C is selected from

[0139] In some embodiments, the compound of formula (I), or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof is a compound of formula (VIIIa)

[0140]

[0141] In another aspect, the present invention provides the following compounds, or tautomers, cis or trans isomers, meso-isomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, solvates, or prodrugs thereof.

[0142] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula as defined above, or its tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0143] In some embodiments, in the above-mentioned pharmaceutical composition, the amount of the compound, or its tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, is about 0.1-95% by weight of the free base; preferably about 5-70%, for example 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%.

[0144] In some embodiments, the above-mentioned pharmaceutical composition is formulated into a tablet, capsule, liquid form or injection form.

[0145] In some embodiments, in the above-mentioned pharmaceutical composition, the amount of the compound, or its tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture, or its pharmaceutically acceptable salt is about 1-1000 mg; preferably about 1-500 mg, more preferably about 1 mg, 2 mg, 3 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg, 300 mg, 400 mg or 500 mg.

[0146] In some embodiments, the compound, or its tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture, or a pharmaceutically acceptable salt thereof, can be administered by any suitable route of administration, such as oral, parenteral, buccal, sublingual, intranasal, rectal, intrathecal or transdermal administration, and the pharmaceutical composition is adapted accordingly.

[0147] In some embodiments, the compound, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof is formulated in a solid or liquid form, such as a syrup, suspension, emulsion, tablet, capsule, powder, granule, or lozenge.

[0148] In another aspect, the present invention relates to a method for treating a disease mediated by RAS mutations, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) to Formula (VIIIa) as defined above, or a tautomer, cis or trans isomer, meso isomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising the same.

[0149] In some embodiments, the RAS mutation is selected from a KRAS, HRAS, or NRAS mutation.

[0150] In a preferred embodiment, the RAS mutation is a KRAS mutation selected from KRAS G12C, KRAS G12D, KRAS G12V or KRAS G13D mutations. In another aspect, the present invention relates to a method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) to formula (VIIIa) as defined above, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition comprising the same.

[0151] In one embodiment, the cancer is associated with a KRAS G12C, KRAS G2D, KRAS G12V, or KRAS G13D mutation.

[0152] In a preferred embodiment, the cancer is selected from the group consisting of heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma) urogenital tract: kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroma), adenoma, adenomatoid tumor, lipoma); liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder cancer, ampullary cancer, bile duct cancer; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; nervous system: skull (bone Tumors: cerebral (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, neurothecoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma); Gynecology: uterus (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor cell tumors), dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematologic system: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma. DETAILED DESCRIPTION

[0153] The following are definitions of terms used in this application. Any term not defined herein has the normal meaning as understood by one skilled in the art.

[0154] "Alkyl" refers to a C1-C 20Saturated aliphatic hydrocarbon groups of straight and branched chain groups. Preferably, the alkyl group is an alkyl group having 1 to 12, sometimes more preferably 1 to 6 and sometimes more preferably 1 to 4 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl , 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and branched chain isomers thereof. More preferably, the alkyl group is a lower alkyl group having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably, the substituent is independently selected from one or more of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, thiol, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio and oxo.

[0155] "Alkenyl" refers to an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably C 2-20Alkenyl, more preferably C 2-12 Alkenyl, most preferably C 2-6 Alkenyl. Alkenyl may be substituted or unsubstituted. When substituted, the substituents are preferably independently selected from one or more of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfonyl, alkylamino, mercapto, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclyl, cycloalkylthio, heterocycloalkylthio and oxo, preferably one to five, more preferably one to three.

[0156] "Alkynyl" refers to an alkyl group as defined above having at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc., preferably C 2-20 Alkynyl, more preferably C 2-12 Alkynyl, most preferably C 2-6 Alkynyl. Alkynyl may be substituted or unsubstituted. When substituted, the substituents are preferably independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio and heterocycloalkylthio, sometimes preferably one to five, sometimes more preferably one to three groups.

[0157] "Alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms. A straight or branched group containing 1 to 20 carbon atoms preferably has 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylene may be substituted or unsubstituted. When substituted, the substituents are preferably independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio and heterocycloalkylthio, sometimes preferably one to five, sometimes more preferably one to three groups.

[0158] "Alkenylene" refers to an alkylene group as defined above having at least two carbon atoms and at least one carbon-carbon double bond, preferably C 2-20 Alkenylene, more preferably C2-12 Alkenylene, most preferably C 2-6 Alkenylene. Non-limiting examples of alkenylene include, but are not limited to, -CH=CH-, -CH=CHCH2-, -CH=CHCH2CH2-, -CH2CH=CHCH2-, etc. Alkenylene may be substituted or unsubstituted. When substituted, the substituent is preferably independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio, sometimes preferably one to five, sometimes more preferably one to three groups.

[0159] "Alkyne" refers to an alkynyl group as defined above having at least two carbon atoms and at least one carbon-carbon triple bond, preferably C 2-20 Alkyne, more preferably C 2-12 Alkyne, most preferably C 2-6 Alkynylidene. Non-limiting examples of alkenylene include, but are not limited to, -CH≡CH-, -CH≡CHCH2-, -CH≡CHCH2CH2-, -CH2CH≡CHCH2-, etc. Alkynylidene may be substituted or unsubstituted. When substituted, the substituent is preferably independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio, sometimes preferably one to five, sometimes more preferably one to three groups.

[0160] "Cycloalkyl" refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyls include cycloalkyls having spirocyclic, condensed or bridged rings.

[0161] "Spirocycloalkyl" refers to a 5 to 20-membered polycyclic group in which the ring is connected via a common carbon atom (called a spiral atom), wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, the spirocycloalkyl is 6 to 14 yuan, more preferably 7 to 10 yuan, and most preferably 7 to 8 yuan. According to the number of common spiral atoms, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl or a double spiral cycloalkyl, more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan of single spiral cycloalkyl. Representative examples of spirocycloalkyl include, but are not limited to, the following substituents:

[0162]

[0163] "Fused cycloalkyl" refers to a 5-20 membered polycyclic hydrocarbon group, wherein each ring in the system shares a pair of adjacent carbon atoms with another ring, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, the fused cycloalkyl is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. According to the number of constituent rings, the fused cycloalkyl is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic fused cycloalkyl, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl. Representative examples of fused cycloalkyls include, but are not limited to, the following substituents:

[0164]

[0165] "Bridged cycloalkyl" refers to a 5-20 membered polycyclic hydrocarbon group, wherein each two rings in the system share two unconnected carbon atoms, the rings may have one or more double bonds, but do not have a completely conjugated π-electron system. Preferably, the bridged cycloalkyl is 6-14 members, more preferably 7-10 members, and most preferably 7-8 members. According to the number of constituent rings, the bridged cycloalkyl is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:

[0166]

[0167] Cycloalkyl can be fused with the ring of aryl, heteroaryl or heterocycloalkyl, wherein the ring connected to the parent structure is cycloalkyl. Representative examples include but are not limited to indanylacetic acid (indanylacetic), tetralin, benzocycloheptyl etc. Cycloalkyl is optionally substituted or unsubstituted. When substituted, substituents are preferably independently selected from alkyl, halogen, alkoxy, alkenyl, alkynyl, alkyl sulfonyl, alkylamino, sulfhydryl, hydroxyl, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclic radical, cycloalkylthio, heterocycloalkylthio and oxo, one or more, sometimes preferably one to five, sometimes more preferably one to three substituents. Representative examples include but are not limited to the following substituents:

[0168]

[0169] "Heterocyclyl" refers to a 3- to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having a radical selected from N, O and S(O) m (wherein m is 0, 1 or 2), one or more, sometimes preferably one to five, sometimes more preferably one to three heteroatoms as ring atoms, but the ring does not include -OO-, -OS- or -SS-, and the remaining ring atoms are C. Preferably, the heterocyclyl is a 3- to 12-membered heterocyclyl having 1 to 4 heteroatoms; more preferably a 3- to 10-membered heterocyclyl having 1 to 3 heteroatoms; most preferably a 5- to 6-membered heterocyclyl having 1 to 2 heteroatoms. Representative examples of monocyclic heterocyclyls include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclyls include heterocyclyls having spiro, fused or bridged rings.

[0170] "Spiro heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group wherein the rings are linked via a common carbon atom (called a spiro atom) and wherein the rings have a carbon atom selected from N, O and S(O). m (wherein m is 0, 1 or 2) one or more, sometimes preferably one to five, sometimes more preferably one to three heteroatoms as ring atoms, the remaining ring atoms are C, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system. Preferably, the spiro heterocyclic group is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. According to the number of shared spiro atoms, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group or a dispiro heterocyclic group, more preferably a 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospiro heterocyclic group. Representative examples of spiro heterocyclic groups include, but are not limited to, the following substituents:

[0171]

[0172] "Fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl, wherein each ring in the system shares a pair of adjacent carbon atoms with the other rings, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron system, and wherein the rings have a substituted aryl radical selected from N, O and S(O) p (wherein p is 0, 1 or 2) one or more, sometimes preferably one to five, sometimes more preferably one to three heteroatoms as ring atoms, the remaining ring atoms are C. Preferably, the fused heterocyclic group is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. According to the number of constituent rings, the fused heterocyclic group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic fused heterocyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Representative examples of fused heterocyclic groups include, but are not limited to, the following substituents:

[0173]

[0174] "Bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocycloalkyl group, wherein each two rings in the system share two non-connected atoms, the rings may have one or more double bonds, but do not have a completely conjugated π-electron system, and the rings have a cycloalkyl radical selected from N, O and S(O) m (wherein m is 0, 1 or 2) as ring atoms, and the remaining ring atoms are C. Preferably, the bridged heterocyclic group is 6 to 14 members, more preferably 7 to 10 members, and most preferably 7 to 8 members. According to the number of constituent rings, the bridged cycloalkyl group is divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic bridged heterocyclic group, more preferably a bicyclic or tricyclic bridged heterocyclic group. Representative examples of bridged heterocyclic groups include, but are not limited to, the following groups:

[0175]

[0176] The ring of the heterocyclic group can be fused with the ring of aryl, heteroaryl or cycloalkyl, wherein the ring connected to the parent structure is the heterocyclic group. Representative examples include, but are not limited to, the following groups:

[0177] wait.

[0178] The heterocyclyl radical is optionally substituted or unsubstituted. When substituted, the substituents are preferably independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and -NR 9 R 10 One or more, sometimes preferably one to five, sometimes more preferably one to three groups.

[0179] "Aryl" refers to a 6- to 14-membered all-carbon monocyclic or polycyclic condensed ring (a "condensed" ring system means that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) group, and has a completely conjugated π-electron system. Preferably, the aryl group is 6 to 10 members, such as phenyl and naphthyl, and most preferably phenyl. The aryl group can be fused with a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl group. Representative examples include, but are not limited to, the following substituents:

[0180]

[0181] Aryl may be substituted or unsubstituted. When substituted, the substituents are preferably independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycle and alkylthio, preferably one to five, more preferably one to three substituents.

[0182] "Heteroaryl" refers to an aryl system having 1 to 4 heteroatoms selected from O, S and N as ring atoms and having 5 to 14 ring atoms. Preferably, the heteroaryl is 5 to 10-membered, more preferably 5 or 6-membered, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group can be fused to the ring of an aryl, heterocyclyl or cycloalkyl group, wherein the ring connected to the parent structure is a heteroaryl group. Representative examples include, but are not limited to, the following substituents:

[0183]

[0184]

[0185] The heteroaryl group may be substituted or unsubstituted. When substituted, the substituents are preferably independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and -NR 9 R 10 One or more, sometimes preferably one to five, sometimes more preferably one to three substituents.

[0186] "Alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc. Alkoxy may be substituted or unsubstituted. When substituted, the substituent is preferably independently selected from one or more of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio, sometimes preferably one to five, sometimes more preferably one to three substituents.

[0187] "Bond" refers to a covalent bond using the symbol "—".

[0188] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0189] "Hydroxy" refers to an -OH group.

[0190] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0191] "Amino" refers to a -NH2 group.

[0192] "Cyano" refers to a -CN group.

[0193] "Nitro" refers to a -NO2 group.

[0194] "Oxo" refers to a =0 group.

[0195] "Carboxy" refers to a -C(O)OH group.

[0196] "Carboxylate" means -C(O)O(alkyl) or -C(O)O(cycloalkyl) wherein alkyl and cycloalkyl are as defined above.

[0197] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance may or may not occur. For example, "heterocyclyl optionally substituted with alkyl" means that alkyl may but need not be present, and that the description includes instances where heterocyclyl is substituted with alkyl and instances where heterocyclyl is not substituted with alkyl.

[0198] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions. Those skilled in the art can determine possible or impossible substitutions (by experiment or theory) without paying too much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as olefinic).

[0199] "Pharmaceutical composition" refers to a mixture of one or more compounds according to the present invention or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components (such as physiologically / pharmaceutically acceptable carriers and excipients). The purpose of a pharmaceutical composition is to facilitate the administration of the compound to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0200] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention which is safe and effective when used in mammals and has the corresponding biological activity.

[0201] Example

[0202] The following examples are used to illustrate the present invention, but these examples should not be considered to limit the scope of the present invention. If the specific conditions of the experimental method are not specified in the examples of the present invention, they are usually consistent with the conventional conditions or recommended conditions of the raw material and product manufacturers. Reagents without specifying the specific source are commercially available conventional reagents.

[0203] The structures of the compounds were identified by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR chemical shifts (δ) were expressed in 10 -6 (ppm) are given. NMR was measured by Varian Mercury 300MHz Bruker Avance III 400MHz instruments. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD).

[0204] High performance liquid chromatography (HPLC) was measured on an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6 mm column). Liquid chromatography-mass spectrometry (LCMS) was measured on an Agilent 1200 high pressure liquid chromatograph and mass spectrometer (Sunfire C18 4.6*50 mm 3.5 um column) and an Agilent 19091S-433HP-5 high pressure liquid chromatograph and mass spectrometer (XBridge C18 4.6x50 mm 3.5 um column).

[0205] Chiral high performance liquid chromatography (HPLC) was performed on SFC Thar 80&150&200 (waters.).

[0206] Average rate and IC of ATPase inhibition 50 The values ​​were determined by Victor Nivo multimode plate reader (PerkinElmer, USA).

[0207] The thin layer silica gel plate used for thin layer chromatography is Yantai Xinnuo silica gel plate. The specification of the plate used in TLC is 0.15mm to 0.2mm, and the specification of the plate used in the thin layer chromatography for product purification is 0.4mm to 0.5mm.

[0208] Column chromatography usually uses Qingdao Ocean 200 to 300 mesh silica gel as the carrier.

[0209] The known starting materials of the present invention can be prepared by conventional synthesis methods in the prior art or can be purchased from ABCR MBH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology Co., Ltd. or Darui Chemical Company, etc.

[0210] MS is mass spectrometry, where (+) indicates the positive mode, usually giving the M+1 (or M+H) absorption, where M = molecular weight.

[0211] Synthesis Procedure

[0212] Synthesis of 3-bromo-2-(1-methoxyethyl)pyridine (Int A):

[0213]

[0214] Step 1: Synthesis of 1-(3-bromopyridin-2-yl)ethan-1-ol (Int A-1)

[0215] To a solution of 3-bromo-2-pyridinecarboxaldehyde (CAS: 405174-97-2, 1.80 g, 9.70 mmol) in THF (35 mL) was added a solution of MeMgBr in diethyl ether (6.50 mL, 19.4 mmol). The solution was stirred at -78 ° C for 30 minutes and then warmed to 25 ° C over 1.5 hours. The suspension was partitioned between NH4Cl aqueous solution (50 mL) and EtOAc (50 mL*3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column (petroleum ether / EtOAc=10:1) to give 1-(3-bromopyridin-2-yl)ethan-1-ol (Int A-1) (1.80 g, yield: 87%) as a yellow oil. ESI-MS [M+H] + :201.9,203.9.

[0216] Step 2: Synthesis of 3-bromo-2-(1-methoxyethyl)pyridine (Int A)

[0217] To a solution of Int A-1 (1.80 g, 8.90 mmol) in DMF (30 mL) was added sodium hydride (0.71 g, 18 mmol) at 0°C. The resulting mixture was stirred at 0°C for 45 minutes. Methyl iodide (2.53 g, 17.8 mmol) was added dropwise to the above mixture. The resulting mixture was stirred at 25°C for 2 hours. The suspension was partitioned between H2O (100 mL) and EtOAc (50 mL*3). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel column (petroleum ether / EtOAc=10:1) to give 3-bromo-2-(1-methoxyethyl)pyridine (Int A) (2.1 g, yield: 95%) as a brown oil. ESI-MS [M+H] + :215.8,217.8.

[0218] Synthesis of di-tert-butyl 1-(5-(methoxycarbonyl)thiophen-2-yl)hydrazine-1,2-dicarboxylate, Int BS

[0219]

[0220] A solution of isopropylmagnesium bromide (2.8M, 19.39mL) was added dropwise to a stirred solution of methyl 5-bromothiophene-2-carboxylate (10g, 45.23mmol) in THF (100mL) at -40°C. The reaction mixture was stirred at -40°C for 30 minutes, and then a solution of di-tert-butyl azodicarboxylate (11.46g, 49.76mmol) in THF (50mL) was added dropwise. The solution was warmed to room temperature over 3 hours. LCMS indicated that the reaction was complete. The mixture was quenched with saturated aqueous ammonium chloride, extracted with EA, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (20% EA in PE) to give 37-2 (11g, 65% yield).

[0221] Mass Spectrometry C 16 H 24 N2O6S calculated 372.1, measured 217.1 (M-Boc-tBu) + .

[0222] 1 H NMR (400MHz, CDCl3) δ: 7.59 (d, J = 4.0 Hz, 1H), 6.84 (s, 1H), 6.79 (d, J = 4.0 Hz, 1H), 3.85 (s, 3H), 1.53 (m, 18H).

[0223] Synthesis of 2-(2-bromo-5-hydrazinophenyl)ethan-1-ol, Int BT

[0224]

[0225] Borane-THF complex (1 M, 11.8 mL, 11.8 mmol) was added to a solution of ((5-amino-2-bromo-phenyl)-acetic acid (CAS: 1261666-52-7 1.00 g, 4.37 mmol) in dry THF (10 mL) under argon over 20 minutes. Once effervescence ceased, the reaction mixture was heated to 50°C for 2 hours. The mixture was left to cool and then concentrated in vacuo. The residue was redissolved in DCM (25 mL) and treated with MeOH (2 mL). The mixture was stirred vigorously and then concentrated in vacuo. The residue was dissolved in MeOH (25 mL) and re-concentrated in vacuo. The residue was purified by column chromatography using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (0.54 g). LCMS (ESI): m / z 216 [MH + ].

[0226] The intermediate Int B-T' (0.54 g, 2.51 mmol) was dissolved in concentrated aqueous HCl (5 mL) and cooled to -5 °C. A solution of sodium nitrite (0.18 g, 2.63 mmol) in water (0.75 mL) was added dropwise. Stirring was continued for 5 minutes, then tin (II) chloride (1.01 g, 5.52 mmol) in concentrated aqueous HCl (2.2 mL) was added. The reaction mixture was stirred below 0 °C for 40 minutes, then basified with aqueous NaOH (4 M, 30 mL). The mixture was then stirred at room temperature for 1.5 hours. It was extracted into EtOAc (3 x 50 mL). The combined organics were washed with brine (2 x 50 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (294 mg, 51%). LCMS (ESI): m / z 231 [MH + ].

[0227] The following compounds were synthesized in a similar route to Int B using appropriate starting materials:

[0228]

[0229] Synthesis of 2-(2-bromo-5-hydrazinophenyl)ethan-1-ol, Int BU

[0230]

[0231] To a solution of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (15 g, 43.86 mmol) and piperazine-1-carboxylic acid benzyl ester (8.7 g, 39.48 mmol) in toluene (150 mL) was added cesium carbonate (71.46 g, 219.32 mmol), BINAP (0.55 g, 0.88 mmol) and palladium acetate (0.49 g, 2.19 mmol) in batches. The reaction mixture was stirred at 90 ° C for 12 hours under an argon atmosphere. The resulting mixture was cooled to room temperature, filtered and the filter cake was washed with EtOAc (150 mL x 3). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (16 g, 84% yield) as a solid. LCMS (ESI): m / z [M+H] calcd. for C^HbsNeOy 433.1; found 434.0.

[0232] Synthesis of 3-(1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (Int B):

[0233]

[0234] Step 1: Synthesis of 5-(2-(methoxymethyl)pyridin-3-yl)-2,2-dimethyl-5-oxopentanoic acid (Int B-1)

[0235]

[0236] At -10 °C, N 2Under atmosphere, i-PrMgCl·LiCl (1.30M in THF, 21.4mL, 27.8mmol) was added dropwise to a solution of 3-bromo-2-(methoxymethyl)pyridine (5.00g, 24.9mmol) in THF (15mL). The resulting mixture was warmed to -5°C and stirred at -5°C for 1 hour. Then a solution of 3,3-dimethyltetrahydropyran-2,6-dione (cas: 2938-48-9) (3.70g, 26.1mmol) in THF (36mL) was added dropwise at -5°C. The resulting mixture was warmed to 0°C and stirred at 0°C for 1.5 hours. The resulting mixture was then warmed to room temperature and stirred at room temperature overnight. The reaction was quenched with HCl / dioxane (4.0M, 4.4mL, 17mmol) and H2O (22mL). The mixture was stirred and separated. The aqueous layer was extracted with EtOAc (30mL*3). The organic layers were combined and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH=50:1 to 20:1). 5-(2-(methoxymethyl)pyridin-3-yl)-2,2-dimethyl-5-oxopentanoic acid (IntB-1) (3.70 g, 14.0 mmol, 55% yield) was obtained as a light yellow solid. ESI-MS [M+H] + :265.98.

[0237] Step 2: Synthesis of 3-(5-bromo-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoic acid (Int B-2); 3-(5-bromo-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoic acid ethyl ester (Int B-2')

[0238]

[0239] To a solution of 5-(2-(methoxymethyl)pyridin-3-yl)-2,2-dimethyl-5-oxopentanoic acid (Int B-1) (3.70 g, 14.0 mmol) in EtOH (92 mL) was added (4-bromophenyl)hydrazine HCl salt (cas 622-88-8) (3.50 g, 15.7 mmol). The resulting mixture was stirred at 85°C for 2 hours. Then HCl / dioxane (4M, 3.5 mL, 14.0 mmol) was added to the mixture. The resulting mixture was stirred at 85°C for another 3 hours. The mixture was concentrated under vacuum. Trifluoroacetic acid (53.80 g, 471.9 mmol) was added to the residue. The mixture was stirred at 60°C for another 1.5 hours. The mixture was cooled to room temperature and concentrated under vacuum. The pH of the residue was adjusted to 5-6 with saturated aqueous NaHCO3 (54 mL), and EtOAc (128 mL) was added to the mixture. The mixture was stirred and separated. The organic layer was washed with brine (50 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum. 3-(5-bromo-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoic acid (Int B-2) and 3-(5-bromo-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoic acid ethyl ester (Int B-2) were obtained. ’ The mixture of ) (8.70 g, 20.8 mmol) was used directly in the next step without purification. ESI-MS [M+H] + :416.74,418.77,444.79,446.81.

[0240] Step 3: Synthesis of ethyl 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoate (Int B-3)

[0241]

[0242] To 3-(5-bromo-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoic acid (Int B-2) and 3-(5-bromo-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoic acid ethyl ester (Int B-2 ’) in DMF (64 mL) was added Cs2CO3 (24.4 g, 74.1 mmol). Then a solution of iodoethane (11.6 g, 75.0 mmol) in DMF (16 mL) was added. The resulting mixture was stirred at room temperature overnight. H2O (300 mL) and EtOAc (300 mL) were added to the mixture. The mixture was stirred and separated. The organic layer was washed with brine (200 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=3:1 to 1:1). Ethyl 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoate (Int B-3) (3.8 g, 8.5 mmol, 57% two-step yield) was obtained as a brown liquid. ESI-MS [M+H] + :473.03,474.94.

[0243] Step 4: Synthesis of 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (Int B-4)

[0244]

[0245] To a solution of ethyl 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropanoate (Int B-3) (3.8 g, 8.0 mmol) in THF (159 mL) was added LiBH4 (2.00 M in THF, 23.8 mL 47.6 mmol). The resulting mixture was stirred at 60 ° C overnight. The reaction mixture was quenched with saturated NH4Cl aqueous solution (66 mL) at 0 ° C. H2O (22 mL) and EtOAc (88 mL) were added to the mixture. The mixture was stirred and separated. The organic layer was washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM / MeOH=100:1 to 50:1). 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (Int B-4) (1.3 g, 3.1 mmol, 38% yield) was obtained as a pale yellow solid. ESI-MS [M+H] + :432.93.

[0246] The following compounds were synthesized in a similar route to Int B using appropriate starting materials:

[0247]

[0248] Step 5: Synthesis of 3-(1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (Int B)

[0249]

[0250] Under N2 atmosphere, bis(pinacolato)diboron (1.1 g, 4.5 mmol), potassium acetate (589 mg, 6.00 mmol) and Pd(dppf)Cl2 (222 mg, 0.303 mmol) were added to a solution of 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (Int B-4) (1.3 g, 3.0 mmol) in toluene (35 mL) under N2 atmosphere. The resulting mixture was stirred at 90°C overnight. The mixture was concentrated to dryness under vacuum and the residue was purified by silica gel column chromatography (DCM / MeOH=100:1 to 50:1). 3-(1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (Int B) was obtained as a light yellow solid (600 mg, 1.25 mmol, 41% yield). 1 H NMR(400MHz,DMSO-d6)δ8.74-8.68(m,1H),8.03(s,1H),7.90-7.84(m,1H),7.56-7.44(m,3 H),4.45(t,J=5.4Hz,1H),4.22(d,J=10.8Hz,1H),4.15(d,J=10.8Hz,1H),4.04-3.94(m,1H) ,3.92-3.81(m,1H),3.14(s,3H),3.07-3.01(m,1H),2.98-2.92(m,1H),2.66(d,J=14.0Hz, 1H), 2.29 (d, J = 14.0Hz, 1H), 1.32 (s, 12H), 1.02 (t, J = 7.2Hz, 3H), 0.60 (s, 3H), 0.53 (s, 3H). ESI-MS[M+H] + :479.11

[0251] The following compounds were synthesized in a similar route to Int B using appropriate starting materials:

[0252]

[0253] Synthesis of (S)-2-bromo-4-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-6-ethyl-5-(2-(1-methoxyethyl)pyridin-3-yl)-6H-thieno[2,3-b]pyrrole, Int B-S4

[0254]

[0255] To a solution of tert-butyl-[3-[6-ethyl-5-[2-[(1S)-1-methoxyethyl]-3-pyridyl]thieno[2,3-b]pyrrol-4-yl]-2,2-dimethyl-propoxy]-diphenyl-silane, Int B-S4-H (350 mg, 572.90 μmol), NBS (112.16 mg, 630.20 μmol) in DMF (5 mL) was added TEA (507.85 mg, 5.02 mmol, 700.00 μL) dropwise and stirred at room temperature for 3 hours. LCMS indicated that the reaction was complete. The reactants were extracted with EA, washed with water, and the organic phase was concentrated in vacuo to give the crude product. The crude product was purified by flash chromatography (100% PE to 30% EA in PE) to give Int B-S4 (350 mg, 88% yield). Mass Spectrum C 37 H 45 BrN2O2SSi calculated 688.2, found 689.2, 691.2 (M+H) + .

[0256] 1 H NMR(400MHz, DMSO-d6)δ:8.69(m,1H),7.64(m,1H),7.45(m,11H),7.21(m,1H),4.18-4.02(m,1H),3.72-3.47(m,2H),3. 16(m,1H),3.02(s,2H),2.89(s,2H),2.56-2.47(m,1H),2.34-2.18(m,1H),1.36-1.13(m,6H),0.92(m,9H),0.69(m,6H).

[0257] Synthesis of 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (Int B-Ac)

[0258]

[0259] To a solution of 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropan-1-ol (3.2 g, 7.4 mmol) (Int B-4) in DCM (15 mL) was added AcCl (1.0 M in DCM, 8.9 mL, 8.9 mmol) at 0°C. The reaction mixture was stirred at room temperature overnight. LC-MS indicated complete conversion. The reaction mixture was washed with water, concentrated and purified on a silica gel column (0-5% MeOH / DCM) to give 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (Int B-Ac) (3.3 g, 94% yield) as a yellow solid.

[0260] 1 H NMR (400MHz, CD3OD) δ8.71 (dd, J=4.9, 1.6Hz, 1H), 7.91 (dd, J=7.8, 1.6Hz, 1H), 7.77 (d, J=1.8Hz,1H),7.55(dd,J=7.8,4.9Hz,1H),7.38(d,J=9.1Hz,1H),7.30(dd,J=8.7,1.8Hz ,1H),4.29-4.24(m,2H),4.07-3.85(m,2H),3.62-3.55(m,2H),3.25(s,3H),2.76-2.70( m,1H),2.50-2.46(m,1H),1.94(s,3H),1.10(t,J=7.2Hz,1H),0.77(s,3H),0.75(s,3H). ESI-MS[M+H] + :473.1,475.1

[0261] The following compounds were synthesized in a similar route to Int B-Ac using appropriate starting materials:

[0262]

[0263] Synthesis of (S)-5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Int Bi)

[0264]

[0265] Step 1: Ethyl 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carboxylate (Int Bi-1)

[0266] At 0°C, tert-butyl(chloro)diphenylsilane (21 mL, 83 mmol) and imidazole (8.61 g, 126 mmol) were added to a solution of ethyl 1-(hydroxymethyl)cyclobutane-1-carboxylate (CAS: 1195-81-9 10 g, 63 mmol) in DCM (80 mL), and the reaction was warmed to 25°C and stirred for 16 hours. The reaction was quenched with H2O (80 mL) and extracted with DCM (100 mL*3). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel combi-flash (petroleum ether / EtOAc=15:1) to give ethyl 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carboxylate (Int Bi-1) (19.5 g, 77% yield) as a colorless oil. ESI-MS [M+Na] + :419.0.

[0267] Step 2: 1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carboxylic acid (Int Bi-2)

[0268] To a stirred solution of ethyl 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carboxylate (Int Bi-1) (19.5 g, 49.2 mmol) in MeOH (10 mL) was added KOH (80 mL, 5.0 M, 0.4 mmol) dropwise. The reaction mixture was stirred at 100 °C for 19 hours. The reaction was quenched with HCl (50 mL, 6.0 M) and extracted with EtOAc (150 mL*3). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel combi-flash (petroleum ether / EtOAc=20:1) to give 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carboxylic acid (Int Bi-2) (9.10 g, 49% yield) as a colorless oil. ESI-MS [M+H] + :369.0.

[0269] Step 3: 1-(((tert-Butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbonyl chloride (Int Bi-3)

[0270] A solution of 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carboxylic acid Int Bi-2 (9.10 g, 24.7 mmol) and sulfenyl chloride (8.78 g, 73.5 mmol) in DCM (80 mL) was stirred at 25° C. for 3 h. The solvent was removed in vacuo to give crude 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbonyl chloride (Int Bi-3) (8.5 g, 74% yield). ESI-MS [M+H] + :387.1.

[0271] Step 4: (5-Bromo-1H-indol-3-yl)(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanone (Int Bi-4)

[0272] To a stirred solution of 1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutane-1-carbonyl chloride (Int Bi-3) (8.5 g, 21 mmol) in DCM (60 mL) was added a solution of SnCl4 (6.27 g, 23.9 mmol) in DCM (15 mL) dropwise at -15 °C under nitrogen for 30 minutes. The reaction mixture was added dropwise with a solution of 5-bromo-1H-indole (4.69 g, 23.9 mmol) in DCM (15 mL). The reaction was quenched with H2O (60 mL) and extracted with DCM (80 mL*3). The organic layers were combined, washed with brine (60 mL), and dried over Na2SO4 to give (5-bromo-1H-indol-3-yl)(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanone (Int Bi-4) (3.7 g, 31% yield) as a white solid. ESI-MS [M+H] + :546.1,548,0.

[0273] Step 5: (5-Bromo-1H-indol-3-yl)(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol (Int Bi-5)

[0274] To a solution of (5-bromo-1H-indol-3-yl)(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanone (Int Bi-4) (3.70 g, 6.76 mmol) in THF (30 mL) was added LiBH4 (0.89 g, 40.7 mmol). The reaction mixture was heated to 60 °C and stirred for 20 hours. After cooling, the reaction was quenched with ice water (50 mL) and extracted with EtOAc (80 mL*3). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by combi-flash (petroleum ether / EtOAc=2:1) ​​to give (5-bromo-1H-indol-3-yl)(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol (Int Bi-5) (3.56 g, 90% purity, 86% yield) as a white solid. ESI-MS [M+Na] + =570.1,572.1.

[0275] Step 6: 5-Bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-1H-indole (Int Bi-6)

[0276] To a solution of (5-bromo-1H-indol-3-yl)(1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methanol (Int Bi-5) (3.56 g, 6.49 mmol) in DCM (30 mL) was added dihydropyridine (0.66 g, 2.60 mmol) and p-toluenesulfonic acid monohydrate (0.06 g, 0.3 mmol). The reaction mixture was stirred at 10 °C for 1 hour. The filtrate was filtered and concentrated to give a crude product, which was purified by combi-flash (petroleum ether / EtOAc=3:1) to give 5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-1H-indole (Int Bi-6) (3.41 g, 90% purity, 89% yield) as a white solid. ESI-MS [M+Na] + :553.7,555.7.

[0277] Step 7: 5-Bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-2-iodo-1H-indole (Int Bi-7)

[0278] To a solution of 5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-1H-indole (Int Bi-6) (3.4 g, 6.4 mmol) and I2 (1.6 g, 6.4 mmol) in THF (20 mL) was added AgOTf (1.97 g, 7.6 mmol). The reaction mixture was stirred at 25 °C for 2 hours. Filtered, the filtrate was diluted with H2O (50 mL) and extracted with EtOAc (80 mL*3). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel combi-flash (petroleum ether / EtOAc=1:1) to give 5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-2-iodo-1H-indole (Int Bi-7) (4.0 g, 90% purity, 86% yield) as a yellow solid. ESI-MS [M+Na] + :680.1,682.1.

[0279] Step 8: (S)-(2-(1-methoxyethyl)pyridin-3-yl)boronic acid

[0280] Under nitrogen, a solution of (S)-3-bromo-2-(1-methoxyethyl)pyridine (CAS: 2641451-44-5, 13.60 g, 62.96 mmol), B2Pin2 (24.03 g, 94.44 mmol), Pd(dppf)Cl2 (4.61 g, 6.30 mmol) and KOAc (12.39 g, 125.9 mmol) in dioxane (100 mL) was stirred at 80 °C for 16 hours. The reactants were purified by reverse phase chromatography (30% water / 70% acetonitrile) to give compound (S)-(2-(1-methoxyethyl)pyridin-3-yl)boronic acid (8.5 g, 74% yield) as a white solid. ESI-MS [M+H] + :182.0.

[0281] Step 9: (S)-5-Bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Int Bi-8)

[0282] To a solution of 5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-2-iodo-1H-indole (Int Bi-7) (4.0 g, 6.1 mmol) in dioxane (10 mL) and H2O (2.5 mL) was added (S)-(2-(1-methoxyethyl)pyridin-3-yl)boronic acid (1.32 g, 7.30 mmol), [1,1 / / '-bis(diphenylphosphino)ferrocene]dichloropalladium(II) DCM (490 mg, 0.600 mmol) and K2CO3 (2.11 g, 15.2 mmol). The reaction mixture was stirred at 70°C under N2 for 12 hours. Filtered, the filtrate was diluted with H2O (100 mL) and extracted with EtOAc (80 mL*3). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel combi-flash (petroleum ether / EtOAc=3:1) to give (S)-5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Int Bi-8) (1.1 g, 90% purity, 21% yield) as a yellow oil. ESI-MS [M+H] + :667.0,669.0.

[0283] Step 10: (S)-5-Bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Int Bi)

[0284] To a solution of (S)-5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Int Bi-8) (1.1 g, 1.6 mmol) in DMF (10 mL) was added iodoethane (500 mg, 3.20 mmol) and Cs2CO3 (1.04 g, 3.20 mmol). The reaction mixture was stirred at 25 °C for 12 hours. The reaction was diluted with H2O (80 mL) and extracted with EtOAc (50 mL*3). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, and concentrated in vacuo to give a crude product, which was purified by silica gel combi-flash (petroleum ether / EtOAc=2:1) ​​to give (S)-5-bromo-3-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclobutyl)methyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Int Bi) (1.0 g, yield 81%) as a yellow oil. ESI-MS [M+H] + :695.1,697.1.

[0285] Synthesis of methyl (2S)-3-(5-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-5-yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2-(((benzyloxy)carbonyl)amino)propanoate (Int Bii)

[0286]

[0287] Step 1: N-((Benzyloxy)carbonyl)-O-(methylsulfonyl)-L-serine methyl ester (Int Bii-1)

[0288] MsCl (33.92 g, 296.1 mmol) was added dropwise to a solution of ((benzyloxy)carbonyl)-L-serine methyl ester (50.0 g, 197 mmol) in DCM (300 mL) and TEA (29.97 g, 296.1 mmol) at 0°C and stirred at room temperature for 1 hour. The reaction solution was washed with water and brine, the organic layer was dried over Na2SO4, and concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel flash chromatography (0-5% MeOH / DCM) to give N-((benzyloxy)carbonyl)-O-(methylsulfonyl)-L-serine methyl ester (Int Bii-1) (39.0 g, 60% yield). ESI-MS [M+Na] + :354.0.

[0289] Step 2: (3aR,6aS)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylic acid tert-butyl ester (Int Bii-2)

[0290] To tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (5.5 g, 25 mmol), N-((benzyloxy)carbonyl)-O-(methylsulfonyl)-L-serine ester (Int Bii-1) (15 g, 45 mmol) in DMF (10 mL) and H2O (1 mL) was added K2CO3 (2.2 g, 16 mmol) and stirred at 90°C for 10 minutes. Additional N-((benzyloxy)carbonyl)-O-(methylsulfonyl)-L-serine ester (12 g, 36 mmol) and K2CO3 (2.5 g, 18 mmol) were added. The reaction was diluted with H2O (50 mL) and extracted with EtOAc. The organic layer was washed with H2O and brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0-4% MeOH / DCM) to give tert-butyl (3aR,6aS)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (Int Bii-2) (7.0 g, 60% yield) as a brown oil. ESI-MS [M+H] + :448.3.

[0291] Step 3: (S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-((3aR,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)propanoate (Int Bii-3)

[0292] A solution of tert-butyl (3aR,6aS)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropyl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (Int Bii-2) (7.0 g, 15 mmol) in TFA (20 mL) and DCM (20 mL) was stirred at room temperature for 1 hour. The reaction was concentrated, adjusted to pH = 8 with NaHCO3 (sat., aqueous solution), and extracted with EtOAc / MeOH (9:1), the organic phase was concentrated and purified by silica gel flash chromatography (0-20% MeOH in DCM) to give (S)-methyl 2-(((benzyloxy)carbonyl)amino)-3-((3aR,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)propanoate (Int Bii-3) (3.2 g, 36% yield, brown oil).

[0293] 1 H NMR(400MHz, CDCl3)δ:8.92(br,1H),7.61-7.58(m,1H),7.50-7.15(m,5H),5.10-4.99(m,2H),4.25-4.1 2(m,1H),3.66-3.56(m,3H),3.19-2.58(m,9H),2.21-2.14(m,1H),2.05-1.99(m,1H),1.57-1.46(m,1H). ESI-MS[M+H] + :348.3.

[0294] Step 4: (S)-3-((3aR,6aS)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-5-yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2-(((benzyloxy)carbonyl)amino)propanoic acid methyl ester (Int Bii)

[0295] A solution of (S)-2-(((benzyloxy)carbonyl)amino)-3-((3aR,6aS)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)propanoate (3.0 g, 9.3 mmol), 3-(5-bromo-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropyl acetate (4.4 g, 8.6 mmol), Ruphos (1.6 g, 3.4 mmol), Pd2(dba)3 (0.79 g, 0.86 mmol), and cesium carbonate (8.4 g, 26 mmol) in toluene (50 mL) was stirred at 105° C. under argon for 15 hours. The reaction was concentrated under vacuum and purified by preparative HPLC (C18, 0.01M NH4HCO3 in H2O, ACN) to give (S)-methyl 3-((3aR,6aS)-5-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-(methoxymethyl)pyridin-3-yl)-1H-indol-5-yl)hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl)-2-(((benzyloxy)carbonyl)amino)propanoate (Int Bii) (2.2 g, 34% yield). ESI-MS [M+H] + :740.4.

[0296] As described above, the compounds in the following table were synthesized using appropriate starting materials in a similar route to Int Bii:

[0297]

[0298] Synthesis of tert-butyl (3aS,6aR)-4-((S)-2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate, Int Biii-3

[0299]

[0300] Step 1: tert-butyl (3aR,6aR,Z)-4-(methoxymethylene)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Int Biii-a)

[0301] At 0 ° C, under N2, 4-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1.00 g, 4.44 mmol) was added to a solution of (methoxymethyl)triphenylphosphine chloride (2.74 g, 7.99 mmol) and potassium tert-butoxide (996 mg, 8.88 mmol) in THF (30 mL), and the solution was stirred at 25 ° C for 16 hours. TLC (petroleum ether / EtOAc=5:1) showed that the product was formed (Rf=0.65, 0.7). The concentrated residue was purified by silica gel flash chromatography (0-10% EtOAc / petroleum ether) to give Int Biii-a (0.52 g, 42% yield).

[0302] 1 H NMR(400MHz,DMSO-d6)δ:5.95(m,1H),3.51(m,2H),3.47(m,1H),3.03(m,1H),3.00(m,1H), 2.62(m,1H),1.93(m,2H),1.72(m,1H),1.46(m,1H),1.40(s,9H),1.30(m,2H),0.87(m,1H). ESI-MS[M-tBu+MeCN] + :239.2.

[0303] Step 2: (3aR,6aR)-4-Formylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Int Biii-b)

[0304] To a solution of (3aR,4Z,6aR)-4-(methoxymethylene)-1,3,3a,5,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester Int Biii-a (1.00 g, 3.95 mmol) in MeCN (25 mL) was added 2,2,2-trichloroacetic acid (812 mg, 4.97 mmol) at 25°C. The solution was stirred at 25°C for 16 hours. TLC indicated that the reaction was complete, and the reaction mixture was acidified with aqueous NaHCO3 to pH = 7-8 and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the product Int Biii-b. ESI-MS [M-tBu+MeCN] + :224.9.

[0305] Step 3: (3aR,6aR)-4-(Hydroxymethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (IntBiii-c)

[0306] At 0 ° C, sodium borohydride (592 mg, 15.6 mmol) was added to a solution of (3aR, 6aR)-4-formyl-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta [c] pyrrole-2-carboxylic acid tert-butyl ester (2.50 g, 10.4 mmol) in MeOH (50 mL). The solution was stirred at 25 ° C for 2 hours. TLC showed that the reaction was complete. The solution was quenched with NH4Cl (aqueous solution), the solvent was evaporated under reduced pressure, and the aqueous layer was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by flash chromatography on silica gel (0-20% EtOAc / petroleum ether) to give Int Biii-c (1.7 g, 61% yield). 1 H NMR(400MHz,DMSO-d6)δ:12.4(s,1H),4.51(s,1H),3.36(m,1H),3.30(m,3H),3.15(dd,J1 =11.2Hz, J1=3.6Hz,1H),3.00(m,1H),2.26(m,1H),1.79(m,3H),1.38(s,9H),1.32(m,2H). ESI-MS[M-tBu+MeCN] + :227.1.

[0307] Step 4: (3aR,6aR)-4-(iodomethyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (IntBiii-d)

[0308] At 15 ° C, to (3aR, 6aR) -4- (iodomethyl) hexahydrocyclopenta [c] pyrrole -2 (1H) -carboxylic acid tert-butyl ester (500mg, 1.86mmol), imidazole (279mg, 4.10mmol), triphenylphosphine (782mg, 2.98mmol) in DCM (2.5mL) and THF (0.3mL) solution was added I2 (757mg, 2.98mmol). The suspension was stirred at 25 ° C for 1 hour, and TLC (petroleum ether / EtOAc = 5: 1) showed that the reaction was complete (product Rf = 0.7). The reaction was then quenched with Na2SO3, the resulting product was extracted with EtOAc, washed with water and brine, and the organic phase was concentrated in vacuo to give a crude product. The crude product was purified by silica gel combi-flash (0-13% EtOAc / petroleum ether) to give Int Biii-d (550mg, 80% yield).

[0309] 1 H NMR (400MHz, DMSO-d6) δ: 3.36 (m, 4H), 3.20 (dd, J1=12.0Hz, J2=3.2Hz, 1H), 3 .00(m,1H),2.67(s,1H),2.22(s,1H),1.91(m,3H),1.39(s,9H),1.34(m,2H).

[0310] ESI-MS [M-tBu+MeCN] + :377.1.

[0311] Step 5: (3aS,6aR)-tert-butyl 4-(((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Int Biii-e)

[0312] At -78 ° C, 3-isopropyl-2,5-dimethoxy-1,4-dihydropyrazine (1.26 g, 6.82 mmol) in THF (20 mL) was added dropwise with n-butyl lithium (2.50 M, 2.73 mL) and stirred for 15 minutes. (3aR, 6aR)-4-(iodomethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester, IntBiii-d (2.10 g, 5.68 mmol) in THF (10 mL) was added and stirred for 2 hours at 25 ° C. TLC (petroleum ether / EtOAc=5:1) showed that the reaction was complete. The reaction was then quenched with water, and the resulting product was extracted with EtOAc and washed with water. The organic phase was concentrated in vacuo to give a crude product. The crude product was purified by silica gel combi-flash (0-13% petroleum ether / EtOAc) to afford Int Biii-e (2.0 g, 77% yield).

[0313] 1 H NMR(400MHz,DMSO-d6)δ:4.00(m,1H),3.91(m,1H),3.61(m,6H),3.25(m,2H),3.00(m,1H),2.57(s,1H),2.1 7(m,2H),1.85(m,3H),1.69(m,2H),1.37(s,9H),1.23(m,3H),1.00(d,J=4.0Hz,3H),0.62(d,J=6.0Hz,3H). ESI-MS[M+H] + :408.4

[0314] Step 6: (3aS,6aR)-tert-butyl 4-((S)-2-amino-3-methoxy-3-oxopropyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Int Biii-f)

[0315] To a solution of (3aS,6aR)-4-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (3.0 g, 7.3 mmol) in MeCN (36 mL) and water (36 mL) was added hydrochloric acid (1.0 M, 30 mL) at 25°C. The solution was stirred at 25°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction solution was adjusted to pH = 9 with aqueous NaHCO3. The crude solution of Int Biii-f was used directly in the next step. ESI-MS [M+H] + :313.2

[0316] Step 7: (3aS,6aR)-4-((S)-2-(((benzyloxy)carbonyl)amino)-3-methoxy-3-oxopropyl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Int Biii-3)

[0317] To the crude solution of Int Biii-f was added benzyl chloroformate (3.74 g, 21.9 mmol, 3.11 mL, 3 equiv) at 0 °C. The solution was stirred at 25 °C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was extracted with EtOAc, washed with water and brine, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography on silica gel (0-30% EtOAc / petroleum ether) to give Int Biii-3 (1.8 g, 80% two-step yield) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ:7.82(m,1H),7.36(m,5H),5.05(s,2H),4.02(m,1H),3.64(s,3H),3.40(m,1H), 3.20(s,1H),3.00(m,1H),2.60(s,1H),2.15(s,1H),1.86(m,2H),1.70(m,3H),1.38(s,9H),1.23(m,3H). ESI-MS[M+Na] + :469.2.

[0318] Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester Int C:

[0319]

[0320] Step 1: 1,2-di-tert-butyl 3-methyl (S)-tetrahydropyridazine-1,2,3-tricarboxylate Int C-1

[0321] To a solution of (S)-tetrahydropyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester (CAS: 156699-39-7, 10.00 g, 30.28 mmol) in MeOH (150 mL) was added a solution of TMSCHN2 (2M in Et2O) (66 mL, 150 mmol) dropwise at 0°C. The mixture was stirred at room temperature for 16 hours. The reaction was then quenched with 10% AcOH aqueous solution (100 mL). The mixture was extracted with ethyl acetate (3*300 mL), and the combined extracts were washed with NaHCO3 (saturated, 300 mL) and washed with anhydrous Na2SO 24Dry, filter and concentrate. The residue was purified by silica gel column (eluent: ethyl acetate / petroleum ether = 1:3) to obtain colorless oily 1,2-di-tert-butyl 3-methyl (S)-tetrahydropyridazine-1,2,3-tricarboxylate, Int C-1 (8.5 g, yield: 82%). MS: m / z = 345.2 (M+1, ESI+).

[0322] Step 2: (S)-hexahydropyridazine-3-carboxylic acid methyl ester Int C-2

[0323] To a solution of 1,2-di-tert-butyl 3-methyl (S)-tetrahydropyridazine-1,2,3-tricarboxylate, Int C-1 (8.50 g, 24.7 mmol) in dichloromethane (20 mL) was added TFA (20 mL) at 0°C. The mixture was left at room temperature for 3 hours. The mixture was concentrated in vacuo to give crude (S)-hexahydropyridazine-3-carboxylic acid methyl ester, Int C-2 (9.20 g, yield: 100%) as a colorless oil. MS: m / z = 145.0 (M+1, ESI+). The material was used directly in the next step.

[0324] Step 3: (S)-1-((S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester Int C-3

[0325] To a solution of (2S)-3-(3-bromophenyl)-2-[(2-methylpropane-2-yl)oxycarbonylamino]propionic acid (CAS: 82278-73-7, 3.01 g, 8.77 mmol), HOBt (1.13 g, 12.45 mmol) and EDCI (1.60 g, 12.45 mmol) in dichloromethane (50 mL) was added (S)-methyl hexahydropyridazine-3-carboxylate, Int C-2 (3.26 g, 8.30 mmol) and NMM (7.64 g, 74.9 mmol) at 0 °C. The resulting mixture was degassed and refilled with nitrogen three times and then stirred at 25 °C for 16 hours. The suspension was partitioned between NH4Cl (50 mL) aqueous solution and DCM (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by elution with a silica gel column (eluent: ethyl acetate / petroleum ether = 1:5) to give (S)-1-((S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester, Int C-3 (1.20 g, yield: 40%) as a yellow solid. MS: m / z = 469.7, 471.7 (M+1, ESI+).

[0326] As described above, the compounds in the following table were synthesized using appropriate starting materials in a similar route to Int C-3:

[0327]

[0328]

[0329] Step 4: (S)-1-((S)-2-((tert-Butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester Int C

[0330] To a mixture of (S)-1-((S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester, Int C-3 (1.20 g, 2.54 mmol), potassium acetate (0.76 g, 7.63 mmol) and bis(pinacolato)diboron (1.30 g, 5.10 mmol) in dioxane (25 ml) was added Pd(dppf)Cl2 (0.19 g, 0.25 mmol). The resulting mixture was degassed and refilled with nitrogen three times and then stirred at 80°C for 4 hours. The suspension was partitioned between aqueous NH4Cl solution (50 mL) and ethyl acetate (3*50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO2, filtered and concentrated. The crude product was purified by silica gel column (eluent: ethyl acetate / petroleum ether=1:10) to give (S)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylate, Int C (0.75 g, yield: 55%) as a yellow solid. MS: m / z=517.8 (M+1, ESI+).

[0331] Synthesis of methyl N-methyl-N-((S)-1-(4-morpholinobut-2-ynyl)pyrrolidine-3-carbonyl)-L-valine Int D:

[0332]

[0333] Step 1: (S)-3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester

[0334] To a stirred solution of methyl-L-valine tert-butyl ester (CAS: 5616-87-5, 750 mg, 4.00 mmol) and DIPEA (1.03 g, 8.00 mmol) in dichloromethane (30 mL) at 0°C, (S)-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid (CAS: 192214-00-9, 998 mg, 4.00 mmol) and CIP (1.67 g, 6.00 mmol) were added portionwise. The resulting mixture was stirred at 25°C for 2 hours. The mixture was washed with brine (30 mL). The organic phase was dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo, and the residue was purified by flash column (eluent: petroleum ether / ethyl acetate = 75:25) silica gel chromatography to give (S)-3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester Int D-1 (1.60 g, yield: 85%) as a white solid. MS: m / z = 418.9 (M+1, ESI+).

[0335] Step 2: N-methyl-N-((S)-pyrrolidine-3-carbonyl)-L-valine tert-butyl ester Int D-2

[0336] A solution of (S)-3-(((S)-1-(tert-butoxy)-3-methyl-1-oxobutan-2-yl)(methyl)carbamoyl)pyrrolidine-1-carboxylic acid benzyl ester Int D-1 (1.00 g, 2.40 mmol) and Pd / C (0.50 g) in THF (20 mL) was stirred at 25 °C for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give N-methyl-N-((S)-pyrrolidine-3-carbonyl)-L-valine tert-butyl ester Int D-2 (480 mg, 63% yield) as a brown oil, which was used in the next step without purification. MS: m / z = 284.9 (M+1, ESI+).

[0337] Step 3: N-methyl-N-((S)-1-(4-morpholinobut-2-ynyl)pyrrolidine-3-carbonyl)-L-valine tert-butyl ester, Int D-3

[0338] A solution of N-methyl-N-((S)-pyrrolidine-3-carbonyl)-L-valine tert-butyl ester Int D-2 (142 mg, 0.50 mmol), 4-morpholinobut-2-ynoic acid (CAS: 38346-95-1, 169 mg, 1.00 mmol), CIP (278 mg, 1.00 mmol) and DIPEA (258 mg, 4.00 mmol) in DMF (4 mL) was stirred at 0° C. for 2 hours. The mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2*20 mL). The organic phase was dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo, and the residue was purified by flash column (eluent: dichloromethane / methanol=40:1) silica gel chromatography to obtain colorless oily N-methyl-N-((S)-1-(4-morpholinobutyl-2-ynyl)pyrrolidine-3-carbonyl)-L-valine tert-butyl ester, Int D-3 (100 mg, yield: 41%). MS: m / z=435.9 (M+1, ESI+).

[0339] Step 4: N-methyl-N-((S)-1-(4-morpholinobut-2-ynyl)pyrrolidine-3-carbonyl)-L-valine, Int-D

[0340] N-methyl-N-((S)-1-(4-morpholinobutyl-2-ynyl)pyrrolidine-3-carbonyl)-L-valine tert-butyl ester, Int D-3 (100 mg, 0.23 mmol) and TFA (1 mL) in dichloromethane (3 mL) were stirred for 2 hours at 25° C. The mixture was concentrated in vacuo to give N-methyl-N-((S)-1-(4-morpholinobutyl-2-ynyl)pyrrolidine-3-carbonyl)-L-valine, Int-D (120 mg, crude) as a brown oil, which was used in the next step without purification. MS: m / z=379.9 (M+1, ESI+).

[0341] Synthesis of N-methyl-N-((S)-1-(2-oxopropanoyl)pyrrolidine-3-carbonyl)-L-valine, Int Di

[0342]

[0343] To a solution of Int D-2 (202 mg, 0.71 mmol) and Et3N (86 mg, 0.85 mmol) in DCM (3 mL) was added a solution of 2-oxopropanoyl chloride (69 mg, 0.78 mmol) at 0°C. The reactants were stirred at room temperature for 3 hours. The reaction was quenched with water (20 mL) and extracted with DCM (20 mL*3). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give a crude product, which was purified by silica gel combi-flash (petroleum ether / EtOAc=5:1) to give ketoamide (200 mg, 79% yield) as a colorless oil. ESI-MS [M+H] + : 355.2. TFA (100 mg, 0.87 mmol) was added to a solution of ketoamide (200 mg, 0.58 mmol) in DCM (6 mL) and the reaction was stirred at 25 °C for 3 hours. Evaporation gave N-methyl-N-((S)-1-(2-oxopropanoyl)pyrrolidine-3-carbonyl)-L-valine Int Di (135 mg, 77% yield) as a colorless oil. ESI-MS [M+H] + :299.10

[0344] Synthesis of 2-amino-2-(6-bromo-2,3-dihydro-1H-inden-1-yl)acetic acid Int E:

[0345]

[0346] Step 1: Synthesis of diethyl 2-((diphenylmethylene)amino)malonate IntE-1

[0347]

[0348] A mixture of benzophenone imine (CAS: 1013-88-3, 25.0 g, 138 mmol) and dimethyl 2-aminomalonate hydrochloride (25.0 g, 136 mmol) in DCM (300 mL) was stirred at room temperature for 3 days. The solid matter was filtered off and the filtrate was concentrated in vacuo. The residue was redissolved in TBME and washed with water, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 15-100% EtOAc in heptane) to give the title compound (27.0 g, 64%) as a colorless oil, which was left to solidify. 1H NMR (300 MHz, chloroform-d) d 7.78-7.63 (m, 2H), 7.51-7.28 (m, 6H), 7.24-7.11 (m, 2H), 4.90 (s, 1H), 3.78 (s, 6H); LCMS (ES): m / z = 312.2 [M+H] + .

[0349] Step 2: Synthesis of dimethyl 2-(diphenylmethyleneamino)-2-[(lR)-6-bromoindan-l-yl]malonate, IntE-2

[0350]

[0351] A solution of 6-bromoindan-l-ol (6.5 g, 31 mmol), Int E-1 (14.0 g, 46 mmol) and trimethylphosphine (1 M solution in THF, 46 mL, 46 mmol) in toluene (100 g) was cooled to -75°C. Diethyl azodicarboxylate (40 wt% solution in toluene, 21 g, 48 mmol) was added dropwise over 30 minutes and the solution was stirred at -75°C for 1.5 hours and at room temperature for 3 hours to give a dark brown solution. The solution was concentrated in vacuo and the residue was purified by column chromatography (silica gel, eluted with heptane / ethyl acetate 4:1) to give the title compound (9.6 g, 62%) as a yellow oil. 1H NMR(300MHz, chloroform-d)d7.84(dd,J=1.9,0.9Hz,1H),7.64-7.49(m,2H),7.47-7.22(m,7H),7.22-7.14(m,2H),7.05(dd,J=8.0,1.1Hz,1H),4.26-4 .03(m,1H),3.44(s,3H),3.25(s,3H),2.94(ddd,J=15.6,9.2,6.0Hz,1H),2.76(ddd,J=15.6,9.1,5.9Hz,1H),2.55-2.17(m,2H); LCMS(METHOD) 3) (ES): m / z=506.3,508.3[M+H]+.

[0352] Step 3: Synthesis of 2-amino-2-[(1R)-6-bromoindan-1-yl]acetic acid hydrobromide, Int E

[0353]

[0354] At room temperature, concentrated HCI (10 mL) (exothermic) was added to a solution of Int E-2 (9.6 g, 19 mmol) in THF (30 mL). The solution was stirred at room temperature for 30 minutes, then diluted with TBME (70 mL) and water (30 mL). Each phase was separated, and the aqueous phase was extracted twice with TBME, then concentrated in vacuo to obtain the crude 2-amino-2-[(1R)-6-bromoindan-1-yl] dimethyl malonate hydrochloride of a colorless oil, which can be used without further purification.

[0355] To a solution of dimethyl 2-amino-2-[(lR)-6-bromoindan-l-yl]malonate hydrochloride in water (20 mL) was added concentrated HBr (48% HBr, 20 mL) at room temperature. The solution was heated to reflux for 3 hours and the product precipitated. The suspension was cooled to room temperature and filtered. The filter cake was washed with TBME and dried in vacuo to give the title compound (5.2 g, 78%) as a white solid, which was a mixture of diastereomers. 1H NMR (300 MHz, deuterium oxide + 1 drop of DCI) d 7.38 (s, 0.33H), 7.34-7.21 (m, 1.67H), 7.15-6.96 (m, 1H), 4.41 (d, J = 4.0 Hz, 0.33H), 4.32 (d, J = 3.7 Hz, 0.67H), 3.91-3.81 (m, 0.33H), 3.75 (dt, J = 9.3, 4.8 Hz, 0.67H), 3.07-2.54 (m, 2H), 2.50-2.01 (m, 1H), 1.99-1.64 (m, 1H); LCMS (METHOD 3) (ES): m / z 270.2, 272.2 [M+H]+.

[0356]

[0357] Dioxane (20mL) was added to the crude amino acid solution, followed by Boc anhydride (2.0g, 9.2mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with DCM (2x 50mL), EtOAc (50mL) was added, and the mixture was acidified to pH 2 with 4N HCI. The layers were separated and the aqueous phase was extracted with additional EtOAc (30mL). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the title compound as a mixture of 2 diastereomers (1.22g, 90%). LCMS (ES): m / z 382.4, 384.4 [M+H]+.

[0358] Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(1,4-diazepan-1-yl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester, Int-F

[0359]

[0360] Step 1: Synthesis of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1,4-diazepane-1-carboxylic acid benzyl ester Int F-1:

[0361] To a solution of benzyl 1,4-diazepane-1-carboxylate (1.0 g, 4.3 mmol) and (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropionate (4.20 g, 12.8 mmol) in acetonitrile (20 mL) was added triethylamine (2.75 g, 21.4 mmol) at 70°C under nitrogen. The resulting solution was then heated at the same temperature overnight. After 16 hours, water (60 mL) was added to the reaction solution and extracted with dichloromethane (30 x 3 mL). The organic layer was separated and evaporated to dryness. The residue was then purified by column chromatography (0-60% ethyl acetate in petroleum ether) to give (S)-benzyl 4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1,4-diazepane-1-carboxylate Int F-1 (631 mg, 1.45 mmol, 34% yield) as a white solid. MS: m / z = 436.2 (M+1, ESI+).

[0362] Step 2: Synthesis of (S)-3-(4-((benzyloxy)carbonyl)-1,4-diazepan-1-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid Int F-2

[0363] To a solution of (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl)-1,4-diazepane-1-carboxylic acid benzyl ester Int F-1 (630 mg, 1.45 mmol) in MeOH (9 mL) cooled to 0° C. was slowly added a solution of LiOH (120 mg, 5.0 mmol) in water (1 mL) via a syringe over 2 minutes. After addition, the solution was slowly warmed to room temperature and stirred for another 3 hours. After complete hydrolysis, the solution was evaporated to dryness and diluted with water, neutralized with 0.1N HCl solution, and extracted with DCM (20 x 2 mL). The collected organic phases were combined, dried over sodium sulfate, then filtered and concentrated to give (S)-3-(4-((benzyloxy)carbonyl)-1,4-diazepan-1-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid IntF-2 (400 mg, 65% yield) as a white solid, which was pure according to LCMS. It was used as is in the next step without further purification. MS: m / z=422.3 (M+1, ESI+).

[0364] Step 3: Synthesis of 4-((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-(methoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-3-oxopropyl)-1,4-diazepane-1-carboxylic acid benzyl ester Int F-3

[0365] To a solution of crude (S)-hexahydropyridazine-3-carboxylic acid methyl ester (CAS: 138323-07-6, 350 mg, 0.95 mmol) in dichloromethane (5 mL) was added N-methylmorpholine (1.0 g, 9.5 mmol) and (S)-3-(4-((benzyloxy)carbonyl)-1,4-diazepan-1-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid Int F-2 (400 mg, 0.95 mmol) at 0°C, followed by HOBt (27 mg, 0.2 mmol) and EDCI (570 mg, 1.5 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction solution was then diluted with dichloromethane (30 mL) and washed with H2O (3 x 10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The mixture was then purified by column chromatography (0-50% ethyl acetate in petroleum ether) to give benzyl 4-((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-(methoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-3-oxopropyl)-1,4-diazepane-1-carboxylate Int F-3 (400 mg, 0.7 mmol, 76% yield) as a white solid. MS: m / z = 548.3 (M+1, ESI+).

[0366] Step 4: Synthesis of (S)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3-(1,4-diazepan-1-yl)propanoyl)hexahydropyridazine-3-carboxylate, Int-F

[0367] To a solution of benzyl 4-((S)-2-((tert-butoxycarbonyl)amino)-3-((S)-3-(methoxycarbonyl)tetrahydropyridazin-1(2H)-yl)-3-oxopropyl)-1,4-diazepane-1-carboxylate Int F-3 (150 mg, 0.27 mmol) in MeOH (5 mL) at room temperature under nitrogen atmosphere was added Pd / C (30 mg, 10 wt%), and the mixture was then degassed and backfilled with hydrogen three times, and then stirred at room temperature under H2 atmosphere for 2 hours. Afterwards, the palladium catalyst was filtered off, the filter cake was washed with more methanol, the filtrate was evaporated to dryness, purified by reverse phase column chromatography (C18 column, eluted with 0-20% acetonitrile in water for 20 minutes) to give the desired fractions, which were lyophilized to dryness to give (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(1,4-diazepan-1-yl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester, Int-F (24 mg, 0.060 mmol, 21% yield) as a white solid. MS: m / z=414.2 (M+1, ESI+). 1H NMR (400MHz, CD3OD) δ5.21(ddd,J=46.2,8.4,3.9Hz,1H),4.32(d,J=12.2Hz,1H),3.73(t,J=6.2Hz,3H),3.71–3.57(m,1H),3.62–3.34(m ,2H),3.22–3.12(m,3H),3.09–2.95(m,1H),2.83(ddt,J=35.6,26.3,13.1Hz,5H),2.68–2.55(m,1H),2.13–1.57(m,7H),1.45(s,9H)ppm.

[0368] Synthesis of (3S)-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-(1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecane-4-yl)amino)-3-methyl-1-oxobutane-2-yl)-N-methyl-1-(4-morpholinobut-2-ynyl)pyrrolidine-3-carboxamide Example 1:

[0369]

[0370] Step 1: Synthesis of (3S)-1-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester 1

[0371] A solution of Int-C (290 mg, 0.56 mmol), Int Bi (249 mg, 0.56 mmol), Pd(DTBPF)Cl2 (417 mg, 0.56 mmol) and Na2CO3 (83 mg, 1.40 mmol) in dioxane / H2O (12 mL, 5:1) was stirred at room temperature for 16 h. The mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 98:2-95:5) to give a brown solid compound, (3S)-1-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester 1 (110 mg, yield: 23%). MS: m / z = 756.3 (M+1, ESI+).

[0372] The compounds in the following table were synthesized using appropriate starting materials in a similar route to Int 1 as described above:

[0373]

[0374]

[0375] Step 2: Synthesis of (3S)-1-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid, 2

[0376] A solution of (3S)-1-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester 1 (110 mg, 0.15 mmol) and trimethyltin hydroxide (132 mg, 0.73 mmol) in dichloroethane (2 mL) was stirred at 65° C. for 16 hours. The mixture was diluted with dichloromethane (20 mL) and filtered, and the filtrate was washed with citric acid (10% in water). The organic phase was dried over anhydrous Na2SO4. After filtration, the solvent was concentrated in vacuo to give (3S)-1-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid, 2 (130 mg, yield: 96%) as a brown solid, which was used in the next step without purification. MS: m / z=742.4 (M+1, ESI+).

[0377] The compounds in the following table were synthesized using appropriate starting materials in a similar route to Int 1 as described above:

[0378]

[0379] Synthesis of Example 16:

[0380]

[0381] Step 1: (S)-1-((S)-3-((3aR,4R,6aS)-2-(3-(3-acetoxy-2,2-dimethylpropyl)-1-ethyl-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)octahydrocyclopenta[c]pyrrol-4-yl)-2-(((benzyloxy)carbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester

[0382] To a solution of Int B-vi (2.00 g, 4.10 mmol) in dioxane (10 mL) was added methyl Int C3-iii (2.25 g, 4.92 mmol), Ruphos Pd G4 (697 mg, 0.82 mmol), Ruphos (765 mg, 1.64 mmol) and Cs2CO3 (2.67 g, 8.21 mmol). The reaction mixture was stirred at 100 °C for 12 hours under N2. After filtration, the solvent was removed in vacuo and the residue was purified by silica gel chromatography using a flash column (eluent: PE / EA = 80:20-10:90) to give compound 16A (1.31 g, yield: 29%) as a white solid. MS: m / z = 865.0 (M+H, ESI+).

[0383] Step 2: (S)-1-((S)-2-(((benzyloxy)carbonyl)amino)-3-((3aR,4R,6aS)-2-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)octahydrocyclopenta[c]pyrrol-4-yl)propanoyl)hexahydropyridazine-3-carboxylic acid

[0384] To a solution of 16A (1.31 g, 1.51 mmol) in THF (13 mL) and water (6 mL) was added LiOH·H2O (252 mg, 6.01 mmol), and the mixture was stirred at room temperature for 16 hours. The mixture was adjusted to pH = 5-6 with HCl (1 mol / mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with NaCl (saturated, 20 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was removed to give crude 16B (1 g) as a light yellow solid, which was used in the next step without further purification. MS: m / z = 809.0 (M+H, ESI+).

[0385] Step 3: Benzyl ((23aR,24R,26aS,63S,4S)-11-ethyl-12-(2-((S)-1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-21,22,23,23a,24,25,26,26a,61,62,63,64,65,66-tetradecahydro-11H-8-oxa-1(5,3)-indol-2(2,4)-cyclopenta[c]pyrrolo[6(1,3)-pyridazinylheterocycloundecane-4-yl)carbamate

[0386] A mixture of 16B (500 mg, 0.62 mmol), Py2S2 (1.91 g, 6.20 mmol) and PPh3 (1.63 g, 6.20 mmol) in toluene (5 mL) was stirred at 85 °C under N2 for 3 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with NaCl (20 mL) and dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by flash column (eluent: DCM / MeOH = 0–5%) silica gel chromatography to give compound 20C (385 mg, impure) as a yellow solid. The product was then purified by preparative HPLC (column: Gemini-C18 150 x 21.2 mm, 5 μm, ACN-H2O (0.05% NH3.H2O), flow rate: 20 ml / min; wavelength: 214 nm / 254 nm. 10 min gradient maintained at 25-40% CH3CN) to obtain P1: 20 mg, P2: 8 mg, P3: 10 mg, P4: 45 mg as a yellow solid.

[0387] MS: m / z=791.0 (M+1, ESI+).

[0388] Step 4: (4R,5S,8R,10S,16S)-10-amino-24-ethyl-23-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-20,20-dimethyl-18-oxa-2,12,24,30-tetraazahexacyclo[20.5.2.1^{2,5}.1^{12,16}.0^{4,8}.0^{25,29}]trione-1(27),22,25,28-tetraene-11,17-dione

[0389] 16C (45 mg, 0.06 mmol) was added to t Pd / C (30 mg, 0.28 mmol) was added to a solution in BuOH (4 mL) and stirred at 40° C. under a H 2 balloon atmosphere for 2 hours. t The filtrate was collected by filtration of cite washed with BuOH (5 mL) and MeOH (5 mL). After evaporation, 16D (23 mg, yield: 58%) was obtained as a colorless oil. MS: m / z=657.1 (M+H, ESI+).

[0390] Step 5: (1R,2R)-N-[(4R,5S,8R,10S,16S)-24-ethyl-23-{2-[(1S)-1-methoxyethyl]pyridin-3-yl}-20,20-dimethyl-11,17-dioxo-18-oxa-2,12,24,30-tetraazahexacyclo[20.5.2.1^{2,5}.1^{12,16}.0^{4,8}.0^{25,29}]triacontahedral-1(28),22,25(29),26-tetraen-10-yl]-2-methylcyclopropane-1-carboxamide

[0391] To a stirred solution of compound 16D (23 mg, 0.03 mmol), (1R,2R)-2-methylcyclopropane-1-carboxylic acid (CAS: 6202-94-4; 7 mg, 0.07 mmol) and N,N-diisopropylethylamine (23 mg, 0.17 mmol) in DMF (3 mL) was added dropwise a solution of COMU (30 mg, 0.07 mmol) in DMF (0.5 mL) at -20 °C. The reaction mixture was stirred at 25 °C for 2 hours. It was quenched with saturated NH4Cl (100 mL), extracted with DCM (20 mL x 3), and washed with brine (10 mL x 3). The organic layer was dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo and the residue was purified by preparative HPLC (column: Gemini-C18 150x21.2 mm, 5 μm, ACN--H2O (0.1% FA), flow rate: 20 ml / min; wavelength: 214 nm. Sample injected in DMF, 12 min linear gradient from 45% to 95% CH3CN) to give 5 isomers of Example 16.

[0392] Example 16 Isomer 1 (1.27 mg)

[0393] MS: m / z=739.0 (M+1, ESI+). Retention time (min): 1.150 min.

[0394] 1HNMR(400MHz,MeOD)δ8.67(s,2H),8.06(d,J=8.1Hz,1H),8.00(d,J=7.4Hz,1H),7.84(s,1H),7.77–7.69(m,2H),7.55(dd,J=13.0 ,7.8Hz,1H),7.47(d,J=7.6Hz,1H),5.28–5.21(m,3H),4.67–4.59(m,2H),4.39(s,2H),4.34–4.28(m,1H),3.77(dd,J=16.6,11.8H z,2H),3.52(d,J=18.7Hz,3H),3.38(s,1H),3.24(d,J=8.7Hz,3H),3.03(s,2H),2.80(s,2H),2.56(s,3H),2.18(s,1H),2.14–2.03 (m,3H),1.93(d,J=4.4Hz,3H),1.57–1.46(m,3H),1.35(dd,J=12.2,5.9Hz,2H),1.19(s,12H),0.80(t,J=6.4Hz,4H),0.50(s,1H).

[0395] Example 16 Isomer 2 (0.86 mg)

[0396] MS: m / z=739.5 (M+1, ESI+). Retention time (min): 1.281 min.

[0397] 1HNMR(400MHz,MeOD)δ8.62(d,J=5.1Hz,1H),8.42(s,1H),7.81(d,J=7.8Hz,1H),7.41(d d,J=7.5,4.7Hz,1H),7.23–7.16(m,1H),7.00(s,1H),6.73(d,J=8.9Hz,1H),5.27–5.16( m,2H),4.51(s,1H),4.16(dt,J=14.7,7.3Hz,1H),3.86(dd,J=17.6,9.5Hz,1H),3.62–3. 46(m,3H),3.43–3.30(m,2H),3.13(dd,J=14.9,10.3Hz,3H),2.98(d,J=12.6Hz,1H),2.8 8(d,J=8.9Hz,1H),2.74(d,J=12.7Hz,1H),2.58(d,J=14.0Hz,2H),2.47(s,2H),2.17(d, J=15.0Hz,2H),2.08(dd,J=17.1,9.4Hz,2H),1.93(d,J=5.7Hz,2H),1.83(d,J=6.8Hz,2H ),1.67(s,2H),1.49(d,J=17.1Hz,2H),1.27–1.17(m,11H),1.16–1.11(m,1H),1.08(d,J =6.4Hz, 1H), 1.02 (d, J = 2.8Hz, 1H), 0.81 (dd, J = 13.9, 7.4Hz, 3H), 0.45 (d, J = 26.5Hz, 2H).

[0398] Example 16 Isomer 3 (1.12 mg)

[0399] MS: m / z=739.4 (M+1, ESI+). Retention time (min): 1.290 min.

[0400] 1HNMR(400MHz,MeOD)δ8.63(d,J=4.6Hz,1H),8.05(m,1H),7.81–7.75(m,1H),7.57–7.52( m,1H),7.21(d,J=8.9Hz,1H),6.88(s,1H),6.72(d,J=8.5Hz,1H),5.48(s,1H),5.27–5.22( m,1H),4.63(dd,J=13.8,7.9Hz,1H),4.42(d,J=12.4Hz,1H),4.33–4.26(m,1H),4.22–4.1 4(m,1H),4.06(dd,J=12.5,6.1Hz,1H),3.90(dd,J=19.8,9.3Hz,2H),3.80–3.68(m,2H),3. 60–3.52(m,2H),3.49–3.43(m,2H),3.13(s,3H),3.00(d,J=14.6Hz,2H),2.75(s,1H),2.5 7(d,J=11.1Hz,2H),2.22–2.16(m,1H),2.09(t,J=7.5Hz,2H),1.95–1.85(m,4H),1.71(s,1 H),1.62(dd,J=14.0,5.6Hz,1H),1.49(d,J=12.8Hz,2H),1.34(s,1H),1.21(d,J=17.6Hz, 12H), 1.12 (s, 3H), 1.00 (t, J = 5.8Hz, 2H), 0.84 (s, 2H), 0.79 (d, J = 6.9Hz, 3H), 0.49 (s, 2H).

[0401] Example 16 Isomer 4 (2.35 mg)

[0402] MS: m / z=739.4 (M+1, ESI+). Retention time (min): 1.291 min.

[0403] 1HNMR(400MHz,MeOD)δ8.60(d,J=3.5Hz,1H),8.41(s,1H),7.69(d,J=7.7Hz,1H),7.41(dd,J= 7.7,4.8Hz,1H),7.22(d,J=8.8Hz,1H),6.97(s,1H),6.72(d,J=8.9Hz,1H),5.23(dd,J=13.2, 8.5Hz,2H),4.36–4.27(m,1H),4.11(dd,J=14.6,7.2Hz,1H),3.97(dd,J=14.7,7.2Hz,1H),3. 88–3.74(m,2H),3.59(d,J=11.0Hz,1H),3.38(d,J=7.9Hz,1H),3.27(s,3H),3.13(s,1H),3.0 0(d,J=7.7Hz,1H),2.92–2.78(m,2H),2.64(d,J=7.4Hz,2H),2.43(d,J=14.2Hz,1H),2.10(dd ,J=16.3,8.8Hz,3H),1.93(d,J=5.8Hz,1H),1.84(dd,J=15.2,10.5Hz,2H),1.65(s,1H),1.50 (d,J=6.4Hz,2H),1.33(d,J=6.1Hz,3H),1.21(d,J=17.5Hz,9H),1.00(d,J=4.4Hz,2H),0.96– 0.87(m,1H),0.79(d,J=6.1Hz,3H),0.74(t,J=6.9Hz,1H),0.48(d,J=7.6Hz,1H),0.33(s,2H).

[0404] Example 16 Isomer 5 (4.38 mg)

[0405] MS: m / z=739.4 (M+1, ESI+). Retention time (min): 1.324 min.

[0406] 1HNMR(400MHz,MeOD)δ8.68–8.58(m,1H),8.20–8.02(m,1H),7.68(dd,J=7.7,1.4Hz,1H) ,7.41(dd,J=7.7,4.8Hz,1H),7.22(d,J=8.3Hz,1H),6.86(s,1H),6.71(d,J=7.9Hz,1H), 5.47(d,J=5.5Hz,1H),5.35–5.15(m,1H),4.42(d,J=12.9Hz,1H),4.26(dd,J=12.2,6.0H z,1H),4.09(d,J=6.0Hz,1H),3.95(d,J=6.6Hz,1H),3.85(d,J=10.8Hz,2H),3.69(d,J=10 .9Hz,1H),3.39(s,1H),3.24(d,J=17.2Hz,3H),3.02(dd,J=32.1,17.1Hz,3H),2.77(d,J =18.6Hz,1H),2.65–2.52(m,1H),2.29(d,J=14.4Hz,1H),2.22–2.00(m,1H),1.99–1.79( m,3H),1.78–1.58(m,3H),1.55–1.44(m,1H),1.33(t,J=14.0Hz,3H),1.29–1.09(m,5H), 1.07–0.86(m,3H),0.86(s,2H),0.75(dd,J=20.2,13.2Hz,3H),0.47(s,1H),0.32(s,2H).

[0407] Step 3: ((6 3 S,4S)-1 1 -Ethyl-1 2 -(2-(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 tert-butyl H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecane-4-yl)carbamate, 3

[0408] To a solution of (3S)-1-((2S)-2-((tert-butoxycarbonyl)amino)-3-(3-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)phenyl)propanoyl)hexahydropyridazine-3-carboxylic acid, 2 (100 mg, 0.14 mmol), diisopropylethylamine (52 mg, 0.40 mmol) in dichloromethane (2 mL) at 0°C were added HOBt (27 mg, 0.20 mmol) and EDCI (38 mg, 0.20 mmol). The mixture was stirred at 25°C for 16 hours. The mixture was diluted with dichloromethane (20 mL) and washed with brine. The organic phase was dried over anhydrous Na2SO4. After filtration, the solvent was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: dichloromethane / methanol = 99:1-95:5) to give (6 3 S,4S)-1 1 -Ethyl-1 2 -(2-(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-tert-butyl 8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecane-4-yl)carbamate, 3 (20 mg, yield: 19%). MS: m / z=724.3 (M+1, ESI+).

[0409] Step 4: (6 3 S,4S)-4-amino-1 1 -Ethyl-1 2 -(2-(1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -Hexahydro-1 1 Synthesis of H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzeneheterocycloundecane-5,7-dione,4

[0410] At 25°C, ((6 3 S,4S)-1 1 -Ethyl-1 2-(2-(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 A solution of tert-butyl H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecane-4-yl)carbamate, 3 (20 mg, 0.03 mmol) and TFA (0.50 mL) in dichloromethane (1 mL) was stirred for 1 hour. The mixture was concentrated in vacuo to give ((63S,4S)-4-amino-11-ethyl-12-(2-(1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzeneheterocycloundecane-5,7-dione, 4 (25 mg, crude) as a brown solid which was used in the next step without purification. MS: m / z = 624.3 (M+1, ESI+).

[0411] Step 5: Synthesis of (3S)-N-((2S)-1-(((63S,4S)-11-ethyl-12-(2-(1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecane-4-yl)amino)-3-methyl-1-oxobutane-2-yl)-N-methyl-1-(4-morpholinobut-2-ynyl)pyrrolidine-3-carboxamide Example 1

[0412] In an ice-salt bath, N-methyl-N-((S)-1-(4-morpholinobut-2-ynyl)pyrrolidine-3-carbonyl)-L-valine, Int D (6 mg, 0.016 mmol), ((63S,4S)-4-amino-11-ethyl-12-(2-(1-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexahydro-11H-8-oxa-1(5,3)-indol-6(1,3)-pyridazin-2(1,3)-benzheterocycloundecane-5,7-dione, 4 (10 mg, 0.016 mmol) and DIPEA were added to the mixture. To a solution of 1,4-dihydro-2-nitropropene (21 mg, 0.16 mmol) in DMF (1 mL) was added COMU (14 mg, 0.032 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (5 mL). The organic phase was dried over anhydrous Na2SO4. After filtration, the solvent was removed in vacuo and the residue was purified by preparative HPLC (Gemini 5u C 18 150x21.2mm, acetonitrile (0.1% formic acid) in water, flow rate: 20mL / min; wavelength: 214nm. Injection of sample in DMSO, 12.5min linear gradient from 20% to 95% acetonitrile) to obtain Example 1 (9mg, yield: 56%). MS: m / z=1007.4 (M+Na, ESI+). 1H NMR(400MHz, DMSO)δ8.80–8.67(m,1.14H),8.29(t,J=8.7Hz,0.16H),8.16–7.79(m,2.7H),7.76–7.40(m,4.3H),7.33–7.15 (m,1H),7.12–6.95(m,1H),5.70–5.46(m,0.2H),5.45–5.21(m,0.8H),5.15–4.95(m,0.5H),4.75–4.55(m,0.5H),4.40–3.35 (m,19H),3.29–3.22(m,1H),3.19–3.00(m,4H),2.99–2.84(m,2H),2.82–2.71(m,2H),2.71–2.59(m,2H),2.59–2.49(m,1H), 2.45–2.27(m,2H),2.26–1.85(m,4H),1.85–1.40(m,3H),1.34–1.14(m,3H),1.12–0.55(m,13.6H),0.45(d,J=3.3Hz,1.4H).

[0413] Analysis conditions

[0414] Equipment: SFC Thar X-5

[0415] Column: CHIRALPAK OJ-H 250mm x 4.6mm, 5μm

[0416] Mobile phase: 40% EtOH (NH4OH 0.2%)

[0417] Total flow rate: 2.5mL / min

[0418] Retention time = 8.44 min

[0419] The compounds in the following table were synthesized in a similar manner to Example 1 using appropriate starting materials.

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439]

[0440]

[0441]

[0442]

[0443]

[0444]

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460]

[0461]

[0462]

[0463]

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477] Bioassay

[0478] Biological Example 1: TR-FRET assay of the compounds of the present invention disrupting the interaction between Raf1Ras binding domain (RBD) and KRAS (Raf1 disrupts TR-FRET)

[0479] Materials and reagents

[0480] 1. His-tagged recombinant human KRASG12C / G12D (aa1-164, N-terminal His-tagged, GppNHp-loaded, prepared in-house)

[0481] 2. FLAG-tagged recombinant human Raf1Ras binding domain (aa54-131, C-terminal FLAG tag, produced in-house)

[0482] 3. LANCE detection buffer (10x) (PerkinElmer, CAT#CR97-100)

[0483] 4. Eu-W1024 labeled anti-6xHis antibody (PerkinElmer, CAT#AD0401)

[0484] 5. Anti-FLAG IgG coupled to SureLight-allophycocyanin (PerkinElmer, CAT#AD0059F)

[0485] 6. GppNHP (non-hydrolyzable GTP analog) (Abcam, CAT# ab146659)

[0486] 7. Bovine serum albumin heat shock fraction (Sigma-Aldrich, CAT#A9647-100G)

[0487] 8. DMSO (Thermo Fisher Scientific)

[0488] 9. Compound - stock solution in 10 mM DMSO

[0489] 10. Victor Nivo Multimode Plate Reader (PerkinElmer)

[0490] 11. OptiPlate-384, white opaque 384-well microplate (PerkinElmer)

[0491] Experimental Procedure

[0492] The disruption of Raf1-KRAS protein-protein binding of the test compound was determined using the time-resolved fluorescence resonance energy transfer (TR-FRET) technique. The assay buffer contained 1X LANCE detection buffer supplemented with 5mM MgCl2, 10μM GppNHp, and 2.5μg / mL BSA. His-KRas (GppNHp loading) was pre-incubated with a 4-fold dilution series of compounds at 8 points (starting at a final concentration of 10μM). After incubation at room temperature for 20 hours, a mixture of FLAG-RAF1 RBD, anti-His Eu-W1024, and anti-FLAG allophycocyanin was then added to the test sample wells at final concentrations of 50nM, 2nM, and 100nM, respectively. The reactants were incubated at room temperature for another 1 hour or 20 hours (for covalent compounds). The TR-FRET signal was read on a microplate reader with an excitation wavelength of 340nm and a detection wavelength of 615 and 665nm. Binding disruption curves were fitted in GraphPad Prism using a sigmoidal dose-response curve with a variable slope model. Compounds that caused a decrease in the TR-FRET ratio relative to the DMSO control wells were identified as compounds that promoted disruption of the Raf1-KRas complex, IC 50 The values ​​(nM) are shown in Table 1 below.

[0493] Table 1. IC of compounds that disrupt TR-FRET in Raf1 50 Value (nM)

[0494]

[0495] Biological Example 2: Pharmacokinetic Evaluation Experiment in Mice

[0496] Purpose:

[0497] Using LC / MS / MS method and male C57BL / 6 mice as test animals, the drug concentration in plasma at different times after intravenous and intragastrical administration to mice was determined; the pharmacokinetic behavior of the test compound in mice was studied and its pharmacokinetic properties were evaluated.

[0498] Experimental plan: 36 healthy adult male C57BL / 6 mice were used as experimental animals and divided into 4 groups according to the principle of similar weight, IV group (2 groups) with 9 mice in each group and PO group (2 groups) with 9 mice in each group. These animals were purchased from Jihui Experimental Animal Co., Ltd.

[0499] Drug preparation: Prepare IV and PO dosing solutions in 10% DMSO + 40% PEG300 + 5% Tween 80 + 45% saline at a concentration of 1 mg / mL.

[0500] Administration: After overnight fasting, each rat in the IV group was intravenously administered with a volume of 1 mL / kg and a dose of 1 mg / kg; each mouse in the PO group was orally administered with a volume of 5 mL / kg and a dose of 5 mg / kg.

[0501] Experimental procedures: After administration of the test compound to each male C57BL / 6 mouse in the IV group, 100ul blood samples were collected at 0.0833, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours and placed in a commercial anticoagulation tube pre-filled with EDTA-K 2. After administration of the test compound to each rat in the PO group, 100ul blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours and placed in a commercial anticoagulation tube pre-filled with EDTA-K 2. The tubes were centrifuged for 15 minutes to separate the plasma and stored at -70°C. Two hours after administration, the animals could be fed. After intravenous and intragastrical administration to rats, the content of the test compound in plasma was determined by LC / MS / MS method. The linear range of the method is 2.00 to 6000nM; plasma samples were analyzed after protein precipitation by acetonitrile treatment.

[0502] Experimental results: The experimental results are shown in Table 2.

[0503] Experimental conclusion: In the pharmacokinetic evaluation experiment in rats, the compound of the present invention showed higher exposure and better oral availability than the reference compound RM-018.

[0504] Table 2: Evaluation of pharmacokinetic results in rats

[0505] Grouping RM-018 Example 12 Isomer 2 IV Cl (mL / min / Kg) 58.5 21.4 IV T 1 / 2(h) 0.55 1.8 PPBm (% combined) 99.3 95.0 PO AUC (ng*h / mL) 28 355 PO C max (ng / mL) 18.1 75.5 %F(Oral) 2.0 9.2

[0506] Note: Cl: clearance; AUC: exposure; T 1 / 2: half-life; C max: maximum compound concentration after oral administration; F: bioavailability

[0507] RM-018 Group and Example A Group

[0508] Embodiment A is a compound selected from the above novel embodiments

[0509] Biological Example 3: CypA-compound-KRAS tri-complex formation TR-FRET assay using the compounds of the present invention (tri-complex formation TR-FRET)

[0510] Materials and reagents

[0511] 12.avi-labeled, biotinylated recombinant human KRAS G12C (biotin-KRAS G12C , aa1-164, C-terminally biotinylated, GppNHp-loaded, prepared in-house)

[0512] 13. His-cyclophilin A recombinant human (His-CypA, aa1-165, N-terminal His tag, prepared in-house)

[0513] 14. LANCE detection buffer (10x) (PerkinElmer, CAT#CR97-100)

[0514] 15. LanthaScreen Eu-Streptavidin (Invitrogen, CAT#PV5899)

[0515] 16. SureLight Allophycocyanin Anti-6His Antibody (PerkinElmer, CAT#AD0059H)

[0516] 17. GppNHP (non-hydrolyzable GTP analog) (Abcam, CAT# ab146659)

[0517] 18. Bovine serum albumin heat shock fraction (Sigma-Aldrich, CAT#A9647-100G)

[0518] 19. MgCl2 (Sigma-Aldrich, CAT#M0250-500G)

[0519] 20. DMSO (Thermo Fisher Scientific)

[0520] 21. Compound - stock solution in 10 mM DMSO

[0521] 22. Victor Nivo Multimode Plate Reader (PerkinElmer)

[0522] 23. OptiPlate-384, white opaque 384-well microplate (PerkinElmer)

[0523] Experimental Procedure

[0524] The time-resolved fluorescence resonance energy transfer (TR-FRET) technique was used to determine the CypA-compound--KRAS G12C The assay buffer contained 1X LANCE detection buffer supplemented with 5 mM MgCl2, 10 μM GppNHp, and 2.5 μg / mL BSA. G12C (GppNHp loading, final concentration of 30 nM) and his-CypA (final concentration of 300 nM) were incubated at room temperature for 1 hour in the presence of an 8-point 5-fold dilution series of test compounds (starting at a final concentration of 10 μM). A mixture of Eu-streptavidin and allophycocyanin anti-His Ab was then added to the test sample wells at final concentrations of 2 nM and 100 nM, respectively. The reactions were incubated at room temperature for an additional 1 hour or 19 hours (for covalent compounds). TR-FRET signals were read on a microplate reader with an excitation wavelength of 340 nm and detection wavelengths of 615 and 665 nm. Binding curves were fit in GraphPad Prism using a four-parameter sigmoidal dose-response curve with a variable slope model. Compounds that caused an increase in the TR-FRET ratio relative to the DMSO control wells were identified as compounds that promoted the formation of the ternary complex, EC 50 The values ​​(nM) are shown in Table 3 below.

[0525] Table 3. EC values ​​of compounds in TR-FRET for ternary complex formation 50 Value (nM)

[0526]

[0527] Conclusion: The compounds of the present invention disrupt the protein-protein binding between Raf1 RBD and KRAS.

Claims

1. A compound of formula (I), formula (II) or formula (III): or a tautomer, cis or trans isomer, meso racemate, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in, Ring A and Ring B are each independently selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; R is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, haloalkyl, C 3-12 Cycloalkyl, C 3-12 One or more substituents in the heterocyclic group are substituted, wherein the C 3-12 The heterocyclyl group is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, heterocyclyl; L and M are each independently selected from alkyl, alkoxy, alkyl-OC(O)-, alkoxy-OC(O)-, -alkyl-cycloalkyl-alkyl-OC(O)-; R2, R3, R4, R5, R6, R7 and R8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, cycloalkyl and heterocyclyl; Alternatively, R4 and R5 together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group, wherein each of the cycloalkyl group or the heterocyclic group is optionally substituted with one or more substituents selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxyl, hydroxyalkyl, and haloalkyl; n is 1, 2 or 3; G is Among them, R a and R b Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl; Or, R a and R b Together with the nitrogen atom to which they are attached they form heterocyclyl and heteroaryl groups; K is selected from vinyl ketone, vinyl sulfone, alkynyl ketone, alkynyl sulfone, -S(O)2 and alkyl, -C(O)-C(O)-alkyl; J is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl and NR c R d , or J is absent, provided that K is selected from alkyl, -C(O)-C(O)-alkyl; R c and R d Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkenyl, alkynyl, alkoxy, hydroxy, hydroxyalkyl, and haloalkyl.

2. The compound according to claim 1, or its tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture, or its pharmaceutically acceptable salt, solvate or prodrug, which is a compound of formula (Ia), formula (IIa) or formula (IIIa): in, R 13 is selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, heteroaryl; m is 1, 2 or 3; Preferably, R 13 Selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl; m is 1.

3. A compound according to any one of claims 1 to 2, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound of formula (Ib), formula (IIb) or formula (IIIb): in, X1 is a bond, C or N; X2 is C, O, or N; R9, R 10 , R 11 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, alkyl, alkoxy, hydroxy, hydroxyalkyl, haloalkyl, cycloalkyl and heterocyclyl.

4. A compound according to any one of claims 1 to 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: Ring A is selected from C 5-10 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 5-10 Heterocyclic group, C 3-12 The aryl group and the C 5-10 heteroaryl; and ring B is each independently selected from C 3-10 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 5-10 Heterocyclic group, C 3-12 The aryl group and the C 5-10 heteroaryl; More preferably, ring B is selected from C 5-10 A bridged cycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O, S 5-10 A bridged heterocyclic group, a C 5-10 fused heterocyclic group; More preferably, Ring A and Ring B are each independently selected from: More preferably, ring A is selected from Ring B is selected from Phenyl, More preferably, ring B is selected from Phenyl or Preferably, ring A is a 7-12 membered fused heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S; ring B is a 7-12 membered fused heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S; More preferably, ring A is Ring B is selected from Preferably, ring B is selected from 5. A compound according to any one of claims 1 to 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R1 is selected from C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C 3-12 The aryl group and the C 5-12 Heteroaryl, wherein the C 3-12 Cycloalkyl, C 5-12 Heterocyclic group, C 3-12 Aryl and C 5-12 Each of the heteroaryl groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-10 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group, C containing 1 to 3 heteroatoms independently selected from N, O or S 7-10 One or more substituents in the bridged heterocyclic group are substituted, wherein the C 3-6 Heterocyclic and C 7-10 Each of the bridged heterocyclic groups is optionally selected from C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 3-5 One or more substituents in the heterocyclic group; R1 is selected from C 5-8 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 5-8 Heterocyclic group, C 5-8 The aryl group and the C 5-8 Heteroaryl, wherein the C 5-8 Cycloalkyl, C 5-8 Heterocyclic group, C 5-8 Aryl and C 5-8 Each of the heteroaryl groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxyalkyl, hydroxy, C 1-4 Hydroxyalkyl, C 1-4 haloalkyl, C containing 1 to 2 heteroatoms independently selected from N 3-6 Heterocyclic group, containing 1 to 3 heteroatoms independently selected from N or O 7-10 One or more substituents in the bridged heterocyclic group are substituted, wherein the C 3-6 Heterocyclic and C 7-10 Each of the bridged heterocyclic groups is optionally selected from C 1-6 Alkyl, C containing a heteroatom selected from O 3-5 One or more substituents in the heteroaryl group; R1 is selected from phenyl, pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, wherein each of the phenyl, pyridyl, pyrimidinyl, pyrazolyl and imidazolyl is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkoxyalkyl, hydroxy, C 1-4 Hydroxyalkyl, C 1-4 Halogenated alkyl, One or two substituents are substituted.

6. A compound according to any one of claims 1 to 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: L and M are each independently selected from a bond, C 1-8 Alkyl, C 1-8 Alkoxy, C 1-8 Alkyl-OC(O)-, C 1-8 Alkoxy-OC(O)-, -C 1-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Alkyl-OC(O)-; Preferably, L is independently selected from a linear or branched C 3-6 Alkyl, linear or branched C 3-6 Alkoxy, linear or branched C 3-6 Alkyl-OC(O)-, linear or branched C 3-6 Alkoxy-OC(O)-, -C 1-3 Alkyl-C 3-6 Cycloalkyl-C 1-3 Alkyl-OC(O)-, linear or branched C 1-6 Alkyl; M is independently selected from a bond, C 1-3 Alkyl, branched or straight chain C 1-3 Alkoxy.

7. A compound according to any one of claims 1 to 3, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group; Alternatively, R4 and R5 together with the carbon atom to which they are attached form C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Each of the heterocyclic groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 One or more substituents in the haloalkyl group are substituted; Preferably, R2, R3, R4, R5, R6, R7, and R8 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group; Alternatively, R4 and R5 together with the carbon atom to which they are attached form C 3-6 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group, wherein the C 3-6 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Each of the heterocyclic groups is optionally selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 One or two substituents in the haloalkyl group are substituted.

8. The compound according to claim 3, or its tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture, or its pharmaceutically acceptable salt, solvate or prodrug, wherein: R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-12 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group; Preferably, R9, R 10 , R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl, C 3-6 Cycloalkyl and C containing 1 to 2 heteroatoms independently selected from N, O or S 3-6 Heterocyclic group; More preferably, R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 One or more substituents in the alkyl group are substituted; preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S 8-12 Fused heterocyclic group.

9. A compound according to any one of claims 1 to 2, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: n is 1.

10. The compound according to claim 1, or a tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in, G is Among them, R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl; Or, R a and R b Together with the carbon atom to which they are attached, they form C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C 3-12 The aryl group and the C 3-12 heteroaryl; G is Among them, R a and R b are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; Or, R a and R b Together with the nitrogen atom to which they are attached, they form a C containing 1 to 2 heteroatoms independently selected from N, O or S. 3-8 The heterocyclic group and the C containing 1 to 2 heteroatoms independently selected from N, O or S 3-8 heteroaryl; Preferably, G is selected from pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl.

11. The compound according to claim 1, or its tautomer, cis or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture, or its pharmaceutically acceptable salt, solvate or prodrug, wherein: K is selected from C 2-6 Vinyl ketone, C 2-6 Vinyl sulfone, C 3-6 Alkynone, C 2-6 Alkynyl sulfone, C 1-3 Alkyl, -C(O)-C(O)-C 1-3 alkyl; Preferably, K is selected from C 3-6 Vinyl ketone, C 3-6 Vinyl sulfone, C 4-6 Alkynone, C 3-6 Alkynyl sulfone, methyl, ethyl, propyl, -C(O)-C(O)-methyl, -C(O)-C(O)-ethyl, -C(O)-C(O)-propyl; More preferably, K is Among them, R 12 C 1-6 alkyl; More preferably, R 12 C 1-3 alkyl.

12. The compound according to claim 1, or its tautomer, cis or trans isomer, meso-isomer, racemate, enantiomer, diastereomer, or mixture, or its pharmaceutically acceptable salt, solvate or prodrug, wherein: J is selected from C 3-12 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, C 3-12 Aryl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-12 Heteroaryl and NR c R d ; R c and R d are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Alkenyl, C 1-3 Alkynyl, C 1-3 Alkoxy, hydroxyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl; Or J does not exist, provided that K is C 1-3 alkyl; Preferably, J is selected from C 3-8 Cycloalkyl, C containing 1 to 2 heteroatoms independently selected from N, O or S 3-8 Heterocyclic group, C 3-8 The aryl group and the C 3-8 heteroaryl; More preferably, J is selected from pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl.

13. A compound according to any one of claims 1 to 12, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in, X2 is N, CH; R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 The alkyl group is substituted with one or more substituents; Preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S 8-12 fused heterocyclic group; R 10 are independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; Or two R3 together with the atoms of ring B to which they are attached form C 3-8 bridged cycloalkyl; Preferably, ring B is C containing 1, 2 or 3 heteroatoms independently selected from N, O, S 5-10 Fused heterocyclic group; R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; r is 0, 1, 2 or 3; s is 0, 1, 2, or 3.

14. A compound according to any one of claims 1 to 13, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound of formula (IIIc) or (IIId): in, X2 is N, CH; X3 is N, CH and S; R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 The alkyl group is substituted with one or more substituents; Preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S 8-12 fused heterocyclic group; R 10 are independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; Or two R3 together with the ring B to which they are connected form C 3-8 bridged cycloalkyl; R 13 Selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyl, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl; m is 1; r is 0, 1, 2, or 3; s is 0, 1, 2, or 3.

15. A compound according to any one of claims 1 to 16, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, which is a compound of formula (Id) in, X2 is N, CH; X3 is N, CH and S; R 11 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-6 Alkyl, C 1-6 Alkenyl, C 1-6 Alkoxy, hydroxyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and C containing 1, 2 or 3 heteroatoms independently selected from N, O or S 3-12 Heterocyclic group, wherein the C 3-8 Cycloalkyl and C 3-8 The heterocyclic group is optionally selected from hydrogen, deuterium, halogen, C 1-6 The alkyl group is substituted with one or more substituents; Preferably, the C 3-12 The heterocyclic group is a C containing 1, 2 or 3 heteroatoms independently selected from N, O or S. 3-7 A monocyclic group or a C group containing 1, 2 or 3 heteroatoms independently selected from N, O or S 8-12 fused heterocyclic group; R 10 are independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; R3 is independently selected from hydrogen, deuterium, halogen, amino, nitro, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, hydroxyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkyl; Or two R3 together with the ring B to which they are connected form C 3-8 bridged cycloalkyl; r is 0, 1, 2, or 3; s is 0, 1, 2, or 3.

16. A compound according to any one of claims 1 to 17, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 11 Selected from straight or branched chain C 1-3 Alkoxy, C 1-4 Alkoxyalkyl, C 2-4 haloalkenyl, C containing 1, 2 or 3 heteroatoms selected from N, O, S 5-8 A monocyclic group, a C group containing 1, 2 or 3 heteroatoms selected from N, O, S 5-12 The mono-heterocyclic group and the fused heterocyclic group are optionally selected from hydrogen, deuterium, halogen, C 1-3 The alkyl group is substituted with one or more substituents; Preferably, R 11 Selected from branched C 1-3 Alkoxy, C 1-4 Alkoxyalkyl, C 2-4 Fluoro-alkenyl, r is 1 or 2.

17. A compound according to any one of claims 1 to 18, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein: R 13 selected from C containing 1, 2 or 3 heteroatoms selected from N, O or S 5-7 heteroaryl; Preferably, R 13 Selected from pyridyl, pyrimidinyl, pyrazolyl, imidazolyl, piperidinyl, piperazinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, morpholinyl, thiomorpholinyl.

18. A compound according to any one of claims 1 to 17, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein the compound is 19. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claims 1-23, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

20. A method for treating a disease mediated by a RAS mutation, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 23, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, or a pharmaceutical composition according to claim 19.

21. The method of claim 20, wherein the RAS mutation comprises a KRAS G12C, KRAS G12D, KRASG12V, KRAS G13D, KRAS G12 R, HRAS or NRAS mutation.

22. A method of treating cancer comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-18, or a tautomer, cis or trans isomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition according to claim 19, wherein the disease or condition is selected from the group consisting of cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, enchondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary Tract: Kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); Liver: liver cancer (hepatocellular carcinoma), bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder cancer, ampullary cancer, bile duct cancer; Bones: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningosarcomas, gliomatosis), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pineal tumors), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas); Gynecology: uterus (uterus) Endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); Hematologic system: blood (myeloid leukemia (acute and chronic), acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: neuroblastoma.

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