Polycyclic fused ring derivatives and their uses

Abstract

K-Ras mutant protein inhibitors of formula (I), compositions comprising same, and uses thereof are provided. [Formula 1] JPEG2024534610000123.jpg47170

Description

[Technical field]

[0001] The present invention relates to compounds that inhibit the activity of multiple forms of the K-Ras protein, including wild-type and mutant forms of K-Ras, compositions containing same, and methods of using them.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to PCT / CN2021 / 120863, filed September 27, 2021; PCT / CN2022 / 081601, filed March 18, 2022; PCT / CN2022 / 102280, filed June 29, 2022; and PCT / CN2022 / 120205, filed September 21, 2022, all of which are incorporated by reference in their entireties. [Background technology]

[0003] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog ("K-Ras") is a small GTPase and a member of the RAS family of oncogenes. K-Ras functions as a molecular switch that cycles between inactive (GDP-bound) and active (GTP-bound) states, transmitting upstream cellular signals received from multiple tyrosine kinases to downstream effectors and controlling various processes including cell proliferation. Aberrant expression of K-Ras accounts for up to 20% of all cancers, with oncogenic K-Ras mutations that stabilize GTP binding and constitutively activate K-Ras. K-Ras mutations at codons 12, 13, 61, and other positions in the primary amino acid sequence of K-Ras are present in 88% of patients with pancreatic adenocarcinoma, 50% of patients with colorectal adenocarcinoma, and 32% of patients with lung adenocarcinoma. Recent reports have also suggested that wild-type K-Ras inhibition may be an effective therapeutic strategy to treat K-Ras wild-type-dependent cancers.

[0004] Allele-specific K-Ras G12C inhibitors such as sotorasib (AMG510) and adagrasib (MRTX849) are currently changing the treatment paradigm for patients with K-Ras G12C mutant non-small cell lung cancer and colorectal cancer. The success in addressing previously elusive K-Ras alleles has stimulated drug discovery activities against all K-Ras mutants. Multiple K-Ras inhibitors have the potential to address a broad patient population, including cancers with K-Ras G12C mutations, K-Ras G12D mutations, K-Ras G12V mutations, K-Ras G13D mutations, K-Ras G12R mutations, K-Ras G12S mutations, K-Ras G12A mutations, K-Ras Q61H mutations, and K-Ras wild-type amplification.

[0005] Therefore, there is an unmet need for the development of new multiple K-Ras inhibitors to treat K-Ras-mediated cancers. Summary of the Invention

[0006] Provided is a compound of formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof: [ka] In the formula, the definitions of each variable are as follows:

[0007] Also provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, as defined herein, and a pharma- ceutically acceptable excipient.

[0008] Also provided is a method of treating cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), its stereoisomer, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugate thereof, or a pharmaceutical composition as defined herein.

[0009] Also provided is a method of treating cancer in a subject in need thereof, comprising: (a) determining whether the cancer is associated with a K-Ras G12C mutation, a K-Ras G12D mutation, a K-Ras G12V mutation, a K-Ras G13D mutation, a K-Ras G12R mutation, a K-Ras G12S mutation, a K-Ras G12A mutation, a K-Ras Q61H mutation, and / or a K-Ras wild-type amplification; and (b) if associated, administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugate thereof, or a pharmaceutical composition thereof, as defined herein.

[0010] There is also provided a compound of formula (I) as defined herein, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugate thereof, or a pharmaceutical composition for use in therapy.

[0011] There is also provided a compound of formula (I) as defined herein, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugate thereof, or a pharmaceutical composition for use as a medicament.

[0012] There is also provided a compound of formula (I) as defined herein, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugate thereof, or a pharmaceutical composition for use in a method for the treatment of cancer.

[0013] There is also provided the use of a compound of formula (I) as defined herein, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugate thereof, or a pharmaceutical composition thereof, for the treatment of cancer.

[0014] There is also provided the use of a compound of formula (I) as defined herein, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, a conjugate thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of cancer.

[0015] There is also provided a process for preparing a compound of formula (I) as defined herein.

[0016] Also provided are intermediates for the preparation of compounds of formula (I) as defined herein.

[0017] The following disclosure is provided: [1]. A compound of formula (I), its stereoisomer, its pharma- ceutically acceptable salt, its stereoisomer's pharma- ceutically acceptable salt, its prodrug, its deuterated molecule, or its conjugate, comprising: [ka] During the ceremony, X1 is selected from CR3 or N; R3 is hydrogen, deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O)2(C 1-6 alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is 1, 2, or 3 of R 3a is optionally substituted independently with; Each R 3a are deuterium, halogen, and -C, respectively, if present. 1-3 Alkyl, haloC 1-3 Alkyl, haloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3Alkynyl, -CN, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl), -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O)2(C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 alkyl), -N(C 1-3 Alkyl)C(=O)(C 1-3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2N(C 1-3 alkyl)2, -NHS(=O)2(C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O)2(C 1-3 alkyl), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; X2 is selected from NR1, O or S; R1 is hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; 1-6 Alkyl and 3-6 membered cycloalkyl, when present, are each represented by -OH, deuterium, halogen, -CN, oxo, -C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, or -N(C 1-6 alkyl)2; X3 is a CR 71 R 72 , C=O, NR 71 , O, S, S=O, or O=S=O; (R 71 , R 72 ) are hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; 1-6 Alkyl and 3-6 membered cycloalkyl are -OH, deuterium, halogen, -CN, oxo, -C 1-6 Alkoxy, -NH2, -NHC 1-6 Alkyl, or -N(C 1-6 alkyl)2, each independently optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from; each of (n1, n2, n3, n4 and n5), when present, is independently selected from 0, 1, 2 or 3; Each R S0 are deuterium, halogen, and -C, respectively, if present. 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(HaloC 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)H, -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -NO2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O)2(C 1-6 alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is 1, 2 or 3 R 1a is optionally substituted independently with; Arbitrarily, two adjacent R S0 along with the carbon atom to which they are both attached [ka] forming a 3-10 membered carbocyclic or 3-10 membered heterocyclic ring; [ka] A 3-10 membered carbocyclic or heterocyclic ring may have one or more R 1a is optionally substituted with; Optionally, two R S0 together with the carbon atom to which they are each attached form a 3- to 10-membered carbocyclic or heterocyclic ring, each of which may be joined by one or more R 1a is optionally substituted with; Each R 1a Deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, -CN, oxo, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, or deuterium, halogen, haloC 1-6 Alkyl, -CN, -OH, -NH2, -NH(C 1-6 alkyl), -N(C1-6 Alkyl)2, -OC 1-6 -C substituted with 1, 2 or 3 substituents selected from alkyl or cyclopropyl 1-6 independently selected from alkyl; m is selected from 0, 1, 2, 3, 4, 5 or 6; Y is a bond, O, S, S(=O), S(=O)2 or NR 81 and; R2 is -L-(3-12 membered heterocyclyl), -L-(3-12 membered cycloalkyl), -L-(6-12 membered aryl), -L-(5-12 membered heteroaryl), -L-NR 91 R 92 , [ka] Selected from; Each L is a bond or one or more R 16 C optionally substituted with 1-10 independently selected from alkylene; (R 91 , R 92 ) is hydrogen, deuterium, or one or more R 16 -C optionally substituted with 1-10 independently selected from alkyl; The 3- to 12-membered heterocyclyl in the -L-(3- to 12-membered heterocyclyl) is one or more R 16 is optionally substituted with; The 3- to 12-membered cycloalkyl in the -L-(3- to 12-membered cycloalkyl) is one or more R 16 is optionally substituted with; The 6- to 12-membered aryl in -L-(6- to 12-membered aryl) is one or more R 16 is optionally substituted with; The 5- to 12-membered heteroaryl in -L-(5- to 12-membered heteroaryl) is one or more R 16 is optionally substituted with; Y1 or Y2, each when present, is -C(R 61 R 62 )-independently selected from; Ring F or Ring G is a 3-10 membered heterocycle optionally further containing 1, 2, or 3 heteroatoms selected from N, O, or S; Ring A is a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring; -(Y1) r -and-(Y2) s -R 11 are attached to the same or different atoms of ring A; R 11 -NR 81 R 82 , -OR 81 , -SR 81 , 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl or 5-10 membered heteroaryl is selected from one or more R 16 is optionally substituted independently with; R 12 and R 13 Each of the following, when present, is a deuterium, a halogen, or -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO2, -N3, oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O)2R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82, -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O)2OR 81 , -OS(=O)2R 82 , -S(=O)2NR 81 R 82 , -NR 81 S(=O)2R 82 , -OS(=O)2OR 81 , -NR 81 S(=O)2OR 82 , -OS(=O)2NR 81 R 82 , -NR 81 S(=O)2NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO2, -N3, oxo, -NR 81 R 82 , -OR 81 , -SR81 , -S(=O)R 81 , -S(=O)2R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O)2OR 81 , -OS(=O)2R 82 , -S(=O)2NR 81 R 82 , -NR 81 S(=O)2R 82 , -OS(=O)2OR 81 , -NR 81 S(=O)2OR 82 , -OS(=O)2NR 81 R 82 , -NR 81 S(=O)2NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , optionally substituted independently with one or more substituents selected from 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Optionally, two R 12 along with the carbon atom to which they are both attached. [ka] forming a 3-10 membered carbocyclic or 3-10 membered heterocyclic ring; [ka] A 3-10 membered carbocyclic or heterocyclic ring may have one or more R 2a is optionally substituted with; Arbitrarily, two adjacent R 12 together with the carbon atom to which they are each attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aryl ring, or a 5- to 10-membered heteroaryl ring, each of which may be joined by one or more R 2a is optionally substituted independently with; Each R 2a Deuterium; halogen; -C 1-6 Alkyl;HaloC 1-6 Alkyl; -CN; oxo; -OH; -NH2; -NH(C 1-6 alkyl);-NH(C 1-6 Alkyl)2;-OC 1-6 Alkyl; or deuterium, halogen, haloC 1-6 Alkyl, -CN, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, -OC 1-6 -C substituted with 1, 2 or 3 substituents selected from alkyl or cyclopropyl 1-6 independently selected from alkyl; each of (r, s, t, p and v), when present, is independently selected from 0, 1, 2, 3, 4, 5 or 6; R4 is a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, [ka] wherein said 6-10 membered aryl, 5-10 membered heteroaryl, [ka] is an R of 1 or more. 41 is optionally substituted independently with; Z, at each occurrence, is independently selected from C or N; when Z is selected from C, ring B, each occurrence, is selected from a 6-membered aryl ring or a 5-6 membered heteroaryl ring, and ring C, each occurrence, is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; when Z is selected from N, ring B, at each occurrence, is selected from a 5-6 membered heteroaryl ring, and ring C, at each occurrence, is a 3-10 membered heterocycle; Ring D, at each occurrence, is selected from a 3- to 10-membered carbocycle, a 3- to 10-membered heterocycle, a 6-membered aryl ring, or a 5- to 6-membered heteroaryl ring; Ring E, at each occurrence, is selected from a 3-10 membered carbocycle, a 3-10 membered heterocycle, a 6 membered aryl ring, or a 5-6 membered heteroaryl ring; R 41 are deuterium, halogen, and -C, respectively, if present. 1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, -CN, -NO2, -N3, oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O)2R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O)2OR 81 , -OS(=O)2R 82 , -S(=O)2NR 81 R 82 , -NR 81 S(=O)2R 82 , -OS(=O)2OR 81 , -NR 81 S(=O)2OR 82 , -OS(=O)2NR 81 R 82 , -NR 81 S(=O)2NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl or R 4a -C 1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO2, -N3, oxo, -NR 81 R 82 , -OR81 , -SR 81 , -S(=O)R 81 , -S(=O)2R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O)2OR 81 , -OS(=O)2R 82 , -S(=O)2NR 81 R 82 , -NR 81 S(=O)2R 82 , -OS(=O)2OR 81 , -NR 81 S(=O)2OR 82 , -OS(=O)2NR 81 R 82 , -NR 81 S(=O)2NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , optionally substituted independently with one or more substituents selected from 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R 4a is a structure capable of forming a prodrug; R5 is hydrogen, deuterium, halogen, -C1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, -CN, -NO2, -N3, oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O)2R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O)2OR 81 , -OS(=O)2R 82 , -S(=O)2NR 81 R 82 , -NR 81 S(=O)2R 82 , -OS(=O)2OR 81 , -NR 81 S(=O)2OR 82 , -OS(=O)2NR 81 R 82 , -NR 81 S(=O)2NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R82 , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO2, -N3, oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O)2R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R82 , -S(=O)2OR 81 , -OS(=O)2R 82 , -S(=O)2NR 81 R 82 , -NR 81 S(=O)2R 82 , -OS(=O)2OR 81 , -NR 81 S(=O)2OR 82 , -OS(=O)2NR 81 R 82 , -NR 81 S(=O)2NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , optionally substituted independently with one or more substituents selected from 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; R 61 or R 62 are hydrogen, deuterium, halogen, and -C, respectively, when present. 1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, -CN, -NO2, -N3, oxo, -NR a R b , -OR a , -SR a , -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR a R b , -NR a C(=O)R b , -OC(=O)OR a , -NR a C(=O)OR b , -OC(=O)NR a R b , -NR aC(=O)NR a R b , -S(=O)OR a , -OS(=O)R a , -S(=O)NR a R b , -NR a S(=O)R b , -S(=O)2OR a , -OS(=O)2R a , -S(=O)2NR a R b , -NR a S(=O)2R b , -OS(=O)2OR a , -NR a S(=O)2OR b , -OS(=O)2NR a , -NR a S(=O)2NR a R b , -PR a R b , -P(=O)R a R b , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -N3, oxo, -NR c R d , -OR c , -SR c , -S(=O)R c , -S(=O)2R c , -C(=O)Rc , -C(=O)OR c , -OC(=O)R c , -C(=O)NR c R d , -NR c C(=O)R d , -OC(=O)OR c , -NR c C(=O)OR d , -OC(=O)NR c R d , -NR c C(=O)NR c R d , -S(=O)OR c , -OS(=O)R c , -S(=O)NR c R d , -NR c S(=O)R d , -S(=O)2OR c , -OS(=O)2R c , -S(=O)2NR c R d , -NR c S(=O)2R d , -OS(=O)2OR c , -NR c S(=O)2OR d , -OS(=O)2NR c , -NR c S(=O)2NR c R d , -PR c R d , -P(=O)R c R d , optionally substituted independently with one or more substituents selected from 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Optionally, R 61 and R 62 together with the carbon atom to which they are both attached form a 3- to 10-membered carbocyclic or heterocyclic ring, said 3- to 10-membered carbocyclic or heterocyclic ring being bound to one or more R 16 is optionally substituted independently with; R81 or R 82 are hydrogen, deuterium, and -C, respectively, if present. 1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, -S(=O)R a , -S(=O)2R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -S(=O)OR a , -S(=O)NR a R b , -S(=O)2OR a , -S(=O)2NR a R b , -P(=O)R a R b , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-10 Alkyl, haloC 1-10 Alkyl, haloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -N3, oxo, -NR c R d , -OR c , -SR c , -S(=O)R c , -S(=O)2R c , -C(=O)R c , -C(=O)OR c , -OC(=O)Rc , -C(=O)NR c R d , -NR c C(=O)R d , -OC(=O)OR c , -NR c C(=O)OR d , -OC(=O)NR c R d , -NR c C(=O)NR c R d , -S(=O)OR c , -OS(=O)R c , -S(=O)NR c R d , -NR c S(=O)R d , -S(=O)2OR c , -OS(=O)2R c , -S(=O)2NR c R d , -NR c S(=O)2R d , -OS(=O)2OR c , -NR c S(=O)2OR d , -OS(=O)2NR c , -NR c S(=O)2NR c R d , -PR c R d , -P(=O)R c R d , optionally substituted with one or more substituents independently selected from 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; Optionally, R 81 and R 82 together with the nitrogen atom to which they are both attached form a 3-10 membered heterocyclic or 5-10 membered heteroaryl ring, said 3-10 membered heterocyclic or 5-10 membered heteroaryl ring being bound to one or more R 16 is optionally substituted independently with; R a , R b , R cor R d are hydrogen, deuterium, and -C, respectively, if present. 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is selected from the group consisting of one or more R 16 is optionally substituted independently with; Optionally, (R a and R b ) or (R c and R d ) together with the atom to which they are both attached form a 3-6 membered heterocyclic ring, said 3-6 membered heterocyclic ring being joined by one or more R 16 is optionally substituted independently with; R 16 are deuterium, halogen, and -C, respectively, if present. 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)C(=O)NH2, -N(C 1-6 Alkyl)C(=O)NH(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)N(C 1-6 Alkyl)2, -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH2, -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl)2, -NHS(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O)(C 1-6 alkyl), -S(=O)2(OC 1-6 alkyl), -OS(=O)2(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O)2(C 1-6 alkyl), -OS(=O)2O(C 1-6alkyl), -NHS(=O)2O(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O)2O(C 1-6 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-6 alkyl), -OS(=O)2N(C 1-6 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1-6 alkyl), -NHS(=O)2N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)S(=O)2NH2, -N(C 1-6 Alkyl)S(=O)2NH(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O)2N(C 1-6 alkyl)2, -PH(C 1-6 alkyl), -P(C 1-6 alkyl)2, -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl is optionally substituted with deuterium, halogen, -C 1-3 Alkyl, haloC 1-3 Alkyl, haloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -CN, -NO2, -N3, oxo, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl), -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -S(=O)(C 1-3alkyl), -S(=O)2(C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -C(=O)NH2, -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl)2, -NHC(=O)(C 1-3 alkyl), -N(C 1-3 Alkyl)C(=O)(C 1-3 alkyl), -OC(=O)O(C 1-3 alkyl), -NHC(=O)(OC 1-3 alkyl), -N(C 1-3 Alkyl)C(=O)(OC 1-3 alkyl), -OC(=O)NH(C 1-3 alkyl), -OC(=O)N(C 1-3 alkyl)2, -NHC(=O)NH2, -NHC(=O)NH(C 1-3 alkyl), -NHC(=O)N(C 1-3 Alkyl)2, -N(C 1-3 Alkyl)C(=O)NH2, -N(C 1-3 Alkyl)C(=O)NH(C 1-3 alkyl), -N(C 1-3 Alkyl)C(=O)N(C 1-3 Alkyl)2, -S(=O)(OC 1-3 alkyl), -OS(=O)(C 1-3 alkyl), -S(=O)NH2, -S(=O)NH(C 1-3 alkyl), -S(=O)N(C 1-3 alkyl)2, -NHS(=O)(C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O)(C 1-3 alkyl), -S(=O)2(OC 1-3 alkyl), -OS(=O)2(C 1-3 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-3 alkyl), -S(=O)2N(C 1-3 alkyl)2, -NHS(=O)2(C 1-3alkyl), -N(C 1-3 Alkyl)S(=O)2(C 1-3 alkyl), -OS(=O)2O(C 1-3 alkyl), -NHS(=O)2O(C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O)2O(C 1-3 alkyl), -OS(=O)2NH2, -OS(=O)2NH(C 1-3 alkyl), -OS(=O)2N(C 1-3 alkyl)2, -NHS(=O)2NH2, -NHS(=O)2NH(C 1-3 alkyl), -NHS(=O)2N(C 1-3 Alkyl)2, -N(C 1-3 Alkyl)S(=O)2NH2, -N(C 1-3 Alkyl)S(=O)2NH(C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O)2N(C 1-3 alkyl)2, -PH(C 1-3 alkyl), -P(C 1-3 alkyl)2, -P(=O)H(C 1-3 alkyl), -P(=O)(C 1-3 alkyl) optionally substituted with one or more substituents selected from 2, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6 membered aryl, or 5-6 membered heteroaryl; each of (heterocyclyl and heteroaryl), when present, independently contains 1, 2, 3, or 4 heteroatoms selected from N, O, S, S(=O) or S(=O)2; A compound of formula (I), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

[0018] [2]. A compound of formula (I) according to [1], wherein X1 is N, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

[0019] [3]. A compound of formula (I) according to [1], wherein X1 is CR3, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

[0020] [4].R3 is -H, deuterium, -F, -Cl, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CN, -COOH, -CH2OH, -OH, -OCH3, -OCH2CH3, -CF3, -CHF2, -NH2, -NHCH3, -N(CH3)2, -CH2NH 2, -CH2CH2NH2, -CH2OH, -CH2CH2OH, -SH, -S-CH3, -S-CHF2, -S-CF3, -CH2SH, -CH2CH2SH, -CH=CH2, -C≡CH, -CHCH=CH2, -OCF3, -OCHF2, -C(=O)NH2, -C(=O)OCH3, [ka] A compound of formula (I) according to [1] or [3], a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, selected from the group consisting of:

[0021] [5].R3 is -H, deuterium, -F, -Cl, -CH3, -CH(CH3)2, -CF3, -S-CF3 or [ka] A compound of formula (I) according to [1], [3] or [4], a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, selected from:

[0022] [6]. A compound of formula (I) according to [1], wherein X2 is O, S, NH or NCH3, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

[0023] [7].X3, CR 71 R 72 or O.

[0024] [8].(R 71 and R 72 ) are hydrogen, deuterium, -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -F, -Cl, -CN, -CH2OH, -OH, -OCH3, -OCH2CH3, -CF3, -CHF2, -S-CH3, -S-CHF2, -S-CF3, [ka] are independently selected from; Preferably, R 71 , R 72 is hydrogen, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof.

[0025] [9]. A compound of formula (I) according to any one of [1] to [8], wherein n1, n4, and n5 are each 1, or n1 and n4 are each 1 and n5 is 0, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof.

[0026]

[10] . A compound of formula (I) according to any one of [1] to [9], wherein n2 and n3 are each 1, or n3 is 0 and n2 is 2, or n3 is 0 and n2 is 1, or n3 is 1 and n2 is 0, or n3 is 0 and n2 is 0, or a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof.

[0027]

[11] .Each R S0 When present, deuterium, halogen, -C 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl), -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 Alkyl), -S(HaloC 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O)2(C 1-6 alkyl), -C(=O)H, -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH2, -NO2, -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl)2, -NHC(=O)(C 1-6 alkyl), -N(C 1-6 Alkyl)C(=O)(C 1-6 alkyl), -S(=O)2NH2, -S(=O)2NH(C 1-6 alkyl), -S(=O)2N(C 1-6 alkyl)2, -NHS(=O)2(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O)2(C 1-6alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl, 1-6 Alkyl, haloC 1-6 Alkyl, haloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl is 1, 2 or 3 R 1a is optionally substituted independently with; Optionally, two R S0 along with the carbon atom to which they are both attached. [ka] forming a 3-10 membered carbocyclic or 3-10 membered heterocyclic ring; [ka] A 3-10 membered carbocyclic or heterocyclic ring may have one or more R 1a is optionally substituted with; Arbitrarily, two adjacent R S0 together with the carbon atom to which they are each attached form a 3- to 10-membered carbocyclic or heterocyclic ring, each of which is joined to one or more of R 1a is optionally substituted independently with; Each R 1a But deuterium, halogens, -C 1-6 Alkyl, haloC 1-6 Alkyl, -CN, oxo, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, -OC 1-6 Alkyl, or deuterium, halogen, haloC 1-6 Alkyl, -CN, -OH, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)2, -OC 1-6 -C substituted with 1, 2 or 3 substituents selected from alkyl or cyclopropyl 1-6independently selected from alkyl; q m is independently selected from 0, 1, 2 or 3. A compound of formula (I) according to any one of [1] to

[10] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof.

[0028]

[12] . A compound of formula (I) according to any one of [1] to

[11] , wherein the compound is selected from the formulas in Table 1, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof. [Table 1] JPEG2024534610000017.jpg207170JPEG2024534610000018.jpg61170

[0029]

[13] .-Y-R2 is [ka] A compound of formula (I) according to any one of [1] to

[12] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, selected from the group consisting of:

[0030]

[14] . A compound of formula (I) according to any one of [1] to

[13] , wherein the compound is a compound of formula (II), a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof. [ka]

[0031]

[15] .-Y-R2 or [ka] but, [ka] A compound of formula (I) according to any one of [1] to

[14] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, selected from the group consisting of:

[0032]

[16] .-Y-R2 or [ka] but, [ka] A compound of formula (I) according to any one of [1] to

[15] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, selected from the group consisting of:

[0033]

[17] . [ka] is selected from any one of Table 2, a compound of formula (I) according to any one of [1] to

[16] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof. [Table 2]

[0034]

[18] . [ka] but, [ka] A compound of formula (I) according to any one of [1] to

[17] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, selected from the group consisting of:

[0035]

[19] . The compound is selected from the formulas in Table 3. The compound of formula (I) according to any one of [1] to

[18] , its stereoisomer, its pharma- ceutically acceptable salt, its stereoisomer's pharma- ceutically acceptable salt, their prodrug, their deuterated molecule, or their conjugate. [Table 3] JPEG2024534610000030.jpg225170

[0036]

[20] .R4 is selected from one of Table 4: [Table 4] R4 is 1, 2, 3, 4, 5 or 6 41 is optionally substituted independently with; Each R 41 -Deuterium, -F, -Cl, -C 1-3 Alkyl, haloC 1-3 Alkyl, haloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -CN, -NH2, -NH(C 1-3 alkyl), -N(C 1-3 alkyl), -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), 3-6 membered cycloalkyl or 3-6 membered heterocyclyl or R 4a -C 1-3 Alkyl, haloC 1-3 Alkyl, haloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-6Alkynyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl is -F; -C 1-3 Alkyl;HaloC 1-3 Alkyl; -CN; -OH; -NH2; -NH(C 1-3 alkyl);-NH(C 1-3 Alkyl)2;-OC 1-3 Alkyl; or -F, haloC 1-3 Alkyl, -CN, -OH, -NH2, -NH(C 1-3 alkyl), -NH(C 1-3 Alkyl)2 or -OC 1-3 -C substituted with 1, 2 or 3 substituents selected from alkyl 1-3 A compound of formula (I) according to any one of [1] to

[19] , which is optionally substituted with 1, 2 or 3 substituents independently selected from alkyl, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof.

[0037]

[21] . A compound of formula (I) according to any one of [1] to

[20] , wherein R4 is selected from any one of Table 5, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof. [Table 5]

[0038]

[22] .R4, [ka] and; Preferably, R4 is [ka] The compound of formula (I) according to any one of [1] to

[21] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, wherein

[0039]

[23] . The compound is selected from the formulas in Table 6. The compound of formula (I) according to any one of [1] to

[22] , its stereoisomer, its pharma- ceutically acceptable salt, its stereoisomer's pharma- ceutically acceptable salt, their prodrug, their deuterated molecule, or their conjugate. [Table 6] JPEG2024534610000036.jpg157170

[0040]

[24] . A compound of formula (I) according to any one of [1] to

[23] , wherein R5 is selected from deuterium, halogen, preferably R5 is selected from -F, a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

[0041]

[25] . The compound is selected from the formulas in Table 7. The compound of formula (I) according to any one of [1] to

[24] , its stereoisomer, its pharma- ceutically acceptable salt, its stereoisomer's pharma- ceutically acceptable salt, their prodrug, their deuterated molecule, or their conjugate. [Table 7] JPEG2024534610000038.jpg156170

[0042]

[26] . The compound is selected from the formulas in Table 8. The compound of formula (I) according to any one of [1] to

[25] , its stereoisomer, its pharma- ceutically acceptable salt, its stereoisomer's pharma- ceutically acceptable salt, their prodrug, their deuterated molecule, or their conjugate. [Table 8] JPEG2024534610000040.jpg194170JPEG2024534610000041.jpg198170JPEG20245346100 00042.jpg193170JPEG2024534610000043.jpg217170JPEG2024534610000044.jpg200170

[0043]

[27] . The compound of formula (I) according to any one of [1] to

[26] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, wherein the conjugate is a PROTAC molecule.

[0044]

[28] . An intermediate for preparing a compound of formula (I), wherein the intermediate is selected from the compounds in Table 9. [Table 9] JPEG2024534610000046.jpg228170JPEG2024534610000047.jpg232170JPEG2024534610000048.jpg233170JPEG2024534610 000049.jpg222170JPEG2024534610000050.jpg205170JPEG2024534610000051.jpg231170JPEG2024534610000052.jpg44170

[0045]

[29] . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of [1] to

[28] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, and a pharma- ceutically acceptable excipient.

[0046]

[30] . A method for treating cancer in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) described in any one of [1] to

[28] , its stereoisomer, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, or a pharmaceutical composition described in

[29] .

[0047]

[31] .(a) determining whether the cancer is associated with a K-Ras G12C mutation, a K-Ras G12D mutation, a K-Ras G12V mutation, a K-Ras G13D mutation, a K-Ras G12R mutation, a K-Ras G12S mutation, a K-Ras G12A mutation, a K-Ras Q61H mutation, and / or a K-Ras wild-type amplification; and (b) Where relevant, administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of [1] to

[28] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, or a pharmaceutical composition according to

[29] . 23. A method of treating cancer in a subject, comprising:

[0048]

[32] . A compound of formula (I) according to any one of [1] to

[28] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, or a pharmaceutical composition according to

[29] , for use in therapy.

[0049]

[33] . A compound of formula (I) according to any one of [1] to

[28] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of the stereoisomer, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, or a pharmaceutical composition according to

[29] , for use as a medicine.

[0050]

[34] . A compound of formula (I) according to any one of [1] to

[28] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, or a pharmaceutical composition according to

[29] , for use in a method for treating cancer.

[0051]

[35] . Use of a compound of formula (I) according to any one of [1] to

[28] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, or a pharmaceutical composition according to

[29] , for the treatment of cancer.

[0052]

[36] . Use of a compound of formula (I) according to any one of [1] to

[28] , a stereoisomer thereof, a pharma- ceutically acceptable salt thereof, a pharma- ceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, or a pharmaceutical composition according to

[29] , for the manufacture of a medicament for the treatment of cancer.

[0053]

[37] . The cancer is selected from pancreatic cancer, colorectal cancer, lung cancer (e.g. non-small cell lung cancer), breast cancer, colon cancer, gastric cancer, endometrial cancer, esophageal cancer or gastroesophageal junction cancer. The method for treating cancer described in

[30] , the use in the method for treating cancer described in

[34] , the use for treating cancer described in

[35] , or the use for manufacturing a medicament for treating cancer described in

[36] .

[0054]

[38] . A method for treating cancer according to

[30] or

[37] , wherein the cancer is associated with at least one of K-Ras G12C mutation, K-Ras G12D mutation, K-Ras G12V mutation, K-Ras G13D mutation, K-Ras G12R mutation, K-Ras G12S mutation, K-Ras G12A mutation, K-Ras Q61H mutation and / or K-Ras wild-type amplification; a use in the method for treating cancer according to

[34] or

[37] ; a use for treating cancer according to

[35] or

[37] ; or a use for manufacturing a medicament for treating cancer according to

[36] or

[37] .

[0055]

[39] . A method for treating cancer according to

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras G12C-associated cancer; use in the method for treating cancer according to

[34] ,

[37] or

[38] ; use for treating cancer according to

[35] ,

[37] or

[38] ; or use for the manufacture of a medicament for treating cancer according to

[36] ,

[37] or

[38] .

[0056]

[40] . A method for treating cancer according to

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras G12D-associated cancer; use in the method for treating cancer according to

[34] ,

[37] or

[38] ; use for treating cancer according to

[35] ,

[37] or

[38] ; or use for the manufacture of a medicament for treating cancer according to

[36] ,

[37] or

[38] .

[0057]

[41] . A method for treating cancer described in

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras G12V-associated cancer; use in the method for treating cancer described in

[34] ,

[37] or

[38] ; use for treating cancer described in

[35] ,

[37] or

[38] ; or use for manufacturing a medicament for treating cancer described in

[36] ,

[37] or

[38] .

[0058]

[42] . A method for treating cancer according to

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras G13D-associated cancer; use in the method for treating cancer according to

[34] ,

[37] or

[38] ; use for treating cancer according to

[35] ,

[37] or

[38] ; or use for the manufacture of a medicament for treating cancer according to

[36] ,

[37] or

[38] .

[0059]

[43] . A method for treating cancer according to

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras G12R-associated cancer; use in the method for treating cancer according to

[34] ,

[37] or

[38] ; use for treating cancer according to

[35] ,

[37] or

[38] ; or use for the manufacture of a medicament for treating cancer according to

[36] ,

[37] or

[38] .

[0060]

[44] . A method for treating cancer according to

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras G12S-associated cancer; use in the method for treating cancer according to

[34] ,

[37] or

[38] ; use for treating cancer according to

[35] ,

[37] or

[38] ; or use for the manufacture of a medicament for treating cancer according to

[36] ,

[37] or

[38] .

[0061]

[45] . A method for treating cancer according to

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras G12A-associated cancer; use in the method for treating cancer according to

[34] ,

[37] or

[38] ; use for treating cancer according to

[35] ,

[37] or

[38] ; or use for the manufacture of a medicament for treating cancer according to

[36] ,

[37] or

[38] .

[0062]

[46] . A method for treating cancer according to

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras Q61H-associated cancer; use in the method for treating cancer according to

[34] ,

[37] or

[38] ; use for treating cancer according to

[35] ,

[37] or

[38] ; or use for the manufacture of a medicament for treating cancer according to

[36] ,

[37] or

[38] .

[0063]

[47] . A method for treating cancer described in

[30] ,

[37] or

[38] , wherein the cancer is a K-Ras wild-type amplification-associated cancer; use in the method for treating cancer described in

[34] ,

[37] or

[38] ; use for treating cancer described in

[35] ,

[37] or

[38] ; or use for manufacturing a medicament for treating cancer described in

[36] ,

[37] or

[38] .

[0064] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, and publications mentioned herein are incorporated by reference.

[0065] As used herein, the terms "a," "an," "the," and similar terms are intended to include both the singular and the plural, unless otherwise specified.

[0066] The terms "halogen" or "halo," as used interchangeably herein, refer to fluoro, chloro, bromo, or iodo, unless otherwise specified. Preferred halogen groups include -F, -Cl, and -Br.

[0067] The term "alkyl," as used herein, unless otherwise specified, refers to a saturated monovalent hydrocarbon radical having a linear or branched arrangement. 1-10 Alkyl C 1-10is defined to identify the group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms in a linear or branched arrangement. Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl.

[0068] The term "haloalkyl," as used herein, unless otherwise specified, refers to an alkyl as described above substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens (e.g., -F, -Cl, or -Br). In some embodiments, haloalkyl is an alkyl group, such as the interchangeable -C 1-10 Haloalkyl or HaloC 1-10 alkyl, where -C 1-10 Haloalkyl or HaloC 1-10 C in alkyl 1-10 indicates that the total carbon atoms in the alkyl are 1 to 10. 1-10 Haloalkyl is -C 1-6 In some embodiments, -C 1-6 Haloalkyl is -C 1-3 In some embodiments, -C 1-3 Haloalkyl is substituted with 1, 2, 3, 4, 5, or 6 -F (methyl, ethyl, propyl, or isopropyl); preferably -C 1-3 Haloalkyl is -CF3.

[0069] The term "alkylene," as used herein, unless otherwise specified, refers to a divalent group obtained by further removing a hydrogen atom from an alkyl group as defined above. In certain embodiments, alkylene is a C 0-6 In some embodiments, C is an alkylene. 0-6 Alkylene is C 0-3 It is an alkylene. C before alkylene 0-6indicates that the total carbon atoms in the alkylene are 0 to 6, and C0 indicates that both ends of the alkylene are directly bonded. Alkylene includes, but is not limited to, methylene (i.e., -CH2-), ethylene (i.e., -CH2-CH2- or -CH(CH3)-), and propylene (i.e., -CH2-CH2-CH2-, -CH(-CH2-CH3)-, or -CH2-CH(CH3)-).

[0070] The term "alkenyl," as used herein, unless otherwise specified, refers to a straight or branched chain hydrocarbon radical containing one or more double bonds and typically having from 2 to 20 carbon atoms in length. In some embodiments, alkenyl is defined as -C 2-10 In some embodiments, -C is alkenyl. 2-10 Alkenyl is a -C group containing 2 to 6 carbon atoms. 2-6 Alkenyl includes, but is not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl, and the like.

[0071] The term "haloalkenyl," as used herein, unless otherwise specified, refers to an alkenyl as described above substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) halogens (e.g., -F, -Cl, or -Br). In some embodiments, haloalkenyl is an alkenyl group, such as the interchangeable -C 2-10 Haloalkenyl or HaloC 2-10 alkenyl, where -C 2-10 Haloalkenyl or HaloC 2-10 Alkenyl C 2-10 indicates that the total carbon atoms in the alkenyl are 2 to 10. 2-10 Haloalkenyl is -C 2-6 In some embodiments, -C is haloalkenyl. 2-6 Haloalkenyl is -C 2-3 In some embodiments, -C is haloalkenyl. 2-3 Haloalkenyl is substituted with 1, 2, 3, 4, 5, or 6 -F (ethenyl or propenyl).

[0072] The term "haloalkoxy" as used herein, unless otherwise specified, refers to an alkoxy as described above substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, haloalkoxy is an alkoxy group as described above, which is interchangeable with -C. 1-10 Haloalkoxy or HaloC 1-10 In some embodiments, haloalkoxy is an alkoxy group, which is interchangeable with -C 1-6 Haloalkoxy or HaloC 1-6 Alkoxy, where -C 1-6 Haloalkoxy or HaloC 1-6 C in alkoxy 1-6 indicates that the total carbon atoms in the alkoxy are 1 to 6. 1-6 Haloalkoxy is -C 1-3 In some embodiments, -C 1-3 Haloalkoxy is substituted with 1, 2, 3, 4, 5, or 6 -F (methoxy, ethoxy, propoxy, or isopropoxy); preferably -C 1-3 Haloalkoxy is -OCF3.

[0073] The term "carbocycle" as used herein means a fully saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring containing only carbon atoms as ring members, unless otherwise specified. The term "carbocyclyl" as used herein means a monovalent group obtained by removing a hydrogen atom on a ring carbon atom from a carbocycle as defined in the present invention, unless otherwise specified. In the present invention, carbocycle is interchangeable with carbocyclyl ring. In some embodiments, the carbocycle is a 3-20 membered (e.g., 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, 14-, 15-, 16-, 17-, 18-, 19-, or 20-membered) carbocycle that is fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, e.g., 1, 2, 3, 4, 5, or 6, are also included in this definition. Carbocycles include cycloalkyl rings in which all ring carbon atoms are saturated, cycloalkenyl rings containing at least one double bond (preferably containing one double bond), and cycloalkynyl rings containing at least one triple bond (preferably containing one triple bond). Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Cycloalkenyls include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl, and the like. Carbocyclyl rings include monocyclic carbocyclyl rings, bicyclic or polycyclic carbocyclyl rings in which one, two or more atoms are shared between the rings. The term "spirocyclic carbocycle" refers to a carbocyclic ring in which each ring shares only one ring atom with the other ring. In some embodiments, the spirocycle is a bicyclic spirocycle. Spirocyclic carbocycles include spirocyclic cycloalkyl rings, spirocyclic cycloalkenyl rings, and spirocyclic cycloalkynyl rings. The term "fused carbocycle" refers to a carbocycle in which each of the rings shares two adjacent ring atoms with the other ring. In some embodiments, the fused ring is a bicyclic fused ring. Fused carbocycles include fused cycloalkyl rings, fused cycloalkenyl rings, and fused cycloalkynyl rings.Monocyclic carbocycles fused to aromatic rings (e.g., phenyl) are also included in the definition of fused carbocycles. The term "bridged carbocycle" refers to a carbocycle containing at least two bridgehead carbon ring atoms and at least one bridging carbon atom. In some embodiments, the bridged ring is a bicyclic bridged ring. Bridged carbocycles include bicyclic bridged carbocycles containing two bridgehead carbon atoms and polycyclic bridged carbocycles containing two or more bridgehead carbon atoms. Bridged carbocycles include bridged cycloalkyl rings, bridged cycloalkenyl rings and bridged cycloalkynyl rings. Examples of monocyclic and bicyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-L-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl and 1-cyclohexyl-3-enyl.

[0074] The term "heterocycle" as used herein refers to a fully saturated or partially saturated monocyclic, bicyclic, bridged, fused, or spirocyclic non-aromatic ring that contains not only carbon atoms as ring members, but also one or more (e.g., 1, 2, 3, 4, 5, or 6) heteroatoms as ring members, unless otherwise specified. Preferred heteroatoms include N, O, S, N-oxide, sulfur oxide, and sulfur dioxide. The term "heterocyclyl" as used herein refers to a monovalent group obtained by removing a hydrogen atom on a ring carbon atom or a ring heteroatom from a heterocycle as defined in the present invention, unless otherwise specified. Heterocycle is interchangeable with heterocyclyl ring in the present invention. In certain embodiments, the heterocycle is a 3-20 membered (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 membered) heterocycle that is fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, e.g., 1, 2, 3, 4, 5, or 6, are included within this definition. Heterocycles include heterocycloalkyl rings in which all ring carbon atoms are saturated, heterocycloalkenyl rings that contain at least one double bond (preferably containing one double bond), and heterocycloalkynyl rings that contain at least one triple bond (preferably containing one triple bond). Heterocyclyl rings include monocyclic heterocyclyl rings and bicyclic or polycyclic heterocyclyl rings in which one, two, or more than two atoms are shared between the rings. The term "spirocyclic heterocycle" refers to a heterocycle in which each ring shares only one ring atom with the other ring. In some embodiments, the spirocyclic ring is a bicyclic spirocyclic ring. Spirocyclic heterocycles include spirocyclic heterocycloalkyl rings and spirocyclic heterocycloalkenyl rings and spirocyclic heterocycloalkynyl rings. The term "fused heterocycle" refers to a heterocycle in which each of the rings shares two adjacent ring atoms with the other ring. In some embodiments, the fused ring is a bicyclic fused ring. Fused heterocycles include fused heterocycloalkyl rings and fused heterocycloalkenyl rings and fused heterocycloalkynyl rings. Monocyclic heterocycles fused with aromatic rings (e.g., phenyl) are included in the definition of fused heterocycles.The term "bridged heterocycle" refers to a heterocycle containing at least two bridgehead ring atoms and at least one bridge atom. In some embodiments, the bridged ring is a bicyclic bridged ring. Bridged heterocycles include bicyclic bridged heterocycles containing two bridgehead atoms and polycyclic bridged heterocycles containing more than two bridgehead atoms. Bridged heterocycles include bridged heterocycloalkyl rings, bridged heterocycloalkenyl rings and bridged heterocycloalkynyl rings. Examples of such heterocyclyls include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.

[0075] The term "aryl" as used herein, unless otherwise specified, refers to a monocyclic or polycyclic aromatic ring system containing only carbon ring atoms. Preferred aryls are monocyclic or bicyclic 6-10 membered aromatic rings. Phenyl and naphthyl are preferred aryls.

[0076] The term "heteroaryl" as used herein, unless otherwise specified, refers to an aromatic ring containing carbon and one or more (e.g., 1, 2, 3, or 4) heteroatoms selected from N, O, or S. Monocyclic heteroaryl groups may have 1-4 heteroatoms in the ring, and polycyclic heteroaryls may contain 1-10 heteroatoms. Polycyclic heteroaryl rings may contain fused ring junctions, e.g., bicyclic heteroaryls are polycyclic heteroaryls. Bicyclic heteroaryl rings may contain 8-12 member atoms. Monocyclic heteroaryl rings may contain 5-8 member atoms (carbon and heteroatoms), with preferred monocyclic heteroaryls being 5-membered heteroaryls containing 1, 2, 3, or 4 heteroatoms selected from N, O, or S, or 6-membered heteroaryls containing 1 or 2 heteroatoms selected from N. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl, or isoquinolinyl.

[0077] The term "one or more", as used herein, unless otherwise specified, refers to one or more than one. In certain embodiments, "one or more" refers to one, two, three, four, five, or six. In certain embodiments, "one or more" refers to one, two, three, or four. In certain embodiments, "one or more" refers to one, two, or three. In certain embodiments, "one or more" refers to one or two. In certain embodiments, "one or more" refers to one. In certain embodiments, "one or more" refers to two. In certain embodiments, "one or more" refers to three. In certain embodiments, "one or more" refers to four. In certain embodiments, "one or more" refers to five. In certain embodiments, "one or more" refers to six.

[0078] In this specification, the term "substituted" means that the hydrogen atom on the carbon atom or the hydrogen atom on the nitrogen atom is replaced with a substituent, unless otherwise specified.In the present invention, the substitution of one or more substituents on the ring means that each substituent may be independently substituted on all ring atoms of the ring, not limited to the carbon atom on the ring or the nitrogen atom on the ring.In addition, when the ring is a polycyclic ring such as a condensed ring, a bridged ring, or a spiro ring, each substituent may be independently substituted on all ring atoms of the polycyclic ring.

[0079] The term "oxo" refers to an oxygen atom, together with the carbon atom to which it is attached, [ka] This means that the compound forms a group represented by the formula:

[0080] The term "composition" as used herein is intended to include those consisting of the specified components in the specified amounts, and those resulting directly or indirectly from the combination of the specified components in the specified amounts. Thus, pharmaceutical compositions containing the compounds of the present invention as active ingredients and methods for preparing instant compounds are also part of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs, which are intended to be included in the present invention. Furthermore, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be included in the scope of the present invention.

[0081] The term "pharmaceutical acceptable salt" refers to a salt prepared from a pharmaceutical non-toxic base or acid. If the compound of the present invention is acidic, its corresponding salt can be easily prepared from a pharmaceutical non-toxic base, including inorganic bases and organic bases. If the compound of the present invention is basic, its corresponding salt can be easily prepared from a pharmaceutical non-toxic acid, including inorganic acids and organic acids. Since the compound of the present invention is intended for pharmaceutical use, it is preferably provided in a substantially pure form, for example at least 60% pure, more preferably at least 75% pure, particularly at least 98% pure (% is by weight).

[0082] The present invention includes within its scope prodrugs of the compounds of the present invention. In general, such prodrugs will be functional derivatives of the compounds that are easily converted in vivo into the required compound. Thus, in the treatment methods of the present invention, the term "administering" is intended to encompass treatment of the various disorders described with a specifically disclosed compound or a compound that is not specifically disclosed but is converted in vivo into the specified compound after administration to a subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

[0083] It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of the invention can be selected by those skilled in the art to provide compounds that are chemically stable and readily synthesized by techniques well known in the art as well as the methods described herein.

[0084] The present invention includes all stereoisomers of the compounds and their pharma- ceutically acceptable salts. In addition, mixtures of stereoisomers and isolated specific stereoisomers are also included. During the synthetic procedures used to prepare such compounds, or when using racemization or epimerization procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers. As used in the present invention, the term "stereoisomer" refers to isomers in which atoms or groups of atoms in a molecule are bonded to each other in the same order, but differ in spatial arrangement, including conformational and configurational isomers. Configurational isomers include geometric isomers and optical isomers, and optical isomers primarily include enantiomers and diastereomers. The present invention includes all possible stereoisomers of the compounds.

[0085] The present invention is intended to include all isotopes of atoms occurring in the compounds of the present invention. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of hydrogen include: 1 H (hydrogen), 2 H (deuterium) and 3 H (tritium). Deuterium is generally represented as D and tritium as T. In this specification, CD3 represents a methyl group in which all hydrogen atoms are deuterium. Carbon isotopes include: 13 C and 14 C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using the appropriate isotopically labeled reagent in place of the non-labeled reagent.

[0086] The term "deuterated derivative" as used herein, unless otherwise specified, refers to a compound having the same chemical structure as the reference compound, but with one or more hydrogen atoms replaced with a deuterium atom ("D"). It will be recognized that in synthesized compounds, there will be some variation in natural isotopic abundance depending on the source of the chemicals used in the synthesis. Regardless of this variation, the concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution of the deuterated derivatives described herein. Thus, unless otherwise specified, when referring to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen is replaced with deuterium far in excess of its natural isotopic abundance, which is typically about 0.015%. In certain embodiments, the deuterated derivatives of the present disclosure have an isotopic enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium), at least 4500, (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation).

[0087] When tautomers of the compounds of the present invention exist, the present invention includes any possible tautomers and pharma- ceutically acceptable salts thereof, as well as mixtures thereof, unless otherwise specified.

[0088] "Conjugate" as used herein refers to a compound described herein conjugated to another agent, with or without a linker, where the compound functions as a binder or inhibitor of K-Ras protein (including K-Ras G12C, K-Ras G12D, K-Ras G12V, K-Ras G13D, K-Ras G12R, K-Ras G12S, K-Ras G12A, K-Ras Q61H mutant protein and K-Ras wild-type protein). For example, the conjugate is a PROTAC molecule, e.g., the compound is incorporated into a proteolytic targeting chimera (PROTAC). PROTACs are bifunctional molecules, one capable of binding to E3 ubiquitin ligase and the other capable of binding to target proteins that are degraded by protein quality control mechanisms in cells. When a target protein is recruited to a specific E3 ligase, the protein is tagged for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. Preferably, the portion of the PROTAC that engages the E3 ligase is linked to the portion of the PROTAC that engages the target protein via a linker consisting of a variable chain of atoms. Thus, recruitment of the K-Ras protein to the E3 ligase results in the destruction of the K-Ras protein. The variable chain of atoms can, for example, include rings, heteroatoms, and / or repeating polymerization units. It can be rigid or flexible. It can be attached to the two moieties described above using standard techniques in the art of organic synthesis.

[0089] The pharmaceutical compositions of the present invention comprise, as an active ingredient, a compound of the present invention (or a pharma- ceutically acceptable salt thereof), a pharma- ceutically acceptable carrier, and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is to be administered. The pharmaceutical compositions are conveniently presented in unit dosage form and can be prepared by methods well known in the pharmaceutical arts.

[0090] In practice, the compounds of formula (I) as defined herein, their stereoisomers, their pharma- ceutically acceptable salts, their stereoisomers' pharma- ceutically acceptable salts, their prodrugs, their deuterated molecules or their conjugates can be formulated as active ingredients in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can be in a wide variety of forms, depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be provided as discrete units suitable for oral administration, such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient. Furthermore, the compositions can be provided as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil liquid emulsion. In addition to the common dosage forms described above, the compounds of the present invention or their pharma- ceutically acceptable salts can also be administered by controlled release means and / or delivery systems. The compositions can be prepared by pharmaceutical methods. In general, such methods include the step of combining the active ingredient with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredients with liquid carriers or finely divided solid carriers or both, after which the preparation can be shaped into the desired presentation.

[0091] Thus, the pharmaceutical compositions of the invention may comprise a pharma- ceutically acceptable carrier and the compound or a pharma- ceutically acceptable salt thereof. The compounds of the invention or pharma- ceutically acceptable salts thereof may also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0092] The pharmaceutical carrier employed may be, for example, solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, and the like. Examples of liquid carriers include sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. When preparing compositions for oral dosage forms, any convenient pharmaceutical medium may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs, and solutions; whereas carriers such as starch, sugar, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules, tablets, and the like. Because of ease of administration, tablets and capsules are the preferred oral dosage units in which solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

[0093] The tablet containing the composition of the present invention can be prepared by compression or molding, and may optionally contain one or more accessory ingredients or adjuvants.Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent or dispersant, in a suitable machine.Molded tablets can be produced by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0094] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as a solution or suspension of the active compound in water. A suitable surfactant, for example, hydroxypropylcellulose, can be included. Additionally, a preservative can be included to prevent the detrimental growth of microorganisms.

[0095] The pharmaceutical compositions of the present invention suitable for injection use include sterile aqueous solutions or dispersions. Moreover, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and effectively fluid. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, they should preferably be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0096] The pharmaceutical composition of the present invention can be in a form suitable for topical use, such as, for example, an aerosol, cream, ointment, lotion, powder, etc. Furthermore, the composition of the present invention can be in a form suitable for use in a transdermal device. These formulations can be prepared by conventional processing methods utilizing the compound of the present invention or a pharma- ceutically acceptable salt thereof. As an example, a cream or ointment is prepared by mixing about 0.05 wt% to about 10 wt% of the compound with a hydrophilic material and water to produce a cream or ointment having a desired consistency.

[0097] The pharmaceutical composition of the present invention can be in a form suitable for rectal administration, in which the carrier is solid.Preferably, the mixture forms a unit dose suppository.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppository can be conveniently formed by first mixing the composition with softened or melted carrier, and then cooling and shaping in a mold.

[0098] In addition to the above carrier components, the above pharmaceutical formulations may optionally include one or more additional carrier components, such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants). In addition, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. The compositions containing the compounds described herein or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates. In addition, other adjuvants may be included to make the formulation isotonic with the blood of the intended recipient. The compositions containing the compounds described herein or pharmaceutically acceptable salts thereof may also be prepared in the form of powders or liquid concentrates.

[0099] Unless otherwise clear from the context, when a value is expressed as "about" X or "approximately" X, the stated value of X is understood to be accurate to ±10%, preferably ±5%, ±2%.

[0100] The term "subject" refers to an animal. In some embodiments, an animal is a mammal. A subject also refers to, for example, a primate (e.g., human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In some embodiments, a subject is a human. As used herein, a "patient" refers to a human subject. As used herein, a subject is said to be "in need" of a treatment if such a subject would benefit biologically, medically, or in quality of life from such a treatment. In some embodiments, a subject is experiencing and / or exhibiting at least one symptom of a cancer to be treated and / or prevented. In certain embodiments, the subject has been identified or diagnosed as having a cancer with wild-type K-Ras or a K-Ras G12A, K-Ras G12C, K-Ras G12D, K-Ras G12R, K-Ras G12S, K-Ras G12V, K-Ras G13D and / or K-Ras Q61H mutation.

[0101] The terms "inhibition," "inhibiting," and "inhibit" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0102] The terms "treat", "treating" or "treatment" of a disease or disorder refer in one embodiment to ameliorating the disease or disorder (i.e., slowing or arresting or alleviating the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat", "treating" or "treatment" refers to alleviating or improving at least one physical parameter, including one that may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0103] As used herein, "K-Ras G12A" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of alanine for glycine at amino acid position 12. "K-Ras G12A inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras G12A. As used herein, "K-Ras G12A-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras G12A mutation.

[0104] As used herein, "K-Ras G12C" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of cysteine ​​for glycine at amino acid position 12. "K-Ras G12C inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras G12C. As used herein, "K-Ras G12C-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras G12C mutation.

[0105] As used herein, "K-Ras G12D" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 12. "K-Ras G12D inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras G12D. As used herein, "K-Ras G12D-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras G12D mutation.

[0106] As used herein, "K-Ras G12R" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of arginine for glycine at amino acid position 12. "K-Ras G12R inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras G12R. As used herein, "K-Ras G12R-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras G12R mutation.

[0107] As used herein, "K-Ras G12S" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of serine for glycine at amino acid position 12. "K-Ras G12S inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras G12S. As used herein, "K-Ras G12S-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras G12S mutation.

[0108] As used herein, "K-Ras G12V" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of valine for glycine at amino acid position 12. "K-Ras G12V inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras G12V. As used herein, "K-Ras G12V-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras G12V mutation.

[0109] As used herein, "K-Ras G13D" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of aspartic acid for glycine at amino acid position 13. "K-Ras G13D inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras G13D. As used herein, "K-Ras G13D-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras G13D mutation.

[0110] As used herein, "K-Ras Q61H" refers to a mutant form of a mammalian K-Ras protein that contains an amino acid substitution of histidine for glutamine at amino acid position 61. "K-Ras Q61H inhibitor" refers to a compound that can negatively regulate or inhibit all or part of the function of K-Ras Q61H. As used herein, "K-Ras Q61H-associated cancer" refers to a cancer that is associated with, mediated by, or has a K-Ras Q61H mutation.

[0111] All methods described herein can be performed in any suitable order unless otherwise specified herein or clearly contradicted by context. Any examples provided herein, or the use of exemplary language (e.g., "such as"), are intended merely to better illustrate the invention and do not limit the scope of the invention as described in the claims.

[0112] These and other aspects will become apparent from the following description of the invention. EXAMPLES

[0113] Preparation method The compounds of the present invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples illustrating specific synthetic routes and the following general schemes are intended to provide guidance to the ordinary skilled synthetic chemist, and it will be readily understood that the solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, etc. can be modified as necessary within the skill and judgment of the ordinary skilled artisan.

[0114] The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are in degrees Celsius unless otherwise indicated. The following abbreviations in Table 10 are used in the examples: [Table 10]

[0115] Preparation of intermediates INT 1 [ka]

[0116] INT1 was synthesized starting from naphthalene-1,3-diol according to the procedure described in WO2021041671.

[0117] INT 2 [ka]

[0118] INT2 was synthesized starting from 2-(4-fluorophenyl)acetic acid according to the procedure in WO2021041671.

[0119] INT 3 [ka]

[0120] A mixture of 2,6-dichloropyridin-4-amine (35.7 g, 219.0 mmol), 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (93.1 g, 262.8 mmol) in DMF (357 mL) and CH3CN (357 mL) was stirred at 80 °C for 6 h. The reaction mixture was quenched with water (400 mL) and extracted with DCM (400 mL × 3), the organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (eluted with petroleum ether: EtOAc = 30: 1, v / v) to give INT3-1 (12.6 g, purity: approx. 50%). MS (ESI, m / z): 181 [M+H] + .

[0121] A mixture of INT 3-1 (2.0 g, 11.05 mmol), NIS (2.98 g, 13.26 mmol) and p-toluenesulfonic acid monohydrate (105 mg, 0.55 mmol) in CH3CN (8.4 mL) was stirred at 70 °C for 4 h under nitrogen atmosphere. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL × 3), the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified on a silica gel column (eluted with petroleum ether: EtOAc = 50: 1 ~ 20: 1, v / v) to give INT 3-2 (3.6 g). MS (ESI, m / z): 307 [M + H] + .

[0122] A mixture of INT 3-2 (1.0 g, 3.26 mmol), Pd(PPh3)2Cl2 (229 mg, 0.33 mmol) and Et3N (1.19 g, 11.77 mmol) in EtOH (17.0 mL) was stirred in a sealed tube under carbon monoxide atmosphere (1.5 MPa) at 80 °C for 20 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give INT 3-3 (1.2 g). MS (ESI, m / z): 253 [M+H] + .

[0123] A mixture of INT 3-3 (800 mg, 3.16 mmol) and trichloroacetyl isocyanate (714 mg, 3.79 mmol) in THF (8 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE to give INT 3-4 (880 mg).

[0124] A mixture of INT 3-4 (780 mg, 1.77 mmol), NH3 / MeOH (1.26 mL, 7 M, 8.85 mmol) and MeOH (7.8 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was triturated with MTBE to give INT 3-5 (550 mg). MS (ESI, m / z): 250 [M+H] + .

[0125] A mixture of INT 3-5 (375 mg, 1.50 mmol), DIPEA (595 mg, 4.60 mmol) and POCl3 (15 mL) was stirred at 105 °C for 17 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with 1,4-dioxane (5 mL) and the resulting solution was added dropwise to aq.K2CO3 (20%, 30 mL). The mixture was stirred at room temperature for 2 h, adjusted to pH 2-3, filtered, and the filter cake was collected and dried to give INT 3 (344 mg). MS (ESI, m / z): 268 [M+H] + .

[0126] INT 4 [ka]

[0127] A solution of 1-bromo-2,5-difluoro-3-nitrobenzene (3.11 g, 13.06 mmol), iron (2.12 g, 37.96 mmol) and NH4Cl (3.49 g, 65.24 mmol) in ethanol (60 mL) and water (12 mL) was stirred at 80 °C for 2 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (100 mL), washed with brine (2 × 30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give INT 4-1 (2.49 g, 11.97 mmol, 91.6% yield). MS (ESI, m / z): 208 [M+H] + .

[0128] To a solution of INT 4-1 (2.49 g, 11.97 mmol), hydroxylammonium chloride (2.49 g, 35.83 mmol), Na2SO4 (11.64 g, 95.76 mmol), and chloral hydrate (2.56 g, 17.95 mmol) in water (50 mL) and ethanol (7 mL) was added hydrochloric acid (1.75 mL). The reaction mixture was stirred at 60 °C for 16 h. The resulting mixture was cooled to room temperature, filtered, and the filter cake was dried to give INT 4-2 (3.295 g, 11.80 mmol, 98.6% yield). MS (ESI, m / z): 279 [M+H] + .

[0129] INT 4-2 (3.295 g, 11.80 mmol) was added in portions to sulfuric acid (29.5 mL) at 60° C. The reaction was stirred at 90° C. for 1 h. The resulting mixture was cooled to room temperature and added slowly to ice water. The resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give INT 4-3 (2.173 g, 8.29 mmol, 70.2% yield). MS (ESI, m / z): 262[M+H] + .

[0130] To a solution of INT 4-3 (2.173 g, 8.29 mmol) in NaOH (2 M, 46 mL, 93.50 mmol) was added hydrogen dioxide (5.2 mL) dropwise at 0° C. The reaction mixture was stirred at room temperature for 16 h. Excess hydrogen dioxide was quenched with excess sodium sulfite and the mixture was neutralized to pH=7. The mixture was filtered, the filtrate was acidified to pH=2 with concentrated hydrochloric acid, and the resulting precipitate was collected by filtration, washed with water, and dried under reduced pressure to give INT 4-4 (1.782 g, 7.07 mmol, 69.8% yield). MS (ESI, m / z): 252 [M+H] + .

[0131] To a solution of INT 4-4 (1.782 g, 7.07 mmol) in dichloromethane (20 mL) was added chlorosulfonyl isocyanate (1.33 g, 9.39 mmol) dropwise at 0° C. The reaction mixture was stirred at room temperature for 6 h and concentrated under reduced pressure. Concentrated hydrochloric acid (20 mL) was then added and stirred at 100° C. for 16 h. The resulting mixture was cooled to room temperature, filtered, and the filter cake was washed with water and dried under reduced pressure to give INT 4-5 (0.83 g, 2.99 mmol, 75.5% yield). MS (ESI, m / z): 275 [M-1] - .

[0132] To a solution of INT 4-5 (0.83 g, 2.99 mmol) in POCl3 (15 mL) was added N,N-diisopropylethylamine (2 mL). The reaction mixture was stirred at 105 °C for 2 h. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with DCM (50 mL), washed with water (2 × 30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give INT 4-6 (1.87 g, 5.95 mmol, 113.8% yield).

[0133] A suspension of INT4-6 (4.96 g, 15.80 mmol) in 5% aqueous sodium hydroxide (150 mL) was stirred at room temperature for 4 h. After completion, the mixture was adjusted to pH 9-10 with 5% NaHCO3 and extracted twice with EA. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was triturated with EA:Hex=1:8 (35 mL). The suspension was filtered and the filter cake was dried under reduced pressure to give INT 4 (3.76 g, 12.73 mmol). MS: m / z 295 [M+1] + .

[0134] INT 5 [ka]

[0135] A solution of 1,4-oxazepan-5-one, 1,4-oxazepan-5-one-1 (4.03 g, 35.00 mmol) in THF (80 mL) was cooled to -78 °C, n-BuLi (15.5 mL) was added dropwise, and stirred for 30 min. Phenylmethyl chloroformate (6.58 g, 38.57 mmol) was added at -70 °C and stirred for 1 h. Quenched with NH4Cl (aq., 50 mL) and extracted with EtOAc (2 x 100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-25% hex in EtOAc, v / v) to give INT 5-1 (4.09 g, 16.40 mmol, 46.9% yield). MS m / z: 250 [M+H] + .

[0136] A solution of INT 5-1 (4.09 g, 16.40 mmol) in THF (120 mL) was cooled to -70 °C, KHMDS (1 M, 20 mL) was added dropwise, stirred for 90 min, diphenylchlorophosphate (5.18 g, 19.28 mmol) in THF (20 mL) was added and stirred at -70 °C for 60 min. The reaction mixture was quenched with 5% NaOH (aq., 60 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-25% hex in EtOAc, v / v) to give INT 5-2 (5.82 g, 12.09 mmol, 73.7% yield). MS m / z: 482 [M+H] + .

[0137] A mixture of INT5-2 (9 g, 18.7 mmol), Pd(OAc)2 (420 mg, 1.87 mmol) and PPh3 (981 mg, 3.74 mmol) in DMF (192 mL) was evacuated / backfilled with carbon monoxide three times. The resulting mixture was stirred at 25 °C for 30 min. TEA (3.80 g, 37.4 mmol) and MeOH (24 g, 748 mmol) were added and stirred at 45 °C for 1.5 h. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with petroleum ether: EtOAc = 5: 1, v / v) to give INT 5-3 (4.5 g). MS m / z: 292 [M+H] + .

[0138] To a solution of INT 5-3 (1.9 g, 6.52 mmol) in methanol (20 mL) was added 10% Pd / C (1.07 g, 1.00 mmol). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give INT 5-4 (994 mg, 6.24 mmol, 95.7% yield). MS m / z: 160 [M+H] + .

[0139] A solution of INT5-4 (994 mg, 6.24 mmol) in THF (10 mL) was cooled to 0 °C, LiAlH4 (1 M, 10 mL) was added dropwise, and the mixture was stirred at room temperature for 90 min. The reaction mixture was quenched with water (0.5 mL), followed by the addition of 15% NaOH (aq., 0.5 mL) and water (1.5 mL). The resulting mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0–10% methanol in DCM, v / v) to give INT 5 (419 mg, 3.19 mmol, 51.2% yield).

[0140] INT 6 [ka]

[0141] 3-(Benzylamino)propan-1-ol (18.0 g, 108 mmol) and TEA (12.1 g, 119 mmol) were added in DCM (126 mL). A solution of 2-chloroacetyl chloride (12.3 g, 108 mmol) in DCM (30.0 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 30 / 1 to 1 / 1, v / v) to give INT 6-1 (21.0 g, 86.8 mmol, 79.7% yield). LCMS: 242 [M+1].

[0142] 1 H NMR(400 MHz, CDCl3): δ 7.19-7.41 (m, 5H), 4.61-4.63 (m, 2H), 4.27 (s, 1H), 4.08 (s, 1H), 3.57-3.65 (m, 3H), 3.45-3.56 (m, 1H), 3.23-3.27 (m, 1H), 1.66-1.82 (m, 2H).

[0143] To a solution of INT 6-1 (21.0 g, 86.8 mmol) in THF (147 mL) was added NaH (3.82 g, 95.5 mmol, 60% content) at 0 °C. The resulting mixture was stirred at 20 °C for 5 h. NH4Cl (aq., 50.0 mL) was added at 0 °C, extracted with EtOAc (3 × 100 mL), and washed with brine (3 × 50.0 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 40 / 1 → 1 / 1, v / v) to give INT 6-2 (12.2 g, 59.4 mmol, 68.4% yield). LCMS: 206 [M+1].

[0144] 1H NMR (400 MHz, CDCl3): δ 7.11-7.19 (m, 5H), 4.46 (s, 2H), 4.16 (s, 2H), 3.64-3.66 (m, 2H), 3.25-3.27 (m, 2H), 1.64-1.70 (m, 2H).

[0145] INT 6-2 (0.500 g, 2.44 mmol), TMDS (649 mg, 4.87 mmol), IrCl(CO[P(C6H5)3])2 (19.0 mg, 24.3 μmol), and TMSCN (483 mg, 4.87 mmol) were added to toluene (5.00 mL) at 20 °C. The resulting mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition; Phenomenex Luna C18 75 × 30 mm × 3 μm; mobile phase: [water (TFA)-CH3CN]; gradient: 20% to 50%, 7 min) to give INT 6-3 (0.800 g, 3.70 mmol, 37.9% yield). LCMS: 217 [M+1].

[0146] 1 H NMR(400 MHz, CDCl3) :δ 7.33-7.39 (m, 5H), 3.76-3.94 (m, 7H), 2.92-2.96 (m, 2H), 1.96-2.41 (m, 2H).

[0147] A solution of INT 6-3 (251 mg, 1.16 mmol) in hydrochloric acid (3 mL) was stirred at 100° C. overnight. The mixture was concentrated to give INT 6-4 (357 mg, 1.52 mmol, crude). MS: m / z 236 (M+H). + .

[0148] To a solution of INT 6-4 (357 mg, 1.52 mmol) in THF (10 mL) at 0° C., LiAlH4 (221 mg, 5.8235 mmol) was added. The mixture was stirred at 0° C. for 2 h. The mixture was quenched with ice water (5 mL), filtered, and the filtrate was concentrated. The residue was purified by pre-TLC to give INT 6-5 (145 mg, 655.23 μmol, 43.18% yield). MS: m / z 222 (M+H) + .

[0149] A solution of INT 6-5 (145 mg, 655.23 μmol) and Pd / C (10%, 185 mg, 1.74 mmol) in MeOH (5 mL) was stirred under hydrogen atmosphere at 50 °C overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give INT 6 (92 mg, 701.37 μmol, 107.04% yield). MS: m / z 132 (M+H) + .

[0150] INT 7 [ka]

[0151] A mixture of INT 3-3 (4.53 g, 17.90 mmol), NaOH (2.99 g, 74.76 mmol) in EtOH (50 mL) and water (10 mL) was stirred at 50 °C for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (40 mL) and extracted with EtOAc (2 x 30 mL). The pH of the aqueous phase was adjusted to 2 and extracted with EtOAc (2 x 30 mL), the organic layers were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give INT 7-1 (2.68 g, 11.91 mmol, 66.54% yield). MS: m / z 225 (M+H) + .

[0152] A mixture of INT 7-1 (2.44 g, 10.84 mmol) and SOCl2 (15 mL) was stirred at 70 °C for 2 h. The mixture was concentrated under reduced pressure. A solution of the resulting residue in CH3CN (10 mL) was added dropwise to a mixture of ammonium thiocyanate (2.22 g, 29.16 mmol) in CH3CN (40 mL) and stirred for 1.5 h. The reaction mixture was filtered and the filter cake was collected and dried to give INT 7-2 (2.21 g, 8.31 mmol, 76.59% yield). MS: m / z 264 (MH) - .

[0153] To a mixture of INT 7-2 (2.01 g, 7.55 mmol), NaOH (aq. 0.1 M, 150 mL) and MeOH (150 mL) was added CHI (2.22 g, 15.64 mmol). The mixture was stirred at RT for 0.5 h. The aqueous phase was adjusted to pH 3 with hydrochloric acid and extracted with EtOAc (1×200 mL, 1×100 mL), the organic layers were combined and concentrated under reduced pressure. The residue was triturated with water (20 mL) to give INT 7 (1.88 g, 6.71 mmol, 88.85% yield). MS: m / z 278 (MH) - .

[0154] INT 8 [ka]

[0155] INT 8-1 was prepared following the procedure in WO2013064231 starting from N-((benzyloxy)carbonyl)-O-(tert-butyl)-L-serine.

[0156] To a mixture of INT 8-1 (3.85 g, 13.68 mmol) in DMF (32 mL) was added 3-bromoprop-1-ene (6.96 g, 57.5 mmol) and TBAI (506 mg, 1.37 mmol). The resulting mixture was stirred at 0 °C, and NaH (2.74 g, 68.4 mmol, 60%) was added in portions. The reaction mixture was stirred at room temperature for 1.5 h, diluted with water (20 mL), extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether: EtOAc = 40: 1, v / v) to give INT 8-2 (4.1 g). MS m / z: 362 [M+H] + .

[0157] A mixture of INT 8-2 (1.2 g, 3.32 mmol) and Grubs-I (120 mg) in DCM (86.3 mL) was stirred at reflux temperature for 21 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether: EtOAc = 40: 1, v / v) to give INT 8-3 (550 mg). MS m / z: 334 [M+H] + .

[0158] To a solution of INT 8-3 (516 mg, 1.55 mmol) in MeOH (15 mL) was added Pd / C (467 mg). The reaction mixture was stirred at room temperature for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give INT 8-4 (459 mg, 2.28 mmol). MS m / z: 202 [M+H] + .

[0159] To a solution of INT 8-4 (438 mg, 2.18 mmol) in DCM (3 mL) was added TFA (3 mL). The reaction mixture was stirred at room temperature for 8 h and then concentrated under reduced pressure. The residue was lyophilized to give INT 8 (434 mg, 1.67 mmol, TFA salt). MS m / z: 146 [M+H] + .

[0160] INT 9 [ka]

[0161] To a 100 mL three-neck round-bottom flask was added tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (3000 mg, 15.06 mmol) and THF (30 mL) at room temperature. To the above mixture was added MeMgBr (2693.09 mg, 22.58 mmol) dropwise at -78 °C under argon atmosphere. The resulting mixture was stirred at room temperature for another 3 h. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layer was dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 50% in 30 min; detector, UV 254 nm) to give INT 9-1 (2.4 g, 74.04%). LC-MS: (ES, m / z): [M+H-CH3] + : 201.09.

[0162] 1 H NMR (400 MHz, chloroform-d) δ 3.98 - 3.90 (m, 1H), 3.79 - 3.63 (m, 1H), 3.60 - 3.43 (m, 1H), 3.26 - 3.23 (m, 1H), 1.97 (m, 1H), 1.85-1.76 (m, 3H), 1.47 (s, 9H), 1.15 (d, J = 5.9 Hz, 2H), 1.09 (d, J = 6.4 Hz, 1H).

[0163] In a 250 mL round bottom flask, INT 9-1 (2200 mg, 10.22 mmol), DCM (30 mL), DIEA (3962.18 mg, 30.657 mmol) and DMAP (249.68 mg, 2.044 mmol) were added at room temperature. To the above mixture, CbzCl (3486.39 mg, 20.438 mmol) was added dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water / ice at room temperature. The resulting mixture was extracted with DCM (3 x 40 mL). The combined organic layer was dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN (0.1% FA) in water, gradient from 10% to 100% in 30 min; detector, UV 254 nm) to give INT 9-2 (2.51 g, 69.67%). LC-MS (ES, m / z): [M+H-Boc] + : 220.10.

[0164] 1 H NMR (400 MHz, chloroform-d) δ 8.06 (m, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 5.56-5.22 (m, 1H), 4.18 -4.01 (m, 1H), 3.90 - 3.21 (m, 2H), 2.13-1.77 (m, 4H), 1.34 (m, 12H).

[0165] A solution of sodium hydroxide (209 mg, 5.23 mmol) in water (4 mL) was added to INT 9-2 (300 mg, 939.28 μmol) in methanol (10 mL). The mixture was stirred at 50° C. for 16 h. Anhydrous sodium sulfate was added and the mixture was filtered and washed with DCM. The filtrate was concentrated under reduced pressure to give crude INT 9-3 (202 mg). MS: m / z: 216 [M+H] + .

[0166] A solution of INT 9-3 (202 mg) and HCl (4 M in 1,4-dioxane, 2 mL) in DCM (5 mL) was stirred at room temperature for 1.5 h. The solution was concentrated under reduced pressure to give crude INT 9 (108 mg). MS: m / z: 116 [M+H] + .

[0167] INT 10A and INT 10B [ka]

[0168] To a 500 mL three-neck round bottom flask was added oxalyl dichloride (7.01 g, 55.232 mmol) and DCM (75 mL) at room temperature under nitrogen atmosphere. To the above mixture was added a solution of DMSO (4.32 g, 55.232 mmol) in DCM (75 mL) at -78 °C. The resulting mixture was stirred at -78 °C for an additional 5 min. To the above mixture was added tert-butyl (3R)-3-(hydroxymethyl)morpholine-4-carboxylate (6 g, 27.615 mmol) in DCM (50 mL). The resulting mixture was stirred at -78 °C for an additional 15 min. To the above mixture was added TEA (16.77 g, 165.696 mmol). The resulting mixture was stirred at -78 °C for an additional 15 min, slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water at room temperature. The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (2×100 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in INT 10-1 (6.2 g crude), which was used directly in the next step without further purification. LC-MS: (ES, m / z): [M+H] + : 216, [M-CH3+H] + : 201, [M-C4H9+H] + : 160, [M-C5H9O2+H] + : 116.

[0169] In a 500 mL three-neck round-bottom flask, INT 10-1 (6.2 g crude) and THF (50 mL) were added at room temperature under nitrogen atmosphere. The mixture was cooled to -78 °C. To the above mixture, MeMgBr (10 mL, 30.0 mmol, 3 mol / L) in THF was added dropwise at -78 °C. The resulting mixture was stirred at room temperature for another 2 h. The reaction mixture was quenched with sat. NH4Cl (aq.). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 60 mL). The combined organic layers were washed with brine (2 x 60 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient from 0% to 100% in 80 min; detector, UV 220 nm) to give INT 10-2 (4.000 g). LC-MS: (ES, m / z): [M+H] + : 232, [M-CH3+H] + : 217, [M-C4H9+H] + : 176, [M-C5H9O2+H] + : 132.

[0170] In a 100 mL 3-neck round bottom flask, INT 10-2 (4 g, 17.294 mmol), DCM (40 mL, 43.235 mmol), TEA (5.25 g, 51.882 mmol), and DMAP (2.11 g, 17.294 mmol) were added under nitrogen atmosphere at room temperature. To the above mixture, benzoyl chloride (6.08 g, 43.235 mmol) was added at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with water / ice at room temperature. The resulting mixture was extracted with DCM (3×40 mL). The combined organic layers were washed with brine (2×40 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (column, C18 silica gel; mobile phase, MeCN in water, gradient from 0% to 100% in 80 min; detector, UV 254 nm) to give INT 10A-3 (1st peak, 1.627 g, 23.42%) and INT 10B-3 (2nd peak, 0.890 g, 14.35%).

[0171] INT 10A-3 LC-MS:(ES, m / z): [M+H] + : 336, [M-CH3+H] + : 321, [M-C4H9+H] + : 280, [M-C5H9O2+H] + : 236, [M +Na] + : 358. 1 H NMR (300 MHz, クロロホルム-d) δ 8.05 (d, J = 7.6 Hz, 2H), 7.53 (m, 1H), 7.41 (m, 2H), 5.74 (m, 1H), 4.25-4.05 (m, 1H), 3.98 (d, J = 12.1 Hz, 1H), 3.89-3.77 (m, 1H), 3.63 (d, J = 12.9 Hz, 2H), 3.54-3.40 (m, 1H), 3.29 (m, 1H), 1.49-1.31 (m, 12H).

[0172] INT 10B-3 LC-MS:(ES, m / z): [M+H] + : 336, [M-CH3+H] + : 321, [M-C4H9+H] + : 280, [M-C5H9O2+H] + : 236, [M+Na] + : 358 1 H NMR (300 MHz, クロロホルム-d) δ 8.10-8.00 (m, 2H), 7.62-7.51 (m, 1H), 7.45 (dd, J = 8.4, 7.0 Hz, 2H), 5.61 (dq, J = 9.6, 6.4 Hz, 1H), 4.11 (s, 1H), 3.97 (d, J = 11.9 Hz, 1H), 3.86 (d, J = 11.7 Hz, 2H), 3.57 - 3.48 (m, 1H), 3.45 (dd, J = 11.7, 3.1 Hz, 1H), 3.12 (d, J = 12.9 Hz, 1H), 1.49 (s, 9H) 1.36 (d, J = 6.3 Hz, 3H).

[0173] A solution of INT 10A-3 (510 mg, 1.52 mmol), NaOH (244 mg, 6.10 mmol) in MeOH (10 mL) was stirred at room temperature for 18 h. The pH of the solution was adjusted to 7-8 with 1 N hydrochloric acid at 0-10 °C and concentrated under reduced pressure. The residue was extracted with EtOAc (20 mL × 3), washed with NaCl (aq. 30 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give INT 10A (393.8 mg, crude), which was used directly in the next step without purification. MS: m / z: 232 [M+H] + .

[0174] To a solution of INT 10B-3 (362 mg, 1.08 mmol) in MeOH (9 mL) was added a solution of NaOH (89 mg, 2.23 mmol) in water (3 mL) at room temperature and stirred for 5 h. Then the mixture was quenched with hydrochloric acid (1 N) and adjusted to pH=7. The resulting mixture was extracted with EtOAc (30 mL×2) and the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give INT 10B (0.23 g, crude). MS: m / z: 232 [M+H] + .

[0175] INT 11 [ka]

[0176] To a solution of oxepan-4-one (15.0 g, 131.4 mmol) in EtOH (150 mL) and H2O (150 mL) was added (NH4)2CO3 (37.8 g, 394.26 mmol) at room temperature. Then, NaCN (9.7 g, 197.1 mmol) was added to the mixture under argon atmosphere. The mixture was then heated to 65 °C and stirred for 12 h. After cooling to room temperature, the reaction mixture was quenched with NaClO (450 mL) and stirred for 10 min. Then, the mixture was cooled to 0 °C and adjusted to pH < 2 with 6 N hydrochloric acid. The resulting mixture was extracted with chloroform / isopropyl alcohol = 5:1 (500 mL × 3), and the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give INT 11-1 (16.0 g, crude), which was used directly in the next step without further purification. LCMS: 185.2 [M+H] + .

[0177] A solution of INT 11-1 (16.0 g, crude, 140.2 mmol) in 6 N KOH (160 mL) was stirred at 120 °C for 12 h. Upon completion, the solution was adjusted to pH 9 with 4 N hydrochloric acid and the mixture was concentrated under reduced pressure to give INT 11-2 (65.0 g, crude, high in salts), which was used directly in the next step without further purification. LCMS: 160.2 [M+H] + .

[0178] To a solution of INT 11-2 (65.0 g, crude, 140.2 mmol, rich in salt, 1.0 eq) in MeOH (400 mL) was added concentrated H2SO4 (20 mL). The mixture was then heated to 70 °C and stirred for 12 h. After completion of the reaction, the mixture was cooled to 0 °C, adjusted to pH = 9 with 2 N NaOH, and concentrated under reduced pressure to give the crude product. The residue was purified by silica gel chromatography (eluted with MeOH / DCM = 1:10, v / v) to give INT 11-3 (20.0 g, crude). LCMS: 174.2 [M+H] + .

[0179] To a solution of INT 11-3 (16.0 g, crude, 92.4 mmol) in THF (300 mL) was added TEA (47.0 g, 461.9 mmol) at room temperature. The reaction mixture was cooled to 0 °C under argon atmosphere and picolinoyl chloride (19.6 g, 138.5 mmol) in THF (300 mL) was added. The mixture was stirred at 25 °C under argon atmosphere for 1 h. After completion, the reaction mixture was poured into water, the mixture was extracted with EtOAc (600 mL x 3), and the combined organic layer was washed with brine (500 mL x 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc = 5:1) to give INT 11-4 (5.0 g, 13.7% yield, 4 steps). LCMS: 279.1 [M+H] + .

[0180] To a solution of INT 11-4 (100 mg, 0.36 mmol) in 1,1,2,2-tetrachloroethane (1.5 mL), Pd(OAc)2 (8 mg, 0.04 mmol), AgOAc (180 mg, 1.08 mmol), 2,3,4,5,6-pentafluoro-1-iodobenzene (1.06 g, 3.6 mmol), 1,4-benzoquinone (20 mg, 0.18 mmol) and Na3PO4 (177 mg, 1.08 mmol) were added at room temperature. The reaction mixture was degassed with argon for 5 min. The mixture was heated to 130 °C and stirred for 12 h. After completion, the mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc = 5:1) to give INT 11-5 (35 mg, 35.3% yield). LCMS: 277.2 [M+H] + .

[0181] A solution of INT 11-5 (1.5 g, 5.4 mmol) in EtOH (15 mL) and ether (15 mL) was cooled to 0 °C under argon atmosphere, and LiBH4 (40.5 mL, 2 mol / L in THF, 81 mmol) was added in three portions over 30 min. The mixture was stirred at 0 °C for 2 h. Upon completion, the reaction mixture was quenched with 1 N hydrochloric acid and stirred for 10 min. The mixture was then cooled to 0 °C and adjusted to pH = 8 with 1 N NaOH. The mixture was extracted with EtOAc (80 mL x 3), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give INT 11-6 (1.0 g, crude, salts included), which was used directly in the next step without further purification. LCMS: 249.2 [M+H] + .

[0182] To a solution of INT 11-6 (1.0 g, crude, salt included) in EtOH (10.2 mL) and H2O (1.7 mL) at room temperature was added NaOH (1.4 g, 35.0 mmol). The mixture was heated to 130 °C and stirred in a 30 mL autoclave for 12 h. After cooling to room temperature, excess (Boc)2O was added and the mixture was stirred at 40 °C for 6 days. Then, the reaction mixture was poured into water, the mixture was extracted with EtOAc (10 mL × 3), and the combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with petroleum ether / EtOAc = 15:1, v / v) to give INT 11-7 (360 mg, 27.3% yield, 2 steps).

[0183] 1H NMR (300 MHz, CDCl3): δ 4.15-4.08 (m, 2H), 3.90 (d, J = 12.5 Hz, 2H), 3.80 (d, J = 11.7 Hz, 1H), 3.68 (d, J = 12.3 Hz, 2H), 2.56 (d, J = 14.1 Hz, 1H), 2.19 (t, J = 8.7 Hz, 1H), 2.06-1.92 (m, 1H), 1.78-1.68 (m, 2H), 1.46 (s, 9H). LCMS: 188.2 [M-56+H] + .

[0184] To a solution of INT 11-7 (0.14 g, 0.58 mmol) in DCM (5 mL) was added TFA (1.5 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated under reduced pressure to give INT 11 (crude). MS m / z: 144[M+H] + .

[0185] INT 12 [ka]

[0186] A solution of N-BOC-O-benzyl-D-serine (70.59 g, 239.02 mmol) and triethylamine (29.70 g, 293.50 mmol) in THF (1000 mL) was cooled to -15°C and isobutyl carbonochloridate (36.31 g, 265.85 mmol) was added. The solution was stirred at the same temperature for 2 h and then filtered. The filtrate was cooled to 0°C and added dropwise to a solution of NaBH4 (16.71 g, 441.68 mmol) in water (200 mL). The solution was stirred at 0°C for 1 h. The resulting mixture was quenched with water (200 mL) and extracted with EtOAc (1000 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-50% EtOAc in Hex) to give INT 12-1 (74.35 g, 264.26 mmol, 110.5% yield). MS (ESI, m / z): 282 [M+H]+ .

[0187] A mixture of INT 12-1 (60.00 g, 213.26 mmol) and Cs2CO3 (70.76 g, 217.17 mmol) in tert-butanol (500 mL) and tert-butyl acrylate (500 mL) was stirred at room temperature for 16 h. The resulting mixture was quenched with water (200 mL), extracted with EtOAc (500 mL), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-20% EtOAc in Hex) to give INT 12-2 (87.16 g, 212.83 mmol, 99.8% yield). MS (ESI, m / z): 410 [M+H] + .

[0188] To a solution of INT 12-2 (87.16 g, 212.83 mmol) in DCM (300 mL) was added TFA (300 mL). The solution was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to give INT 12-3, and the residue was used directly in the next step without further purification.

[0189] To a solution of INT 12-3 (27 g, 106.59 mmol) in DCM (500 mL) was added HATU (49.19 g, 129.36 mmol) and TEA (48.04 g, 474.75 mmol). The solution was stirred at room temperature for 3 h. The mixture was then quenched with aq. NaHCO3 (sat., 300 mL) and extracted with DCM (200 mL), and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 10-100% EtOAc in hex) to give INT 12-4 (49.54 g, 210.55 mmol, 197.5% yield). MS (ESI, m / z): 236 [M+H] + .

[0190] A solution of LiAlH4 (15.76 g, 415.28 mmol) in THF (200 mL) was cooled to 0 °C and a solution of INT 12-4 (49.54 g, 210.55 mmol) in THF (200 mL) was added dropwise. The reaction mixture was stirred at room temperature for 5 h. The resulting mixture was quenched with water (15 mL), 15% NaOH (15 mL), and water (45 mL). The solution was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 0-5% methanol in DCM) to give INT 12-5 (44.93 g, 203.03 mmol, 96.4% yield). MS (ESI, m / z): 222 [M+H] + .

[0191] To a solution of INT 12-5 (19.12 g, 86.40 mmol) in THF (200 mL) was added di-tert-butyl dicarbonate (21.05 g, 96.45 mmol) and N,N-diisopropylethylamine (16.17 g, 125.11 mmol). The reaction mixture was stirred at room temperature for 3 h. The solution was diluted with water (100 mL) and extracted with EtOAc (2×500 mL), and the combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 0–10% EtOAc in hex) to give INT 12-6 (18.02 g, 56.06 mmol, 64.8% yield). MS (ESI, m / z): 322 [M + H] + .

[0192] To a solution of INT 12-6 (7.00 g, 21.77 mmol) in methanol (140 mL) was added Pd / C (3.60 g, 3.38 mmol). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 16 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give INT 12 (5.29 g, 22.87 mmol, 105.0% yield). MS (ESI, m / z): 232 [M+H] + .

[0193] INT 13 [ka]

[0194] INT 13 was prepared according to the synthetic procedure of INT12 using O-benzyl-N-(tert-butoxycarbonyl)-L-serine.

[0195] INT 14 [ka]

[0196] To a solution of INT 12 (1332 mg, 5.76 mmol) in DCM (15 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 2 h. The solution was concentrated under reduced pressure. To a solution of the residue in DCM (15 mL) and DIEA (5 mL) was added (bromomethyl)benzene (1122 mg, 6.56 mmol). After stirring the reaction mixture at room temperature for 2.5 h, it was diluted with water (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on a silica gel column to give INT 14-1 (995 mg, 1.27 mmol). MS m / z: 222 [M+H] + .

[0197] To a solution of INT 14-1 (447 mg, 2.02 mmol), TEA (642 mg, 6.34 mmol) in THF (5 mL) was added MsCl (114 mg, 1.00 mmol) at -10 °C. The reaction mixture was stirred at room temperature for 20 min, then diluted with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give INT 14-2 (611 mg, 2.04 mmol).

[0198] To a solution of INT 14-2 (611 mg, 2.04 mmol), DIEA (1322 mg, 10.23 mmol) in acetonitrile (10 mL) was added methylamine hydrochloride (279 mg, 4.13 mmol). The reaction mixture was stirred at room temperature for 1.5 h, then diluted with water (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give INT 14-3 (crude). MS m / z: 235 [M+H] + .

[0199] To a solution of INT 14-3 (crude) and DIEA (0.5 mL) in THF (10 mL) was added di-tert-butyl dicarbonate (902 mg, 4.13 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with water (30 mL), and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column to give INT 14-4 (127 mg, 0.38 mmol). MS m / z: 335 [M+H] + .

[0200] To a solution of INT 14-4 (107 mg, 0.32 mmol) in MeOH (5 mL) was added Pd(OH)2 / C (122 mg, 10% content). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give INT 14 (77 mg, 0.32 mmol). MS m / z: 245 [M+H] + .

[0201] INT 15 [ka]

[0202] To a solution of INT 14-2 (0.5 g, 1.67 mmol), cesium fluoride (1.23 g, 8.10 mmol) in DMF (10 mL) was added cyanotrimethylsilane (0.74 g, 7.46 mmol). The reaction mixture was stirred at 80° C. for 4.5 h, then diluted with water (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column to give INT 15-1 (257 mg, 1.12 mmol). MS m / z: 231 [M+H] + .

[0203] A solution of INT 15-1 (217 mg, 0.94 mmol) in concentrated hydrochloric acid (8 mL) was stirred at 80° C. for 3.5 hours. The reaction mixture was concentrated under reduced pressure. To a mixture of the residue in THF (10 mL) was added TEA (2 mL). The mixture was concentrated under reduced pressure to give INT 15-2 (crude). MS m / z: 250 [M+H] + .

[0204] To a mixture of INT 15-2 (crude) in THF (10 mL) was added LiAlH4 (216 mg, 5.69 mmol). The reaction mixture was stirred at room temperature for 1 h and then quenched with water (0.3 mL), aq.NaOH (0.5 mL, 15%wt), and water (1 mL). The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column to give INT 15-3 (141 mg, 0.60 mmol). MS m / z: 236 [M+H] + .

[0205] To a solution of INT 15-3 (141 mg, 0.60 mmol) in MeOH (15 ml) was added Pd(OH)2 / C (144 mg, 10% content). The reaction mixture was stirred at room temperature under hydrogen atmosphere for 5.5 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give INT 15 (89 mg, 0.61 mmol). MS m / z: 146 [M+H] + .

[0206] Example 1 [ka]

[0207] To a solution of INT 5 (280 mg, 2.13 mmol) in dry THF (25 mL) was added sodium hydride (60% in oil, 293 mg, 7.33 mmol) under nitrogen atmosphere at 0° C. and stirred at room temperature for 30 min. A solution of INT 4 (629 mg, 2.13 mmol) in dry THF (5 mL) was added to the reaction mixture and stirred at room temperature for 24 h. After completion, the reaction mixture was diluted with EtOAc (50 mL) and water (40 mL). The organic layer was separated and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH=10:1, v / v) to give compound 1-1 (377 mg, 0.93 mmol). MS: m / z 406 [M+H] + .

[0208] To a solution of compound 1-1 (352 mg, 0.87 mmol) and DIEA (0.3 mL) in DCM (10 mL) was added phosphorus oxychloride (0.5 mL) under nitrogen atmosphere and stirred for 1 h. After completion, the residue was diluted with DCM (30 mL), quenched with saturated NaHCO3 (50 mL) and separated. The combined organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with Hex:EtOAc=3:1, v / v) to give compound 1-2 (157 mg, 0.40 mmol). MS: m / z 388 [M+H] + .

[0209] To a solution of compound 1-2 (144 mg, 0.37 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (86 mg, 0.54 mmol) in THF (5 mL) and DMF (5 mL), DABCO (19 mg, 0.17 mmol) and Cs2CO3 (341 mg, 1.05 mmol) were added, and the mixture was purged with nitrogen and then stirred at room temperature for 16 h. The mixture was diluted with EtOAc (30 mL) and water (30 mL), and the organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH=15:1, v / v) to give compound 1-3 (142 mg, 0.28 mmol). MS: m / z 511 [M+H] + .

[0210] To a solution of compound 1-3 (142 mg, 0.28 mmol), INT 2 (208 mg, 0.41 mmol) and Cs2CO3 (267 mg, 0.82 mmol) in toluene (8 mL) and water (2 mL), cataCXium A Pd G3 (22 mg, 0.030 mmol) was added, and the mixture was purged with nitrogen and then stirred at 100 °C for 16 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc (40 mL) and water (30 mL), and the organic layer was separated. The organic layer was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH = 15:1, v / v) to give compound 1-4 (197 mg, 0.24 mmol). MS: m / z 817 [M+1] + .

[0211] To a solution of compound 1-4 (197 mg, 0.24 mmol) in CH3CN (5 mL) was added HCl / 1,4-dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated under reduced pressure, the residue was diluted with EtOAc (30 mL) and water (20 mL), and the mixture was adjusted to pH=8-9 with saturated NaHCO3. The organic layer was separated and concentrated under reduced pressure to give compound 1-5 (181 mg, crude). MS: m / z 773 [M+H] + .

[0212] To a mixture of compound 1-5 (181 mg, crude) in DMF (5 mL) was added CsF (399 mg, 2.63 mmol). The mixture was stirred at room temperature for 4 h. After completion, the mixture was diluted with EtOAc (30 mL) and water (20 mL) and the mixture was adjusted to pH=8-9 with saturated NaHCO3. The organic layer was separated and concentrated under reduced pressure. The residue was purified by Pre-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 45% B in 40 min at a flow rate of 60 mL / min, 230 nm) and the product fraction was lyophilized to give compound 1 (144.5 mg, 0.20 mmol, TFA salt). MS: m / z 617 [M+H] + .

[0213] 1 H NMR (600 MHz, MeOD) δ 7.87-7.81 (m, 1H), 7.35-7.28 (m, 2H), 7.14-7.01 (m, 2H), 5.59-5.46 (m, 1H), 4.73-4.62 (m, 2H), 4.48-4.42 (m, 1H), 4.41-4.31 (m, 1H), 4.01-3.89 (m, 4H), 3.89- 3.74 (m, 2H), 3.74-3.59 (m, 2H), 3.50-3.39 (m, 2H), 2.72-2.56 (m, 2H), 2.56-2.38 (m, 2H), 2.37- 2.26 (m, 2H), 2.26-2.16 (m, 1H), 2.16-1.98 (m, 3H).

[0214] Example 2 [ka]

[0215] A solution of INT 5 (127 mg, 968.19 μmol), NaH (170 mg, 4.25 mmol, 60% wt) in THF (5 mL) was stirred at 0° C. for 0.5 h, and INT 3 (215 mg, 800.87 μmol) was added. The mixture was stirred at 0° C. for 2.5 h and quenched with water (1 mL). The solution was purified by reverse phase flash chromatography (20% MeCN / water) to give compound 2-1 (242 mg, 666.35 μmol). MS m / z: 363 / 365 [M+H] + .

[0216] POCl3 (493 mg, 3.22 mmol) was added to a solution of compound 2-1 (229 mg, 630.56 μmol) and DIEA (297 mg, 2.30 mmol) in DCM (8 mL) and stirred at -10°C for 1 h. The mixture was quenched with sat.NaHCO3 (20 mL) and partitioned with water and EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by pre-TLC (eluted with MeOH:DCM=1:15, v / v) to give compound 2-2 (98 mg, 283.93 μmol). MS m / z: 345 / 347 [M+H] + .

[0217] A solution of compound 2-2 (98 mg, 283.93 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (73 mg, 458.54 μmol), and KF (56 mg, 963.91 μmol) in DMSO (4 mL) was stirred overnight at 90° C. under nitrogen atmosphere. The mixture was partitioned between water and EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with MeOH:DCM=1:10, v / v) to give compound 2-3 (28 mg, 59.84 μmol). MS m / z: 468 / 470 [M+H] + .

[0218] To a solution of compound 2-3 (28 mg, 59.84 μmol), INT 2 (54 mg, 105.36 mmol) in toluene (5 mL) and water (1 mL), Cs2CO3 (63 mg, 193.36 μmol) and cataCXium A Pd G3 (12 mg, 16.48 μmol) were added. The reaction mixture was stirred overnight at 100° C. under nitrogen atmosphere. The reaction mixture was extracted with EtOAc (20 mL) and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH=10:1, v / v) to give compound 2-4 (57 mg, 69.68 mmol). MS m / z: 818 [M+H] + .

[0219] A solution of compound 2-4 (57 mg, 69.68 mmol), HCl (1 mL, 4 M in dioxane) in MeCN (3 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure. The residue was diluted with saturated NaHCO3 (20 mL) and extracted with EtOAc (2×20 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was dissolved in DMF (3 mL) and CsF (181 mg, 1.19 mmol) was added. The reaction mixture was stirred at 45° C. under nitrogen atmosphere for 2 h. The reaction mixture was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 35% B, 32 min, flow rate 40 mL / min, 240 nm), and the product fraction was lyophilized to give compound 2 (10.2 mg, 0.789 mmol, TFA salt). MS m / z: 618 [M+H] + .

[0220] Example 3 [ka]

[0221] To a solution of INT 6 (92 mg, 701.37 μmol) in THF (10 mL) at 0° C. was added NaH (106 mg, 4.42 mmol). The mixture was stirred at 0° C. for 1 h. INT 3 (190 mg, 707.74 μmol) was added to the reaction mixture. The mixture was stirred at 0° C. for 1 h. The mixture was quenched with ice water (5 mL), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give compound 3-1 (175 mg, 481.87 μmol, yield 68.1%). MS: m / z 363(M+H) + .

[0222] To a 0°C solution of compound 3-1 (142 mg, 391.00 μmol) and DIEA (185 mg, 1.43 mmol) in DCM (5 mL) was added phosphorus oxychloride (400 mg, 2.61 mmol). The mixture was stirred at 0°C for 1 h. The mixture was quenched with sat.NaHCO3 (aq., 20 mL) and extracted with DCM (10 mL×2). The combined organic extracts were washed with brine (10 mL×3) and dried over anhydrous Na2SO4. The mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give compound 3-2 (23 mg, 66.64 μmol, 17.04% yield). MS: m / z 345(M+H) + .

[0223] A solution of compound 3-2 (23 mg, 66.64 μmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (61 mg, 383.16 μmol), DIEA (24 mg, 185.70 μmol) and several molecular sieves in 1,4-dioxane (5 mL) was stirred at 100° C. overnight. The mixture was concentrated and purified by reverse phase flash chromatography to give compound 3-3 (82 mg, 175.25 μmol, crude). MS: m / z 468 (M+H) + .

[0224] A solution of compound 3-3 (82 mg, 175.25 μmol), INT 2 (241 mg, 470.21 μmol), cataCXium A Pd G3 (64 mg, 87.88 μmol) and Cs2CO3 (203 mg, 623.05 μmol) in toluene (10 mL) and H2O (2 mL) was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride (10 mL × 3) and dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated and purified by flash chromatography to give compound 3-4 (62 mg, 75.79 μmol, 43.25% yield). MS: m / z 818 (M+H) + .

[0225] To a solution of compound 3-4 (62 mg, 75.79 μmol) in MeCN (5 mL) was added HCl solution (1 mL, 4 M in dioxane). The mixture was stirred at RT for 2 h. TEA was added to adjust pH=8. The mixture was filtered, the filtrate was collected and concentrated under reduced pressure. The residue was dissolved in DMF (5 mL) and CsF (1656 mg, 10.90 mmol) was added. The reaction mixture was stirred at 45°C for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 40% B, 36 min, flow rate 60 mL / min, 230 nm) and the product fraction was lyophilized to give compound 3 (6.8 mg, 11.01 μmol, 14.52% yield, TFA salt). MS: m / z 618 (M+H) + .

[0226] Example 4 [ka]

[0227] To a solution of compound 1 (37.1 mg, 0.052 mmol) in MeOH (10 mL) was added Pd(OH)2 / C (21 mg, 10% content). The suspension was degassed under reduced pressure and purged with hydrogen three times. The mixture was stirred at room temperature for 3 h. Upon completion, the mixture was filtered and concentrated under reduced pressure. The residue was purified by Pre-HPLC (C18 column, A: The residue was purified with 0.1% TFA in water, B:CH3CN, gradient: 15% B to 40% B, 30 min, flow rate 40 mL / min, 230 nm) and lyophilized to give compound 4 (18.1 mg, 24.64 μmol, TFA salt). MS: m / z 621 [M+H] + .

[0228] Example 5 [ka]

[0229] A solution of INT 7 (807 mg, 2.88 mmol) and INT 12 (799 mg, 3.45 mmol) in THF (20 mL) was cooled to -5 °C, and NaH (451 mg, 11.27 mmol, 60%) was added. The reaction mixture was stirred at -5 °C for 2 h. Then, the mixture was quenched with HCl (1 N), adjusted to pH = 3, and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase flash (eluted with 5-35% CH3CN in water containing 0.1% NH3·H2O) to give compound 5-1 (993 mg, 2.09 mmol, 72.5% yield). MS (ESI, m / z): 475 [M+H] + .

[0230] To a solution of compound 5-1 (870 mg, 1.83 mmol) in acetonitrile (20 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 5 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was dissolved in toluene (20 mL) and N,N-diisopropylethylamine (2.3675 g, 18.31 mmol) was added followed by POCl3 (1.4044 g, 9.15 mmol). The reaction mixture was stirred at room temperature for 1 h. Then the mixture was quenched with aq.NaHCO3 (sat.,30 mL) and extracted with EtOAc (50 mL), and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluted with 0-50% EtOAc in hex) to give compound 5-2 (326 mg, 913.67 μmol, 49.8% yield). MS (ESI, m / z): 357 [M+H] + .

[0231] To a solution of compound 5-2 (226 mg, 633.40 μmol) in DCM (15 mL) was added m-CPBA (272 mg, 1.57 mmol) at room temperature and stirred for 1 h. Another batch of m-CPBA (51 mg, 295.53 μmol) was added and stirred for 1 h. Then the mixture was quenched with aq.NaHCO3 (30 mL), extracted with DCM (2×50 mL), and the organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (EtOAc) to give compound 5-3 (194 mg, 498.96 μmol, 78.7% yield). MS (ESI, m / z): 389 [M+H] + .

[0232] A solution of compound 5-3 (174 mg, 447.52 μmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (139 mg, 873.11 μmol) in THF (15 mL) was cooled to -30 °C, and then t-BuONa (48 mg, 499.46 μmol) was added. The reaction mixture was stirred at -30 °C for 0.5 h. Then, the mixture was quenched with aq. NH4Cl (sat., 30 mL), extracted with EtOAc (50 mL × 2), and the combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH = 15:1, v / v) to give compound 5-4 (185 mg, 395.38 μmol, 88.3% yield). MS (ESI, m / z): 468 [M+H] + .

[0233] A solution of compound 5-4 (185 mg, 395.38 μmol), INT 2 (404 mg, 788.23 μmol), cataCXium A Pd G3 (64 mg, 87.87 μmol), and Cs2CO3 (378 mg, 1.16 mmol) in toluene (8 mL) and water (2 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH = 15:1, v / v) to give compound 5-5 (296 mg, 361.85 μmol, 91.5% yield). MS (ESI, m / z): 818 [M+H] + .

[0234] To a solution of compound 5-5 (296 mg, 361.85 μmol) in CH3CN (15 mL) was added HCl (4 M in 1,4-dioxane, 5 mL). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with aq.NaHCO3 (saturated, 2×30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 5-6 (316 mg, 408.29 μmol, 112.8% yield). MS (ESI, m / z): 774 [M+H] + .

[0235] CsF (0.62 g, 4.08 mmol) was added to a solution of compound 5-6 (316 mg, 408.29 μmol) in DMF (4 mL). The reaction mixture was stirred at 40°C for 3 hours, then filtered to collect the filtrate. The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (YMC-Triart C18-S12 nm, phase A: 0.05% NH4OH in water, phase B: CH3CN, gradient: 15% B to 70% B, 25 min, flow rate 70 mL / min, 240 nm) and lyophilized to give compound 5 (112.9 mg, 182.79 μmol, 44.7% yield). MS (ESI, m / z): 618 [M+H] + .

[0236] 1H NMR (600 MHz, MeOD) δ 7.86-7.78 (m, 1H), 7.33-7.27 (m, 2H), 7.24-7.14 (m, 1H), 5.37- 5.17 (m, 2H), 4.75-4.68 (m, 1H), 4.56 (dd, J = 13.3, 3.1 Hz, 1H), 4.42-4.34 (m, 1H), 4.32-4.27 (m, 1H), 4.25-4.12 (m, 2H), 4.02-3.93 (m, 1H), 3.86-3.77 (m, 1H), 3.68-3.62 (m, 1H), 3.58-3.51 (m, 1H), 3.50-3.41 (m, 1H), 3.41-3.34 (m, 1H), 3.26-3.14 (m, 2H), 3.06-2.96 (m, 1H), 2.39-2.08 (m, 4H), 2.04-1.81 (m, 4H).

[0237] Example 6 [ka]

[0238] Compound 6 was prepared according to the synthetic procedure for compound 5 using INT 7 and INT 13.

[0239] Example 7 [ka]

[0240] A solution of INT 7 (604 mg, 2.15 mmol) and INT 10A (412 mg, 1.78 mmol) in THF (100 mL) was cooled to -5 °C, and NaH (387 mg, 9.68 mmol, 60% content) was added at 0-5 °C. The reaction mixture was stirred at room temperature for 19 h, quenched with hydrochloric acid (1 N), adjusted to pH = 7, and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% NH3.H2O in water, B: CH3CN, gradient: 5% B to 85% B in 35 min at a flow rate of 60 mL / min, 254 nm) to give compound 7A-1 (242.6 mg, 23.76% yield). MS: m / z: 475 [M+H] + .

[0241] A solution of compound 7A-1 (242.6 mg, 510.81 μmol) in HCl (4 M in 1,4-dioxane, 5 mL) was stirred at room temperature for 1 h and then concentrated under reduced pressure. Toluene (5 mL), N,N-diisopropylethylamine (1 mL) and POCl3 (0.5 mL) were added to the residue. The reaction mixture was stirred at room temperature for 1 h, then quenched with anhydrous NaHCO3 (saturated, 20 mL) and extracted with EtOAc (20 mL×2), the combined organic layer was dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 0-50% EtOAc in hex) to give compound 7A-2 (38.6 mg, 21.18% yield). MS: m / z: 357 [M+H] + .

[0242] To a solution of compound 7A-2 (38.6 mg, 108.18 μmol) in DCM (15 mL) was added m-CPBA (36 mg, 208.62 μmol) at room temperature and stirred for 1 h. Another portion of m-CPBA (9 mg, 52.15 μmol) was added and stirred for 1 h. The mixture was then quenched with aq.NaHCO3 (30 mL) and extracted with DCM (20 mL×2), the combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 7A-3 (31 mg, 73.70% yield), which was used directly in the next step without purification. MS: m / z: 389 [M+H] + .

[0243] A solution of compound 7A-3 (31 mg, 79.73 μmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (31 mg, 194.72 μmol) in THF (15 mL) was cooled to 0-5 °C, and t-BuONa (11 mg, 114.46 μmol) was added. The reaction mixture was stirred at 0-5 °C for 1 h. The mixture was quenched with aq. NH4Cl (sat.,10 mL) and extracted with EtOAc (15 mL × 2), the combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 7A-4 (34.7 mg, 93.01% yield). MS: m / z: 468 [M+H] + .

[0244] To a solution of compound 7A-4 (34.7 mg, 74.16 μmol) in toluene (15 mL) and water (3 mL), INT 2 (99 mg, 193.16 μmol), cataCXium A Pd G3 (50 mg, 68.66 μmol) and cesium carbonate (132 mg, 193.16 μmol) were added. The reaction mixture was stirred at 100° C. under nitrogen atmosphere for 16 h. The mixture was cooled to room temperature, diluted with sat NaHCO3 (50 mL) and extracted with DCM (30 mL×2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC to give compound 7A-5 (34.3 mg, 56.54% yield). MS: m / z: 818 [M+H] + .

[0245] A solution of compound 7A-5 (34.3 mg, 41.93 μmol), HCl (4 M in 1,4-dioxane, 2 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The solution was diluted with 10% aqueous NaHCO3 (50 mL) and extracted with DCM (30 mL x 2). The combined organic layers were washed with sat.NaCl (aq. 50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 7A-6 (18.2 mg, 56.08% yield). MS: m / z: 774 [M+H] + .

[0246] CsF (59 mg, 388.40 μmol) was added to a solution of compound 7A-6 (18.2 mg, 23.52 μmol) in DMF (10 mL). The reaction mixture was stirred at 35° C. for 16 h under nitrogen atmosphere. The solution was diluted with saturated NaHCO3 (50 mL), extracted with EtOAc (30 mL×2), washed with sat.NaCl (aq.50 mL×2), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A phase: 0.05% NH3-H2O in water, B phase: CH3CN, gradient: 20% B to 47% B in 30 min at a flow rate of 40 mL / min, 230 nm) to give compound 7A (0.9 mg, 6.41% yield). MS: m / z: 618 [M+H] + .

[0247] Compound 7B was prepared according to the synthetic procedure of compound 7A using INT 7 and INT 10B as starting materials.

[0248] Example 8 [ka]

[0249] To a solution of INT 7 (398 mg, 1.42 mmol), POCl3 (1.88 g, 12.26 mmol) in toluene (5 mL) was added N,N-diisopropylethylamine (1.61 g, 12.45 mmol). The reaction mixture was stirred at 80 °C for 1 h and concentrated under reduced pressure. A solution of the residue in DCM (5 mL) and N,N-diisopropylethylamine (1.22 g, 9.44 mmol) was added to a solution of INT 9 (131 mg, 1.14 mmol) in DCM (5 mL). The reaction mixture was stirred at 0 °C for 1 h, then quenched with water and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (Hex: EtOAc = 1: 2, v / v) to give compound 8A-1 (153 mg, 405.55 μmol, 35.66% yield) and compound 8B-1 (154 mg, 408.20 μmol, 35.89% yield). MS: m / z: 377 [M+H] + .

[0250] A solution of compound 8A-1 (153 mg, 405.55 μmol) in THF (5 mL) was cooled to −5° C. and NaH (129 mg, 3.23 mmol, 60% content) was added. The reaction mixture was stirred at room temperature for 1 h, quenched with saturated aqueous ammonium chloride solution, and extracted with EtOAc (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 8A-2 (170 mg). MS: m / z: 341 [M+H] + .

[0251] To a solution of compound 8A-2 (170 mg, 498.82 μmol) in DCM (5 mL) was added m-CPBA (219.3 mg, 1.27 mmol) and stirred at room temperature for 1 h. The mixture was quenched with aq.NaHCO3 (30 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (EtOAc) to give compound 8A-3 (77 mg, 206.54 μmol). MS: m / z: 373[M+H]+ .

[0252] A solution of compound 8A-3 (77 mg, 206.54 μmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (59 mg, 370.60 μmol) in THF (5 mL) was cooled to -10 °C, and t-BuONa (26 mg, 270.54 μmol) was added. The reaction mixture was stirred at -10 °C for 0.5 h, quenched with saturated aq. NH4Cl (30 mL), and extracted with EtOAc (50 mL × 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give compound 8A-4 (76 mg, 81.43% yield). MS: m / z: 452 [M+H] + .

[0253] A solution of compound 8A-4 (76 mg, 168.18 μmol), INT 2 (147 mg 286.81 μmol), cataCXium A Pd G3 (67 mg 92.00 μmol), and cesium carbonate (229 mg 702.84 μmol) in toluene (10 mL) and water (2 mL) was stirred at 100 °C for 16 h under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with sat.aq.NaHCO3 (50 mL), and extracted with EtOAc (30 mL × 2). The combined organic layer was washed with saturated NaCl (50 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with MeOH:DCM = 1:17, v / v) to give compound 8A-5 (134 mg, 167.08 μmol, yield 99.35%). MS: m / z: 802[M+H] + .

[0254] A solution of compound 8A-5 (134 mg, 167.08 μmol) and HCl (4 M in 1,4-dioxane, 1 mL) in DCM (5 mL) was stirred at room temperature for 1 h. The mixture was diluted with 10% aqueous NaHCO3 (50 mL) and extracted with DCM (30 mL×2). The combined organic layer was washed with saturated aq. NaCl (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give crude compound 8A-6 (144 mg, 189.98 μmol). MS m / z: 758[M+H] + .

[0255] A solution of compound 8A-6 (144 mg, 189.98 μmol), CsF (204 mg, 1.3430 mmol) in DMF (6 mL) was stirred at room temperature under nitrogen atmosphere for 16 h. The solution was diluted with saturated NaHCO3 (50 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with saturated aq.NaCl (50 mL×2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 45% B, 40 min, flow rate 60 mL / min, 240 nm), and the pH of the product fraction was adjusted to 10 and lyophilized to give compound 8A (31.6 mg, 27.65% yield). MS m / z: 602 [M+H] + .

[0256] Compound 8B was prepared according to the synthetic procedure for compound 8A (25.7 mg).

[0257] Example 9 [ka]

[0258] To a solution of INT 7 (90 mg, 0.32 mmol), DIEA (0.5 ml) in toluene (10 mL) was added POCl3 (0.25 mL). The reaction mixture was stirred at 80° C. for 1.5 h and concentrated under reduced pressure. The residue in DCM (5 mL) was added to a solution of INT 14 (77 mg, 0.32 mmol) and DIEA (1 mL) in DCM (10 mL). The reaction mixture was stirred at room temperature for 0.5 h, diluted with water (30 mL), and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Pre-TLC to give compound 9-1 (77 mg, 0.15 mmol). MS m / z: 506 [M+H] + .

[0259] To a solution of compound 9-1 (77 mg, 0.15 mmol) in acetonitrile (3 mL) was added HCl (1 mL, 4 mol / L in dioxane). The reaction mixture was stirred at room temperature for 1 h. The solution was concentrated under reduced pressure. To a solution of the residue in acetonitrile (5 mL), DIEA (1 mL) was added. The reaction mixture was stirred at 80° C. for 1.5 h, diluted with water (30 mL), and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Pre-TLC to give compound 9-2 (51 mg, 0.14 mmol). MS m / z: 370 [M+H] + .

[0260] According to the synthesis procedure of compound 5 in Example 5, crude compound 9 was prepared starting from compound 9-2, and purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 10% B to 33% B in 38 min at a flow rate of 40 mL / min, wavelength 285 nm), and lyophilized to obtain compound 9 (7.1 mg, 9.53 μmol, TFA salt).

[0261] Example 10 [ka]

[0262] To a solution of INT 8 (375 mg, 1.45 mmol) in THF (10 mL) was added NaH (345 mg, 8.63 mmol, 60% content). After stirring for 10 min, INT 3 (382 mg, 1.42 mmol) was added. The reaction mixture was stirred at room temperature for 4 h and then quenched with water (0.5 mL). The mixture was purified by reverse phase flash chromatography to give compound 10-1 (367 mg, 0.97 mmol). LCMS: 377 [M+H] + .

[0263] To a solution of compound 10-1 (315 mg, 0.84 mmol) and DIEA (3 mL) in DCM (9 mL) was added POCl3 (15 drops) at -30°C. The reaction mixture was stirred at -30°C for 3 h, then quenched with sat.aq.NaHCO3 (20 mL) and extracted with DCM (20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Pre-TLC to give compound 10-2 (47 mg, 0.13 mmol). LCMS: 359 [M+H] + .

[0264] A solution of compound 10-2 (47 mg, 0.13 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (44 mg, 0.28 mmol) and KF (33 mg, 0.57 mmol) in DMSO (5 mL) was stirred at 95 °C for 22 h under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The organic layer was washed with anhydrous NaCl (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC to give compound 10-3 (17 mg, 35.28 μmol). MS: m / z: 482 [M+H] + .

[0265] To a solution of compound 10-3 (17 mg, 35.28 μmol), INT 2 (33 mg, 64.39 μmol) in toluene (6 mL) and water (1.5 mL), Cs2CO3 (34 mg, 104.35 μmol) and cataCXium A Pd G3 (19 mg, 26.09 μmol) were added. The mixture was stirred overnight at 100 °C under nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The organic layer was washed with anhydrous NaCl (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Pre-TLC (eluted with DCM:MeOH = 15:1, v / v) to give compound 10-4 (20 mg, 24.04 μmol). MS m / z: 832 [M+H] + .

[0266] A solution of compound 10-4 (20 mg, 24.04 μmol), HCl (4 M in 1,4-dioxane, 1 mL) in CH3CN (3 mL) was stirred at RT for 1 h. The solution was concentrated under reduced pressure, diluted with saturated aq. NaHCO3 (20 mL), and extracted with EtOAc (30 mL×2). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 10-5 (crude, 29 mg, 36.80 μmol). MS m / z: 788 [M+H] + .

[0267] A solution of compound 10-5 (29 mg, 36.80 μmol), CsF (0.26 g, 1.71 mmol) in DMF (5 mL) was stirred at 40 °C for 2 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 40% B in 37 min at a flow rate of 40 mL / min, 235 nm), and the product fraction was lyophilized to give compound 10 (6.1 m). g, 8.18 μmol, TFA salt). MS m / z: 632 [M+H] + .

[0268] 1 H NMR (600 MHz, MeOD) δ 7.93-7.83 (m, 1H), 7.43-7.32 (m, 2H), 7.23 (m, 1H), 5.58 (d, 1H), 4.84-4.73 (m, 2H), 4.68-4.49 (m, 2H), 4.38-3.77 (m, 7H), 3.70-3.43 (m, 5H), 2.75-2.54 (m, 2H), 2.53-2.23 (m, 4H), 2.16 (s, 1H), 1.91-1.51 (m, 3H).

[0269] Example 11 [ka]

[0270] To a solution of morpholin-3-ylmethanol (81 mg, 0.69 mmol) in THF (5 mL) was added NaH (111 mg, 4.63 mmol, 60% content) at -10 °C. After stirring for 10 min, INT 3 (152 mg, 0.57 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and then quenched with water (0.5 mL). The mixture was purified by reverse phase flash chromatography to give compound 11-1 (181 mg, 0.52 mmol). MS m / z: 349 [M+H] +.

[0271] To a solution of compound 11-1 (168 mg, 0.48 mmol) and DIEA (379 mg, 2.93 mmol) in DCM (5 mL) was added POCl3 (0.8 ml) at -30°C. The reaction mixture was stirred at -30°C for 1.5 h, then quenched with saturated aq.NaHCO3 (30 mL) and extracted with DCM (30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography to give compound 11-2 (62 mg, 0.19 mmol). MS m / z: 331 [M+H] + .

[0272] Compound 11-5 was prepared using compound 11-2 according to the procedure for the synthesis of compound 12-5 in Example 12.

[0273] A solution of compound 11-5 (49 mg, 64.48 μmol), CsF (0.50 g, 3.29 mmol) in DMF (4 mL) was stirred at 40 °C for 20 h. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 40% B in 31 min at a flow rate of 40 mL / min, 230 nm), and the product fraction was lyophilized to give compound 11 (26.6 mg, 37.07 μmol, TFA salt). MS m / z: 604 [M+H] + .

[0274] 1 H NMR (600 MHz, MeOD) δ 7.95-7.82 (m, 1H), 7.42-7.30 (m, 2H), 7.24 (s, 1H), 5.58 (d, 1H), 5.23 (d, 1H), 4.80-4.50 (m, 4H), 4.33-4.20 (m, 1H), 4.16-3.81 (m, 4H), 3.78-3.63 (m, 2H), 3.54 (s, 1H), 3.52-3.36 (m, 3H), 2.77-2.55 (m, 2H), 2.50-2.39 (m, 1H), 2.41-2.29 (m, 2H), 2.17 (s, 1H).

[0275] Example 12 [ka]

[0276] To a solution of ethyl 2-(morpholin-3-yl)acetate (314 mg, 1.81 mmol) in THF (10 mL) was added LiAlH4 (132 mg, 3.48 mmol) in portions. The mixture was stirred at room temperature for 1.5 h, then quenched with water (1 mL), filtered, and concentrated under reduced pressure to give compound 12-1 (164 mg, 1.25 mmol). MS m / z: 132 [M+H] + .

[0277] To a solution of compound 12-1 (95 mg, 0.72 mmol) in THF (20 mL) was added NaH (142 mg, 3.55 mmol, 60% content) at 0° C. After stirring for 20 min, INT 3 (233 mg, 0.87 mmol) was added. The reaction mixture was stirred at room temperature for 3 h, then quenched with water (2 mL) and purified by reverse phase flash chromatography to give compound 12-2 (185.9 mg, 0.51 mmol). MS m / z: 363 [M+H] + .

[0278] To a solution of compound 12-2 (402 mg, 1.11 mmol), DIEA (454 mg, 3.51 mmol) in acetonitrile (20 mL) was added POCl3 (552 mg, 3.60 mmol). The reaction mixture was stirred at 0 °C for 0.5 h, then quenched with sat. aq. NaHCO3 and extracted with EtOAc (30 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-TLC to give compound 12-3 (29 mg, 0.084 mmol). MS m / z: 345 [M+H] + .

[0279] To a solution of compound 12-3 (29 mg, 0.084 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (19 mg, 0.012 mmol) in THF (5 mL), t-BuONa (15 mg, 0.016 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 2 days. The mixture was concentrated under reduced pressure and purified by Pre-TLC to give compound 12-4 (20 mg, 0.043 mmol). MS: m / z: 468 [M+H] + .

[0280] Compound 12-6 was prepared using compound 12-4 according to the synthetic procedure for compound 12-5 in Example 12.

[0281] A solution of compound 12-6 (14 mg, 0.017 mmol), CsF (352 mg, 2.32 mmol) in DMF (5 mL) was stirred at RT for 16 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 10% B to 36% B in 36 min at a flow rate of 40 mL / min, 234 nm) and the product fraction was lyophilized to give compound 12 (2.4 mg, 3.28 μmol, TFA salt). MS m / z: 618 [M+H] + .

[0282] Example 13 [ka]

[0283] To a 0°C solution of INT 12 (1059 mg, 4.58 mmol) in DCM (20 mL) was added Dess-Martin periodinane (2224 mg, 5.23 mmol). The mixture was stirred at room temperature for 2 h. The mixture was quenched with sat. aq. NaHCO3 (20 mL) and extracted with DCM (10 mL x 2). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The mixture was purified by reverse phase chromatography to give compound 13-1 (2210 mg, 9.64 mmol). MS: m / z 230 (M+H) + .

[0284] To a solution of compound 13-1 (946 mg, 4.13 mmol) in THF (20 mL) at -78 °C under nitrogen atmosphere was added methylmagnesium bromide (1.0 M in THF, 20 mL, 20 mmol). The mixture was stirred at -10 °C for 2 h. The mixture was quenched with sat. aq. NH4Cl (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic extracts were washed with brine (10 mL x 3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The mixture was purified by reverse phase chromatography to give compound 13-2 (711 mg, 70.24% yield). MS: m / z 246 (M+H) + .

[0285] To a solution of compound 13-2 (617 mg, 2.52 mmol) in acetonitrile (20 mL) was added hydrochloric acid (4 M in 1,4-dioxane, 5 mL). The reaction mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The mixture was diluted with DCM:MeOH=10:1 (30 mL) and adjusted to pH=8 with NaHCO3, then filtered and the filtrate was concentrated under reduced pressure. To a 0°C solution of the residue and INT 7 (734 mg, 2.62 mmol) in THF (20 mL) was added NaH (577 mg, 24.04 mmol). The mixture was stirred at room temperature for 2 h. The mixture was quenched with ice / water (5 mL), filtered and the filtrate was concentrated under reduced pressure to give compound 13-3 (1234 mg, crude). MS: m / z 389 (M+H) + .

[0286] To a solution of compound 13-3 (1234 mg, 3.17 mmol) in toluene (10 mL) was added DIEA (1448 mg, 11.20 mmol) and POCl3 (1807 mg, 11.7849 mmol). The mixture was stirred at room temperature for 2 h. The mixture was quenched with sat.aq.NaHCO3 (20 mL) and extracted with DCM (10 mL×2). The combined organic extracts were washed with brine (10 mL×3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give compound 13-4 (141 mg, 11.98% yield). MS: m / z 371 (M+H) + .

[0287] Following the synthesis procedure of compound 5 in Example 5, crude compound 13 was prepared from compound 13-4 as the starting material, and purified by pre-HPLC (C18 column, phase A: 0.1% TFA in water, phase B: CH3CN, gradient: 15% B to 30% B, 40 min, flow rate 60 mL / min, 230 nm), and lyophilized to give compound 13A (first peak, 12.6 mg, TFA salt) and compound 13B (second peak, 19.0 mg, TFA salt). MS: m / z 632 (M+H) + .

[0288] Example 14 [ka]

[0289] To a solution of compound 11 (11 mg, 0.016 mmol) in MeOH (5 ml) was added Pd(OH)2 / C (14 mg, 10% content). The reaction mixture was stirred under hydrogen atmosphere at room temperature for 3 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 45% B, 38 min, flow rate 40 mL / min, 230 nm) and lyophilized to give compound 14 (7.1 mg, 9.53 μmol). MS m / z: 608 [M+H] + .

[0290] Example 15 [ka]

[0291] To a solution of INT 15 (89 mg, 0.61 mmol) in THF (5 mL) was added NaH (145 mg, 3.63 mmol, 60% content) at 0° C. After stirring for 10 min, INT 7 (165 mg, 0.59 mmol) was added. The reaction was stirred at room temperature for 3.5 h and then quenched with water (0.5 mL). The resulting mixture was purified by reverse phase chromatography to give compound 15-1 (158 mg, 0.41 mmol). MS m / z: 389 [M+H] + .

[0292] To a solution of compound 15-1 (158 mg, 0.41 mmol) and DIEA (725 mg, 5.61 mmol) in DCM (30 mL) was added BOP-Cl (456 mg, 1.79 mmol). The reaction mixture was stirred at room temperature for 24 h, then diluted with water (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give compound 15-2 (42 mg, 0.13 mmol). MS m / z: 371 [M+H] + .

[0293] Following the synthesis procedure of compound 5 in Example 5, crude compound 15 was prepared starting from compound 15-2, purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 10% B to 34% B in 34 min at a flow rate of 40 mL / min, 240 nm) and lyophilized to give compound 15 (3.2 mg, 4.29 μmol, TFA salt). MS m / z: 632 [M+H] + .

[0294] Example 16 [ka]

[0295] To a solution of INT 7 (165 mg, 0.59 mmol) and DIEA (1 ml) in toluene (10 mL) was added POCl3 (0.5 ml). The reaction mixture was stirred at 85° C. for 3.5 h and then concentrated under reduced pressure. A solution of the residue in DCM (5 mL) was added to a solution of INT 11 (crude) and DIEA (1 mL) in DCM (5 mL) at −30° C. The reaction mixture was stirred at −30° C. for 1 h, diluted with water (30 mL), and extracted with DCM (30 mL×2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Pre-TLC to give compound 16-1 (73 mg, 0.18 mmol). MS m / z: 405 [M+H] + .

[0296] To a solution of compound 16-1 (61 mg, 0.15 mmol) in DMF (4 mL), NaH (26 mg, 0.65 mmol, 60% content) was added. The reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was purified by reverse phase chromatography to obtain compound 16-2 (58 mg, 0.16 mmol). MS m / z: 369 [M+H] + .

[0297] Following the synthesis procedure of compound 5 in Example 5, crude compound 16 was prepared starting from compound 16-2, and purified by Prep-HPLC (C18 column, A: 0.05% NH3-H2O in water, B: CH3CN, gradient: 25% B to 53% B in 28 min at a flow rate of 40 mL / min, 232 nm), and lyophilized to give compound 16 (7.1 mg, 9.53 μmol). MS m / z: 630 [M+H] + .

[0298] Example 17 [ka]

[0299] To a solution of 1-(tert-butyl) 2-methyl (S)-4-oxopyrrolidine-1,2-dicarboxylate (1.35 g, 5.55 mmol) in THF (20 mL) was added LiBH4 (8 mL, 2 mol / L in THF). The reaction mixture was stirred at room temperature for 2.5 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL×2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column to give compound 17-1 (1.095 g, 5.04 mmol). MS m / z: 218 [M+H] + .

[0300] To a solution of compound 17-1 (1.095 g, 5.04 mmol) in DCM (5 mL) was added TFA (5 mL). The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was dissolved in water (10 mL) and lyophilized to give compound 17-2 (crude). MS m / z: 118 [M+H] + .

[0301] To a solution of INT 7 (1038 mg, 3.71 mmol), DIEA (2 mL) in toluene (20 mL) was added POCl3 (1 mL). The reaction mixture was stirred at 85° C. for 2 h and then concentrated under reduced pressure. A solution of the residue in DCM (10 mL) was added to a solution of compound 17-2 (crude) and DIEA (2 mL) in DCM (10 mL) at −30° C. The reaction mixture was stirred at −30° C. for 15 min, diluted with water (30 mL), and extracted with DCM (30 mL×2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column to give compound 17-3 (753 mg, 1.99 mmol). MS m / z: 379 [M+H] + .

[0302] To a solution of compound 17-3 (753 mg, 1.99 mmol) in DMF (10 mL) was added NaH (248 mg, 6.20 mmol, 60% content) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The solution was diluted with water (30 mL) and extracted with DCM (50 mL x 4). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give compound 17-4 (130 mg, 0.38 mmol). MS m / z: 343 [M+H] + .

[0303] Starting from compound 17-4, crude compound 17 was prepared according to the synthesis procedure of compound 5 in Example 5, purified by Prep-HPLC (C18 column, A: 0.05% NH3-H2O in water, B: CH3CN, gradient: 20% B to 50% B in 28 min at a flow rate of 40 mL / min, 225 nm), and lyophilized to obtain compound 17 (4.4 mg, 7.29 μmol). MS m / z: 604 [M+H] + .

[0304] Example 18 [ka]

[0305] To a solution of tert-butyl 6-oxo-1,4-oxazepane-4-carboxylate (2.04 g, 9.48 mmol) in MeOH (20 mL) was added NaBH4 (0.73 g, 19.30 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL), the pH value was adjusted to 13, and extracted with EtOAc (30 mL×2). The combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give compound 18-1 (2.44 g, 11.23 mmol, HCl salt). MS m / z: 218[M+H] + .

[0306] To a solution of compound 18-1 (1.31 g, 6.03 mmol) in acetonitrile (9 mL) was added HCl (3 mL, 4 mol / L in dioxane). The reaction mixture was stirred at room temperature for 4 h and then concentrated under reduced pressure to give compound 18-2 (0.87 g, 5.66 mmol). MS m / z: 118[M+H] + .

[0307] Following the synthesis procedure of compound 19 in Example 19, crude compound 18 was prepared starting from compound 18-2, purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 35% B in 30 min at a flow rate of 40 mL / min, wavelength 235 nm), and lyophilized to obtain compound 18 (1.7 mg, 2.37 μmol, TFA salt). MS m / z: 604 [M+H] + .

[0308] Example 19 [ka]

[0309] To a solution of piperidin-2-ylmethanol (1.07 g, 9.29 mmol), triethylamine (2.70 g, 26.68 mmol) in DCM (20 mL) was added di-tert-butyl dicarbonate (2.41 g, 11.04 mmol) at 0° C. and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by reverse phase chromatography (C18 column, A: water, B: CH3CN, gradient: 10% B to 100% B in 30 min, flow rate 60 mL / min, wavelength 220 nm) to give compound 19-1 (1.47 g, 6.83 mmol, yield 73.50%). MS: m / z: 216[M+H] + .

[0310] Following the synthesis procedure of compound 5 in Example 5, crude compound 19 was prepared starting from compound 19-1, purified by Prep-HPLC (C18 column, A: 0.05% ammonium hydroxide in water, B: CH3CN, gradient: 35% B to 72% B in 34 min at a flow rate of 70 mL / min, wavelength 230 nm), and lyophilized to obtain compound 19 (42.4 mg, 70.48 μmol, yield 35.61%). MS: m / z: 602 [M+H] + .

[0311] Example 20 [ka]

[0312] To a solution of (S)-1-(tert-butoxycarbonyl)azepane-2-carboxylic acid (0.57 g, 2.34 mmol) in THF (10 mL), borane-tetrahydrofuran complex (5 mL) was added at -10°C and stirred at -10°C overnight. Methanol (15 mL) was added to the reaction solution, which was then heated to 60°C and stirred for 0.5 hours. The reaction solution was concentrated under reduced pressure to give compound 20-1 (673 mg). MS: m / z: 230 [M+H] + .

[0313] Following the synthesis procedure of compound 5 in Example 5, crude compound 20 was prepared starting from compound 20-1, purified by Prep-HPLC (C18 column, A: 0.1% TFA in water, B: CH3CN, gradient: 15% B to 40% B, 50 min, flow rate 40 mL / min, 250 nm), and lyophilized to obtain compound 20 (1.6 mg, 2.5989 μmol, 7.4308% yield, TFA salt). MS: m / z: 616 [M+H] + .

[0314] Example 21 [ka]

[0315] To a solution of INT 3 (500 mg, 1.86 mmol) in POCl3 (6.75 mL) was added DIEA (0.68 mL). The reaction mixture was stirred at 110 °C for 1.5 h. After completion, the reaction mixture was concentrated under reduced pressure. To a solution of the residue (crude, 1.86 mmol) in DCM (10 mL) was added DIEA (1.6 g, 12.5 mmol), pyrrolidin-2-ylmethanol (188.4 mg, 1.86 mmol) at -40 °C. The reaction mixture was stirred at -40 °C for 30 min. After completion, H2O (15 mL) was added to the reaction mixture and extracted with DCM (15 mL × 3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated to give a residue, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 8:1 → 1:1) to give compound 21-1 (370 mg, 1.05 mmol, 56.5% yield). LCMS: 351.0 [M+H] + .

[0316] To a solution of compound 21-1 (370 mg, 1.05 mmol) in THF (9.5 mL) was added NaH (60%, 210 mg, 5.25 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h under nitrogen atmosphere. After completion, H2O (15 mL) was added to the reaction mixture and extracted with EtOAc (15 mL×3). The combined organic phase was dried over anhydrous Na2SO4 and concentrated to give compound 21-2 (200 mg, 0.63 mmol, crude). LCMS: 315.0 [M+H] + .

[0317] To a solution of compound 21-2 (crude, 200 mg, 0.63 mmol) and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (202.2 mg, 1.27 mmol) in dioxane (10 mL), DIEA (246.2 mg, 1.91 mmol) and 4A molecular sieves (200 mg) were added. The mixture was stirred overnight at 90 °C under N2 atmosphere. After the reaction was completed, the reaction mixture was filtered and concentrated to give a residue, which was purified by pre-TLC (dichloromethane / methanol = 15:1) to give compound 21-3 (20 mg, 0.045 mmol, yield 7.1%). LCMS: 438.1 [M+H] + .

[0318] Starting from compound 21-3, crude compound 21 was prepared according to the synthesis procedure of compound 5 in Example 5, and purified by Prep-HPLC (acetonitrile containing 0.1% FA in water) to obtain compound 21 (3.9 mg, 0.007 mmol, yield 20.7%, FA salt).

[0319] 1H NMR (300 MHz, DMSO-d6): δ 10.13 (s, 1H), 7.97-7.92 (m, 1H), 7.48-7.41 (m, 1H), 7.36-7.35 (m, 1H), 7.19-7.09 (m, 1H), 5.36-5.19 (m, 1H), 4.71-4.62 (m, 1H), 4.25-3.97 (m, 5H), 3.85-3.82 (m, 2H), 3.11-3.09 (m, 3H), 3.00 (s, 1H), 2.86-2.78 (m, 1H), 2.03-1.75 (m, 9H). LCMS: 588.2 [M+H] + .

[0320] Example 22 [ka]

[0321] To a solution of ethyl 2-oxocyclohexane-1-carboxylate (5.0 g, 29.4 mmol) in CHCl3 (60 mL) was added MeSO3H (28 g, 294 mmol) at 0 °C. Then, NaN3 (3.8 g, 58.8 mmol) was added to the mixture and heated to reflux for 4 h. The mixture was extracted with DCM (50 mL). The organic layer was quenched with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography on silica gel (eluted with PE / EtOAC = 1:1) to give compound 22-1 (3.5 g, 64.3% yield). LCMS: 186.2 [M+H] + .

[0322] To a solution of compound 22-1 (1.0 g, 5.4 mmol) in THF was added LiAlH4 (863 mg, 21.6 mmol) at 0 °C under N2 atmosphere. The mixture was then heated to reflux for 5 h. Then, H2O (0.8 mL) was added to the mixture at 0 °C and stirred for 15 min. Saturated aqueous 15% NaOH (0.8 mL) was added to the mixture. Then, H2O (2.4 mL) and Na2SO4 were added to the mixture at room temperature. Finally, the mixture was filtered, washed with EtOAc, and the filtrate was concentrated to give compound 22-2 (600 mg, 86.0% yield). LCMS: 130.2 [M+H] + .

[0323] To a solution of INT 3 (300 mg, 1.1 mmol) in THF (3 mL) was added NaH (89.5 mg, 2.2 mmol) and compound 22-2 (433 mg, 3.3 mmol) under N2 atmosphere at 0 °C and stirred for 3 h. The mixture was poured into water (3 mL) and extracted with EtOAc (5 mL × 2). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM / MeOH = 10:1) to give compound 22-3 (100 mg, 24.8% yield). LCMS: 361.1 [M+H] + .

[0324] To a solution of compound 22-3 (80 mg, 0.22 mmol) in DCM, DIEA (100 mg, 0.77 mmol) and POCl3 (170 mg, 1.1 mmol) were added at 0°C under nitrogen atmosphere. After stirring the mixture for 3 hours, the mixture was directly concentrated to give a residue. The residue was purified by Pre-TLC (eluted with PE / EtOAc=10:1) to give compound 22-4 (30 mg, 39.4% yield). LCMS: 343.1 [M+H] + .

[0325] Compound 22-4 (30 mg, 0.08 mmol), ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (28 mg, 0.17 mmol), DIEA (34 mg, 0.26 mmol), and 4A Ms (10 mg) were added to dioxane (6 mL) under N2 atmosphere. The mixture was then cooled to room temperature, poured into water (10 mL), and extracted with DCM (8 mL x 2). The organic layer was washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to dryness. The residue was purified by Pre-TLC (eluted with DCM / MeOH=10:1) to give compound 22-5 (30 mg, 73.7% yield). LCMS: 466.2 [M+H] + .

[0326] Following the synthesis procedure of compound 5 in Example 5, crude compound 22 was prepared from compound 22-5 as the starting material, and purified by Prep-HPLC (FA) to obtain compound 22 (1.1 mg, FA salt). LCMS: 616.2 [M+H] + .

[0327] Example 23 [ka]

[0328] Following the synthesis procedure of compound 15 in Example 15, compound 23 (1.3 mg) was prepared starting from 2-(piperidin-2-yl)ethan-1-ol. LCMS: 616 [M+H] + .

[0329] Example 24 [ka]

[0330] To a solution of INT 12 (509 mg, 2.20 mmol) and triphenylphosphine (1.70 g, 6.48 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (1.34 g, 6.63 mmol) at -10 °C under nitrogen atmosphere. The mixture was stirred at -10 °C for 0.5 h, then ethanethioic acid (342 mg, 4.49 mmol) was added and stirred at -10 °C for 2 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, n-hexane / ethyl acetate = 30 / 1 to 10 / 1, v / v) to give compound 24-1 (564 mg, 88.56% yield). MS: m / z: 290 [M+H] + .

[0331] A solution of compound 24-1 (411 mg, 1.42 mmol), sodium hydroxide (164 mg, 4.10 mmol) in water (2 mL) and THF (15 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was diluted with water, adjusted to pH=3 with HCl (1 N), and extracted with EtOAc (100 mL×2). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18) to give compound 24-2 (229 mg, 65.17% yield). MS: m / z: 248 [M+H] + .

[0332] A solution of compound 24-2 (205 mg, 828.77 μmol), INT 3 (270 mg, 1.01 mmol), and LiOH (40 mg, 1.67 mmol) in THF (10 mL) was stirred at 50 °C under nitrogen atmosphere for 4 h. The mixture was concentrated under reduced pressure, and the residue was purified by reverse phase chromatography (C18 column) to give compound 24-3 (161 mg, 40.53% yield). MS: m / z: 479 [M+H] + .

[0333] A solution of compound 24-3 (146 mg, 304.58 μmol) and hydrochloric acid (1 mL, 4 M in dioxane) in acetonitrile (10 mL) was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to give compound 24-4 (267 mg, crude). MS: m / z: 379 [M+H] + .

[0334] A solution of compound 24-4 (267 mg, 704.05 μmol), N,N-diisopropylethylamine (3 mL), and phosphorus oxychloride (0.5 mL) in toluene (10 mL) was stirred at room temperature for 1 h. The solution was diluted with saturated NaHCO3 (50 mL) and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18 column) to give compound 24-5 (61 mg, 23.99% yield). MS: m / z: 361 [M+H] + .

[0335] Compound 24 was prepared according to the synthetic procedure of compound 10 in Example 10. LCMS: 634 [M+H] + .

[0336] Pharmacological experiments 1. SOS1-catalyzed Nucleotide Exchange Assay The inhibitory activity of each compound against GDP-type K-Ras was evaluated by the SOS1-catalyzed nucleotide exchange assay using K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H, and K-Ras WT proteins.

[0337] Briefly, GDP-preloaded K-Ras (His tag, aa 1-169) was preincubated with each compound in the presence of 10 nM GDP in a 384-well plate (Greiner) for 15–60 min, and then purified SOS1 ExD (Flag tag, aa 564-1049), BODIPY, or 100 mM K-Ras were incubated with 100 mM GDP for 15–60 min. TMFL GTP (Invitrogen) and monoclonal antibody anti 6HIS-Tb cryptate Gold (Cisbio) were added to the assay wells and incubated for 4 hours at 25°C (notably, no SOS1 was added for the K-Ras G13D assay). Wells containing the same percentage of DMSO served as vehicle controls, and wells without K-Ras served as low controls. TR-FRET signals were read on a Tecan Spark multimode microplate reader. Parameters were as follows: F486: excitation 340 nm, emission 486 nm, lag time 100 μs, integration time 200 μs; F515: excitation 340 nm, emission 515 nm, lag time 100 μs, integration time 200 μs. The TR-FRET ratio for each well was calculated by the following formula: TR-FRET ratio = (signal F515 / signal F486). * 10000. The activation rate of compound-treated wells was normalized between vehicle control and low control (% activation = (TR-FRET ratio 化合物処理 -TR-FRET ratio lowコントロール ) / (TR-FRET ratio ビヒクルコントロール -TR-FRET ratio lowコントロール ) * Then, fit a four-parameter logistic model or analyze the data using Excel and calculate the IC 50 The values ​​were calculated and the results are shown in Table 11 below.

[0338] 2. GDP-K-Ras and cRAF Interaction Assay The inhibitory activity of each compound on GTP-type K-Ras was evaluated by GppNp-K-Ras and cRAF interaction assays. GppNp is an analogue of GTP. K-Ras G12D, K-Ras G12V, K-Ras G12C, K-Ras G13D, K-Ras G12A, K-Ras G12R, K-Ras Q61H and K-Ras WT proteins were used in the assays.

[0339] Briefly, GppNp-preloaded K-Ras (His tag, aa 1-169) was preincubated with each compound in the presence of 200 μM GTP in a 384-well plate (Greiner) for 15-60 min, followed by addition of cRAF RBD (GST tag, aa 50-132, CreativeBioMart), monoclonal antibody anti GST-d2 (Cisbio) and monoclonal antibody anti 6HIS-Tb cryptate Gold (Cisbio) to the assay wells and incubation at 25 °C for 2 h. Wells containing the same percentage of DMSO served as vehicle controls and wells without K-Ras served as low controls. TR-FRET signals were read on a Tecan Spark multimode microplate reader and HTRF ratios were calculated according to the manufacturer's instructions. Percent activation of compound-treated wells was normalized between vehicle and low controls (% activation = (HTRF ratio 化合物処理 -HTRF ratio lowコントロール ) / (HTRF ratio ビヒクルコントロール -HTRF ratio lowコントロール ) * Then, fit a four-parameter logistic model or analyze the data using Excel and calculate the IC 50 The values ​​were calculated and the results are shown in Table 11 below.

[0340] [Table 11]

[0341] 3. Phosphorylated ERK1 / 2 (THR202 / TYR204) HTRF Assay The p-ERK (MAPK pathway) inhibitory activity of each compound was evaluated in various K-Ras mutant cell lines and K-Ras WT cell lines shown in Table 12. MKN-1, which has K-Ras WT amplification, is also a K-Ras-dependent cell line.

[0342] [Table 12]

[0343] Each cell in culture medium was seeded in a 96-well plate at the density shown in Table 16 and cultured overnight in a cell incubator. The next day, the medium was removed and compounds diluted in assay medium were added to each well. After 2 hours of incubation in the cell incubator, the assay medium in the 96-well plate was removed, 50 μL of 1X Lysis Buffer with Blocking Reagent (Cisbio) was added, and the plate was incubated at 25 °C for 45 minutes with shaking. 10 μL of cell lysate was transferred from the 96-well plate to a 384-well plate (Greiner) containing 2.5 μL / well of HTRF® Premixed Antibody (Cisbio 64AERPEH). After incubating the plate at 25 °C for 4 hours, the HTRF signal was read on a Tecan Spark multimode microplate reader. The data was analyzed using a four-parameter logistic model to obtain IC 50 The values ​​were calculated and the results are shown in Table 13 below: [Table 13]

[0344] 4. Cell Growth Inhibition Assay A cell proliferation inhibition assay was performed on various K-Ras mutant cell lines and K-Ras WT cell lines shown in Table 14 to test the cell proliferation inhibitory activity of each compound.

[0345] [Table 14]

[0346] Two-dimensional cell proliferation inhibition assay Each cell in culture medium was plated at the density shown in Table 14 on a TC-treated 96-well plate and incubated overnight in a cell incubator. The next day, each compound was diluted in culture medium and added to the plate. After culturing in a cell incubator for 6 days, cell viability was detected using the CellTiter-Glo® Cell Viability Assay kit (Promega). Luminescence signals were read on a Tecan Spark multimode microplate reader and analyzed using a four-parameter logistic model to determine absolute IC 50 The values ​​were calculated and the results are shown in Table 15 below.

[0347] Three-dimensional cell proliferation inhibition assay Each cell in culture medium was plated on an ultra-low adhesion coated 96-well plate at the density shown in Table 14 and incubated overnight in a cell incubator. The next day, each compound was diluted in culture medium and added to the plate. After culturing in a cell incubator for 6 days, cell viability was detected using the CellTiter-Glo® 3D Cell Viability Assay kit (Promega). Luminescence signals were read on a Tecan Spark multimode microplate reader and analyzed using a four-parameter logistic model to determine absolute IC 50 The values ​​were calculated and the results are shown in Table 15 below.

[0348] [Table 15]

Claims

1. A compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof: 【Chemical 1】 During the ceremony, X 1 is CR 3 or N; R 3 is hydrogen, deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O) 2 (C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH 2 , -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl) 2 , -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-6 alkyl), -S(=O) 2 N(C 1-6 alkyl) 2 , -NHS(=O) 2 (C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O) 2 (C 1-6 alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein said -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is one, two, or three of R 3a and optionally substituted independently with Each R 3a are deuterium, halogen, and -C, respectively, if present. 1-3 Alkyl, HaloC 1-3 Alkyl, HaloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -CN, oxo, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O) 2 (C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl) 2 , -NHC(=O)(C 1-3 alkyl), -N(C 1-3 alkyl)C(=O)(C 1-3 alkyl), -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 alkyl), -S(=O) 2 N(C 1-3 alkyl) 2 , -NHS(=O) 2 (C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O) 2 (C 1-3 alkyl), 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; X 2 is NR 1 , O or S; R 1 is hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; 1-6 Alkyl and 3-6 membered cycloalkyl, when present, are each represented by -OH, deuterium, halogen, -CN, oxo, -C 1-6 Alkoxy, -NH 2 , -NHC 1-6 Alkyl, or -N(C 1-6 alkyl) 2 and optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6) substituents independently selected from: X 3 is CR 71 R 72 , C=O, NR 71 , O, S, S=O, or O=S=O; (R 71 , R 72 ) are hydrogen, deuterium, -C 1-6 alkyl or 3- to 6-membered cycloalkyl; 1-6 Alkyl and 3-6 membered cycloalkyl are substituted with -OH, deuterium, halogen, -CN, oxo, -C 1-6 Alkoxy, -NH 2 , -NHC 1-6 Alkyl, or -N(C 1-6 alkyl) 2 optionally substituted with 1, 2, 3, 4, 5, or 6 substituents each independently selected from: (n 1 , n 2 , n 3 , n 4 and n 5 ) each, at each occurrence, is independently selected from 0, 1, 2, or 3; Each R S0 are deuterium, halogen, and -C, respectively, if present. 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O) 2 (C 1-6 alkyl), -C(=O)H, -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH 2 , -NO 2 , -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl) 2 , -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-6 alkyl), -S(=O) 2 N(C 1-6 alkyl) 2 , -NHS(=O) 2 (C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O) 2 (C 1-6 alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is one, two, or three of R 1a and optionally substituted independently with Optionally, two R S0 along with the carbon atom to which they are both attached 【Chemistry 2】 forming a 3-10 membered carbocyclic or 3-10 membered heterocyclic ring; 【Chemistry 3】 A 3-10 membered carbocyclic or 3-10 membered heterocyclic ring may contain one or more R 1a optionally substituted with; Arbitrarily, two adjacent R S0 together with the carbon atoms to which they are each attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring, each ring containing one or more R 1a optionally substituted with; Each R 1a is deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, -CN, oxo, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 Alkyl, or deuterium, halogen, haloC 1-6 Alkyl, -CN, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 -C substituted with 1, 2 or 3 substituents selected from alkyl or cyclopropyl 1-6 independently selected from alkyl; m is selected from 0, 1, 2, 3, 4, 5 or 6; Y is a bond, O, S, S(=O), S(=O) 2 or NR 81 and R 2 is -L-(3-12 membered heterocyclyl), -L-(3-12 membered cycloalkyl), -L-(6-12 membered aryl), -L-(5-12 membered heteroaryl), -L-NR 91 R 92 , 【Chemistry 4】 Selected from: Each L is a bond or one or more R 16 C optionally substituted with 1-10 independently selected from alkylene; (R 91 , R 92 ) each of which is hydrogen, deuterium, or one or more R 16 -C optionally substituted with 1-10 independently selected from alkyl; The 3- to 12-membered heterocyclyl in the -L-(3- to 12-membered heterocyclyl) is one or more R 16 optionally substituted with; The 3- to 12-membered cycloalkyl in the -L-(3- to 12-membered cycloalkyl) is one or more R 16 optionally substituted with; The 6- to 12-membered aryl in the -L-(6- to 12-membered aryl) is one or more R 16 optionally substituted with; The 5- to 12-membered heteroaryl in the -L-(5- to 12-membered heteroaryl) is one or more R 16 optionally substituted with; Y 1 or Y 2 are -C(R 61 R 62 )-independently selected from; Ring F or ring G is a 3-10 membered heterocycle optionally further containing 1, 2, or 3 heteroatoms selected from N, O, or S; Ring A is a 3- to 10-membered carbocyclic ring or a 3- to 10-membered heterocyclic ring; 1 ) r - and -(Y 2 ) s -R 11 are attached to the same or different atoms of ring A; R 11 is -NR 81 R 82 , -OR 81 , -SR 81 , 3-10 membered heterocyclyl, or 5-10 membered heteroaryl, wherein the 3-10 membered heterocyclyl or 5-10 membered heteroaryl is selected from one or more R 16 and optionally substituted independently with R 12 and R 13 Each of the following, when present, is a deuterium, a halogen, or -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O) 2 R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O) 2 OR 81 , -OS(=O) 2 R 82 , -S(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 R 82 , -OS(=O) 2 OR 81 , -NR 81 S(=O) 2 OR 82 , -OS(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally substituted with deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O) 2 R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O) 2 OR 81 , -OS(=O) 2 R 82 , -S(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 R 82 , -OS(=O) 2 OR 81 , -NR 81 S(=O) 2 OR 82 , -OS(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , optionally substituted independently with one or more substituents selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Optionally, two R 12 along with the carbon atom to which they are both attached. 【Chemistry 5】 forming a 3-10 membered carbocyclic or 3-10 membered heterocyclic ring; 【Chemistry 6】 A 3-10 membered carbocyclic or 3-10 membered heterocyclic ring may contain one or more R 2a optionally substituted with; Arbitrarily, two adjacent R 12 together with the carbon atoms to which they are each attached form a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aryl ring, or a 5- to 10-membered heteroaryl ring, each of which may be joined by one or more R 2a and optionally substituted independently with Each R 2a is deuterium; halogen; -C 1-6 Alkyl; HaloC 1-6 Alkyl; -CN; Oxo; -OH; -NH 2 -NH(C 1-6 alkyl); -NH(C 1-6 alkyl) 2 ;-OC 1-6 Alkyl; or deuterium, halogen, haloC 1-6 Alkyl, -CN, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 -C substituted with 1, 2 or 3 substituents selected from alkyl or cyclopropyl 1-6 independently selected from alkyl; each of (r, s, t, p and v), at each occurrence, is independently selected from 0, 1, 2, 3, 4, 5 or 6; R 4 represents a 6- to 10-membered aryl, a 5- to 10-membered heteroaryl, 【Chemistry 7】 the 6-10 membered aryl, 5-10 membered heteroaryl, 【Chemistry 8】 is 1 or more R 41 and optionally substituted independently with Z, at each occurrence, is independently selected from C or N; when Z is selected from C, ring B, each time present, is selected from a 6-membered aryl ring or a 5-6 membered heteroaryl ring, and ring C, each time present, is a 3-10 membered carbocyclic ring or a 3-10 membered heterocyclic ring; when Z is selected from N, ring B, at each occurrence, is selected from a 5-6 membered heteroaryl ring, and ring C, at each occurrence, is a 3-10 membered heterocycle; Ring D, at each occurrence, is selected from a 3- to 10-membered carbocycle, a 3- to 10-membered heterocycle, a 6-membered aryl ring, or a 5- to 6-membered heteroaryl ring; Ring E, at each occurrence, is selected from a 3- to 10-membered carbocycle, a 3- to 10-membered heterocycle, a 6-membered aryl ring, or a 5- to 6-membered heteroaryl ring; R 41 are deuterium, halogen, and -C, respectively, if present. 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O) 2 R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O) 2 OR 81 , -OS(=O) 2 R 82 , -S(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 R 82 , -OS(=O) 2 OR 81 , -NR 81 S(=O) 2 OR 82 , -OS(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl or R 4a -C is independently selected from 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally substituted with deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O) 2 R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O) 2 OR 81 , -OS(=O) 2 R 82 , -S(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 R 82 , -OS(=O) 2 OR 81 , -NR 81 S(=O) 2 OR 82 , -OS(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , optionally substituted independently with one or more substituents selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 4a is a structure capable of forming a prodrug; R 5 is hydrogen, deuterium, halogen, -C 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O) 2 R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O) 2 OR 81 , -OS(=O) 2 R 82 , -S(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 R 82 , -OS(=O) 2 OR 81 , -NR 81 S(=O) 2 OR 82 , -OS(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, HaloC 2-10 Alkenyl, -C 2-10 Alkynyl, HaloC 2-10 Alkynyl, 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl may be substituted with deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, HaloC 2-6 Alkenyl, -C 2-6 Alkynyl, HaloC 2-6 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR 81 R 82 , -OR 81 , -SR 81 , -S(=O)R 81 , -S(=O) 2 R 81 , -C(=O)R 81 , -C(=O)OR 81 , -OC(=O)R 81 , -C(=O)NR 81 R 82 , -NR 81 C(=O)R 82 , -OC(=O)OR 81 , -NR 81 C(=O)OR 82 , -OC(=O)NR 81 R 82 , -NR 81 C(=O)NR 81 R 82 , -S(=O)OR 81 , -OS(=O)R 81 , -S(=O)NR 81 R 82 , -NR 81 S(=O)R 82 , -S(=O) 2 OR 81 , -OS(=O) 2 R 82 , -S(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 R 82 , -OS(=O) 2 OR 81 , -NR 81 S(=O) 2 OR 82 , -OS(=O) 2 NR 81 R 82 , -NR 81 S(=O) 2 NR 81 R 82 , -PR 81 R 82 , -P(=O)R 81 R 82 , optionally substituted independently with one or more substituents selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; R 61 or R 62 are hydrogen, deuterium, halogen, and -C, respectively, when present. 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR a R b , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -C(=O)R a , -C(=O)OR a , -OC(=O)R a , -C(=O)NR a R b , -NR a C(=O)R b , -OC(=O)OR a , -NR a C(=O)OR b , -OC(=O)NR a R b , -NR a C(=O)NR a R b , -S(=O)OR a , -OS(=O)R a , -S(=O)NR a R b , -NR a S(=O)R b , -S(=O) 2 OR a , -OS(=O) 2 R a , -S(=O) 2 NR a R b , -NR a S(=O) 2 R b , -OS(=O) 2 OR a , -NR a S(=O) 2 OR b , -OS(=O) 2 NR a , -NR a S(=O) 2 NR a R b , -PR a R b , -P(=O)R a R b , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally substituted with deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR c R d , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -C(=O)R c , -C(=O)OR c , -OC(=O)R c , -C(=O)NR c R d , -NR c C(=O)R d , -OC(=O)OR c , -NR c C(=O)OR d , -OC(=O)NR c R d , -NR c C(=O)NR c R d , -S(=O)OR c , -OS(=O)R c , -S(=O)NR c R d , -NR c S(=O)R d , -S(=O) 2 OR c , -OS(=O) 2 R c , -S(=O) 2 NR c R d , -NR c S(=O) 2 R d , -OS(=O) 2 OR c , -NR c S(=O) 2 OR d , -OS(=O) 2 NR c , -NR c S(=O) 2 NR c R d , -PR c R d , -P(=O)R c R d , optionally substituted independently with one or more substituents selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Optionally, R 61 and R 62 together with the carbon atoms to which they are both attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring, and the 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring is 16 and optionally substituted independently with R 81 or R 82 are hydrogen, deuterium, and -C, respectively, if present. 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, -S(=O)R a , -S(=O) 2 R a , -C(=O)R a , -C(=O)OR a , -C(=O)NR a R b , -S(=O)OR a , -S(=O)NR a R b , -S(=O) 2 OR a , -S(=O) 2 NR a R b , -P(=O)R a R b , 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, 3-10 membered cycloalkynyl, 3-10 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-10 Alkyl, HaloC 1-10 Alkyl, HaloC 1-10 Alkoxy, -C 2-10 Alkenyl, -C 2-10 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered cycloalkenyl, 3- to 10-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally substituted with deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NR c R d , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -C(=O)R c , -C(=O)OR c , -OC(=O)R c , -C(=O)NR c R d , -NR c C(=O)R d , -OC(=O)OR c , -NR c C(=O)OR d , -OC(=O)NR c R d , -NR c C(=O)NR c R d , -S(=O)OR c , -OS(=O)R c , -S(=O)NR c R d , -NR c S(=O)R d , -S(=O) 2 OR c , -OS(=O) 2 R c , -S(=O) 2 NR c R d , -NR c S(=O) 2 R d , -OS(=O) 2 OR c , -NR c S(=O) 2 OR d , -OS(=O) 2 NR c , -NR c S(=O) 2 NR c R d , -PR c R d , -P(=O)R c R d , optionally substituted independently with one or more substituents selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; Optionally, R 81 and R 82 together with the nitrogen atom to which they are both attached form a 3- to 10-membered heterocyclic or 5- to 10-membered heteroaryl ring, and the 3- to 10-membered heterocyclic or 5- to 10-membered heteroaryl ring is 16 and optionally substituted independently with R a , R b , R c or R d are hydrogen, deuterium, and -C, respectively, if present. 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl may be one or more R 16 and optionally substituted independently with Optionally, (R a and R b ) or (R c and R d ) together with the atom to which they are both attached form a 3-6 membered heterocyclic ring, said 3-6 membered heterocyclic ring being bound to one or more R 16 and optionally substituted independently with R 16 are deuterium, halogen, and -C, respectively, if present. 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O) 2 (C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH 2 , -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl) 2 , -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -OC(=O)O(C 1-6 alkyl), -NHC(=O)(OC 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(OC 1-6 alkyl), -OC(=O)NH(C 1-6 alkyl), -OC(=O)N(C 1-6 alkyl) 2 , -NHC(=O)NH 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl)C(=O)NH 2 , -N(C 1-6 alkyl)C(=O)NH(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)N(C 1-6 alkyl) 2 , -S(=O)(OC 1-6 alkyl), -OS(=O)(C 1-6 alkyl), -S(=O)NH 2 , -S(=O)NH(C 1-6 alkyl), -S(=O)N(C 1-6 alkyl) 2 , -NHS(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)S(=O)(C 1-6 alkyl), -S(=O) 2 (OC 1-6 alkyl), -OS(=O) 2 (C 1-6 alkyl), -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-6 alkyl), -S(=O) 2 N(C 1-6 alkyl) 2 , -NHS(=O) 2 (C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O) 2 (C 1-6 alkyl), -OS(=O) 2 O(C 1-6 alkyl), -NHS(=O) 2 O(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O) 2 O(C 1-6 alkyl), -OS(=O) 2 NH 2 , -OS(=O) 2 NH(C 1-6 alkyl), -OS(=O) 2 N(C 1-6 alkyl) 2 , -NHS(=O) 2 NH 2 , -NHS(=O) 2 NH(C 1-6 alkyl), -NHS(=O) 2 N(C 1-6 alkyl) 2 , -N(C 1-6 Alkyl)S(=O) 2 NH 2 , -N(C 1-6 Alkyl)S(=O) 2 NH(C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O) 2 N(C 1-6 alkyl) 2 , -PH(C 1-6 alkyl), -P(C 1-6 alkyl) 2 , -P(=O)H(C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-6 membered cycloalkynyl, 3-6 membered heterocyclyl, 6-10 membered aryl or 5-10 membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6- to 10-membered aryl or 5- to 10-membered heteroaryl are optionally substituted with deuterium, halogen, -C 1-3 Alkyl, HaloC 1-3 Alkyl, HaloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -CN, -NO 2 , -N 3 , oxo, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), -S(=O)(C 1-3 alkyl), -S(=O) 2 (C 1-3 alkyl), -C(=O)(C 1-3 alkyl), -C(=O)OH, -C(=O)(OC 1-3 alkyl), -OC(=O)(C 1-3 alkyl), -C(=O)NH 2 , -C(=O)NH(C 1-3 alkyl), -C(=O)N(C 1-3 alkyl) 2 , -NHC(=O)(C 1-3 alkyl), -N(C 1-3 alkyl)C(=O)(C 1-3 alkyl), -OC(=O)O(C 1-3 alkyl), -NHC(=O)(OC 1-3 alkyl), -N(C 1-3 alkyl)C(=O)(OC 1-3 alkyl), -OC(=O)NH(C 1-3 alkyl), -OC(=O)N(C 1-3 alkyl) 2 , -NHC(=O)NH 2 , -NHC(=O)NH(C 1-3 alkyl), -NHC(=O)N(C 1-3 alkyl) 2 , -N(C 1-3 alkyl)C(=O)NH 2 , -N(C 1-3 alkyl)C(=O)NH(C 1-3 alkyl), -N(C 1-3 alkyl)C(=O)N(C 1-3 alkyl) 2 , -S(=O)(OC 1-3 alkyl), -OS(=O)(C 1-3 alkyl), -S(=O)NH 2 , -S(=O)NH(C 1-3 alkyl), -S(=O)N(C 1-3 alkyl) 2 , -NHS(=O)(C 1-3 alkyl), -N(C 1-3 alkyl)S(=O)(C 1-3 alkyl), -S(=O) 2 (OC 1-3 alkyl), -OS(=O) 2 (C 1-3 alkyl), -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-3 alkyl), -S(=O) 2 N(C 1-3 alkyl) 2 , -NHS(=O) 2 (C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O) 2 (C 1-3 alkyl), -OS(=O) 2 O(C 1-3 alkyl), -NHS(=O) 2 O(C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O) 2 O(C 1-3 alkyl), -OS(=O) 2 NH 2 , -OS(=O) 2 NH(C 1-3 alkyl), -OS(=O) 2 N(C 1-3 alkyl) 2 , -NHS(=O) 2 NH 2 , -NHS(=O) 2 NH(C 1-3 alkyl), -NHS(=O) 2 N(C 1-3 alkyl) 2 , -N(C 1-3 Alkyl)S(=O) 2 NH 2 , -N(C 1-3 Alkyl)S(=O) 2 NH(C 1-3 alkyl), -N(C 1-3 Alkyl)S(=O) 2 N(C 1-3 alkyl) 2 , -PH(C 1-3 alkyl), -P(C 1-3 alkyl) 2 , -P(=O)H(C 1-3 alkyl), -P(=O)(C 1-3 alkyl) 2 , optionally substituted with one or more substituents selected from 3- to 6-membered cycloalkyl, 3- to 6-membered cycloalkenyl, 3- to 6-membered cycloalkynyl, 3- to 6-membered heterocyclyl, 6-membered aryl, or 5- to 6-membered heteroaryl; (heterocyclyl and heteroaryl), when present, each represents N, O, S, S(=O) or S(=O) 2 and wherein the heteroatoms are independently selected from 1, 2, 3, or 4 heteroatoms. A compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

2. X 1 is N, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

3. X 2 is O, S, NH or NCH 3 2. The compound of formula (I) according to claim 1, wherein:

4. X 3 But, CR 71 R 72 or O; (R 71 and R 72 ) are hydrogen, deuterium, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -F, -Cl, -CN, -CH 2 OH, -OH, -OCH 3 , -OCH 2 CH 3 , -CF 3 , -CHF 2 , -S-CH 3 , -S-CHF 2 , -S-CF 3 , 【Chemistry 9】 10. The compound of formula (I) according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, independently selected from:

5. n 1 , n 4 , and n 5 are each 1, or n 1 and n 4 are each 1 and n 5 is 0, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

6. n 2 and n 3 are each 1 or n 3 is 0 and n 2 is 2 or n 3 is 0 and n 2 is 1 or n 3 is 1 and n 2 is 0 or n 3 is 0 and n 2 is 0, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

7. Each R S0 When present, deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, -CN, oxo, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O(C 1-6 alkyl), -SH, -S(C 1-6 alkyl), -S(haloC 1-6 alkyl), -S(=O)(C 1-6 alkyl), -S(=O) 2 (C 1-6 alkyl), -C(=O)H, -C(=O)(C 1-6 alkyl), -C(=O)OH, -C(=O)(OC 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -C(=O)NH 2 , -NO 2 , -C(=O)NH(C 1-6 alkyl), -C(=O)N(C 1-6 alkyl) 2 , -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -S(=O) 2 NH 2 , -S(=O) 2 NH(C 1-6 alkyl), -S(=O) 2 N(C 1-6 alkyl) 2 , -NHS(=O) 2 (C 1-6 alkyl), -N(C 1-6 Alkyl)S(=O) 2 (C 1-6 alkyl), 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, or 5-10 membered heteroaryl; 1-6 Alkyl, HaloC 1-6 Alkyl, HaloC 1-6 Alkoxy, -C 2-6 Alkenyl, -C 2-6 Alkynyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl is one, two, or three of R 1a and optionally substituted independently with Optionally, two R S0 along with the carbon atom to which they are both attached. 【Chemistry 10】 forming a 3-10 membered carbocyclic or 3-10 membered heterocyclic ring; 【Chemistry 11】 A 3-10 membered carbocyclic or 3-10 membered heterocyclic ring may contain one or more R 1a optionally substituted with; Arbitrarily, two adjacent R S0 together with the carbon atoms to which they are each attached form a 3- to 10-membered carbocyclic or 3- to 10-membered heterocyclic ring, each ring containing one or more R 1a and optionally substituted independently with Each R 1a But deuterium, halogen, -C 1-6 Alkyl, HaloC 1-6 Alkyl, -CN, oxo, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 Alkyl, or deuterium, halogen, haloC 1-6 Alkyl, -CN, -OH, -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OC 1-6 -C substituted with 1, 2 or 3 substituents selected from alkyl or cyclopropyl 1-6 independently selected from alkyl; q m is independently selected from 0, 1, 2 or 3, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

8. 2. A compound of formula (I) according to claim 1, wherein the compound is selected from any one of the formulae in Table 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof. 【Table 1】

9.

12. 【Chemistry 13】 9. The compound of formula (I) according to claim 8, wherein:

10. 【Chemistry 14】 but, 【Chemistry 15】 10. The compound of formula (I) according to claim 9, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, selected from:

11.

16. is selected from any one of Table 2, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof. 【Table 2】

12.

17. but, 【Chemistry 18】 9. The compound of formula (I) according to claim 8, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, selected from:

13. R 4 is selected from any one of Table 4: R 4 is 1, 2, 3, 4, 5 or 6 R 41 and optionally substituted independently with Each R 41 -Deuterium, -F, -Cl, -C 1-3 Alkyl, HaloC 1-3 Alkyl, HaloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-3 Alkynyl, -CN, -NH 2 , -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -OH, -O(C 1-3 alkyl), -SH, -S(C 1-3 alkyl), 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl; 1-3 Alkyl, HaloC 1-3 Alkyl, HaloC 1-3 Alkoxy, -C 2-3 Alkenyl, -C 2-6 Alkynyl, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocyclyl is -F; -C 1-3 Alkyl; HaloC 1-3 Alkyl; -CN; -OH; -NH 2 -NH(C 1-3 alkyl); -NH(C 1-3 alkyl) 2 ;-OC 1-3 Alkyl; or -F, haloC 1-3 Alkyl, -CN, -OH, -NH 2 , -NH(C 1-3 alkyl), -NH(C 1-3 alkyl) 2 Or -OC 1-3 -C substituted with 1, 2 or 3 substituents selected from alkyl 1-3 12. The compound of formula (I) according to claim 11, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, wherein the compound is optionally substituted with one, two or three substituents independently selected from alkyl. 【Table 3】

14. R 4 is selected from any one of Table 5, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof. 【Table 4】

15. R 4 but, 【Chemistry 19】 15. The compound of formula (I) according to claim 14, wherein:

16. R 5 is selected from -F, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof.

17. 10. The compound of formula (I) according to claim 1, wherein the compound is selected from the formulae in Table 8, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof. 【Table 5】

18. 2. The compound of formula (I) according to claim 1, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, wherein the conjugate is a PROTAC molecule.

19. An intermediate for preparing a compound of formula (I), wherein the intermediate is selected from the compounds in Table 9. 【Table 6】

20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 18, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, and a pharmaceutically acceptable excipient.

21. A compound of formula (I) according to any one of claims 1 to 18, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof for use as a pharmaceutical.

22. 20. A compound of formula (I) according to any one of claims 1 to 18, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof for use in a method for the treatment of cancer.

23. 23. The compound of (I) according to claim 22, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of a stereoisomer thereof, a prodrug thereof, a deuterated molecule thereof, or a conjugate thereof, wherein the cancer is selected from pancreatic cancer, colorectal cancer, non-small cell lung cancer, breast cancer, colon cancer, gastric cancer, endometrial cancer, esophageal cancer, or gastroesophageal junction cancer.

24. The compound of (I) according to claim 23, its stereoisomer, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, a prodrug thereof, a deuterated molecule thereof or a conjugate thereof, wherein the cancer is associated with at least one of K-Ras G12C mutation, K-Ras G12D mutation, K-Ras G12V mutation, K-Ras G13D mutation, K-Ras G12R mutation, K-Ras G12S mutation, K-Ras G12A mutation, K-Ras Q61H mutation and / or K-Ras wild-type amplification.

25. The pharmaceutical composition of claim 20 for use as a medicine.

26. The pharmaceutical composition of claim 20 for use in a method for treating cancer.

27. ​​The pharmaceutical composition described in claim 26, wherein the cancer is selected from pancreatic cancer, colorectal cancer, non-small cell lung cancer, breast cancer, colon cancer, gastric cancer, endometrial cancer, esophageal cancer, or gastroesophageal junction cancer.

28. The pharmaceutical composition described in claim 27, wherein the cancer is associated with at least one of K-Ras G12C mutation, K-Ras G12D mutation, K-Ras G12V mutation, K-Ras G13D mutation, K-Ras G12R mutation, K-Ras G12S mutation, K-Ras G12A mutation, K-Ras Q61H mutation and / or K-Ras wild-type amplification.

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