Condensed ring system compound, method for preparing the same, and pharmaceutical use thereof

Abstract

The present disclosure relates to a condensed ring system compound, a method for preparing the same, and its pharmaceutical use. Specifically, the present disclosure relates to a condensed ring system compound represented by general formula (IN), a method for preparing the same, and a pharmaceutical composition containing such a compound, as well as its use as a therapeutic agent, particularly its use in the preparation of an agent for inhibiting KRAS G12D. Among them, each group in general formula (IN) is as defined in the specification. [Chemical 1] JPEG2025524846000273.jpg51143

Description

Technical Field

[0001] The present disclosure belongs to the pharmaceutical field and relates to a fused ring system compound, a method for preparing the same, and its pharmaceutical use. In particular, the present disclosure relates to a fused ring system compound represented by general formula (IN), a method for preparing the same, a pharmaceutical composition containing such a compound, and its use in the preparation of an agent for inhibiting KRAS G12D.

Background Art

[0002] RAS is one of the oncogenic genes with the highest mutation rate in tumors, and about 30% of human malignant tumors are associated with mutations in the RAS gene. The RAS family includes KRAS, NRAS, and HRAS. Among them, KRAS mutations are the most common, accounting for about 85%. KRAS mutations are frequently seen in solid tumors, and high-frequency mutations exist in the three major lethal cancers in humans: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Among the genetic mutations of KRAS, 97% are those in which the 12th or 13th amino acid residue is mutated, and among them, G12D is an important mutation. Data analysis of the European and American populations has shown that in pancreatic cancer, colorectal cancer, and non-small cell lung cancer, G12D mutations account for 36%, 12%, and 4% of patients, respectively.

[0003] After KRAS is activated, various functions such as cell proliferation, survival, migration, and metabolism are regulated by many downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. After the KRAS gene mutates, the protein remains in an activated state continuously, so that the downstream signaling pathway is continuously activated to promote the occurrence of tumors.

[0004] The KRAS protein has no small molecule binding site in the traditional sense on its surface and has an extremely high affinity for guanylic acid and is extremely difficult to inhibit. Therefore, for a long time, it has been regarded as a drug target that is impossible to develop drugs against. However, due to the importance and universality of the abnormal activation of KRAS in cancer progression, KRAS has always been and still is a target that has received great attention in drug development. Currently, in addition to KRAS G12C inhibitors, there is still a shortage of KRAS inhibitors effective against other mutations, so most patients with KRAS mutations still have no therapeutic drugs. Since G12D is a mutant that is widely highly expressed in various tumors, the development of inhibitors targeting it has important clinical significance.

[0005] Currently, the related patent applications that have already been disclosed include WO2023030385A1, WO2023274383A1, WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, and WO2021000885A1, etc.

Summary of the Invention

[0006] The present disclosure aims to provide a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof. [Chemical Formula 1]

Chemical Formula

[0007] In some embodiments of the present disclosure, a compound represented by the above general formula (IN) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IN') or a pharmaceutically acceptable salt thereof, [Chemical Formula 2]

Chemical Formula

[0008] The present disclosure provides a compound represented by the general formula (IM) or a pharmaceutically acceptable salt thereof, [Chemical Formula 3]

Chemical Formula

[0009] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (IM') or a pharmaceutically acceptable salt thereof, [Chemical Formula 4] [Chemical formula] Among them, a is 0, 1, 2, 3 or 4, G 0 , G 1 , G 2 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, t and r are as defined in general formula (IM).

[0010] In some embodiments of the present disclosure, a compound represented by the above general formula (IN) or (IM) or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, [Chemical formula 5] [Chemical formula] Among them, G 0 is selected from O, S, S(O), S(O)2, CR G0a R G0b and NR G0c ; G 1 is selected from CR G1a R G1b , CR G1a R G1b CR G1c R G1d , C=O and C(O)CR G1a R G1b ; G 2 is NR d ; T is a chemical bond or is selected from CR a R b , NR T and O; Q is N or CR 2a ; Ring A is an aryl group or a heteroaryl group, L is selected from a single bond, O and NR e ; R a 、R b 、R G0a 、R G0b 、R G1a 、R G1b 、R G1c and R G1d are the same or different and each independently is selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, or, R G1a 、R G1b forms a cycloalkyl group together with the carbon atom to which it is attached, or, R G1c 、R G1d forms a cycloalkyl group together with the carbon atom to which it is attached, Each R 1 is the same or different and each independently is a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) u -NR f R g 、a hydroxy group, and a hydroxyalkyl group, R 2a and R 4a are the same or different and each independently is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) v -NR h R i 、a hydroxy group, a hydroxyalkyl group, and a cycloalkyl group, Each R 3 is the same or different and each independently is a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) w -NR j R k 、-(CH2) w1 -(O) x1 -C(O)NR j1 R k1 、-(CH2) w2 -(O)x2 -C(O)OR j2 selected from a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g and R 6h are the same or different and each independently is a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH2) y -NR m R n 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2 -(O) z2 -C(O)OR m2 、selected from a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, or R 6a and R 6e form a connecting carbon atom, R 6a and R 6g form a connecting carbon atom, R 6c and R 6e form a connecting carbon atom, or R 6c and R 6g form a bridge together with the connecting carbon atom, the bridge having 1, 2, 3, or 4 CH2s, any one of which may optionally be substituted with O, S, or NH, and the bridge may optionally be substituted with one or more identical or different substituents selected from a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, and a hydroxyalkyl group, or R 6a and R 6b form a connecting carbon atom, R 6c and R 6d form a connecting carbon atom, R 6eand R 6f is a linking carbon atom, or R 6g and R 6h together with the linking carbon atom forms a cycloalkyl group or a heterocyclyl group, and the cycloalkyl group or the heterocyclyl group is optionally substituted with one or more identical or different substituents selected from halogen, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cyano group, amino group, hydroxy group and hydroxyalkyl group, R 5a and R 5b are the same or different and each independently selected from a hydrogen atom, halogen, alkyl group, haloalkyl group, cyano group, hydroxy group and hydroxyalkyl group, or R 5a , R 5b together with the linking carbon atom forms a cycloalkyl group or a heterocyclyl group, and the cycloalkyl group or the heterocyclyl group is each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cyano group, amino group, hydroxy group and hydroxyalkyl group, R G0c , R T , R d , R e , R f , R g , R h , R i , R j , R k , R j1 , R k1 , R j2 , R m , R n , R m1 , R n1 and R m2 are the same or different and each independently selected from a hydrogen atom, alkyl group, alkenyl group, alkynyl group, haloalkyl group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, u, v, w, w1, w2, y, y1 and y2 are the same or different and each independently selected from 0, 1, 2 and 3, x1, x2, z1 and z2 are the same or different and are each independently selected from 0 or 1; r is 0, 1, 2 or 3; p is 0, 1, 2, 3, 4 or 5, and q is 0, 1, 2, 3, 4 or 5.

[0011] In some embodiments of the present disclosure, the compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, [6] [ka] Among them, a is 0, 1, 2, 3 or 4; G 0 , G 1 , G 2 , T, ring A, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , p and r are as defined in general formula (I).

[0012] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein: [ka] and G 0 , G 1 , G 2 , R 1 and p is as defined in general formula (I).

[0013] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G 0 is O, CR G0a R G0b and NR G0c selected from, R G0a and R G0b are the same or different and each independently is a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, R G0c is a hydrogen atom or a C 1-6 alkyl group, preferably, G 0 is selected from O, CH2 and NH, more preferably, G 0 is O.

[0014] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G 1 is CR G1a R G1b 、CR G1a R G1b CR G1c R G1d or C=O, R G1a 、R G1b 、R G1c and R G1d are the same or different and each independently is a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, preferably, G 1 is CH2 or C=O, more preferably, G 1 is CH2.

[0015] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein G 1 is CR G1a H, R G1a is as defined in general formula (IN), preferably, G1 is CR G1a H, and R G1a is a hydrogen atom, halogen, C 1-6 alkyl group, and C 1-6 haloalkyl group, and more preferably, G 1 is CR G1a H, and R G1a is a hydrogen atom or C 1-6 alkyl group, and even more preferably, G 1 is CR G1a H, and R G1a is C 1-6 alkyl group, and still more preferably, G 1 is CR G1a H, and R G1a is a methyl group.

[0016] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein -G 0 -G 1 - is selected from -O-CH2-, -NH-C(O)-, -NH-CH2-, -CH2-CH2- and -O-CH2-CH2-, preferably -O-CH2- or -NH-C(O)-, more preferably -O-CH2-, and in some embodiments, -G 0 -G 1 - is -O-CH(CH3)-.

[0017] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein T is a chemical bond.

[0018] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are the same or different and each independently is a hydrogen atom, halogen, C 1-6 alkyl group, C1-6 Selected from haloalkyl groups, hydroxy groups, and C 1-6 hydroxyalkyl groups, or R 5a , R 5b forms a 3- to 8-membered cycloalkyl group together with the carbon atom to which they are attached, preferably, R 5a and R 5b are hydrogen atoms, or R 5a , R 5b forms a 3- to 6-membered cycloalkyl group together with the carbon atom to which they are attached, more preferably, R 5a and R 5b are hydrogen atoms, or R 5a , R 5b forms a cyclopropyl group together with the carbon atom to which they are attached.

[0019] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein r is 1 or 3.

[0020] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I) or (I') or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0021] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IM), (I) or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II') or a pharmaceutically acceptable salt thereof, [Chemical formula 7]

Chemical formula

[0022] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IM), (I) or (II’) or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, [Chemical Formula 8]

Chemical Formula

[0023] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN’), (IM), (IM’), (I), (I’), (II’), (IVV’) or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III’) or a pharmaceutically acceptable salt thereof, [Chemical Formula 9]

Chemical Formula

[0024] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (IVV') or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, [Chemical Formula 10]

Chemical Formula

[0025] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN') or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IVV') or a pharmaceutically acceptable salt thereof, [Chemical Formula 11] [Chemical Structure] Among them, R 3a and R 3b are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, ring C, G 2 , Q, L, R G1a , R 1 , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (IN), preferably, R G1a is a C 1-6 alkyl group.

[0026] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (IVV') or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV') or (VV') or a pharmaceutically acceptable salt thereof, [Chemical Formula 12] [Chemical Structure] Among them, R x is selected from =N-O-R 61 , =CR 62 R 63 and =N-R 64 and R 61, R 62 , R 63 and R 64 are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, and a cycloalkyl group, t is 0, 1, 2, 3 or 4, R 3a and R 3b are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, Ring B is a heterocyclyl group, R x1 , t1, Ring C, G 2 , Q, L, R G1a , R 1 , R 4a , R 6 and p are as defined in general formula (IN), and preferably, R G1a is a C 1-6 alkyl group.

[0027] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (IVV') or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV') or a pharmaceutically acceptable salt thereof, [Chemical Formula 13] [Chemical Structure] Among them, R x is selected from =N-O-R 61 , =CR 62 R 63 and =N-R 64 R 61 R 62 R 63 and R 64 ​are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, and a cycloalkyl group, t is 0, 1, 2, 3, or 4, R 3a and R 3b are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, Ring B, G 2 , Q, L, R G1a , R 1 , R 4a , R 6 and p are as defined in general formula (IM), and preferably, R G1a is a C 1-6 alkyl group.

[0028] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN') or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VV') or a pharmaceutically acceptable salt thereof, [Chemical formula 14] [Chemical formula] Among them, R 3a and R 3b are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclyl group, Ring C, G 2 , Q, L, R G1a , R 1 , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (IN), and preferably, R G1a is a C 1-6It is an alkyl group.

[0029] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (VV') or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof, [Chemical formula 15] [Chemical formula] Among them, R x is =N-O-R 61 =CR 62 R 63 and =N-R 64 selected from, R 61 R 62 R 63 and R 64 are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cycloalkyl group, t is 0, 1, 2, 3 or 4, R 3a and R 3b are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, Ring B, G 2 Q, L, R G1a R 1 R 4a R 6 and p are as defined in the general formula (IM), preferably, R G1a is a C 1-6 alkyl group.

[0030] In some embodiments of the present disclosure, a compound represented by the above general formula (II) or (III) or a pharmaceutically acceptable salt thereof, among which, [Chemical formula] and G 2 , R 1 and p are as defined in general formula (I).

[0031] In some embodiments of the present disclosure, a compound represented by the above general formula (II’), (III’), (IV’), (V’), (IVV’), (VV’) or a pharmaceutically acceptable salt thereof, wherein [Chemical formula] and in this paragraph, R G1a is selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, and G 2 , R 1 and p are as defined in general formula (I).

[0032] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN’), (IM), (IM’), (I), (I’), (II’), (III’), (IV’), (IVV’) or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III’-1) or a pharmaceutically acceptable salt thereof, [Chemical formula 16] [Chemical formula] wherein R G1a is selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, preferably, R G1a is a C 1-6 alkyl group, G 2 , Q, L, R 1 , R 3a , R 3b , R 4a , R6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and p are as defined in general formula (III’).

[0033] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN’), (IM), (IM’), (IV’), (IVV’) or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (IV’-1) or a pharmaceutically acceptable salt thereof, [Chemical formula 17] [Chemical formula] Among them, R G1a is selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, preferably, R G1a is a C 1-6 alkyl group, Ring B, G 2 , Q, L, R 1 , R 3a , R 3b , R 4a , R 6 , R x , t and p are as defined in general formula (IV’).

[0034] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN’), (VV’) or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (VV’-1) or a pharmaceutically acceptable salt thereof, [Chemical formula 18] [Chemical formula] Among them, R G1ais selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, preferably, R G1a is C 1-6 an alkyl group, ring C, G 2 , Q, L, R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (VV’).

[0035] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN’), (IM), (IM’), (V’), (VV’) or a pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V’-1) or a pharmaceutically acceptable salt thereof, [Chemical formula 19] [Chemical formula] Among them, R G1a is selected from a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, preferably, R G1a is C 1-6 an alkyl group, G 2 , Q, L, R 1 , R 3a , R 3b , R 4a , R 6 , R x , t and p are as defined in general formula (V’).

[0036] In some embodiments of the present disclosure, a compound represented by the above general formula (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered heterocyclyl group, preferably, ring B is a morpholinyl group,

Chemical formula

[0037] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein ring C is a 3- to 8-membered heterocyclyl group, preferably, ring C is an azetidinyl group, a morpholinyl group,

Chemical formula

[0038] In some embodiments of the present disclosure, a compound represented by the above general formula (IM), (IM') or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0039] In some embodiments of the present disclosure, a compound represented by the above general formula (IM), (IM') or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0040] In some embodiments of the present disclosure, a compound represented by the above general formula (IM), (IM') or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0041] In some embodiments of the present disclosure, it is a compound represented by the above general formula (IM) or (IM'), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0042] In some embodiments of the present disclosure, it is a compound represented by the above general formula (IV'), (IV'-1), (V'), (V'-1), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0043] In some embodiments of the present disclosure, it is a compound represented by the above general formula (IV'), (IV'-1), (V'), (V'-1), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

Chemical formula

[0044] In some embodiments of the present disclosure, it is a compound represented by the above general formula (IV'), (IV'-1), (V'), (V'-1), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0045] In some embodiments of the present disclosure, it is a compound represented by the above general formula (IV'), (IV'-1), (V'), (V'-1), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0046] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, among which,

Chemical formula

Chemical formula

[0047] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IVV') or a pharmaceutically acceptable salt thereof, among which,

Chemical formula

Chemical formula

[0048] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IVV') or a pharmaceutically acceptable salt thereof, among which,

Chemical formula

[0049] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, among which,

Chemical formula

[0050] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein t1 is 0 or 1, preferably, t1 is 0.

[0051] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein each R 6 is the same or different and each is independently selected from =N-O-R 61 , =CR 62 R 63 , =N-R 64 and an oxo group, and R 61 , R 62 , R 63 and R 64 are as defined in general formula (IN), preferably, each R 6 is the same or different and each is independently selected from =N-O-R 61 , =CR 62 R 63 , =N-R 64 and an oxo group, R 61 is a C 1-6 alkyl group, R 62 and R 63 are the same or different and each is independently a hydrogen atom or a halogen, and R 64 is a hydrogen atom or a C 1-6 alkyl group, more preferably, each R 6 is the same or different and each is independently =CR 62 R 63 or an oxo group, and R 62 and R 63 are the same or different and each is independently a hydrogen atom or a halogen.

[0052] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R 61is a hydrogen atom or a C 1-6 alkyl group, preferably, R 61 is a C 1-6 alkyl group, more preferably, R 61 is a methyl group.

[0053] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen, preferably, R 62 and R 63 are the same or different and each independently is a hydrogen atom or F.

[0054] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R 64 is a hydrogen atom or a C 1-6 alkyl group, preferably, R 64 is a hydrogen atom or a methyl group.

[0055] In some embodiments of the present disclosure, a compound represented by the above general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0056] In some embodiments of the present disclosure, a compound represented by the above general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0057] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (III'), (IV'), (V'), (IVV'), (VV') or a pharmaceutically acceptable salt thereof, wherein R G1a is a hydrogen atom, a halogen, C 1-6 alkyl group and C 1-6 haloalkyl group, preferably, R G1a is a hydrogen atom or C 1-6 alkyl group, more preferably, R G1a is C 1-6 alkyl group, even more preferably, R G1a is a methyl group.

[0058] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (III'), (III'-1), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is a halogen, C 1-6 alkyl group and C 1-6 haloalkyl group, preferably, R G1a is C 1-6 alkyl group, even more preferably, R G1a is a methyl group.

[0059] In some embodiments of the present disclosure, a compound represented by the above general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6c and R 6g form a bridge together with the carbon atoms to which they are attached, and the above bridge further has 1, 2, 3 or 4 CH2s in addition to the bridgehead carbon atom, preferably, R 6c and R 6gforms a bridge together with the connecting carbon atom, said bridge having one further CH2 in addition to the bridgehead carbon atom.

[0060] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b are both hydrogen atoms, or R 6a and R 6b forms a 3- to 6-membered cycloalkyl group together with the carbon atom to which it is attached, and preferably, R 6a and R 6b are both hydrogen atoms, or R 6a and R 6b together with the carbon atom to which it is attached form a cyclopropyl group.

[0061] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6c and R 6d are both hydrogen atoms, or R 6c and R 6d forms a 3- to 6-membered cycloalkyl group together with the carbon atom to which it is attached, and preferably, R 6c and R 6d are both hydrogen atoms, or R 6c and R 6d together with the carbon atom to which it is attached form a cyclopropyl group.

[0062] In some embodiments of the present disclosure, there is provided a compound represented by the above general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6e and R 6f are both hydrogen atoms.

[0063] In some embodiments of the present disclosure, a compound represented by the above general formula (I), (I'), (II'), (II), (III'), (III'-1) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6g and R 6h are both hydrogen atoms.

[0064] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein Q is N or CH, preferably N.

[0065] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R 2a is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, preferably, R 2a is a hydrogen atom or a C 1-6 alkyl group, more preferably, R 2a is a hydrogen atom.

[0066] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II') or (II), or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group, preferably, ring A is selected from a naphthyl group, a phenyl group, a pyridyl group, a benzothienyl group, a benzothiazolyl group and a benzopyrazolyl group, more preferably, ring A is selected from a naphthyl group, a phenyl group and a benzothienyl group, still more preferably, ring A is a phenyl group or a naphthyl group, and even more preferably a naphthyl group.

[0067] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IM), (I), (II'), (II), or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

Chemical formula

Chemical formula

[0068] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1), or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group and a C 1-6 haloalkyl group, preferably a hydrogen atom or a halogen, more preferably a halogen, and even more preferably F.

[0069] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R d is a hydrogen atom or a C 1-6 alkyl group, preferably, R d is a hydrogen atom.

[0070] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein G 2 is NH.

[0071] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein L is selected from CH2, NH and O, preferably O.

[0072] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R e is a hydrogen atom or a C 1-6 alkyl group, preferably, R e is a hydrogen atom.

[0073] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein each R 1 is the same or different and each is independently halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, cyano group, amino group, -(CH2) u -NR f R g , hydroxy group and C 1-6 hydroxyalkyl group, R f and R g are the same or different and each is independently a hydrogen atom or a C 1-6 alkyl group, u is 0 or 1, and preferably each R 1 is the same or different and each is independently halogen, C 1-6 alkyl group and C 1-6 haloalkyl group.

[0074] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1, and preferably 0.

[0075] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II') or (II) or a pharmaceutically acceptable salt thereof, wherein each R 3 is the same or different and each is independently halogen, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C1-6 a haloalkyl group, C 1-6 a haloalkoxy group, a cyano group, an amino group, -(CH2) w -NR j R k , a hydroxy group and C 1-6 selected from hydroxyalkyl groups, R j and R k are the same or different and each independently is a hydrogen atom or a C 1-6 alkyl group, w is 0 or 1, and preferably each R 3 is the same or different and each independently is halogen, C 1-6 alkyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, hydroxy group, -O-C(O)NHC 1-6 alkyl group, amino group, cyano group, C 1-6 selected from hydroxyalkyl groups and 3- to 8-membered cycloalkyl groups, more preferably, R 3 is the same or different and each independently is halogen, C 1-6 alkyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, hydroxy group, C 1-6 selected from hydroxyalkyl groups and 3- to 8-membered cycloalkyl groups, even more preferably, each R 3 is the same or different and each independently is halogen, C 1-6 alkyl group, C 2-6 alkynyl group, C 1-6 selected from haloalkyl groups, hydroxy group and cyclopropyl group, even more preferably, each R 3 is the same or different and each independently is halogen, C 1-6 selected from alkyl group and hydroxy group, most preferably, each R 3 is the same or different and each independently is selected from F, ethyl group and hydroxy group, and in some embodiments, each R 3 is the same or different and each independently is halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, hydroxy group, -O-C(O)NHC 1-6Selected from an alkyl group, an amino group, and a cyano group, and in some embodiments, each R 3 is the same or different and each is independently selected from a halogen, C 1-6 alkyl group, C 1-6 haloalkyl group, and cyano group.

[0076] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IM), (I), (II’), or (II) or a pharmaceutically acceptable salt thereof, wherein q is 2, 3, or 4, preferably q is 2 or 3, more preferably 3.

[0077] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (IM), (I), (II’), (II) or a pharmaceutically acceptable salt thereof, wherein q1 is 2 or 3, preferably 2.

[0078] In some embodiments of the present disclosure, a compound represented by the above general formula (III’), (III’-1), (III), (IV’), (IV’-1), (V’), (V’-1), (IVV’), (VV’), (VV’-1) or a pharmaceutically acceptable salt thereof, wherein R 3a is selected from a hydrogen atom, a halogen, C 1-6 alkyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group, and a 3- to 8-membered cycloalkyl group, preferably R 3a is selected from a hydrogen atom, a halogen, and C 1-6 alkyl group, more preferably R 3a is a halogen, still more preferably R 3a is F.

[0079] In some embodiments of the present disclosure, a compound represented by the above general formula (III’), (III’-1), (III), (IV’), (IV’-1), (V’), (V’-1), (IVV’), (VV’), (VV’-1) or a pharmaceutically acceptable salt thereof, wherein R 3bis selected from a hydrogen atom, a halogen, C 1-6 alkyl group, C 2-6 alkynyl group, C 1-6 haloalkyl group, C 1-6 hydroxyalkyl group and a 3- to 8-membered cycloalkyl group, preferably, R 3b is selected from a hydrogen atom, a halogen and C 1-6 alkyl group, more preferably, R 3b is C 1-6 alkyl group, still more preferably, R 3b is an ethyl group.

[0080] In some embodiments of the present disclosure, a compound represented by the above general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, G 1 is CR G1a H, R G1a is C 1-6 alkyl group, T is a single bond, Q is N, R 4a is a halogen, G 2 is NH, L is O, p is 0,

Chemical formula

[0081] In some embodiments of the present disclosure, a compound represented by the above general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, G 1 is CR G1a H, R G1a is C 1-6 alkyl group, T is a single bond, Q is N, R 4a is a halogen, G 2 is NH, L is O,

Chemical formula

[0082] In some embodiments of the present disclosure, a compound represented by the above general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, G 1 is CR G1a H, R G1a is a methyl group, T is a single bond, Q is N, R 4a is a halogen, G 2 is NH, L is O, [[ID=1X]]

Chemical formula

[0083] In some embodiments of the present disclosure, a compound represented by the above general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, G 1 is CR G1a H, R G1a is a methyl group, T is a single bond, Q is N, R 4a is a halogen, G 2 is NH, L is O,

Chemical formula

[0084] In some embodiments of the present disclosure, a compound represented by the above general formula (IM) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, G 1 is CR G1a H, R G1a is a methyl group, T is a single bond, Q is N, R 4a is a halogen, G 2 is NH, L is O,

Chemical formula

[0085] In some embodiments of the present disclosure, a compound represented by the above general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0is O, and G 1 is CR G1a H, and R G1a is C 1-6 an alkyl group, T is a single bond, Q is N, and R 4a is a halogen, and G 2 is NH, and L is O,

Chemical formula

[0086] In some embodiments of the present disclosure, a compound represented by the above general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, and G 1 is CR G1a H, and R G1a is a methyl group, T is a single bond, Q is N, and R 4a is a halogen, and G 2 is NH, and L is O,

Chemical formula

[0087] In some embodiments of the present disclosure, a compound represented by the above general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, and G 1 is CR G1a H, and R G1a is a methyl group, T is a single bond, Q is N, and R 4a is a halogen, and G 2 is NH, and L is O,

Chemical formula

[0088] In some embodiments of the present disclosure, a compound represented by the above general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 is O, and G 1 is CR G1a H, and RG1a is a methyl group, T is a single bond, Q is N, and R 4a is a halogen, and G 2 is NH, L is O, and

Chemical formula

[0089] In some embodiments of the present disclosure, a compound represented by the above general formula (II’) or a pharmaceutically acceptable salt thereof, wherein R G1a is C 1-6 is an alkyl group,

Chemical formula

[0090] In some embodiments of the present disclosure, a compound represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[0091] In some embodiments of the present disclosure, a compound represented by the above general formula (III’) or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chem.

[0092] In some embodiments of the present disclosure, a compound represented by the above general formula (III'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chem.

[0093] In some embodiments of the present disclosure, a compound represented by the above general formula (III'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chem.

[0094] In some embodiments of the present disclosure, a compound represented by the above general formula (III) or a pharmaceutically acceptable salt thereof, wherein,

Chem.

[0095] In some embodiments of the present disclosure, a compound represented by the above general formula (IV’) or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chemical formula

[0096] In some embodiments of the present disclosure, a compound represented by the above general formula (IV’-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chemical formula

[0097] In some embodiments of the present disclosure, a compound represented by the above general formula (IV'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chemical formula

[0098] In some embodiments of the present disclosure, a compound represented by the above general formula (IV') or (V') or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chemical formula

[0099] In some embodiments of the present disclosure, a compound represented by the above general formula (IV'-1) or (V'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is a methyl group,

Chemical formula

[0100] In some embodiments of the present disclosure, a compound represented by the above general formula (IN) or a pharmaceutically acceptable salt thereof, wherein Q is N, G 0 is O, G 1 is CR G1a H, R G1a is a hydrogen atom or C 1-6 is an alkyl group, G 2 is NH, T is a chemical bond, and R 4a is halogen, L is O, ring A is a naphthyl group, each R 3 is the same or different and is independently selected from halogen, C 1-6 is an alkyl group and a hydroxy group, q is 2 or 3, R 5a and R 5b is a hydrogen atom, or R 5a and R 5b form a cyclopropyl group together with the carbon atoms to which they are attached, r is 1 or 3, ring C is a 3- to 8-membered heterocyclyl group, R 6 is =CR 62 R 63 or an oxo group, R x1 is =N-O-R 61 =CR 62 R 63 and =N-R 64 is selected from, R 61 is C 1-6 is an alkyl group, R 62 and R 63 is the same or different and is independently a hydrogen atom or halogen, R 64 is a hydrogen atom or C 1-6 is an alkyl group, t1 is 0 or 1, and p is 0.

[0101] In some embodiments of the present disclosure, a compound represented by the above general formula (IVV’), (VV’) or a pharmaceutically acceptable salt thereof, wherein R G1a is a hydrogen atom or C1-6 is an alkyl group,

Chemical formula

[0102] In some embodiments of the present disclosure, a compound represented by the above general formula (VV'), (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R G1a is C 1-6 is an alkyl group,

Chemical formula

[0103]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

[0104] Another aspect of the present disclosure relates to a compound represented by the general formula (INA) or a salt thereof, [Chemical formula 20] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, G 0 、 G 1 、 T, ring A, ring C, Q, L, R 1 、 R 3 、 R 4a 、 R 5a 、 R 5b 、 R 6 、 R x1 、 p, q, t1, and r are as defined in general formula (IN).

[0105] Another aspect of the present disclosure relates to a compound represented by general formula (IN’A) or a salt thereof, [Chemical formula 21]

Chemical formula

[0106] Another aspect of the present disclosure relates to a compound represented by general formula (IMA) or a salt thereof, [Chemical formula 22]

Chemical formula

[0107] Another aspect of the present disclosure relates to a compound represented by general formula (IM’A) or a salt thereof, [Chemical formula 23]

Chemical formula

[0108] Another aspect of the present disclosure relates to a compound represented by general formula (IA) or a salt thereof, [Chemical formula 24]

Chemical formula

[0109] Another aspect of the present disclosure relates to a compound represented by general formula (I’A) or a salt thereof, [Chemical formula 25] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, a is 0, 1, 2, 3, or 4, G 0 、 G 1 、 T, ring A, Q, L, R 1 、 R 3 、 R 4a 、 R 5a 、 R 5b 、 R 6a 、 R 6b 、 R 6c 、 R 6d 、 R 6e 、 R 6f 、 R 6g 、 R 6h 、 p and r are as defined in general formula (I’).

[0110] Another aspect of the present disclosure relates to a compound represented by general formula (II’A) or a salt thereof, [Chemical formula 26] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, ring A, Q, L, R G1a 、 R 1 、 R 3 、 R 4a 、 R 6a 、 R 6b 、 R 6c 、 R 6d 、 R6e , R 6f , R 6g , R 6h , p and q are as defined in general formula (II’).

[0111] Another aspect of the present disclosure relates to a compound represented by general formula (IIA) or a salt thereof, [Chemical formula 27]

Chemical formula

[0112] Another aspect of the present disclosure relates to a compound represented by general formula (III’A) or a salt thereof, [Chemical formula 28]

Chemical formula

[0113] Another aspect of the present disclosure relates to a compound represented by general formula (III’-1A) or a salt thereof, [Chemical formula 29] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and p is as defined in general formula (III’-1).

[0114] Another aspect of the present disclosure relates to a compound represented by general formula (IIIA) or a salt thereof, [Chemical formula 30] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, Q, L, R 1 , R 3a , R 3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R6g , R 6h and p are as defined in general formula (III).

[0115] Another aspect of the present disclosure relates to a compound represented by general formula (IVV’A) or a salt thereof, [Chemical formula 31] [Chemical formula] wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, ring C, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (IVV’).

[0116] Another aspect of the present disclosure relates to a compound represented by general formula (IV’A) or a salt thereof, [Chemical formula 32] [Chemical formula] wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, ring B, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x , t and p are as defined in general formula (IV’).

[0117] Another aspect of the present disclosure relates to a compound represented by general formula (IV’-1A) or a salt thereof, [Chemical formula 33] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, Ring B, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x , t and p are as defined in general formula (IV'-1).

[0118] Another aspect of the present disclosure relates to a compound represented by general formula (VV'A) or a salt thereof, [Chemical formula 34] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, Ring C, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (VV').

[0119] Another aspect of the present disclosure relates to a compound represented by general formula (VV'-1A) or a salt thereof, [Chemical formula 35] [Chemical formula] Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, rings C, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (VV’-1).

[0120] Another aspect of the present disclosure relates to a compound represented by general formula (V’A) or a salt thereof, [Chemical formula 36]

Chemical formula

[0121] Another aspect of the present disclosure relates to a compound represented by general formula (V’-1A) or a salt thereof, [Chemical formula 37]

Chemical formula

[0122] In some embodiments of the present disclosure, a compound represented by the above general formula (IN), (INA), (IN’), (IN’A), (IVV’), (IVV’A), (VV’), (VV’A), (VV’-1), (VV’-1A) or a pharmaceutically acceptable salt thereof, wherein R x1 is R x and R x is as defined in general formula (IN), preferably, R x1 is =N-O-R 61 、=CR 62 R 63 and =N-R 64 selected from, R 61 is a C 1-6 alkyl group, R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen, and R 64 is a hydrogen atom or a C 1-6 alkyl group.

[0123]

Table 2-1

Table 2-2

Table 2-3

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

[0124] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical Formula 38]

Chemical Formula

[0125] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IN’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 39] [Chemical formula] deprotecting a compound of general formula (IN’A) or a salt thereof to obtain a compound of general formula (IN’) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group before, simultaneously with, or after the deprotection reaction, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, a is 0, 1, 2, 3 or 4, G 2 is NH, G 0 , G 1 , T, ring A, ring C, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , R x1 , p, t1 and r are as defined in general formula (IN’).

[0126] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 40] [Chemical formula] comprising subjecting a compound of general formula (IMA) or a salt thereof to a deprotection reaction to obtain a compound of general formula (IM) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group before, simultaneously with, or after the deprotection reaction, wherein, R is an amino protecting group, preferably Boc, G 2 is NH, G 0 、G 1 、T, ring A, ring B, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、p, q, t and r are as defined in general formula (IM).

[0127] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IM’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 41]

Chemical formula

[0128] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 42] [Chemical formula] subjecting a compound of general formula (IA) or a salt thereof to a deprotection reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group before, simultaneously with, or after the deprotection reaction, wherein R is an amino protecting group, preferably Boc, G 2 is NH, G 0 , G 1 , T, ring A, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , p, q, and r are as defined in general formula (I).

[0129] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 43] [Chemical formula] Reacting a compound of general formula (I’A) or a salt thereof in a deprotection reaction to obtain a compound of general formula (I’) or a pharmaceutically acceptable salt thereof, optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group before, simultaneously with, or after the above deprotection reaction, wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, a is 0, 1, 2, 3 or 4, G 2 is NH, G 0 、G 1 、T, ring A, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、p and r are as defined in general formula (I’).

[0130] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 44]

Chemical formula

[0131] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 45] [Chemical formula] subjecting a compound of general formula (IIA) or a salt thereof to a deprotection reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group before, simultaneously or after the deprotection reaction, Among them, R is an amino protecting group, preferably Boc, G 2 is NH, ring A, Q, L, R 1 , R 3 , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , p and q are as defined in general formula (II).

[0132] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical 46] [Chemistry] including subjecting a compound of general formula (III’A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (III’) or a pharmaceutically acceptable salt thereof, wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and p are as defined in general formula (III’).

[0133] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III’-1) or a pharmaceutically acceptable salt thereof, the method comprising, [Chemical 47] [Chemistry] including subjecting a compound of general formula (III’-1A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (III’-1) or a pharmaceutically acceptable salt thereof, wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Q, L, R G1a , R 1 , R 3a , R3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and p are as defined in general formula (III’-1).

[0134] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 48] [Chemical formula] subjecting a compound of general formula (IIIA) or a salt thereof to a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Q, L, R 1 , R 3a , R 3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and p are as defined in general formula (III).

[0135] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (IVV’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 49] [Chemical formula] Subjecting a compound of general formula (IVV’A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (IVV’) or a pharmaceutically acceptable salt thereof, wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, ring C, Q, L, R G1a 、R 1 、R 3a 、R 3b 、R 4a 、R 6 、R x1 、t1 and p are as defined in general formula (IVV’).

[0136] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IV’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 50]

Chemical formula

[0137] Another aspect of the present disclosure relates to a method for preparing a compound of general formula (IV’-1) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical 51] [Chem.] Including subjecting a compound of general formula (IV'-1A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (IV'-1) or a pharmaceutically acceptable salt thereof, Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Ring B, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x , t and p are as defined in general formula (IV'-1).

[0138] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (VV') or a pharmaceutically acceptable salt thereof, the method comprising [Chemical 52] [Chem.] Subjecting a compound of general formula (VV'A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (VV') or a pharmaceutically acceptable salt thereof, Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Ring C, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (VV').

[0139] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (VV'-1) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 53] [Chemical formula] subjecting a compound represented by the general formula (VV'-1A) or a salt thereof to a deprotection reaction to obtain a compound represented by the general formula (VV'-1) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, ring C, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in the general formula (VV'-1).

[0140] Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 54] [Chemical formula] subjecting a compound represented by the general formula (V'A) or a salt thereof to a deprotection reaction to obtain a compound represented by the general formula (V') or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, ring B, Q, L, R G1a , R 1 , R 3a , R 3b, R 4a , R 6 , R x , t and p are as defined in general formula (V').

[0141] Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 55] [Chemical formula] subjecting a compound of general formula (V'-1A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (V'-1) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, ring B, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x , t and p are as defined in general formula (V'-1).

[0142] Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound represented by general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0143] The present disclosure further relates to the use of a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of an agent for inhibiting KRAS G12D.

[0144] The present disclosure further relates to the use of a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of an agent for treating and / or preventing a KRAS G12D-mediated disease or condition.

[0145] The present disclosure further relates to the use of a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of an agent for treating and / or preventing a tumor, wherein the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, and more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0146] The present disclosure further relates to a method of inhibiting KRAS G12D, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0147] The present disclosure further relates to a method of treating and / or preventing a KRAS G12D-mediated disease or condition, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0148] The present disclosure further relates to a method of treating and / or preventing a tumor, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, and more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0149] The present disclosure further relates to a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicament.

[0150] The present disclosure further relates to a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which inhibits KRAS G12D.

[0151] The present disclosure further relates to a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which treats and / or prevents a KRAS G12D-mediated disease or condition.

[0152] The present disclosure further relates to a compound of general formula (IN), (IN'), (IM), (IM'), (I), (I'), (II'), (II), (III'), (III'-1), (III), (IV'), (IV'-1), (V'), (V'-1), (IVV'), (VV'), (VV'-1) shown in Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, wherein the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, and more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0153] The disease or condition described in the present disclosure is a disease or condition that can be treated and / or prevented by inhibiting KRAS G12D.

[0154] Preferably, the KRAS G12D-mediated disease or condition described in the present disclosure is a tumor, and the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, and more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0155] The colorectal cancer described in the present disclosure is preferably colon cancer or rectal cancer.

[0156] Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma, the soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma, the lymphoma is selected from Hodgkin's disease and non-Hodgkin lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma), the liver cancer is preferably hepatocellular carcinoma, the lung cancer (also referred to as bronchogenic carcinoma) is selected from non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and squamous cell carcinoma, the kidney cancer is selected from renal cell carcinoma, clear cell and renal oncocytoma, the leukemia is selected from chronic lymphocytic leukemia (CLL), chronic granulocytic leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), the skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma, and the myeloma is preferably multiple myeloma.

[0157] The active compound is formulated into a form suitable for administration by any suitable route, and the composition of the present disclosure can be prepared using one or more pharmaceutically acceptable carriers by conventional methods. Accordingly, the active compound according to the present disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure may be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injection solutions, dispersible powders or granules, suppositories, buccal tablets or syrups.

[0158] However, as a general guideline, the active compound of the present disclosure is preferably in the form of a unit dosage form or a form that can be self-administered by the patient as a single agent. The expression form of the unit dosage of the compound or composition according to the present disclosure may be tablets, capsules, cachets, bottled medicaments, drug powders, granules, buccal tablets, suppositories, reconstituted powders or liquid preparations. Suitable unit dosages may be from 0.1 to 1000 mg.

[0159] The pharmaceutical composition according to the present disclosure may contain one or more additives in addition to the active compound, and the above additives are selected from components such as fillers (diluents), binders, wetting agents, disintegrants or excipients. The composition may contain 0.1 to 99% by weight of the active compound depending on the administration method.

[0160] Tablets contain the active ingredient and a non-toxic pharmaceutically acceptable excipient suitable for the preparation of tablets for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may not be coated, or may be coated by known techniques that can achieve a sustained release effect over a long period by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract.

[0161] An oral preparation may be provided by a soft gelatin capsule in which the active ingredient and an inert solid diluent therein, or the active ingredient and a water-soluble carrier or an oily solvent therein are mixed.

[0162] An aqueous suspension contains the active substance and an excipient suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweeteners.

[0163] An oil suspension can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickening agent. In order to provide a palatable preparation, the above sweeteners and flavoring agents may be added. These compositions can be preserved by adding an antioxidant.

[0164] The pharmaceutical composition according to the present disclosure may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may contain sweeteners, flavoring agents, preservatives and antioxidants. Such preparations may contain emollients, preservatives, colorants and antioxidants.

[0165] The pharmaceutical composition according to the present disclosure may be in the form of a sterile aqueous injection solution. Permissible solvents or solubilizers that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injection preparation may be an oil-in-water microemulsion in sterile water for injection in which the active ingredient therein is dissolved in the oil phase, and by injecting a large amount locally, the injection solution or microemulsion can be injected into the patient's bloodstream. Alternatively, it is preferable to administer the solution and microemulsion in a manner capable of maintaining a certain cycle concentration of the compound according to the present disclosure. In order to maintain such a certain concentration, a continuous intravenous administration device can be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 type intravenous injection pump.

[0166] The pharmaceutical composition according to the present disclosure may also be in the form of a sterile aqueous or oily suspension for intramuscular and subcutaneous administration. Such a suspension can be prepared using appropriate dispersants or wetting agents and suspending agents as described above according to known techniques. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a non-parenterally acceptable non-toxic diluent or solvent. Also, a sterile fixed oil can be conveniently used as a solvent or suspending medium. For that purpose, any compounding fixed oil can be used. Also, fatty acids can be used to prepare injections.

[0167] The compounds according to the present disclosure may also be administered in the form of suppositories for rectal administration. Those pharmaceutical compositions can be prepared by mixing the drug with a suitable excipient that is solid at normal temperature but liquid in the rectum and thus dissolves in the rectum to release the drug without irritation.

[0168] The compounds according to the present disclosure can be administered by adding water to prepare aqueous suspension dispersible powders and granules. Those pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant, a wetting agent, a suspending agent, and one or more preservatives.

[0169] As is well known to those skilled in the art, the dosage of a drug is due to many factors, including but not limited to the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the physical condition of the patient, the behavior of the patient, the diet of the patient, the administration time, the administration method, the excretion rate, the composition of the drug, etc. Also, the optimal treatment method, for example, the treatment mode, the daily dosage of the compound or the type of pharmaceutically acceptable salt, etc. can be verified according to the conventional treatment plan.

[0170] Explanation of Terms Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0171] The term "alkyl group" refers to a saturated aliphatic hydrocarbon group that is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkyl group), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6is an alkyl group). Non-limiting examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a 1,1-dimethylpropyl group, a 1,2-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1-ethylpropyl group, a 2-methylbutyl group, a 3-methylbutyl group, an n-hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 2,3-dimethylbutyl group, an n-heptyl group, a 2-methylhexyl group, a 3-methylhexyl group, a 4-methylhexyl group, a 5-methylhexyl group, a 2,3-dimethylpentyl group, a 2,4-dimethylpentyl group, a 2,2-dimethylpentyl group, a 3,3-dimethylpentyl group, a 2-ethylpentyl group, a 3-ethylpentyl group, an n-octyl group, a 2,3-dimethylhexyl group, a 2,4-dimethylhexyl group, a 2,5-dimethylhexyl group, a 2,2-dimethylhexyl group, a 3,3-dimethylhexyl group, a 4,4-dimethylhexyl group, a 2-ethylhexyl group, a 3-ethylhexyl group, a 4-ethylhexyl group, a 2-methyl-2-ethylpentyl group, a 2-methyl-3-ethylpentyl group, an n-nonyl group, a 2-methyl-2-ethylhexyl group, a 2-methyl-3-ethylhexyl group, a 2,2-diethylpentyl group, an n-decyl group, a 3,3-diethylhexyl group, a 2,2-diethylhexyl group, and various branched-chain isomers thereof, etc. The alkyl group may or may not be substituted. When substituted, it may be substituted at any available linking point, and the substituent is preferably one or more selected from a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxy group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

[0172] The term "alkenyl group" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of the alkyl group is as described above, and preferably has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkenyl group), more preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl group). Non-limiting examples include vinyl group, propenyl group, isopropenyl group, butenyl group, etc. The alkenyl group may or may not be substituted. When substituted, the substituent is preferably one or more selected from alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0173] The term "alkynyl group" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of the alkyl group is as described above. Preferably, it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkynyl group), more preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkynyl group). Non-limiting examples include ethynyl group, propynyl group, butynyl group, pentynyl group, hexynyl group, etc. The alkynyl group may or may not be substituted. When substituted, the substituent is preferably one or more selected from alkoxy group, halogen, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0174] The term "cycloalkyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3- to 14-membered cycloalkyl group), preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3- to 8-membered cycloalkyl group), more preferably 3 to 6 carbon atoms (i.e., 3- to 6-membered cycloalkyl group). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cyclohexenyl group, cyclohexadienyl group, cycloheptyl group, cycloheptatrienyl group, and cyclooctyl group, etc. Polycyclic cycloalkyl groups include spirocycloalkyl groups, fused cycloalkyl groups, and bridged cycloalkyl groups.

[0175] The term "spirocycloalkyl group" refers to a polycyclic group having 5 to 20 members, where two monocyclic rings share one carbon atom (referred to as a spiro atom), and it may contain one or more double bonds. Preferably, it has 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Spirocycloalkyl groups can be divided into monospirocycloalkyl groups or polyspirocycloalkyl groups (e.g., biss pirocycloalkyl groups) according to the number of spiro atoms shared by the rings, preferably monospirocycloalkyl groups and biss pirocycloalkyl groups. More preferably, they are 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include

Chem.

[0176] The term "fused cycloalkyl group" refers to a fully carbon polycyclic group having 5 to 20 members, wherein each ring in the system shares a pair of carbon atoms adjacent to another ring in the system, and among them, one or more rings may contain one or more double bonds. Preferably it has 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). Depending on the number of constituent rings, it can be divided into bicyclic or polycyclic fused cycloalkyl groups (for example, tricyclic, tetracyclic), preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of the fused cycloalkyl group are

Chem.

[0177] The term "bridged cycloalkyl group" refers to a fully carbon polycyclic group having 5 to 20 members, which shares two carbon atoms not directly linked to each other in any two rings, and it may contain one or more double bonds. Preferably it has 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). Depending on the number of constituent rings, it can be divided into bicyclic or polycyclic (for example, tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of the bridged cycloalkyl group are

Chem.

Chem.

[0178] The cycloalkyl group may or may not be substituted. When substituted, it may be substituted at any available linking point. The above substituents are preferably one or more selected from halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxo group, heterocyclyloxo group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group.

[0179] The term "alkoxy group" refers to -O-(alkyl group), wherein the definition of the alkyl group is as described above. Non-limiting examples of alkoxy groups include methoxy group, ethoxy group, propoxy group and butoxy group. The alkoxy group may or may not be optionally substituted. When substituted, the substituents are preferably selected from D atom, halogen, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxo group, heterocyclyloxo group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group.

[0180] The term "heterocyclyl group" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, containing 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl group), one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, and said sulfur may optionally be substituted with an oxo group (i.e., form a sulfoxide or sulfone), but does not contain a ring moiety of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 14 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (i.e., 3- to 14-membered heterocyclyl), 1 to 4 (e.g., 1, 2, 3 and 4) of which are heteroatoms, more preferably 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7 and 8) (i.e., 3- to 8-membered heterocyclyl group) or 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14), 1 to 3 of which are heteroatoms (e.g., 1, 2 and 3), more preferably it contains 3 to 8 ring atoms, 1 to 3 (e.g., 1, 2 and 3) of which are heteroatoms, and most preferably it contains 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl), 1 to 3 of which are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl group, tetrahydropyranyl group, 1,2,3,6-tetrahydropyridyl group, piperidinyl group, piperazinyl group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, etc. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups and bridged heterocyclyl groups.

[0181] The term "spiroheterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members and in which two monocyclic rings share one atom (referred to as a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and said sulfur may optionally be substituted with an oxo group (i.e., form a sulfoxide or a sulfone), while the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it has 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 members) (i.e., a 6- to 14-membered spiroheterocyclyl group), more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members) (i.e., a 7- to 10-membered spiroheterocyclyl group). The spiroheterocyclyl group is classified into a monospiroheterocyclyl group or a polyspiroheterocyclyl group (e.g., a biss piroheterocyclyl group) depending on the number of spiro atoms shared by the rings, and is preferably a monospiroheterocyclyl group and a biss piroheterocyclyl group. More preferably, it is a 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered, or 7-membered / 6-membered monospiroheterocyclyl group. Non-limiting examples of the spiroheterocyclyl group are [Chemical formula] including.

[0182] The term "fused heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members, wherein each ring in the system shares a pair of atoms adjacent to another ring in the system, and one or more rings may contain one or more double bonds, among which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may optionally be substituted with an oxo group (i.e., form a sulfoxide or a sulfone), and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6 to 14-membered fused heterocyclyl group), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7 to 10-membered fused heterocyclyl group). Depending on the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclyl groups, preferably bicyclic or tricyclic, more preferably 3-membered / 4-membered, 3-membered / 5-membered, 3-membered / 6-membered, 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 3-membered, 5-membered / 4-membered, 5-membered / 5-membered, 5-membered / 6-membered, 5-membered / 7-membered, 6-membered / 3-membered, 6-membered / 4-membered, 6-membered / 5-membered, 6-membered / 6-membered, 6-membered / 7-membered, 7-membered / 5-membered or 7-membered / 6-membered bicyclic fused heterocyclyl groups. Non-limiting examples of the fused heterocyclyl group are

Chem.

[0183] The term "bridged heterocyclyl group" refers to a polycyclic heterocyclyl group having 5 to 20 members and sharing two atoms that are not directly linked to each other in any two rings, which may contain one or more double bonds, among which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, and the sulfur may optionally be substituted with an oxo group (i.e., forming a sulfoxide or a sulfone), and the remaining ring atoms are carbon. Preferably, it has 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14 members) (i.e., a 6 to 14-membered bridged heterocyclyl group), and more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members) (i.e., a 7 to 10-membered bridged heterocyclyl group). Depending on the number of constituent rings, it can be divided into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of the bridged heterocyclyl group are [Chemical formula] including.

[0184] The above heterocyclyl ring includes those in which the above heterocyclyl groups (including monocyclic, spiroheterocyclic, fused heterocyclic, and bridged heterocyclic rings) are fused to an aryl group, a heteroaryl group, or a cycloalkyl ring, among which the ring linked to the parent structure is a heterocyclyl group, and non-limiting examples thereof are [Chemical formula] etc. including.

[0185] The heterocyclyl group may or may not be substituted. When substituted, it may be substituted at any available linking point, and the above substituents are preferably one or more selected from halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group, and heteroaryl group.

[0186] The term "aryl group" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic group (fused polycycles are rings that share adjacent carbon atom pairs) having a conjugated π electron system, preferably 6- to 10-membered, for example, a phenyl group and a naphthyl group. The aryl ring includes those in which the above aryl ring is fused to a heteroaryl group, a heterocyclyl group or a cycloalkyl ring. Among them, the ring linked to the parent structure is an aryl ring, and non-limiting examples thereof are

Chemical formula

[0187] The aryl group may or may not be substituted. When substituted, it may be substituted at any available linking point. The substituents are preferably one or more selected from halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group.

[0188] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 (for example, 1, 2, 3 and 4) heteroatoms and 5 to 14 ring atoms, among which the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5- to 10-membered (for example, 5, 6, 7, 8, 9 or 10-membered) (i.e., a 5- to 10-membered heteroaryl group), more preferably 8- to 10-membered (for example, 8, 9 or 10-membered), and still more preferably 5-membered or 6-membered (i.e., a 5-membered or 6-membered heteroaryl group), for example, a furanyl group, a thienyl group, a pyridyl group, a pyrrolyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, etc. The heteroaryl ring includes those in which the above heteroaryl group is fused to an aryl group, a heterocyclyl group or a cycloalkyl ring. Among them, the ring linked to the parent structure is a heteroaryl ring, and non-limiting examples thereof are [Chem.] comprises.

[0189] The heteroaryl group may or may not be substituted. When substituted, it may be substituted at any available linking point. The above substituents are preferably one or more selected from halogen, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyloxy group, heterocyclyloxy group, hydroxy group, hydroxyalkyl group, cyano group, amino group, nitro group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group.

[0190] The above cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group include a residue derived by removing one hydrogen atom from the parent ring atoms, or a residue derived by removing two hydrogen atoms from the same or two different ring atoms of the parent, that is, "divalent cycloalkyl group", "divalent heterocyclyl group", "arylene group" and "heteroarylene group".

[0191] The term "amino protecting group" is one that protects an amino group with a group that is easily removable so that the amino group does not change when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl group (SEM), tetrahydropyranyl group, tert-butoxycarbonyl group (Boc), acetyl group, benzyl group, allyl group, p-toluenesulfonyl group (Ts) and p-methoxybenzyl group, etc. These groups may optionally be substituted with 1 to 3 substituents selected from halogen, alkoxy group and nitro group, and the amino protecting group is preferably Boc.

[0192] The term "hydroxy protecting group" refers to a hydroxy derivative that reacts with other functional groups of a compound and is generally used to block or protect a hydroxy group. As examples, preferably, the hydroxy protecting group includes, for example, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group (TBS), a tert-butyldiphenylsilyl group, a methyl group, a tert-butyl group, an allyl group, a benzyl group, a methoxymethyl group (MOM), an ethoxyethyl group, a 2-tetrahydropyranyl group (THP), a formyl group, an acetyl group, a benzoyl group, and a p-nitrobenzoyl group, etc., and the hydroxy protecting group is preferably MOM.

[0193] The term "alkynyl protecting group" refers to a readily removable group introduced into an alkynyl group so that the active hydrogen in acetylene or a terminal alkyne does not change when other parts of the molecule react. Non-limiting examples include a trimethylsilyl group (TMS), a triethylsilyl group (TES), a tert-butyldimethylsilyl group (TBS), a triisopropylsilyl group (TIPS), a tert-butyldimethylsilyl group (TBDMS), a tert-butyldiphenylsilyl group (TBDPS), a methyl group, a tert-butyl, an allyl group, a benzyl group, a methoxymethyl group (MOM), an ethoxyethyl group, a 2-tetrahydropyranyl group (THP), a formyl group, an acetyl group, a benzoyl group, a p-nitrobenzoyl group, etc., and the alkynyl protecting group is preferably TIPS.

[0194] The term "cycloalkyloxy group" refers to cycloalkyl-O-, wherein the cycloalkyl group is as defined above.

[0195] The term "heterocyclyloxy group" refers to heterocyclyl-O-, wherein the heterocyclyl group is as defined above.

[0196] The term "aryloxy group" refers to aryl-O-, wherein the aryl group is as defined above.

[0197] The term "heteroaryloxy group" refers to heteroaryl-O-, wherein the heteroaryl group is as defined above.

[0198] The term "alkylthio group" refers to alkyl-S-, wherein the alkyl group is as defined above.

[0199] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0200] The term "haloalkoxy group" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0201] The term "deuterated alkyl group" refers to an alkyl group substituted with one or more deuterium atoms, wherein the alkyl group is as defined above.

[0202] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group is as defined above.

[0203] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0204] The term "hydroxy group" refers to -OH.

[0205] The term "mercapto group" refers to -SH.

[0206] The term "amino group" refers to -NH2.

[0207] The term "cyano group" refers to -CN.

[0208] The term "nitro group" refers to -NO2.

[0209] The term "oxo group" or "oxo" refers to "=O".

[0210] The term "carbonyl group" refers to C=O.

[0211] The term "carboxy group" refers to -C(O)OH.

[0212] The term "carboxylic acid ester group" refers to -C(O)O(alkyl group), -C(O)O(cycloalkyl group), (alkyl group)C(O)O- or (cycloalkyl group)C(O)O-, where the alkyl group and cycloalkyl group are as defined above.

[0213] MOM refers to a methoxymethyl group.

[0214] Boc refers to a tert-butoxycarbonyl group.

[0215] TIPS refers to a triisopropylsilyl group.

[0216] TBS refers to a tert-butyldimethylsilyl group.

[0217] Compounds according to the present disclosure may include restricted states in all forms of rotational isomers and conformations. Atropisomers are further included, and the term "atropisomer" refers to conformational isomers generated by the rotation around a single bond in a molecule being hindered or greatly slowed down (this is due to the spatial interaction with other parts of the molecule and the substituents at both ends of the single bond being asymmetric), and its tautomerism is slow enough to allow separation and isolation under certain conditions. For example, some compounds according to the present disclosure may exist in the form of a mixture of atropisomers (e.g., an equimolar mixture, a mixture rich in one atropisomer, etc.) or in the form of a purified atropisomer. Compounds and intermediates according to the present disclosure may further exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can be interconverted by a low energy barrier. For example, proton tautomers (also called proton-transfer tautomers) include interconversions by protolysis, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of the keto-enol equilibrium is as follows.

[0218]

Chemical formula

[0219] The compounds according to the present disclosure may be in the form of specific stereoisomers. The term "stereoisomer" refers to isomers that have the same structure but different spatial arrangements of atoms. It includes cis and trans (or Z and E) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Substituents in the compounds according to the present disclosure may have other asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of the present disclosure. Even if only one configuration of any carbon-carbon double bond is named, both the Z configuration and the E configuration are included. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers, and (D)- and (L)-isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or by induction with a chiral auxiliary, or, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), appropriate optically active acids or bases are used to form diastereomeric salts, and then diastereomeric resolution is performed by ordinary methods known in this field to obtain pure isomers. Furthermore, the separation of enantiomers and diastereomers is generally accomplished by chromatography.

[0220] In the chemical structure of the compounds described in the present disclosure, The bond named JPEG2025524846000181.jpg1029 indicates that the configuration is not specified, that is, when chiral isomers exist in the chemical structure, The bond named JPEG2025524846000182.jpg829 May be JPEG2025524846000183.jpg936, or May simultaneously include the two configurations named JPEG2025524846000184.jpg836.

[0221] The compounds according to the present disclosure include all suitable isotope derivatives of the compounds. The term "isotope derivative" refers to a compound in which at least one atom is replaced with an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be introduced into the compounds according to the present disclosure include stable and radioactive isotopes such as hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. For example, each of 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., and preferably deuterium.

[0222] Compared with the non-deuterated agent, the deuterated agent has advantages such as reducing toxicity and side effects, enhancing the stability of the agent, improving the therapeutic effect, and extending the biological half-life of the agent. The conversion of all isotope compositions of the compounds according to the present disclosure is included within the scope of the present disclosure regardless of the presence or absence of radioactivity. Each available hydrogen atom linked to a carbon atom may be independently replaced with a deuterium atom, among which the deuterium substitution may be partial or complete, and the partial deuterium substitution means that at least one hydrogen is replaced with at least one deuterium.

[0223] "Optionally" or "optionally" means that the event or situation described thereafter may or may not occur, and this description includes the cases where the event or situation occurs and does not occur. For example, "optionally substituted with a halogen or a cyano group C 1-6"Alkyl group" means that a halogen or cyano group may or may not be present, and this description includes the case where the alkyl group is substituted with a halogen or cyano group and the case where the alkyl group is not substituted with a halogen or cyano group.

[0224] "Substituted" means that one or more hydrogen atoms in the group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted with the corresponding number of substituents. A person skilled in the art can determine substitutions that are possible or impossible (by experiment or theory) without much effort. For example, when an amino group or a hydroxy group having a free hydrogen binds to a carbon atom having an unsaturated (e.g., olefin) bond, it may become unstable.

[0225] "Pharmaceutical composition" refers to a mixture of one or more compounds described herein or pharmaceutically acceptable salts or prodrugs thereof and other chemical components, and other components such as pharmaceutically acceptable carriers and excipients. The pharmaceutical composition is for promoting administration to a living body, contributing to the absorption of the active ingredient, and further exerting biological activity.

[0226] "Pharmaceutically acceptable salt" refers to a salt of a compound according to the present disclosure, which may be selected from inorganic salts or organic salts. Such salts have safety and efficacy when used in the body of a mammal and have the desired biological activity. The salt may be prepared alone during the final separation and purification process of the compound, or by reacting a suitable group with a suitable base or acid. Generally, bases for forming pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonium. Generally, acids for forming pharmaceutically acceptable salts include inorganic acids and organic acids.

[0227] For a drug or pharmacological agent, the term "therapeutically effective amount" refers to an amount of the drug or agent sufficient to obtain, or at least partially obtain, the desired effect. A therapeutically effective amount is determined by a person and depends on the age and general condition of the subject being administered, as well as on the specific active substance, but a suitable therapeutically effective amount for an individual can be determined by one of ordinary skill in the art by routine testing.

[0228] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions and / or dosage forms are within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, are applicable to contact with the tissues of a patient, have a reasonable benefit / risk ratio, and are effective for the desired use.

[0229] As used herein, the singular forms "a", "an" and "the" include plural references unless the context clearly dictates otherwise, and vice versa.

[0230] The term "about", when used in connection with parameters such as, for example, pH, concentration, temperature, etc., indicates that the parameter may vary by ±10%, and in some cases, more preferably by ±5%. As will be understood by one of ordinary skill in the art, when the parameter is not critical, the numbers are generally presented for illustration purposes and not as a limitation.

[0231] Synthesis Method of Compounds According to the Present Disclosure To achieve the objectives of the present disclosure, the present disclosure adopts the following technical solutions.

[0232] Technical Solution 1-1 The present disclosure provides a method for preparing a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical Formula 56] [Chemical Formula] Reacting a compound of general formula (INA) or a salt thereof under acidic conditions to obtain a compound of general formula (IN) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group under acidic or basic conditions before, simultaneously or after the above deprotection reaction, wherein R is an amino protecting group, preferably Boc, G 2 is NH, G 0 、G 1 、T, ring A, ring C, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、R x1 、p, q, t1 and r are as defined in general formula (IN).

[0233] Technical Solution 1-2 The present disclosure provides a method for preparing a compound represented by general formula (IN') or a pharmaceutically acceptable salt thereof, and the method comprises [Chemical Formula 57]

Chemical Formula

[0234] Technical proposal 1-3 The present disclosure provides a method for preparing a compound represented by general formula (IM) or a pharmaceutically acceptable salt thereof, and the method includes [Chemical formula 58] [Chemical formula] subjecting a compound of general formula (IMA) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (IM) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further including the step of removing the protecting group in the R 3 group under acidic or basic conditions before, simultaneously or after the above deprotection reaction, wherein, R is an amino protecting group, preferably Boc, G 2 is NH, G 0 , G 1 , T, ring A, ring B, Q, L, R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , p, q, t and r are as defined in general formula (IM).

[0235] Technical proposal 1-4 The present disclosure provides a method for preparing a compound represented by general formula (IM') or a pharmaceutically acceptable salt thereof, and the method includes [Chemical formula 59] [Chemical formula] Reacting a compound of general formula (IM’A) or a salt thereof under acidic conditions to obtain a compound of general formula (IM’) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group under acidic or basic conditions before, simultaneously or after the above deprotection reaction, wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, a is 0, 1, 2, 3 or 4, G 2 is NH, G 0 、G 1 、T, ring A, ring B, Q, L, R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、p, t and r are as defined in general formula (IM’).

[0236] Technical solution 2-1 The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, and the method comprises [Chemical formula 60] [Chemical formula] Reacting a compound of general formula (IA) or a salt thereof under acidic conditions to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group under acidic or basic conditions before, simultaneously or after the above deprotection reaction, wherein, R is an amino protecting group, preferably Boc, G 2 is NH, G 0 、G 1 、T, ring A, Q, L, R1 , R 3 , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , p, q, and r are as defined in general formula (I).

[0237] Technical Solution 2-2 The present disclosure provides a method for preparing a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof, the method comprising [Chemical Formula 61]

Chemical Formula

[0238] Technical solution 3-1 The present disclosure provides a method for preparing a compound represented by general formula (II’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 62] [Chemical formula] subjecting a compound of general formula (II’A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (II’) or a pharmaceutically acceptable salt thereof, and optionally, when the R 3 group contains a protecting group, further comprising the step of removing the protecting group in the R 3 group under acidic or basic conditions before, simultaneously with, or after the deprotection reaction, wherein R is an amino protecting group, preferably Boc, G 2 is NH, ring A, Q, L, R G1a , R 1 , R 3 , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , p, and q are as defined in general formula (II’).

[0239] Technical solution 3-2 The present disclosure provides a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 63] [Chemical formula] subjecting a compound of general formula (IIA) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof, and optionally, R 3When a protecting group is included in the base, before, simultaneously with, or after the above deprotection reaction, the protecting group in the R 3 group is further removed under acidic or basic conditions, wherein R is an amino protecting group, preferably Boc, G 2 is NH, ring A, Q, L, R 1 , R 3 , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , p and q are as defined in general formula (II).

[0240] Technical proposal 4-1 The present disclosure provides a method for preparing a compound represented by general formula (III') or a pharmaceutically acceptable salt thereof, and the method includes [Chemical formula 64] [Chemical formula] subjecting a compound of general formula (III'A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (III') or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6hand p is as defined in general formula (III’).

[0241] Technical solution 4-2 The present disclosure provides a method for preparing a compound represented by general formula (III’-1) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 65] [Chemical formula] subjecting a compound of general formula (III’-1A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (III’-1) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and p is as defined in general formula (III’-1).

[0242] Technical solution 4-3 The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 66] [Chemical formula] subjecting a compound of general formula (IIIA) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Q, L, R 1 , R 3a , R 3b , R 4a , R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h and p are as defined in general formula (III).

[0243] Technical solution 5-1 The present disclosure provides a method for preparing a compound represented by general formula (IVV’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 67] [Chemical formula] subjecting a compound of general formula (IVV’A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (IVV’) or a pharmaceutically acceptable salt thereof, wherein, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, ring C, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (IVV’).

[0244] Technical solution 5-2 The present disclosure provides a method for preparing a compound represented by general formula (IV’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical Formula 68] [Chem.] Including subjecting a compound of general formula (IV’A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (IV’) or a pharmaceutically acceptable salt thereof, Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Ring B, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x , t and p are as defined in general formula (IV’).

[0245] Technical Solution 5-3 The present disclosure provides a method for preparing a compound represented by general formula (IV’-1) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical Formula 69] [Chem.] Subjecting a compound of general formula (IV’-1A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (IV’-1) or a pharmaceutically acceptable salt thereof, Among them, R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, Ring B, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x, t, and p are as defined in general formula (IV’-1).

[0246] Technical proposal 6-1 The present disclosure provides a method for preparing a compound represented by general formula (VV’) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 70] [Chemical formula] subjecting a compound of general formula (VV’A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (VV’) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2 is NH, ring C, Q, L, R G1a R 1 R 3a R 3b R 4a R 6 R x1 , t1, and p are as defined in general formula (VV’).

[0247] Technical proposal 6-2 The present disclosure provides a method for preparing a compound represented by general formula (VV’-1) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 71] [Chemical formula] subjecting a compound of general formula (VV’-1A) or a salt thereof to a deprotection reaction under acidic conditions to obtain a compound of general formula (VV’-1) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, R y is a hydroxy protecting group, preferably MOM, G 2is NH, rings C, Q, L, R G1a , R 1 , R 3a , R 3b , R 4a , R 6 , R x1 , t1 and p are as defined in general formula (VV'-1).

[0248] Technical solution 6-3 The present disclosure provides a method for preparing a compound represented by general formula (V') or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 72]

Chemical formula

[0249] Technical solution 6-4 The present disclosure provides a method for preparing a compound represented by general formula (V'-1) or a pharmaceutically acceptable salt thereof, the method comprising [Chemical formula 73]

Chemical formula

[0250] In the above synthesis scheme, the reagent providing acidic conditions includes organic acids or inorganic acids. The above organic acids include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me3SiCl and TMSOTf. The above inorganic acids include, but are not limited to, hydrogen chloride, hydrochloric acid dioxane solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and preferably hydrochloric acid dioxane solution.

[0251] In the above synthesis scheme, the reagents providing basic conditions include organic bases and inorganic bases. The above organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran solution or 1,8-diazabicycloundec-7-ene. The above inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide.

[0252] In the above synthesis scheme, R 3When a terminal alkynyl group is included, the terminal alkynyl group can be protected with TIPS, and the reagent for removing TIPS is preferably a tetrahydrofuran solution of tetrabutylammonium fluoride or cesium fluoride.

[0253] The reaction of the above step is preferably carried out in a solvent, and the solvents used include, but are not limited to, pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and mixtures thereof.

Mode for Carrying Out the Invention

[0254] Hereinafter, the present disclosure will be further described in accordance with examples, but these examples do not limit the scope of the present disclosure.

[0255] Examples The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR shift (δ) is shown in units of 10 -6 (ppm). For the measurement of NMR, a nuclear magnetic resonance apparatus Bruker AVANCE-400 or Bruker AVANCE NEO 500M is used, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard is tetramethylsilane (TMS).

[0256] For MS measurement, an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatograph-mass spectrometer (manufacturer: Agilent, MS model number: 6110 / 6120 Quadrupole MS) was used. A waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model number: waters ACQuity Qda Detector / waters SQ Detector) and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model number: THERMO Q Exactive) were used.

[0257] For high performance liquid chromatography (HPLC) analysis, an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD and a Waters HPLC e2695-2489 high performance liquid chromatographs were used.

[0258] For chiral HPLC analysis measurement, an Agilent 1260 DAD high performance liquid chromatograph was used.

[0259] For preparative high performance liquid chromatography, Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

[0260] For chiral preparative separation, a Shimadzu LC-20AP preparative chromatograph was used.

[0261] As the CombiFlash high speed preparative chromatograph, a Combiflash Rf200 (TELEDYNE ISCO) was used.

[0262] As the silica gel plate for thin layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate is used. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15 mm to 0.2 mm, and the specification for the separation and purification of products by thin layer chromatography is 0.4 mm to 0.5 mm.

[0263] For silica gel column chromatography, generally, silica gel of 200 - 300 mesh made by Yantai Huanghai silica gel is used as the carrier.

[0264] Kinase average inhibition rate and IC 50 For the measurement of values, a plate reader NovoStar (BMG Labtech, Germany) was used.

[0265] The known starting materials according to the present disclosure may be synthesized by or according to known methods in this field, or may be purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, and Darui Chemicals. In the examples, unless otherwise specified, all reactions can be carried out in an argon or nitrogen atmosphere.

[0266] An argon or nitrogen atmosphere means that an argon or nitrogen balloon with a volume of about 1 L is connected to the reaction flask.

[0267] A hydrogen atmosphere means that a hydrogen balloon with a volume of about 1 L is connected to the reaction flask.

[0268] For the catalytic hydrogenation reaction, a Parr 3916EKX type hydrogenation apparatus and a Qinglan QL - 500 type hydrogen generator or an HC2 - SS type hydrogenation apparatus were used.

[0269] The hydrogenation reaction generally involved repeating the operation of evacuating and filling with hydrogen three times.

[0270] For the microwave reaction, a CEM Discover-S 908860 type microwave reactor was used.

[0271] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0272] In the examples, unless otherwise specified, the reaction temperature is room temperature of 20°C to 30°C.

[0273] For monitoring the progress of the reaction in the examples, thin-layer chromatography (TLC) was used. The developing solvent used in the reaction, the eluent system for column chromatography for purifying the compound, and the developing solvent system for thin-layer chromatography include A: dichloromethane / methanol system, B: n-hexane / ethyl acetate, and the volume ratio of the solvents may be adjusted according to the polarity of the compound, or may be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

[0274] Example 1 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1

Chemical formula

[0275] Step 2 tert-Butyl 4-amino-2,6-dichloro-5-fluoronicotinate 1c Compound 1b (1 g, 2.62 mmol) was dissolved in ethyl acetate (8 mL), 4 M hydrochloric acid dioxane solution (3 mL) was added, and the reaction was carried out with stirring for 2 h. The pH was adjusted to neutral with 4 M aqueous sodium hydroxide solution under an ice bath, and it was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by eluent system A to obtain the title compound 1c (500 mg, yield: 67.8%). MS m / z (ESI): 281.1[M+1].

[0276] Step 3 tert-Butyl 2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotinate 1d Compound 1c (500 mg, 1.77 mmol) was dissolved in tetrahydrofuran (10 mL), trichloroacetyl isocyanate (670 mg, 3.55 mmol, Shanghai Hanhong) was added, and the reaction was carried out with stirring for 30 minutes. After the reaction solution was concentrated under reduced pressure, the crude title compound 1d (835 mg) was obtained and used in the next reaction without purification of the product. MS m / z (ESI): 467.9 [M+1].

[0277] Step 4 5,7-Dichloro-8-fluoro-pyrido[4,3-d]pyrimidine-2,4-diol 1e The crude compound 1d (835 mg, 1.77 mmol) was dissolved in 7M ammonia methanol solution (10 mL), and the reaction was carried out with stirring for 1 hour. The reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (10 mL) was added to the residue, and after stirring for 0.5 hour, it was filtered. After the filter cake was dried, the crude title compound 1e (400 mg, yield: 89.9%) was obtained and used in the next reaction without purification of the product. MS m / z (ESI): 249.9 [M+1].

[0278] Step 5 2,4,5,7-Tetrachloro-8-fluoro-pyrido[4,3-d]pyrimidine 1f The crude compound 1e (875 mg, 3.5 mmol) was dissolved in phosphorus oxychloride (25 mL), N,N-diisopropylethylamine (2.3 g, 17.5 mmol) was added, and the reaction was carried out with stirring at 110 °C for 1 hour. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the crude title compound 1f (1.14 g) was obtained and used in the next step without purification of the product. MS m / z (ESI): 285.8 [M+1].

[0279] Step 6 (R)-Methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate 1h (R)-Methyl 2-pyrrolidone-5-carboxylate (1 g, 20 g, 139.7 mmol, Shanghai Bide), dimethyl sulfate (22.1 g, 175.2 mmol) were mixed and reacted at 60 °C for 22 hours. The reaction solution was cooled to room temperature and poured into a solution of triethylamine (20 g) and water (100 mL) under an ice bath. After extraction with methyl tert-butyl ether (60 mL × 6) and concentration under reduced pressure, crude product 1h of the title compound (16.3 g, yield: 74.2%) was obtained and used directly in the next reaction without purification. MS m / z (ESI): 158.1[M+1].

[0280] Step 7 (R)-Methyl 5-(2-methoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate 1i Crude product 1h of the compound (16.3 g, 103.7 mmol) and methyl nitroacetate (13.6 g, 114.2 mmol, Shanghai Shaoyuan) were mixed, heated to 60 °C and reacted with stirring for 24 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1i (8.37 g, yield: 33%). MS m / z (ESI): 245.1[M+1].

[0281] Step 8 (1S,2S,5R)-Methyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate 1j Compound 1i (7.5 g, 30.7 mmol) was dissolved in 150 mL of methanol, 10% palladium on carbon catalyst (wet) (1.5 g) was added, replaced with hydrogen gas three times, heated to 50 °C and reacted with stirring for 24 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to obtain crude product 1j of the title compound (5.6 g), which was used directly in the next reaction without purification of the product. MS m / z (ESI): 185.2[M+1].

[0282] Step 9 8-(tert-Butyl) 2-methyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 1k The crude product, compound 1j (5.65 g, 30.4 mmol), was dissolved in 60 mL of dichloromethane. Triethylamine (6.2 g, 61.27 mmol) and di-tert-butyl dicarbonate (6.6 g, 30.24 mmol) were added under an ice bath, and the reaction was carried out with stirring for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1k (3 g, yield: 34.7%). MS m / z (ESI): 285.2 [M+1].

[0283] Step 10 (1S,2S,5R)-2-(Hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl 1l Compound 1k (3 g, 10.55 mmol) was dissolved in 30 mL of tetrahydrofuran. A 32 mL solution of 1 M lithium aluminum hydride in tetrahydrofuran was added dropwise under an ice bath, and the reaction was carried out with stirring for 4 hours after returning to room temperature. 1.05 mL of water, 1.05 mL of 15% sodium hydroxide solution, and 3.15 mL of water were added in sequence under an ice bath, and the reaction was stirred for 15 minutes after returning to room temperature. Anhydrous magnesium sulfate (1 g) was added, and the mixture was stirred for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1l (2.4 g), which was used directly in the next reaction without purification of the product. MS m / z (ESI): 243.2 [M+1].

[0284] Step 11 (1S,2S,5R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl 1m The crude product, compound 1l (2.4 g, 9.9 mmol), was dissolved in 25 mL of dichloromethane. tert-Butyldimethylsilyl chloride (4.48 g, 29.7 mmol) and 4-dimethylaminopyridine (122 mg, 990 μmol) were added, and triethylamine (4 g, 39.5 mmol) was added dropwise. The reaction was carried out with stirring for 16 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phases were washed with saturated sodium chloride solution and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography using eluent system B to obtain the title compound 1m (1.95 g, yield: 55.2%). MS m / z (ESI): 357.1 [M+1].

[0285] Step 12 (1S,2S,5R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl 1n Compound 1f (50 g, 174 mmol) and N,N-diisopropylethylamine (65 g, 503 mmol) were dissolved in 75 mL of dichloromethane. A solution of compound 1m (60 g, 168.3 mmol) in dichloromethane (250 mL) was added dropwise at -78 °C, and the mixture was allowed to warm to room temperature naturally and reacted for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by eluent system B to obtain the title compound 1n (86 g, yield: 84%). MS m / z (ESI): 606.2 [M+1].

[0286] Step 13 (1S,2S,5R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-3-(5,7-dichloro-8-fluoro-2-((1-(hydroxymethyl)cyclopropyl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl 1o Compound 1n (5 g, 8.23 mmol) was dissolved in 1,4-dioxane (80 mL), and 1,1-bis(hydroxymethyl)cyclopropane (1.3 g, 12.7 mmol, Shanghai Shaoyuan), cesium carbonate (5.4 g, 16.6 mmol), and 4A molecular sieve (5 g) were added. The reaction was carried out with stirring at 110 °C for 14 hours. After the reaction solution was cooled to room temperature, it was filtered and concentrated under reduced pressure to obtain the crude title compound 1o (5.5 g). The product was used in the next step without purification. MS m / z (ESI): 672.2[M+1].

[0287] Step 14 (5aS,6S,9R)-2-Chloro-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 1p The crude compound 1o (5.5 g, 8.2 mmol) was dissolved in tetrahydrofuran (80 mL), and tetrabutylammonium fluoride (5.57 g, 24.7 mmol) and N,N-diisopropylethylamine (5.33 g, 41.2 mmol) were added. After stirring for 1 hour, the mixture was heated to 60 °C and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with water (80 mL), and extracted with ethyl acetate (50 mL × 2). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1p (3 g, yield: 69.7%). MS m / z (ESI): 522.2[M+1].

[0288] Step 15 (5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 1q Compound 1p (2g, 3.83 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.1g, 5.8 mmol), tetrakis(triphenylphosphine)palladium (889mg, 769 μmol), and cesium carbonate (3.8g, 11.66 mmol) were dissolved in a mixed solution of 36 mL of 1,4-dioxane and water (V:V = 10:1). Under a nitrogen atmosphere, the reaction was carried out at 100 °C for 14 hours. After the reaction solution was concentrated under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1q (1g, yield: 36.2%). MS m / z (ESI): 720.2[M+1].

[0289] Step 16 (5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 1r Compound 1q (150 mg, 145.8 μmol), N,N - diisopropylethylamine (55.6 mg, 437.6 μmol) were dissolved in dichloromethane (5 mL). Methanesulfonyl chloride (25 mg, 218.8 μmol) was added under an ice bath, and the reaction was carried out with stirring for 1 hour at the same temperature. A saturated ammonium chloride solution was added to the reaction solution to quench it, and the mixture was extracted with dichloromethane (5 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then the filtrate was concentrated under reduced pressure to obtain the crude title compound 1r (130 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 798.2[M + 1].

[0290] Step 17 (5aS,6S,9R)-2-(8 - ethyl - 7 - fluoro - 3 - (methoxymethoxy)naphthalen - 1 - yl)-1 - fluoro - 12 - ((1 - (morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 14 - carboxylic acid tert - butyl 1s The crude compound 1r (130 mg, 162.9 μmol) was dissolved in acetonitrile (3 mL). Morpholine (28.4 mg, 325.8 μmol), anhydrous potassium carbonate (67.6 mg, 488.8 μmol), and sodium iodide (24.4 mg, 162.9 μmol) were added. The mixture was heated to 80 °C and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (10 mL × 2). The organic phases were combined and concentrated under reduced pressure to obtain the crude title compound 1s (128 mg). The product was used directly in the next reaction without purification. MS m / z (ESI): 789.2 [M + 1].

[0291] Step 18 5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 1 The crude product, compound 1s (128 mg, 162.2 μmol), was dissolved in ethyl acetate (3 mL), and 2 mL of a 4 M hydrochloric acid dioxane solution was added under an ice bath. The reaction was carried out at the same temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 1 (35 mg, yield 33.4%). MS m / z (ESI): 645.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (t, 1H), 7.31 - 7.21 (m, 2H), 7.06 (d, 1H), 5.07 (dd, 2H), 4.62 (dd, 1H), 4.45 (tt, 3H), 4.15 (dd, 1H), 3.77 (s, 1H), 3.66 (d, 4H), 3.25 (s, 1H), 2.57 - 2.43 (m, 6H), 2.22 (d, 1H), 1.90 (dt, 4H), 0.93 (t, 2H), 0.84 (t, 2H), 0.73 (s, 2H), 0.52 (s, 2H).

[0292] Example 2 4-((5aS,6S,9R)-12-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 2

Chem.

[0293] Step 2 4-((5aS,6S,9R)-12-((1-(((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 2 The crude compound 2a (100 mg, 188 μmol) was dissolved in ethyl acetate (3 mL), 2 mL of a 4 M hydrochloric acid dioxane solution was added under an ice bath, the reaction was carried out for 4 hours at the same temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 2 (35 mg, yield 33.4%). MS m / z (ESI): 657.2[M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (s, 1H), 7.27 (d, 2H), 7.06 (d, 1H), 5.36 (s, 1H), 5.06 (dd, 1H), 4.61 (s, 1H), 4.49 (d, 2H), 4.40 (s, 1H), 4.15 (d, 1H), 3.99 (s, 1H), 3.75 (s, 1H), 3.65 (s, 1H), 3.22 (d, 2H), 2.98 (s, 1H), 2.83 (s, 1H), 2.66 (d, 2H), 2.48 (s, 1H), 2.22 (s, 1H), 2.05 (s, 1H), 1.89 (d, 4H), 1.72 (s, 1H), 1.62 (s, 1H), 0.92 (s, 2H), 0.84 (d, 1H), 0.71 (s, 2H), 0.57 (d, 2H).

[0294] Example 3 4-((5aS,6S,9R)-12-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 3 [Chemical formula] Step 1 (5aS,6S,9R)-12-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptane-14-carboxylic acid tert-butyl 3a The crude compound 1r (150 mg, 188 μmol) was dissolved in acetonitrile (3 mL), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (51 mg, 376.1 μmol, Shanghai Leyan), anhydrous potassium carbonate (100 mg, 723.5 μmol), and sodium iodide (28 mg, 187 μmol) were added, heated to 80 °C, and reacted with stirring for 2 hours. The reaction solution was cooled to room temperature, diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phases were combined, concentrated under reduced pressure, and the crude title compound 3a (150 mg) was obtained. Without purifying the product, it was directly used in the next reaction. MS m / z (ESI): 801.2 [M+1].

[0295] Step 2 4-((5aS,6S,9R)-12-((1-(((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 3 The crude compound 3a (100 mg, 124.8 μmol) was dissolved in ethyl acetate (3 mL), 2 mL of a 4 M hydrochloric acid dioxane solution was added under an ice bath, the reaction was carried out at the same temperature for 4 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 3 (10 mg, yield: 12.2%). MS m / z (ESI): 657.2 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (d, 1H), 7.29 (d, 1H), 7.28 - 7.23 (m, 1H), 7.11 (s, 1H), 5.12 - 5.00 (m, 2H), 4.61 (d, 1H), 4.47 (dd, 3H), 4.15 (d, 1H), 4.04 (s, 1H), 3.73 (d, 2H), 3.25 (s, 1H), 3.02 (d, 1H), 2.80 (s, 3H), 2.58 (d, 1H), 2.47 (s, 1H), 2.25 - 2.17 (m, 1H), 2.05 (s, 1H), 2.00 - 1.71 (m, 6H), 0.88 (dq, 3H), 0.79 - 0.52 (m, 4H).

[0296] Example 4 4-((5aS,6S,9R)-12-((1-((4-Oxa-7-azaspiro[2.5]octan-7-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza[6,9]methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 4

Chem.

[0297] Step 2 4-((5aS,6S,9R)-12-((1-((4-Oxa-7-azaspiro[2.5]octan-7-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza[6,9]methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 4 The crude compound 4a (100 mg, 122 μmol) was dissolved in ethyl acetate (3 mL), 2 mL of 4 M hydrochloric acid dioxane solution was added under an ice bath, the reaction was carried out for 4 hours at the same temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 4 (15 mg, yield: 18.2%). MS m / z (ESI): 671.2 [M+1]. 1H NMR (500 MHz, CD3OD): δ 7.67 (ddd, 1H), 7.31 - 7.22 (m, 2H), 7.06 (dd, 1H), 5.08 (ddd, 2H), 4.68 - 4.56 (m, 2H), 4.53 - 4.40 (m, 3H), 4.16 (dd, 1H), 3.82 - 3.72 (m, 3H), 3.67 (d, 1H), 3.27 (d, 1H), 2.70 - 2.43 (m, 6H), 2.29 - 2.19 (m, 1H), 2.05 (d, 1H), 2.01 - 1.79 (m, 4H), 0.92 (td, 2H), 0.84 (t, 1H), 0.78 - 0.67 (m, 3H), 0.56 (d, 3H).

[0298] Example 5 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 5

Chem.

[0299] Step 2 2,5,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 5c The crude compound 1e (2 g, 8 mmol) was dissolved in phosphorus oxychloride (25 mL), N,N-diisopropylethylamine (5.16 g, 40 mmol) was added, and the reaction was carried out with stirring at 110 °C for 14 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. After stirring for 2 hours, it was filtered, the filter cake was washed with water and dried to obtain the crude title compound 5c (1.5 g), and the product was used directly in the next step without purification. MS m / z (ESI): 267.8[M+1].

[0300] Step 3 (1S,2S,5R)-2-((S)-1-((2,7-Dichloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl 5e (1S,2S,5R)-2-((S)-1-Hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl 5d (370 mg, 1.44 mmol, prepared by the method disclosed in Intermediate 29 on page 164 of the specification in Patent Application "WO2022173678A1") was dissolved in tetrahydrofuran (10 mL), sodium hydride (201 mg, 5.2 mmol, 60% purity) was added under an ice bath, and after reacting for 30 minutes, compound 5c (353 mg, 1.31 mmol) was added. The reaction was carried out with stirring for 2 hours. After adding water to the reaction solution to quench it and then concentrating it under reduced pressure, the crude title compound 5e (600 mg) was obtained and used directly in the next step without purifying the product. MS m / z (ESI): 488.2 [M+1].

[0301] Step 4 (5S,5aS,6S,9R)-2,12-Dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 5f Compound 5e (78 mg, 159.7 μmol) was dissolved in dichloromethane (2 mL), N,N-Diisopropylethylamine (61.9 mg, 478.9 μmol) and phosphorus oxychloride (122.4 mg, 798.2 μmol) were added under an ice bath, and the reaction was carried out with stirring for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to quench it, and it was extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure to obtain the crude title compound 5f (75 mg), which was used directly in the next reaction without purifying the product. MS m / z (ESI): 470.2 [M+1].

[0302] Step 5 (5S,5aS,6S,9R)-2-chloro-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 5g Compound 5b (123.8 mg, 722.9 μmol) and crude compound 5f (170 mg, 361 μmol) were dissolved in dimethyl sulfoxide (4 mL), potassium fluoride (105 mg, 1.8 mmol) was added, and the mixture was reacted at 100 °C for 14 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5g (200 mg, yield: 91.4%). MS m / z (ESI): 605.2 [M+1].

[0303] Step 6 (5S,5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-12-((1-(morpholinylmethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 5h Compound 5g (218 mg, 360 μmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (195 mg, 540 μmol, prepared by the method disclosed in Intermediate 18 on page 104 of the specification in Patent Application "WO2021 / 041671") was dissolved in 1,4-dioxane (4 mL) and water (0.5 mL), cesium carbonate (352 mg, 1.08 mmol) and tetrakis(triphenylphosphine)palladium (83.26 mg, 72 μmol) were added, and the reaction was carried out at 110 °C for 14 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 5h (200 mg, yield: 69%). MS m / z (ESI): 803.2 [M+1].

[0304] Step 7 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 5 Compound 5h (200 mg, 249 μmol) was dissolved in ethyl acetate (5 mL), a 1,4-dioxane solution of 4 M hydrogen chloride (2 mL) was added under an ice bath, and the reaction was carried out at the same temperature for 0.5 hour. Then it was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 5 (90 mg, yield: 54.8%). MS m / z (ESI): 659.2 [M+1]. 11H NMR (500 MHz, CD3OD): δ 7.67 (dt, 1H), 7.29 (t, 1H), 7.24 (t, 1H), 7.05 (dd, 1H), 5.40 (ddd, 1H), 4.57 (dt, 1H), 4.51 - 4.36 (m, 2H), 4.11 (t, 1H), 3.74 (d, 1H), 3.70 - 3.60 (m, 5H), 3.21 (t, 1H), 2.60 - 2.39 (m, 7H), 2.21 (ddt, 1H), 2.10 (dq, 1H), 1.94 - 1.75 (m, 3H), 1.58 (dd, 3H), 0.99 (d, 1H), 0.81 (t, 2H), 0.74 (d, 2H), 0.59 - 0.48 (m, 2H).

[0305] Example 6 4 - ((5S,5aS,6S,9R)-12 - ((1 - ((4 - (difluoromethylene)piperidin - 1 - yl)methyl)cyclopropyl)methoxy)-1 - fluoro - 5 - methyl - 5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 2 - yl)-5 - ethyl - 6 - fluoronaphthalen - 2 - ol 6

Chemical Structure

[0306] Step 2 (5S,5aS,6S,9R)-12-((1-(((tert-Butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-oic acid tert-butyl 6c Compound 6b (2 g, 3.07 mmol) and 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.66 g, 4.6 mmol) were dissolved in 1,4-dioxane (40 mL) and water (8 mL), cesium carbonate (3 g, 9.2 mmol) and tetrakis(triphenylphosphine)palladium (710 mg, 615 μmol) were added, and the reaction was carried out at 105 °C for 14 hours under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in ethyl acetate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 6c (2.5 g, yield: 95.8%). MS m / z (ESI): 848.2 [M+1].

[0307] Step 3 (5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-((1-(hydroxymethyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-oic acid tert-butyl 6d Compound 6c (500 mg, 589.58 μmol) was dissolved in tetrahydrofuran (6 mL), tetrabutylammonium fluoride (160 mg, 710.5 μmol) was added, and the mixture was reacted with stirring for 1 hour. Then, ethyl acetate (20 mL) was added to the reaction solution for dilution, and the solution was washed successively with water and saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the solution was concentrated under reduced pressure to obtain the crude title compound 6d (435 mg), which was used in the next reaction without purification. MS m / z (ESI): 734.2 [M+1].

[0308] Step 4 (5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-12-((1-((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-oic acid tert-butyl 6e The crude compound 6d (435 mg, 592.8 μmol) was dissolved in dichloromethane (10 mL), and N,N-diisopropylethylamine (229 mg, 1.77 mmol) and methanesulfonyl chloride (95 mg, 829.3 μmol) were added in an ice bath. The reaction was carried out with stirring at the same temperature for 30 minutes. A saturated ammonium chloride solution was added to the reaction solution to quench it, and the mixture was extracted with dichloromethane (10 mL × 2). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. After concentration under reduced pressure, the crude title compound 6e (480 mg) was obtained and used directly in the next reaction without purification. MS m / z (ESI): 812.2 [M+1].

[0309] Step 5 (5S,5aS,6S,9R)-12-((1-((4-(Difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-oic acid tert-butyl 6f The crude compound 6e (235 mg, 289.4 μmol) and 4-(difluoromethylene)piperidine hydrochloride (74 mg, 436.32 μmol, prepared by the method disclosed in the literature "Bioorganic and Medicinal Chemistry, 2004, vol.12, #7, p.1713 - 1730") were dissolved in acetonitrile (5 mL), and anhydrous potassium carbonate (120 mg, 868.27 μmol) and sodium iodide (44 mg, 293.54 μmol) were added. The reaction was carried out with stirring at 80 °C for 1 hour. After the reaction solution was cooled to room temperature, it was filtered. Water was added to the filtrate, and the mixture was extracted with ethyl acetate (10 mL × 2). The combined organic phases were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. After concentration under reduced pressure, the crude title compound 6f (245 mg) was obtained and used directly in the next reaction without purification. MS m / z (ESI): 849.2 [M+1].

[0310] Step 6 4 - ((5S,5aS,6S,9R)-12 - ((1 - ((4-(Difluoromethylidene)piperidin - 1 - yl)methyl)cyclopropyl)methoxy)-1 - fluoro - 5 - methyl - 5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 2 - yl)-5 - ethyl - 6 - fluoronaphthalen - 2 - ol 6 The crude product, compound 6f (250 mg, 294.5 μmol), was dissolved in ethyl acetate (5 mL), and a 1,4 - dioxane solution of 4 M hydrogen chloride (5 mL) was added under an ice bath. After reacting at the same temperature for 0.5 h, it was concentrated under reduced pressure, and the residue was purified by high - performance liquid preparative chromatography (Waters - 2545, column: YMC Triart - Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 6 (140 mg, yield: 67.4%). MS m / z (ESI): 705.3 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (dt, 1H), 7.32 - 7.22 (m, 2H), 7.12 - 6.98 (m, 1H), 5.40 (ddt, 1H), 4.57 (td, 1H), 4.53 - 4.36 (m, 2H), 4.10 (t, 1H), 3.72 (d, 1H), 3.62 (s, 1H), 3.20 (t, 1H), 2.63 - 2.39 (m, 7H), 2.29 - 2.01 (m, 6H), 1.94 - 1.86 (m, 1H), 1.81 (dt, 2H), 1.58 (dd, 3H), 0.89 (dt, 3H), 0.75 (d, 2H), 0.52 (s, 2H).

[0311] Example 7 4 - ((5S,5aS,6S,9R)-12 - ((1 - ((3-(Difluoromethylene)pyrrolidin - 1 - yl)methyl)cyclopropyl)methoxy)-1 - fluoro - 5 - methyl - 5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 2 - yl)-5 - ethyl - 6 - fluoronaphthalen - 2 - ol 7

Chemical formula

[0312] Step 2 3-(Difluoromethylene)pyrrolidine hydrochloride 7d Compound 7c (167 mg, 761.7 μmol) was dissolved in a 4M hydrogen chloride 1,4 - dioxane solution (2 mL), and the reaction was carried out with stirring for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 7d (118 mg), which was used in the next reaction without purification. MS m / z (ESI): 120.2 [M + 1].

[0313] Step 3 4 - ((5S,5aS,6S,9R)-12 - ((1 - ((3-(difluoromethylene)pyrrolidin - 1 - yl)methyl)cyclopropyl)methoxy)-1 - fluoro - 5 - methyl - 5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 2 - yl)-5 - ethyl - 6 - fluoronaphthalen - 2 - ol 7 According to the synthetic route in Example 6, 4-(difluoromethylene)piperidine hydrochloride, which is the starting compound in Step 5, was replaced with compound 7d to obtain the title compound 7 (3 mg, yield: 12%). MS m / z (ESI): 691.3 [M + 1]. 1 H NMR (500 MHz, CD3OD): δ 7.68 - 7.63 (m, 1H), 7.29 - 7.23 (m, 2H), 7.12 - 7.01 (m, 1H), 5.41 - 5.39 (m, 1H), 4.59 - 4.42 (m, 3H), 4.11 - 4.08 (m, 1H), 3.70 - 3.61 (m,3H), 3.17 - 2.70 (m,3H), 2.70 - 2.44 (m, 7H), 2.21 - 1.79 (m,7H), 1.59 - 1.57 (m, 3H), 0.99 - 0.92 (m, 2H), 0.75 - 0.73 (m, 2H).

[0314] Example 8 1 - ((1 - ((((5S,5aS,6S,9R)-2-(8 - ethyl - 7 - fluoronaphthalen - 1 - yl)-1 - fluoro - 5 - methyl - 5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 12 - yl)oxy)methyl)cyclopropyl)methyl)piperidin - 4 - one O - methyloxime 8

Chemical Structure

[0315] Example 9 4-((1-((((5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)-1-(methylimino)-1λ 6 -thiomorpholine 1-oxide 9

Chemical Structure

[0316] Example 10 4-((1-((((5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)-1-imino-1λ 6 -thiomorpholine 1-oxide 10

Chemical formula

[0317] Example 11 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 11 [Chemical formula] Step 1 (E)-3-(Fluoromethylene)pyrrolidine-1-carboxylic acid tert-butyl 11a-1 (Z)-3-(Fluoromethylene)pyrrolidine-1-carboxylic acid tert-butyl 11a-2 2-((Fluoromethyl)sulfonyl)pyridine (4.7 g, 26.8 mmol, Shanghai Shaoyuan) was dissolved in tetrahydrofuran (100 mL). A solution of 1M bis(trimethylsilyl)aminopotassium in tetrahydrofuran (33 mL) was added at -78 °C. After reacting for 30 minutes at the same temperature, 1-tert-butoxycarbonyl-3-pyrrolidone 7a (5 g, 27 mmol) was added. After reacting for 3 hours at the same temperature, the temperature was restored to room temperature and the reaction was continued for 1 hour. A saturated ammonium chloride solution was added to the reaction mixture to quench it, 3N hydrochloric acid (50 mL) was added, and the mixture was stirred for 1 hour. It was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the desiccant was removed by filtration. Then it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 11a-1 (800 mg, yield: 14.7%) and 11a-2 (800 mg, yield: 14.7%). MS m / z (ESI): 146.2 [M-55]. 11a-1 : 1 H NMR (500 MHz, CDCl3): δ 6.70 (s, 0.5H), 6.54 (s, 0.5H), 3.93 (s, 2H), 3.48 (t, 2H), 2.66 (t, 2H), 1.48 (s, 9H). 11a-2 : 1 H NMR (500 MHz, CDCl3): δ 6.61 (s, 0.5H), 6.45 (s, 0.5H), 4.07 (s, 2H), 3.49 (t, 2H), 2.49 (t, 2H), 1.48 (s, 9H).

[0318] Step 2 (E)-3-(Fluoromethylene)pyrrolidine hydrochloride 11b Compound 11a-1 (700 mg, 3.5 mmol) was dissolved in a 4M hydrogen chloride solution in 1,4-dioxane (10 mL) and reacted with stirring for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the crude title compound 11b (480 mg), which was used directly in the next reaction without purification. MS m / z (ESI): 101.2 [M+1]. Step 3 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 11 According to the synthetic route in Example 6, the starting compound 4-(difluoromethylene)piperidine hydrochloride in Step 5 was replaced with compound 11b to obtain the title compound 11 (5 mg, yield: 12.1%). MS m / z (ESI): 673.3 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (dt, 1H), 7.33 - 7.20 (m, 2H), 7.11 (d, 1H), 6.70 (d, 1H), 5.40 (ddd, 1H), 4.58 (dd, 1H), 4.50 - 4.36 (m, 2H), 4.10 (t, 1H), 3.71 (d, 1H), 3.62 (s, 1H), 3.22 - 3.17 (m, 4H), 2.75 (s, 2H), 2.62 - 2.51 (m, 5H), 2.25 - 2.06 (m, 2H), 1.85 - 1.76 (m, 3H), 1.58 (dd, 3H), 1.31 (s, 2H), 0.98 (t, 1H), 0.81 (t, 2H), 0.74 - 0.58 (m, 3H).

[0319] Example 12 2-((1-((((5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)hexahydrocyclopenta[c]pyrrol-5(1H)-one O-methyloxime 12

Chem.

[0320] Example 13 1-((1-((((5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-12-yl)oxy)methyl)cyclopropyl)methyl)azepan-4-one O-methyloxime 13 (cis-trans isomer mixture)

Chem.

[0321] Example 14 4-((5S,5aS,6S,9R)-12-((1-((5-(Difluoromethylene)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 14

Chem.

[0322] Example 15 4-((5S,5aS,6S,9R)-12-((1-((4-(Difluoromethylene)azepan-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 15 [Chemistry] According to the synthetic route in Example 7, the starting material compound 7a in Step 1 was replaced with tert-butyl 4-oxoazacycloheptane-1-carboxylate (Shanghai Bide) to obtain the title compound 15 (5 mg, yield: 19.3%). MS m / z (ESI): 719.3 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.68 - 7.65 (m, 1H), 7.29 - 7.24 (m, 1H), 7.12 - 7.11 (m, 1H), 6.98 - 6.95 (m, 1H), 5.39 - 5.36 (m, 1H), 4.59 - 4.57 (m, 1H), 4.46 - 4.42 (m, 2H), 4.14 - 4.10 (m, 1H), 3.76 - 3.74 (m, 1H), 3.68 - 3.63 (m, 1H), 3.25 - 3.20 (m, 1H), 2.98 - 2.81 (m, 6H), 2.56 - 2.42 (m, 4H), 2.33 - 2.30 (m, 2H), 2.23 - 2.20 (m, 1H), 2.18 - 2.06 (m, 2H), 1.92 - 1.81 (m, 4H), 1.62 - 1.59 (m, 3H), 0.99 - 0.95 (m, 1H), 0.93 - 0.91 (m, 1H), 0.80 - 0.79 (m, 2H), 0.62 - 0.60 (m, 2H).

[0323] Example 16 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 16 (diastereomer mixture) [Chemistry] Example 16-p1, 16-p2 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((S,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 16-p1 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((R,Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 16-p2 [Chemical formula]

[0324] Example 17 4-((5S,5aS,6S,9R)-12-((2,6-dimethylidene tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 17 [Chemical formula] According to the synthetic route in Example 5, the starting compound 5b in Step 5 was replaced with (2,6-dimethylidene tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (prepared by the method disclosed in Example 4 on page 30 of the specification in the patent application "WO2022247757") to obtain the title compound 17 (20 mg, yield: 24.4%). MS m / z (ESI): 653.3 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.72 - 7.56 (m, 1H), 7.37 - 7.18 (m, 2H), 7.12 - 6.91 (m, 1H), 5.43 - 5.27 (m, 1H), 5.11 - 4.95 (m, 2H), 4.62 - 4.49 (m, 1H), 4.44 - 4.21 (m, 2H), 4.13 - 4.01 (m, 1H), 3.85 - 3.54 (m, 4H), 3.50 - 3.37 (m, 4H), 3.23 - 3.08 (m, 2H), 2.87 - 2.72 (m, 2H), 2.70 - 2.39 (m, 3H), 2.27 - 1.97(m, 2H), 1.97 - 1.66 (m, 3H), 1.60 - 1.46(m, 2H), 1.02 - 0.90(m, 1H), 0.84 - 0.64 (m, 2H).

[0325] Example 18 4 - ((5S,5aS,6S,9R)-12 - ((2-(Difluoromethylene)tetrahydro - 1H - pyrrolidin - 7a(5H)-yl)methoxy)-1 - fluoro - 5 - methyl - 5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 2 - yl)-5 - ethyl - 6 - fluoronaphthalen - 2 - ol 18 (diastereomer mixture)

Chemical Structure

[0326] Example 18-p1, 18-p2 4-((5S,5aS,6S,9R)-12-(((S)-2-(Difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 18-p1 4-((5S,5aS,6S,9R)-12-(((R)-2-(Difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 18-p1

Chem.

[0327] Chiral HPLC analysis method for the isomer mixture: The retention times were 10.274 min and 14.616 min respectively (column: CHIRALPAK IG, 150×4.6 mm, 5 μm, mobile phase A: 90% ethanol (containing 0.1% diethylamine) + 10% dichloromethane, mobile phase B: n-hexane, gradient ratio: A:B: 30:70, flow rate: 1.0 mL / min).

[0328] Compound with a single configuration (relatively short retention time): 10.274 min (10 mg, yield: 33%). MS m / z (ESI): 677.3 [M+1].

[0329] HPLC analysis: Retention time 1.45 minutes, purity: 90% (column: ACQUITY UPLC(R)BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10% - 95%). 11H NMR (500 MHz, CD3OD): δ 7.71 - 7.64 (m, 1H), 7.33 - 7.22 (m, 2H), 7.12 - 6.98 (m, 1H), 5.54 - 5.47 (m, 1H), 4.68 (ddd, 1H), 4.56 - 4.49 (m, 1H), 4.44 (d, 1H), 4.24 (t, 1H), 4.03 (s, 1H), 3.93 (s, 1H), 3.69 (d, 1H), 3.36 (s, 2H), 2.92 (d, 2H), 2.67 (d, 1H), 2.59 - 2.43 (m, 2H), 2.32 - 1.87 (m, 9H), 1.60 (d, 3H), 0.89 (dt, 3H).

[0330] Single stereoconfiguration compound (relatively long retention time): 14.616 min (10 mg, yield: 33%). MS m / z (ESI): 677.3 [M+1].

[0331] HPLC analysis: retention time 1.45 minutes, purity: 90% (column: ACQUITY UPLC(R) BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient composition ratio: acetonitrile 10% - 95%). 1 1H NMR (500 MHz, CD3OD): δ 7.68 (dt, 1H), 7.33 - 7.22 (m, 2H), 7.12 - 6.89 (m, 1H), 5.53 - 5.46 (m, 1H), 4.68 (td, 1H), 4.54 (d, 1H), 4.45 (d, 1H), 4.24 (t, 1H), 3.99 (d, 3H), 3.70 (d, 1H), 3.37 (s, 1H), 3.01 - 2.88 (m, 2H), 2.67 (d, 1H), 2.52 (ddt, 2H), 2.32 - 1.87 (m, 9H), 1.61 (dd, 3H), 0.89 (dt, 3H).

[0332] Example 19 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 19 (diastereomer mixture)

Chem.

Chem.

[0333] Example 20 4-((5aS,6S,9R)-12-((2,6-Dimethylidene-tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 20

Chem.

[0334] Example 21 4-((5aS,6S,9R)-12-((2-(Difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 21 (diastereomer mixture)

Chem.

[0335] Example 21-p1, 21-p2 4-((5aS,6S,9R)-12-(((S)-2-(difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 21-p1 4-((5aS,6S,9R)-12-(((R)-2-(difluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-1-fluoro-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 21-p2

Chem.

[0336] Example 22 4-((5S,5aS,6S,9R)-12-((1-((3-(Difluoromethylene)azetidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-ethyl-6-fluoronaphthalen-2-ol 22

Chemical Structure

[0337] Example 23 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 23

Chem.

[0338] Step 2 4-(Fluoromethylene)piperidine hydrochloride 23c Dissolve compound 23b (1 g, 4.64 mmol) in a 4 M solution of hydrogen chloride in 1,4-dioxane (20 mL), react with stirring for 1 hour, concentrate the reaction solution under reduced pressure to obtain the crude title compound 23c (700 mg), and use it directly in the next reaction without purification. MS m / z (ESI): 116.1 [M+1].

[0339] Step 3 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 23 According to the synthetic route in Example 6, the starting material compound 4-(difluoromethylene)piperidine hydrochloride for Step 5 was replaced with the crude product compound 23c to obtain the title compound 23c (15 mg, yield: 18.1%). MS m / z (ESI): 687.2 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 (dt, 1H), 7.32 - 7.21 (m, 2H), 7.05 (dd, 1H), 6.52 (d, 1H), 5.45 - 5.38 (m, 1H), 4.62 - 4.39 (m, 5H), 4.11 (t, 2H), 3.73 (d, 1H), 3.63 (s, 1H), 3.50 - 3.44 (m, 1H), 3.28 - 3.17 (m, 3H), 2.66 - 2.43 (m, 5H), 2.35 (s, 2H), 2.25 - 2.15 (m, 1H), 2.10 (s, 2H), 1.94 - 1.72 (m, 3H), 1.58 (dd, 3H), 0.98 (t, 1H), 0.84 - 0.71 (m, 2H), 0.54 (s, 1H).

[0340] Example 24 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-naphthalen-2-ol 24 (mixture of isomers) 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((Z)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-naphthalen-2-ol 16 (mixture of diastereomers) 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-(((E)-2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-naphthalen-2-ol 19 (mixture of diastereomers) [Chem.] According to the synthetic route in Example 5, replace the starting compound 5b in Step 5 with (2-(fluoromethylene)tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (prepared by the method disclosed in Example 5 on page 33 of the specification in the patent application "WO2022247757") to obtain the crude title compound 24 (240 mg), and purify it by high-performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain compounds 16 and 19 (10 mg, 10 mg, yield: 15%, 15%).

[0341] Diastereomer mixture (relatively short retention time): (10 mg, yield: 15%). MS m / z (ESI): 659.2 [M+1].

[0342] HPLC analysis: retention time 1.40 minutes, purity: 92% (column: ACQUITY UPLC(R)BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10% - 95%). 1 H NMR (500 MHz, CD3OD): δ 7.65 (dt, 1H), 7.30 - 7.18 (m, 2H), 7.03 (dd, 1H), 6.73 (d, 1H), 5.44 - 5.28 (m, 1H), 4.57 (t, 1H), 4.35 (d, 1H), 4.28 (dd, 1H), 4.09 (t, 1H), 3.71 (dd, 2H), 3.60 (s, 1H), 3.40 (d, 1H), 3.22 - 3.11 (m, 2H), 2.85 (d, 1H), 2.70 (q, 1H), 2.62 - 2.41 (m, 2H), 2.21 - 1.77 (m, 9H), 1.56 (dd, 3H), 0.85 (dt, 3H).

[0343] Diastereomer mixture (relatively long retention time): (10 mg, yield: 15%). MS m / z (ESI): 659.2 [M+1].

[0344] HPLC analysis: retention time 1.41 minutes, purity: 96% (column: ACQUITY UPLC(R) BEH, C18, 1.7 μm, 2.1×50 mm, mobile phase: water (10 mM ammonium bicarbonate), acetonitrile, gradient ratio: acetonitrile 10% - 95%). 1 H NMR (500 MHz, CD3OD): δ 7.66 (dt, 1H), 7.31 - 7.20 (m, 2H), 7.04 (dd, 1H), 6.75 (d, 1H), 5.43 (d, 1H), 4.67 - 4.56 (m, 1H), 4.55 - 4.39 (m, 2H), 4.15 (dd, 2H), 3.77 (s, 2H), 3.45 (s, 1H), 3.30 - 3.13 (m, 2H), 3.04 - 2.80 (m, 2H), 2.65 - 2.38 (m, 2H), 2.32 - 1.81 (m, 9H), 1.58 (d, 3H), 0.96 - 0.74 (m, 3H).

[0345] Example 25 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((Z)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 25

Chemical formula

[0346] Example 26 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-amine 26 [Chemical formula] MS m / z (ESI): 672.3 [M+1].

[0347] Example 27 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((Z)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-amine 27

Chem.

[0348] Example 28 (5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-((1-(((Z)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene 28

Chem.

[0349] Example 29 (5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-((1-(((E)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-29

Chem.

[0350] Example 30 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((Z)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-yl methylcarbamate 30

Chem.

[0351] Example 31 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((E)-3-(fluoromethylene)pyrrolidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-yl methylcarbamate 31

Chem.

[0352] Example 32 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-(((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-amine 32

Chem.

[0353] Example 33 (5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoronaphthalen-1-yl)-1-fluoro-12-((1-(((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalene 33

Chem.

[0354] Example 34 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-yl methylcarbamate 34

Chemical formula

[0355] Example 35 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((5-(fluoromethylene)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 35

Chemical formula

[0356] Step 2 (3aR,6aS)5-(Fluoromethylidene)octahydrocyclopenta[c]pyrrole hydrochloride 35c Dissolve compound 35b (760 mg, 3.1 mmol) in acetonitrile (1.5 mL), add a 4 M solution of hydrogen chloride in 1,4-dioxane (6 mL), react with stirring for 1 hour, concentrate the reaction solution under reduced pressure to obtain the crude title compound 35c (560 mg), and use it directly in the next reaction without purification. MS m / z (ESI): 142.3 [M+1].

[0357] Step 3 5-Ethyl-6-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((5-(fluoromethylene)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)naphthalen-2-ol 35 According to the synthetic route in Example 6, the starting compound 4-(difluoromethylene)piperidine hydrochloride in Step 5 was replaced with compound 35c to obtain the title compound 35 (5 mg, yield: 10.3%). MS m / z (ESI): 713.3 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 7.67 - 7.63 (m, 1H), 7.28 - 7.21 (m, 2H), 7.04 (d, 1H), 6.50 (d, 1H), 5.39 - 5.34 (m, 1H), 4.58 - 4.53 (m, 1H), 4.41 (t, 2H), 4.08 (t, 1H), 3.70 (d, 1H), 3.60 (s, 1H), 3.18 (t, 1H), 2.98 (s, 2H), 2.71 - 2.37 (m, 8H), 2.29 - 2.16 (m, 3H), 2.06 - 2.00 (m, 2H), 1.91 - 1.76 (m, 3H), 1.57 (d, 3H), 0.96 (t, 1H), 0.79 (t, 2H), 0.72 (s, 2H), 0.55 (s, 2H).

[0358] Example 36 3-Chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline 36

Chemical Structure

[0359] Step 2 (5S,5aS,6S,9R)-2-Chloro-1-fluoro-5-methyl-12-((1-((methylsulfonyl)oxy)methyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 36b The crude product, compound 36a (83 mg, 154.9 μmol), and N,N - diisopropylethylamine (60 mg, 464.2 μmol) were dissolved in dichloromethane (3 mL). Methanesulfonyl chloride (25 mg, 218.2 μmol) was added under an ice bath, and the mixture was allowed to naturally return to room temperature and reacted for 30 minutes. An aqueous saturated ammonium chloride solution was added to the reaction solution to quench it, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed successively with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and after filtering off the desiccant, the filtrate was concentrated under reduced pressure to obtain the crude title compound 36b (95 mg). The product was used in the next reaction without purification. MS m / z (ESI): 614.2[M + 1].

[0360] Step 3 (5S,5aS,6S,9R)-2 - chloro - 1 - fluoro - 12 - ((1 - ((4 - (fluoromethylene)piperidin - 1 - yl)methyl)cyclopropyl)methoxy)-5 - methyl - 5a,6,7,8,9,10 - hexahydro - 5H - 4 - oxa - 3,10a,11,13,14 - pentaaza - 6,9 - methanonaphtho[1,8 - ab]heptalen - 14 - oic acid tert - butyl 36c The crude product, compound 36b (95 mg, 154.7 μmol), and compound 23c (35.5 mg, 234.5 μmol) were dissolved in acetonitrile (4 mL). Potassium carbonate anhydrous (64 mg, 463 μmol) and sodium iodide (70 mg, 467 μmol) were added, and the mixture was reacted with stirring at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 36c (80 mg, yield: 81.6%). MS m / z (ESI): 633.2 [M + 1].

[0361] Step 4 (5S,5aS,6S,9R)-2-(5-Amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-(4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 36e Compound 36c (20 mg, 31.6 μmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline 36d (15 mg, 46.6 μmol, prepared by the method disclosed in Example 80 on page 257 of the specification in Patent Application "WO2022148422"), tetrakis(triphenylphosphine)palladium (7 mg, 6.1 μmol), and cesium carbonate (31 mg, 95.1 μmol) were mixed in 1,4-dioxane (1 mL) and water (0.2 mL), reacted at 100 °C for 1 hour under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, ethyl acetate was added for dilution, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure to obtain the crude title compound 36e (20 mg), which was used in the next reaction without purification. MS m / z (ESI): 792.2 [M+1].

[0362] Step 5 3-Chloro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline 36 The crude product, compound 36e (15 mg, 18.9 μmol), was dissolved in dichloromethane (1 mL). A 1,4-dioxane solution of 4 M hydrochloric acid (0.5 mL) was added under an ice bath. After reacting at the same temperature for 0.5 h, it was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 36 (4 mg, yield: 30.5%). MS m / z (ESI): 690.3 [M-1]. 1 H NMR (500 MHz, CD3OD): δ 6.90 (s, 1H), 6.58 (d, 1H), 6.42 (s, 1H), 5.37 (dd, 1H), 4.58 - 4.39 (m, 3H), 4.07 (t, 1H), 3.70 (d, 1H), 3.60 (d, 1H), 3.20 - 3.14 (m, 1H), 2.61 - 2.42 (m, 6H), 2.33 (s, 2H), 2.08 (s, 3H), 1.92 - 1.74 (m, 3H), 1.58 (d, 3H), 0.74 (s, 2H), 0.52 (s, 2H).

[0363] Example 37 2-Amino-7-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)benzo[b]thiophene-3-carbonitrile 37

Chemical Structure

[0364] Example 38 2-Fluoro-3-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-methyl-4-(trifluoromethyl)aniline 38

Chemical formula

[0365] Step 2 (5S,5aS,6S,9R)-2-(3-(Bis(4-methoxybenzyl)amino)-2-fluoro-6-iodo-5-methylphenyl)-12-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 38c The crude compound 38b (280 mg, 285.91 μmol) was dissolved in N,N-dimethylformamide (DMF) (4 mL), and silver acetate (120 mg, 718.9 μmol) and iodine (145 mg, 571.3 μmol) were added in sequence. The mixture was reacted at 15 °C for 1 hour. Water was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 38c (180 mg, yield: 57%). MS m / z (ESI): 1105.2 [M+1].

[0366] Step 3 (5S,5aS,6S,9R)-2-(3-(Bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-12-((1-(((tert-butyldimethylsilyl)oxy)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 38d Compound 38c (150 mg, 135.7 μmol) was dissolved in N,N-dimethylformamide (DMF) (1 mL), and cuprous iodide (125 mg, 656.3 μmol) and methyl fluorosulfonyldifluoroacetate (260 mg, 1.4 mmol, Shanghai Bide) were added in sequence. The mixture was reacted at 100 °C for 1 hour. Water was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 38d (80 mg, yield: 57.6%). MS m / z (ESI): 1047.2 [M+1].

[0367] Step 4 (5S,5aS,6S,9R)-2-(3-(Bis(4-methoxybenzyl)amino)-2-fluoro-5-methyl-6-(trifluoromethyl)phenyl)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 38e According to Steps 1 to 3 of the synthetic route in Example 36, the starting compound 6b in Step 1 was replaced with compound 38d to obtain the title compound 38e (40 mg), which is a crude product. MS m / z (ESI): 1030.2 [M+1].

[0368] Step 5 2-Fluoro-3-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-5-methyl-4-(trifluoromethyl)aniline 38 The crude compound 38e (40 mg, 38.8 μmol) was dissolved in trifluoroacetic acid (1 mL), methanesulfonic acid (0.1 mL) was added under an ice bath, and the reaction was carried out with stirring for 1 hour. Then, the reaction solution was concentrated under reduced pressure, the pH was adjusted to about 7 with a small amount of saturated sodium bicarbonate solution, concentrated under reduced pressure, the residue was dissolved in methanol and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 38 (10 mg, yield: 37.3%). MS m / z (ESI): 690.2 [M+1]. 1 1H NMR (500 MHz, CD3OD): δ 6.87 (d, 1H), 6.51 (d, 1H), 5.41 - 5.34 (m, 1H), 4.61 - 4.39 (m, 3H), 4.08 (t, 1H), 3.70 (d, 1H), 3.60 (s, 1H), 3.47 (q, 1H), 3.18 (d, 1H), 2.61 - 2.29 (m, 7H), 2.21 (t, 1H), 2.07 (s, 2H), 1.83 (dd, 3H), 1.59 (dd, 3H), 1.36 (s, 3H), 0.74 (s, 2H), 0.52 (s, 2H).

[0369] Example 39 3-Chloro-5-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline 39 [Chemical Structure] Step 1 (5S,5aS,6S,9R)-2-Chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-yl) tert-butyl formate 39a The crude product, compound 36c (50 mg, 81.4 μmol), 4-(difluoromethylidene)piperidine hydrochloride (54.2 mg, 319 μmol) were dissolved in acetonitrile (5 mL), potassium carbonate anhydrous (56.3 mg, 407 μmol) and sodium iodide (36.6 mg, 244 μmol) were added, and the reaction was carried out with stirring at 80 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 39a (50 mg, yield: 94.3%). MS m / z (ESI): 651.2 [M+1].

[0370] Step 2 (5S,5aS,6S,9R)-2-(5-Amino-3-chloro-2-(trifluoromethyl)phenyl)-12-((1-(4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 39b Compound 39a (50 mg, 76.8 μmol), compound 36d (37 mg, 115 μmol), tetrakis(triphenylphosphine)palladium (17.7 mg, 15.3 μmol), cesium carbonate (75 mg, 230 μmol) were mixed in 1,4-dioxane (3 mL) and water (0.5 mL), replaced with nitrogen gas, and reacted at 100 °C for 16 hours. After the reaction solution was cooled to room temperature, ethyl acetate was added for dilution, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure to obtain the crude title compound 39b (60 mg), and the product was used in the next reaction without purification. MS m / z (ESI): 810.2 [M+1].

[0371] Step 3 3-Chloro-5-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-4-(trifluoromethyl)aniline 39 The crude product, compound 39b (50 mg, 61.7 μmol), was dissolved in dichloromethane (3 mL), and a 1,4-dioxane solution (1 mL) of 4 M hydrogen chloride was added thereto under an ice bath. After allowing the mixture to naturally return to room temperature and reacting for 1 hour, the mixture was concentrated under reduced pressure, and the residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium hydrogen carbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 39 (4 mg, yield: 9%). MS m / z (ESI): 710.2 [M+1] 1 H NMR (500 MHz, CD3OD): δ 6.90 (d, 1H), 6.56 (s, 1H), 6.42 (s, 1H), 5.38 (d, 1H), 4.44 (s, 3H), 4.10 (s, 2H), 3.71 (d, 2H), 3.20 (d, 1H), 2.63 (s, 5H), 2.26 - 2.05 (m, 3H), 1.82 (s, 2H), 1.59 (d, 2H), 1.31 (s, 3H), 0.77 (s, 2H), 0.56 (s, 2H).

[0372] Example 40 3-((5S,5aS,6S,9R)-12-((1-((4-(Difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline 40

Chem.

[0373] Step 2 3-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-2-fluoro-5-methyl-4-(trifluoromethyl)aniline 40 The crude compound 40a (31 mg, 19.7 μmol) was dissolved in trifluoroacetic acid (1 mL), trifluoromethanesulfonic acid (0.1 mL) was added under an ice bath, and the reaction was carried out with stirring for 1 hour. Then, the reaction solution was concentrated under reduced pressure, the pH was adjusted to about 7 with a small amount of saturated sodium bicarbonate solution, concentrated under reduced pressure, the residue was dissolved in methanol and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 40 (5 mg, yield: 24.6%). MS m / z (ESI): 708.2 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 6.87 (d, 1H), 5.38 - 5.36 (m, 1H), 4.61 - 4.39 (m, 3H), 4.08 (t, 1H), 3.70 (d, 1H), 3.60 (s, 1H), 3.47 (q, 1H), 3.18 (d, 1H), 2.61 - 2.29 (m, 7H), 2.21 (t, 1H), 2.07 (s, 2H), 1.83 (dd, 3H), 1.59 (dd, 3H), 1.35(s, 3H), 0.74 (s, 2H), 0.52 (s, 2H).

[0374] Example 41 2-Amino-4-((5S,5aS,6S,9R)-12-((1-((4-(Difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 41

Chemical Structure

[0375] Step 2 (5S,5aS,6S,9R)-2-(2-((tert-Butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-12-(1-((4-(difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 41b The crude product, compound 41a (31 mg, 47.6 μmol), tert-butyl (3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (26.9 mg, 66.6 μmol), tetrakis(triphenylphosphine)palladium (11 mg, 9.5 μmol), and cesium carbonate (46.5 mg, 142.8 μmol) were mixed in N,N-dimethylformamide (1 mL), reacted at 100 °C for 3 h under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 41b (43 mg), which was used in the next reaction without purification. MS m / z (ESI): 907.2 [M+1].

[0376] Step 3 2-Amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 41 The crude product, compound 41b (40 mg, 44.1 μmol), was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was reacted with stirring for 1 h, then concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 41 (2 mg, yield: 6.4%). MS m / z (ESI): 707.2 [M+1]. 11H NMR (500 MHz, CD3OD): δ 7.39 (dd, 1H), 7.04 (t, 1H), 5.41 (dd, 1H), 4.91 (s, 3H), 4.54 (d, 1H), 4.48 (d, 1H), 4.39 (d, 1H), 4.10 (d, 1H), 3.71 (d, 1H), 3.61 (s, 1H), 3.19 (d, 1H), 2.70 - 2.41 (m, 5H), 2.22 (s, 3H), 2.10 (q, 2H), 2.01 - 1.83 (m, 2H), 1.79 (d, 2H), 1.61 (d, 3H), 0.75 (s, 2H), 0.52 (s, 2H).

[0377] Example 42 4-((5S,5aS,6S,9R)-1-Fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine 42 [Chemical Structure] Step 1 (5S,5aS,6S,9R)-2-(6-(Bis(4-methoxybenzyl)amino)-2-methyl-3-(trifluoromethyl)pyridin-4-yl)-1-fluoro-12-(1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-4-carboxylic acid tert-butyl 42b Compound 36c (100 mg, 157.9 μmol), N,N-bis(4-methoxybenzyl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)pyridin-2-amine 42a (111.4 mg, 205.3 μmol, prepared by the method disclosed in Example 60 on page 244 of the specification in Patent Application "WO2022042630"), tetrakis(triphenylphosphine)palladium (36.5 mg, 31.6 μmol), and cesium carbonate (128.7 mg, 394.8 μmol) were mixed in 1,4-dioxane (2 mL) and water (0.4 mL), reacted at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 42b (160 mg, yield: 99.9%). MS m / z (ESI): 1014.1 [M+1].

[0378] Step 2 4-((5S,5aS,6S,9R)-1-Fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine 42 Compound 42b (15 mg, 157.9 μmol) was dissolved in trifluoroacetic acid (2 mL), reacted at 100 °C for 5 hours, concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was separated, concentrated under reduced pressure, and the residue was purified by high performance preparative liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient composition ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 42 (30 mg, yield: 28.2%). MS m / z (ESI): 673.2 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 6.49 (d, 1H), 5.35 (d, 1H), 4.51 (d, 1H), 4.41 (q, 2H), 4.06 (d, 1H), 3.69 (d, 1H), 3.59 (s, 1H), 3.15 (d, 1H), 2.57 - 2.42 (m, 8H), 2.31 (s, 2H), 2.19 (d, 1H), 2.06 (s, 3H), 1.77 (d, 2H), 1.67 - 1.51 (m, 4H), 0.89 (d, 1H), 0.72 (s, 2H), 0.50 (s, 2H).

[0379] Example 43 2-Fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-3-methyl-4-(trifluoromethyl)aniline 43

Chemical formula

[0380] Step 2 1-Bromo-4-fluoro-2-iodo-3-methyl-5-nitrobenzene 43c At 0 °C, concentrated hydrochloric acid (10 mL) was added to compound 43b (1.5 g, 6.0 mmol), and after stirring for 10 minutes at the same temperature, 2 M aqueous sodium nitrite solution (9 mL) was added. After reacting with stirring at 0 °C for 1 hour, 2 M aqueous potassium iodide solution (12 mL) was added. After stirring for 10 minutes at the same temperature, the mixture was heated to 80 °C and reacted for 1 hour. After the reaction solution was cooled to room temperature, saturated sodium thiosulfate was added to quench it, and it was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure to obtain the crude title compound 43c (2.1 g), which was used directly in the next reaction without purification of the product.

[0381] Step 3 5-Bromo-2-fluoro-4-iodo-3-methylaniline 43d Compound 43c (2.1 g, 5.83 mmol) was mixed with ethanol (20 mL) and water (40 mL), iron powder (1.3 g, 23.3 mmol) and ammonium chloride (6 g, 35 mmol) were added, and the reaction was carried out with stirring at 90 °C for 3 hours. After the reaction solution was cooled to room temperature, it was filtered, and the filtrate was extracted with dichlorohexane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 43d (1.5 g, yield: 77.9%). MS m / z (ESI): 327.9 [M-1].

[0382] Step 4 (5-Bromo-2-fluoro-4-iodo-3-methylphenyl)carbamic acid tert-butyl 43e Compound 43d (0.8 g, 2.42 mmol) was dissolved in 1,4-dioxane (5 mL), di-tert-butyl dicarbonate (BOC anhydride) (3.7 g, 16.9 mmol) was added, and the reaction was carried out with stirring at 100 °C for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 43e (1 g, yield: 95.9%). MS m / z (ESI): 427.9 [M-1].

[0383] Step 5 (5-Bromo-2-fluoro-3-methyl-4-(trifluoromethyl)phenyl)carbamic acid tert-butyl 43f Compound 43e (1.2 g, 2.79 mmol), cuprous iodide (1.32 g, 6.97 mmol), hexamethylphosphoric triamide (1.5 g, 8.37 mmol, Shanghai Shaoyuan), methyl fluorosulfonyldifluoroacetate (1.6 g, 8.37 mmol, Shanghai Shaoyuan) were dissolved in N,N-dimethylformamide (DMF) (10 mL), replaced with nitrogen gas, and the reaction was carried out with stirring at 90 °C for 2 hours. After the reaction solution was cooled to room temperature, it was filtered, ethyl acetate was added to the filtrate for dilution, washed with water, the organic phase was separated, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 43f (500 mg, yield: 48.1%). MS m / z (ESI): 370.0 [M-1].

[0384] Step 6 (5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid 43g Compound 43f (391 mg, 1.05 mmol), bis(pinacolato)diboron (400.2 mg, 1.57 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (76.9 mg, 105.1 μmol), potassium acetate (309.3 mg, 3.15 mmol) were mixed in dimethyl sulfoxide (5 mL), replaced with nitrogen gas three times, heated to 100 °C and reacted for 16 hours. After the reaction solution was cooled to room temperature, it was filtered. Water was added to the filtrate for dilution, and the mixture was extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 43g (100 mg, yield: 40.1%). MS m / z (ESI): 237.9 [M+1].

[0385] Step 7 (5S,5aS,6S,9R)-2-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-14-carboxylic acid tert-butyl 43h Compound 36c (70 mg, 110.5 μmol), compound 43g (26.2 mg, 110.5 μmol), tetrakis(triphenylphosphine)palladium (25.5 mg, 25.2 μmol), cesium carbonate (108 mg, 331.6 μmol) were mixed in 1,4-dioxane (1 mL) and water (0.2 mL), replaced with nitrogen gas, and reacted at 100 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 43h (40 mg, yield: 45.8%). MS m / z (ESI): 790.2 [M+1].

[0386] Step 8 2-Fluoro-5-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-3-methyl-4-(trifluoromethyl)aniline 43 Compound 43h (97.7 mg, 123.7 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the reaction was carried out with stirring for 2 hours, followed by concentration under reduced pressure. The residue was purified by high-performance liquid preparative chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30×150 mm, 5 μm, mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30% - 45%, flow rate: 30 mL / min) to obtain the title compound 43 (5 mg, yield: 5.8%). MS m / z (ESI): 690.2 [M+1]. 1 H NMR (500 MHz, CD3OD): δ 6.87 (d, 1H), 6.52 (d, 1H), 5.38 (d, 1H), 4.57 (d, 2H), 4.53 - 4.31 (m, 2H), 4.09 (d, 1H), 3.71 (s, 1H), 3.61 (s, 1H), 3.47 (s, 1H), 3.17 (d, 2H), 2.55 (s, 5H), 2.36 (t, 4H), 2.10 (s, 3H), 1.90 - 1.76 (m, 3H), 1.60 (d, 3H), 1.33 (d, 2H), 0.75 (d, 2H), 0.53 (d, 2H).

[0387] Example 44 5-((5S,5aS,6S,9R)-12-((1-((4-(Difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-2-fluoro-3-methyl-4-(trifluoromethyl)aniline 44

Chem.

[0388] Example 45 4-((5S,5aS,6S,9R)-12-((1-((4-(Difluoromethylidene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]heptalen-2-yl)-6-methyl-5-(trifluoromethyl)pyridin-2-amine 45

Chem.

[0389] Biological evaluation Test Example 1: Biological evaluation of the AGS cell ERK phosphorylation inhibition experiment (HTRF method) I. Purpose of the test This experiment detected the inhibitory effect of the compound on cell ERK phosphorylation, and evaluated the inhibitory effect of the compound according to the present disclosure on the KRAS target based on the magnitude of IC 50 19

[0390] II. Experimental method AGS cells were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, AGS cells were seeded into a 96-well plate at a density of 40,000 cells / well with 190 μL of cell suspension in each well, and placed in a cell incubator at 37 °C and 5% CO2 for overnight culture. The next day, 10 μL of the compound to be measured, which was prepared with complete medium and serially diluted, was added to each well. The final concentrations of the compound were nine concentration points with a 5-fold serial dilution starting from 10 μM, and a blank control containing 0.5% DMSO was set up. The well plate was placed in a cell incubator at 37 °C and 5% CO2 and incubated for 1 hour. After incubation, the 96-well cell culture plate was taken out, the medium was aspirated off, and 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well for one wash. The PBS was aspirated off, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well. The well plate was placed on a shaker and lysed at room temperature for 40 minutes with shaking. After lysis, pipetting was performed to mix uniformly, and 16 μL of the lysate was transferred from each well to two HTRF 96-well detection plates (Cisbio, 66PL96100). Then, 4 μL of pre-mixed phosphorylated ERK1 / 2 antibody solution (Cisbio, 64AERPEG) or 4 μL of pre-mixed total ERK1 / 2 antibody solution (Cisbio, 64NRKPEG) was added to each well of the two plates respectively. The microplate was sealed with a plate sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight in the dark at room temperature. On the third day, the fluorescence values emitted at wavelengths of 665 nm and 620 nm, which were excited at a wavelength of 337 nm, were read using a multifunctional microplate reader (PerkinElmer, EnVision).

[0391] III. Data Analysis The fluorescence signal ratios at 665 nm and 620 nm of phosphorylated ERK1 / 2 and total ERK1 / 2 at each concentration of the compound were calculated respectively. From the phosphorylated ERK1 / 2 ratio corrected by the compound concentration and total ERK1 / 2 ratio using the software Graphpad Prism, the IC 50 value of the inhibitory activity of the compound was calculated. For the results, please refer to Table 1 below.

[0392]

Table 3

[0393] Conclusion: The compound according to the present disclosure has a relatively good inhibitory effect on AGS cell ERK phosphorylation.

[0394] Test Example 2: Biological evaluation of the 3D growth inhibition experiment of GP2d and AGS cells I. Purpose of the test By testing the 3D growth inhibitory effect of the compound according to the present disclosure on GP2d and AGS cells, the inhibitory effect of the compound according to the present disclosure on the KRAS target was evaluated.

[0395] II. Experimental method GP2d cells were cultured in a complete medium, i.e., DMEM / high glucose medium (Hyclone, SH30243.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded in a 96-well low-attachment plate (Corning, CLS7007-24EA) at a density of 1000 cells / well with 90 μL of cell suspension in each well. After centrifugation at 2000 rpm for 5 minutes at room temperature, they were placed in a cell incubator at 37°C and 5% CO2 and cultured overnight.

[0396] AGS cells were cultured in a complete medium, i.e., RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, AGS cells were seeded in a 96-well low-attachment plate (Corning, CLS7007-24EA) at a density of 1000 cells / well with 90 μL of cell suspension in each well. After centrifugation at 2000 rpm for 5 minutes at room temperature, they were placed in a cell incubator at 37°C and 5% CO2 and cultured overnight.

[0397] On the next day, 10 μL of the compound to be measured, which was prepared with complete medium and serially diluted, was added to each well. The final concentrations of the compound for GP2d cells were nine concentration points serially diluted 5-fold from 1 μM, and the final concentrations of the compound for AGS cells were nine concentration points serially diluted 5-fold from 10 μM. In each case, a blank control containing 0.5% DMSO was set up. The well plate was placed in a cell incubator at 37 °C and 5% CO2 and incubated for 5 days. On the 7th day, the 96-well cell culture plate was taken out, and 50 μL of CellTiter-Glo (R) 3D Cell Viability Assay reagent (Promega, G9682) was added to each well. After shaking at room temperature in the dark for 25 minutes, pipetting was performed to mix uniformly, 100 μL was taken out from each well and transferred to a white opaque 96-well plate (PerkinElmer, 6005290), and the luminescence signal value was read using a multifunctional microplate reader (PerkinElmer, EnVision2105).

[0398] III. Data analysis The IC 50 value of the inhibitory activity of the compound was calculated using the software Graphpad Prism. For the results, please refer to Table 2 below.

[0399]

Table 4

[0400] Conclusion: The compound according to the present disclosure has a relatively good inhibitory effect on the 3D growth of AGS and GP2d cells.

[0401] Test Example 3: Biological evaluation of the 3D growth inhibition experiment of AsPC-1 cells On the first day of the experiment, after digesting AsPC-1 cells with good growth and reaching a confluence of 70% - 80%, they were resuspended in RPMI1640 (Hyclone, SH30809.01) medium containing 10% FBS, and the cell density was adjusted as desired. 90 μL of the cell suspension was added to each well of a U-bottom low-attachment 96-well plate (Corning, CLS7007-24EA), and the cell density was 1500 cells / well. After centrifuging the cell plate at 2500 rmp for 5 minutes, it was placed in an incubator at 37°C and 5% CO2 and cultured overnight. The next day, the test compound at 20 mM dissolved in DMSO was diluted to an initial concentration of 2 mM with DMSO and then serially diluted 5-fold to a total of 9 concentration points, with the control wells being DMSO. Then, the serially diluted compound was further diluted 20-fold with the medium. 10 μL of the test compound diluted with the medium was added to each well of the cell plate, and the final concentration of the compound was 9 concentration points serially diluted 5-fold from the initial concentration of 10 μM. Cell wells containing 0.5% DMSO were used as solvent control wells, and wells containing only the medium and 0.5% DMSO were used as blank control wells. Parallel wells were set up for each concentration of the compound and the control wells, and the final concentration of DMSO in each well was 0.5%. After centrifuging the cell plate at 2500 rmp for 3 minutes, it was placed in an incubator at 37°C and 5% CO2 and cultured for 5 days. On the 7th day, the 96-well cell culture plate was taken out, 50 μL of the luminescent cell viability detection reagent CellTiter-Glo(R) 3D Cell Viability Assay (Promega, G9683) was added to each well, shaken at room temperature in the dark for 25 minutes, then pipetted up and down with a pipette to mix uniformly, and then from each well to a white opaque OptiPlate TM - 100 μL was transferred to a 96-well plate (PerkinElmer, 6005290), and the luminescence signal value was read using a multifunctional microplate reader (PerkinElmer, EnVision2105).

[0402] The inhibition rate was calculated as follows: Inhibition rate = (luminescence value 溶媒対照ウェル - luminescence value 被験化合物 ) / (luminescence value 溶媒対照ウェル - luminescence value ブランク対照ウェル) Calculated by the formula of ×100%. Using the software GraphPad Prism, curves were drawn based on the concentrations of the compounds and the corresponding inhibition rates, and the IC 50 value of the compound was calculated.

[0403]

Table 5

[0404] Conclusion: The compounds according to the present disclosure have a relatively good inhibitory effect on the 3D growth of AsPC-1 cells.

[0405] Test Example 4, Pharmacokinetic Evaluation 1. Summary Using balb / c nude mice as test animals, the plasma drug concentrations of the compounds of the examples at different time points after intragastric administration (i.g.) were measured by LC / MS / MS method. The pharmacokinetic behavior of the compounds according to the present disclosure in the body of balb / c nude mice was studied, and their pharmacokinetic characteristics were evaluated.

[0406] 2. Test Plan 2.1. Test Drug Compounds 37 and 39. 2.2. Test Animals Eighteen female balb / c nude mice, equally divided into 2 groups, provided by Vital River Laboratory Animal Technology Co., Ltd., with the production license number SCXK(Zhe)2019-0001. 2.3. Preparation of Drugs Weighed a certain amount of the test compounds respectively, added 5% DMF + 45% PG + 50% (10% HS15-pH7.4 buffer) + 400mpk of SNAC, and prepared them into a colorless and transparent solution of 4mg / mL. 2.4. Administration The dosage was 40.0mg / kg, and the administration volume was 10mL / kg.

[0407] 3. Operations Blood samples (0.1 mL) were collected from the orbital sinus at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours before and after administration, placed in EDTA-K2 anticoagulant test tubes, centrifuged at 10,000 rpm for 1 minute (4 °C), plasma was separated within 1 hour, and stored at -20 °C for measurement. The process from blood collection to centrifugation was operated under ice bath conditions. The content of the compound to be measured in the plasma of balb / c nude mice after administration of various concentrations of the drug was measured as follows. 25 μL of the plasma sample of balb / c nude mice at each time point after administration and 200 μL of acetonitrile containing an internal standard (for compound 37, the internal standard is verapamil 100 ng / mL; for compound 39, the internal standard is diclofenac 100 ng / mL) were taken, mixed by vortex for 5 minutes, and then centrifuged at 3700 rpm for 20 minutes. The supernatant was mixed with water (1:1). 0.5 - 2 μL of the supernatant was taken for LC / MS / MS analysis.

[0408] 4. Results of Pharmacokinetic Parameters [Table 6]

[0409] Conclusion: The compound according to the present disclosure has relatively good pharmacokinetic advantages in the body of balb / c nude mice.

Claims

1. A compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 among them, ring C is a heterocyclyl group, R ｘ１ is a hydrogen atom or R ｘ and R ｘ is =N−O−R ６１ =CR ６２ R ６３ and =N−R ６４ selected from G ０ is selected from O, S, S(O), S(O) ２ , CR Ｇ０ａ R Ｇ０ｂ and NR Ｇ０ｃ and is selected from G １ is selected from CR Ｇ１ａ R Ｇ１ｂ , CR Ｇ１ａ R Ｇ１ｂ CR Ｇ１ｃ R Ｇ１ｄ , C=O and C(O)CR Ｇ１ａ R Ｇ１ｂ and is selected from G ２ is NR ｄ and T is a chemical bond or is selected from CR ａ R ｂ , NR Ｔ and O, Q is N or CR ２ａ and ring A is an aryl group or a heteroaryl group, L is a single bond, O, or NR ｅ selected from R ａ 、R ｂ 、R Ｇ０ａ 、R Ｇ０ｂ 、R Ｇ１ａ 、R Ｇ１ｂ 、R Ｇ１ｃ and R Ｇ１ｄ are the same or different and each independently is selected from a hydrogen atom, a halogen, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclyl group, or R Ｇ１ａ 、R Ｇ１ｂ forms a cycloalkyl group together with the carbon atoms to which they are attached, or R Ｇ１ｃ 、R Ｇ１ｄ forms a cycloalkyl group together with the carbon atoms to which they are attached, Each R １ is the same or different and each independently is halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH ２ ) ｕ -NR ｆ R ｇ , a hydroxy group or a hydroxyalkyl group, and is selected from R ２ａ and R ４ａ are the same or different and each independently is selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH ２ ) ｖ -NR ｈ R ｉ , a hydroxy group, a hydroxyalkyl group and a cycloalkyl group, Each R ３ is the same or different and each independently is halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH ２ ) ｗ -NR ｊ R ｋ , -(CH ２ ) ｗ１ -(O) ｘ１ -C(O)NR ｊ１ R ｋ１ , -(CH ２ ) ｗ２ -(O) ｘ２ -C(O)OR ｊ２ , a nitro group, a hydroxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, and is selected from Each R ６ is the same or different and each independently is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, -(CH ２ ) ｙ -NR ｍ R ｎ , -(CH ２ ) ｙ１ -(O) ｚ１ -C(O)NR ｍ１ R ｎ１ , -(CH ２ ) ｙ２ -(O) ｚ２ -C(O)OR ｍ２ , =N-O-R ６１ , =CR ６２ R ６３ , =N-R ６４ , and is selected from a nitro group, hydroxy group, hydroxyalkyl group, oxo group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group. R ６１ 、 R ６２ 、 R ６３ and R ６４ are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group and a cycloalkyl group, R ５ａ and R ５ｂ are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxy group and a hydroxyalkyl group, or R ５ａ and R ５ｂ form a cycloalkyl group or a heterocyclyl group together with the carbon atoms to which they are attached, and the cycloalkyl group or heterocyclyl group is each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cyano group, amino group, hydroxy group and hydroxyalkyl group, R Ｇ０ｃ 、R Ｔ 、R ｄ 、R ｅ 、R ｆ 、R ｇ 、R ｈ 、R ｉ 、R ｊ 、R ｋ 、R ｊ１ 、R ｋ１ 、R ｊ２ 、R ｍ 、R ｎ 、R ｍ１ 、R ｎ１ and R ｍ２ are the same or different and each independently is selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. u, v, w, w1, w2, y, y1 and y2 are the same or different and each independently selected from 0, 1, 2 and 3, x1, x2, z1 and z2 are the same or different and each independently selected from 0 or 1, r is 0, 1, 2 or 3, p is 0, 1, 2, 3, 4 or 5, q is 0, 1, 2, 3, 4 or 5, and t1 is 0, 1, 2, 3, 4 or 5, the compound or a pharmaceutically acceptable salt thereof.

2. G １ is CR Ｇ１ａ H, and R Ｇ１ａ is as defined in claim 1, and preferably, G １ is CR Ｇ１ａ H, and R Ｇ１ａ is methyl, The compound or a pharmaceutically acceptable salt thereof according to Claim 1.

3. G ０ is O, The compound or a pharmaceutically acceptable salt thereof according to Claim 1 or 2.

4. 【Fig. 2】 R ６１ 、R ６２ 、R ６３ and R ６４ are as defined in claim 1, The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 3.

5. A compound represented by the general formula (II’) or a pharmaceutically acceptable salt thereof, wherein 【Chemical Formula 3】 among them, R ６ａ 、R ６ｂ 、R ６ｃ 、R ６ｄ 、R ６ｅ 、R ６ｆ 、R ６ｇ and R ６ｈ are the same or different and each independently is a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, -(CH ２ ｙ -NR ｍ R ｎ 、-(CH ２ ｙ１ -(O) ｚ１ -C(O)NR ｍ１ R ｎ１ 、-(CH ２ ｙ２ -(O) ｚ２ -C(O)OR ｍ２ 、nitro group, hydroxy group, hydroxyalkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, or​​​ R ６ａ and R ６ｅ are connected carbon atoms, R ６ａ and R ６ｇ are connected carbon atoms, R ６ｃ and R ６ｅ are connected carbon atoms, or R ６ｃ and R ６ｇ form a bridge together with the connected carbon atoms, and the bridge has 1, 2, 3 or 4 CH ２ and any one of the CH ２ can be optionally substituted with O, S, NH, and the bridge can be optionally substituted with one or more identical or different substituents selected from halogen, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cyano group, amino group, hydroxy group and hydroxyalkyl group, or R ６ａ and R ６ｂ are connected carbon atoms, R ６ｃ and R ６ｄ are connected carbon atoms, R ６ｅ and R ６ｆ are connected carbon atoms, or R ６ｇ and R ６ｈ form a cycloalkyl group or a heterocyclyl group together with the connected carbon atoms, and the cycloalkyl group or the heterocyclyl group is optionally substituted with one or more identical or different substituents selected from halogen, alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, cyano group, amino group, hydroxy group and hydroxyalkyl group. Rings A, G ２ , Q, L, R Ｇ１ａ , R １ , R ３ , R ４ａ , R ｍ , R ｎ , R ｍ１ , R ｎ１ , R ｍ２ , y, y1, y2, z1, z2, p and q are as defined in claim 1, and preferably, R Ｇ１ａ is C １－６ an alkyl group the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 3.

6. Q is N, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 5.

7. A compound represented by the general formula (IV’) or (VV’) or a pharmaceutically acceptable salt thereof, wherein 【Chemical Formula 4】 among them, R ｘ is =N-O-R ６１ =CR ６２ R ６３ and =N-R ６４ selected from R ６１ 、R ６２ 、R ６３ and R ６４ are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, and a cycloalkyl group, t is 0, 1, 2, 3 or 4, R ３ａ and R ３ｂ are the same or different and each independently selected from a hydrogen atom, halogen, alkyl group, alkenyl group, alkynyl group, alkoxy group, haloalkyl group, haloalkoxy group, cyano group, amino group, hydroxy group, hydroxyalkyl group, cycloalkyl group and heterocyclyl group, ring B is a heterocyclyl group, R ｘ１ , t1, ring C, G ２ , Q, L, R Ｇ１ａ , R １ , R ４ａ , R ６ and p are as defined in claim 1, preferably, R Ｇ１ａ is C １－６ an alkyl group the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 3.

8. Ring A is selected from a naphthyl group, a phenyl group, a pyridyl group, a benzothienyl group, a benzothiazolyl group and a benzopyrazolyl group, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 6.

9. R ４ａ is a hydrogen atom or a halogen, The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 8.

10. G ２ is NH, The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 9.

11. L is O, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 10.

12. p is 0, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 11.

13. Each R ３ is the same or different and each is independently selected from halogen, C １－６ alkyl group, C ２－６ alkynyl group, C １－６ haloalkyl group, hydroxy group, -O-C(O)NH C １－６ alkyl group, amino group, cyano group, C １－６ hydroxyalkyl group and a 3- to 8-membered cycloalkyl group, preferably each R ３ is the same or different and each is independently selected from halogen, C １－６ alkyl group, C １－６ haloalkyl group, hydroxy group, -O-C(O)NH C １－６ alkyl group, amino group and cyano group, The compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 6, 8 to 12.

14. 【Fig. 5-1】 【Chemical Formula 5-2】 【Chemical Formula 5-3】 【Chemical Formula 5-4】 【Chemical Formula 5-5】 【Chemical Formula 5-6】 being the compound, the compound or a pharmaceutically acceptable salt thereof according to any one of Claims 1 to 13.

15. A compound represented by the general formula (IN’A) or a salt thereof, wherein 【Chemical Formula 6】 among them, R is an amino protecting group, preferably Boc, R ｙ is a hydroxy protecting group, preferably MOM, a is 0, 1, 2, 3 or 4, G ０ 、G １ 、T, ring A, ring C, Q, L, R １ 、R ３ 、R ４ａ 、R ５ａ 、R ５ｂ 、R ６ 、R ｘ１ 、p, t1 and r are as defined in claim 1, the compound or a salt thereof.

16. 【Fig. 7-1】 【Chemical Formula 7-2】 【Chemical Formula 7-3】 【Chemical Formula 7-4】 【Chemical Formula 7-5】 A compound or a salt thereof, which is the compound.

17. A method for preparing a compound represented by the general formula (IN') or a pharmaceutically acceptable salt thereof, [Chemical Formula 8] A method comprising subjecting a compound of general formula (IN’A) or a salt thereof to a deprotection reaction to obtain a compound of general formula (IN’) or a pharmaceutically acceptable salt thereof, and optionally, when the R ３ group contains a protecting group, further comprising the step of removing the protecting group in the R ３ group before, simultaneously with, or after the deprotection reaction. wherein, R is an amino protecting group, preferably Boc, R ｙ is a hydroxy protecting group, preferably MOM, a is 0, 1, 2, 3 or 4, G ２ is NH, G ０ 、 G １ 、 T, ring A, ring C, Q, L, R １ 、 R ３ 、 R ４ａ 、 R ５ａ 、 R ５ｂ 、 R ６ 、 R ｘ１ 、 p, t1 and r are as defined in claim 1, Method.

18. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. Pharmaceutical composition.

19. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation of a medicament for inhibiting KRAS G12D.

20. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing a KRAS G12D-mediated disease or condition.

21. Use of the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating and / or preventing a tumor, wherein the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma, more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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