Bridged ring compounds, processes for their preparation and their use in medicine

Abstract

The present disclosure relates to bridged cyclic compounds, methods for their preparation and their use in medicine. In particular, the present disclosure relates to a bridged cyclic compound of general formula (I), methods for their preparation, pharmaceutical compositions containing such compounds and their use as therapeutic agents, in particular their use in the preparation of a medicament for inhibiting KRAS G12D and / or KRAS G12V. Wherein the groups in general formula (I) are as defined in the specification.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to a bridged-ring compound, its preparation method, and its pharmaceutical application. In particular, this disclosure relates to a bridged-ring compound of general formula (I), its preparation method, and pharmaceutical compositions containing such compounds, as well as its use in the preparation of medicaments for inhibiting KRAS G12D and / or KRAS G12V. Background Technology

[0002] RAS (Rapid Acid Spectroscopy) genes are among the most frequently mutated oncogenes in tumors, with approximately 30% of human malignancies associated with RAS gene mutations. The RAS family includes KRAS, NRAS, and HRAS, with KRAS mutations being the most common, accounting for about 85%. KRAS mutations are frequently found in solid tumors, exhibiting high frequency in the three leading causes of cancer death in humans—lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). In KRAS gene mutations, 97% involve mutations at amino acid residues 12 or 13, with G12D and G12V being key mutations. Data analysis of populations in Europe and America shows that G12D mutations account for 36%, 12%, and 4% of patients with pancreatic cancer, colorectal cancer, and non-small cell lung cancer, respectively.

[0003] Once activated, KRAS regulates various functions of cell proliferation, survival, migration, and metabolism through numerous downstream signaling pathways, including RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. Mutations in the KRAS gene result in a persistently activated protein, leading to continued activation of downstream signaling pathways and promoting tumorigenesis.

[0004] Because the KRAS protein lacks traditional small-molecule binding sites and has an extremely high affinity for guanosine monophosphate (GMP), making it very difficult to inhibit, it has long been considered an untreatable drug target. However, given the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS remains a highly anticipated target in drug development. Currently, apart from KRAS G12C inhibitors, there are still no effective KRAS inhibitors against other mutations, leaving most patients with KRAS mutations without a cure. Developing inhibitors for G12D and / or G12V, as mutants widely and highly expressed in various tumors, has significant clinical implications.

[0005] Currently published related patent applications include WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1 and WO2021000885A1, etc. Summary of the Invention

[0006] The purpose of this disclosure is to provide a compound of general formula (I) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in:

[0009] G 1 Selected from O, NR a and CR b R c ;

[0010] G 2 For NR d ;

[0011] Ring A is aryl or heteroaryl;

[0012] Ring B is selected from cycloalkyl, heterocyclic, aryl, and heteroaryl groups;

[0013] L is selected from single bond, O, and NR. e ;

[0014] R 1 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, and -(CH2). u -NR f R g hydroxyl and hydroxyalkyl;

[0015] R 2 and R 4 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, and -(CH2). v -NR h R i hydroxyl, hydroxyalkyl, and cycloalkyl;

[0016] R 3 and R 6 They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, and -(CH2). w -NR j R k Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0017] R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, alkyl groups, haloalkyl groups, cyano groups, hydroxyl groups, and hydroxyalkyl groups;

[0018] R band R c They may be the same or different, and each is independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, and -(CH2). x -NR m R n Nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl;

[0019] R a R d R e R f R g R h R i R j R k R m and R n They may be the same or different, and each is independently selected from hydrogen atoms, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0020] u, v, w, and x may be the same or different, and each is independently selected from 0, 1, 2, and 3;

[0021] r is 0, 1, or 2;

[0022] p is 0, 1, 2, 3, 4 or 5;

[0023] q is 0, 1, 2, 3, 4, or 5; and

[0024] t can be 0, 1, 2, 3, 4 or 5.

[0025] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 1 For O or CR b R c R b and R c As defined in general formula (I); preferably, G 1 For O or CH2; more preferably, G 1 It is O.

[0026] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a naphthalene ring; and / or ring B is... R 6 It can be replaced at any position in ring B.

[0027] Another aspect of this disclosure relates to a compound of general formula (II) or a pharmaceutically acceptable salt thereof:

[0028]

[0029] in

[0030] G 1 G 2 L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (I).

[0031] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein R d It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R d It is a hydrogen atom.

[0032] Another aspect of this disclosure relates to a compound of general formula (III) or a pharmaceutically acceptable salt thereof:

[0033]

[0034] in,

[0035] y is 0, 1, 2, 3 or 4;

[0036] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 p, r and t are as defined in general formula (I).

[0037] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for The ring C is a 6-membered aryl or 5-6-membered heteroaryl, z is 0, 1 or 2, R 3 As defined in general formula (III); preferably, for R 3 As defined in general formula (III).

[0038] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein for R 3a and R 3b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) w -NR j R k and C 1-6 Hydroxyalkyl, R j and R k They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, where w is 0 or 1; preferably, for R 3a and R 3b They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl groups and C 1-6 Hydroxyalkyl; more preferably, for R 3a R is a hydrogen atom or a halogen. 3b Selected from halogens, C 1-6 Alkyl and C 2-6 alkynyl group; most preferably, for R 3a It is a hydrogen atom or F, R 3b Selected from F, ethyl and ethynyl groups.

[0039] In some embodiments of this disclosure, the compound represented by general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G 1 For O or CR b R c R b and R c As defined in general formula (I); preferably, G 1 For O or CH2; more preferably, G 1 It is O.

[0040] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein G 2 It is NH.

[0041] In some embodiments of this disclosure, the compound represented by general formula (I) or (III) or its pharmaceutically usable salt, wherein ring A is a bicyclic aryl or bicyclic heteroaryl; preferably, ring A is an 8-10 membered bicyclic aryl or 8-10 membered bicyclic heteroaryl; more preferably, naphthyl.

[0042] In some embodiments of this disclosure, the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3-8 membered heterocyclic group; preferably, ring B is R 6 It can be replaced at any position in ring B.

[0043] In some embodiments of this disclosure, the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof, wherein for R 6 As defined in general formula (I); preferably, for R 6 It is halogen; more preferably, for R 6 It is a halogen; R 6 F is a further preferred option.

[0044] In some embodiments of this disclosure, the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof, wherein for Preferred

[0045] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein L is O.

[0046] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R e It is a hydrogen atom or a carbon atom. 1-6 Alkyl; preferably, R e It is a hydrogen atom.

[0047] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, amino, -(CH2) u -NR f R g hydroxyl and C 1-6 Hydroxyalkyl, R f and R g They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, u is 0 or 1; preferably, R 1 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms.1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 1 It is a hydrogen atom.

[0048] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) v -NR h R i hydroxyl and C 1-6 Hydroxyalkyl, R h and R i They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, v is 0 or 1; preferably, R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 2 It is a hydrogen atom.

[0049] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) w -NR j R k hydroxyl and C 1-6 Hydroxyalkyl, R j and R k They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, w is 0 or 1; preferably, R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl and C 1-6 Hydroxyalkyl; more preferably, R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C2-6 Alkyne and hydroxyl groups; most preferably, R 3 They may be the same or different, and each is independently selected from halogen, ethyl, ethynyl and hydroxyl.

[0050] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) v -NR h R i hydroxyl and C 1-6 Hydroxyalkyl, R h and R i They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, v is 0 or 1; preferably, R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 4 It is a halogen; most preferably, R 4 It is F.

[0051] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 5 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl and C 1-6 Hydroxyalkyl; preferably, R 5 Whether the atoms are the same or different, and each is independently selected from hydrogen atoms, C atoms 1-6 Alkyl, hydroxyl and C 1-6 Hydroxyalkyl; more preferably, R 5 It is a hydrogen atom.

[0052] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) w -NR j R k hydroxyl and C1-6 Hydroxyalkyl, R j and R k They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, w is 0 or 1; preferably, R 6 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl and C 1-6 Halogenated alkyl; more preferably, R 6 It is a halogen; most preferably, R 6 It is F.

[0053] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1, preferably 1.

[0054] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1, preferably 1.

[0055] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein p is 0.

[0056] In some embodiments of this disclosure, the compound represented by general formula (I) or (II) or a pharmaceutically acceptable salt thereof, wherein q is 1, 2 or 3; preferably, q is 1 or 2; more preferably, q is 2.

[0057] In some embodiments of this disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein y is 0 or 1, preferably 1.

[0058] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or its pharmaceutically usable salt is used, wherein t is 1 or 2, preferably 1.

[0059] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or its pharmaceutically acceptable salt is used, wherein t is 0 or 1.

[0060] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.

[0061] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein v is 0 or 1.

[0062] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or its pharmaceutically acceptable salt thereof, wherein w is 0 or 1.

[0063] In some embodiments of this disclosure, the compound represented by general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein x is 0 or 1.

[0064] In some embodiments of this disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein G 1 For O or CH2; G 2 NH; L is selected from single bonds, O, and NR. e ;R e It is a hydrogen atom or a carbon atom. 1-6 Alkyl group; ring A is an 8-10 membered bicyclic aryl or 8-10 membered bicyclic heteroaryl; ring B is a 3-8 membered heterocyclic group; p is 0 or 1; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, cyano, amino, -(CH2) u -NR f R g hydroxyl and C 1-6 Hydroxyalkyl, R f and R g They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, u is 0 or 1; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) v -NR h R i hydroxyl and C 1-6 Hydroxyalkyl, R h and R i They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, v is 0 or 1; q is 1 or 2; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) w -NR j R k hydroxyl and C1-6 Hydroxyalkyl, R j and R k They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, w is 0 or 1; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) v -NR h R i hydroxyl and C 1-6 Hydroxyalkyl, R h and R i They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, v is 0 or 1; r is 0 or 1; R 5 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl and C 1-6 Hydroxyalkyl; t is 0 or 1; R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy, cyano, amino, -(CH2) w -NR j R k hydroxyl and C 1-6 Hydroxyalkyl, R j and R k They may be the same or different, and each is independently a hydrogen atom or a carbon atom. 1-6 Alkyl group, where w is 0 or 1.

[0065] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 1 For O or CH2; G 2 NH; L is O; p is 1; R 1 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl; R 2 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; q is 1 or 2; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Halogenated alkyl, hydroxyl and C 1-6Hydroxyalkyl; R 4 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Haloalkyl; r is 0 or 1; R 5 Selected from hydrogen atoms, C 1-6 Alkyl, hydroxyl and C 1-6 Hydroxyalkyl; t is 1; and R 6 Selected from hydrogen atoms, halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

[0066] In some embodiments of this disclosure, the compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, wherein G 1 For O or CH2; G 2 NH; L is O; p is 0; R 2 For hydrogen atoms; q is 1, 2, or 3; R 3 They may be the same or different, and each is independently selected from hydrogen atoms, halogens, and carbon atoms. 1-6 Alkyl, C 2-6 alkynyl and hydroxyl groups; R 4 It is a halogen; r is 1; R 5 It is a hydrogen atom; t is 1; and R 6 It is a halogen.

[0067] Table A lists typical compounds disclosed herein, including but not limited to:

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

[0078] Another aspect of this disclosure relates to compounds of general formula (IA) or salts thereof.

[0079]

[0080] in,

[0081] R is an amino protecting group; preferably Boc;

[0082] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (I).

[0083] Another aspect of this disclosure relates to compounds of general formula (IIA) or salts thereof.

[0084]

[0085] in,

[0086] R is an amino protecting group; preferably Boc;

[0087] G 1 L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (II).

[0088] Another aspect of this disclosure relates to compounds of general formula (IIIA) or salts thereof.

[0089]

[0090] in,

[0091] R is an amino protecting group; preferably Boc;

[0092] R 0 It is a hydroxyl protecting group; preferably MOM;

[0093] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 y, p, r and t are as defined in general formula (III).

[0094] Typical intermediate compounds disclosed herein include, but are not limited to:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0101]

[0102] A compound of general formula (IA) or a salt thereof undergoes a deprotection reaction to yield a compound of general formula (I) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the removal of R is also included before or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0103] Where R is an amino protecting group; preferably Boc;

[0104] G 2 For NH;

[0105] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (I).

[0106] Another aspect of this disclosure relates to a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0107]

[0108] A compound of general formula (IA) or a salt thereof undergoes a deprotection reaction to yield a compound of general formula (I) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the removal of R is also included before, during, or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0109] Where R is an amino protecting group; preferably Boc;

[0110] G 2 For NH;

[0111] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (I).

[0112] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0113]

[0114] A compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction to yield a compound of general formula (II) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the removal of R is also included before or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0115] Where R is an amino protecting group; preferably Boc;

[0116] G 2 For NH;

[0117] G 1 L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (II).

[0118] Another aspect of this disclosure relates to a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0119]

[0120] A compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction to yield a compound of general formula (II) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the removal of R is also included before, during, or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0121] Where R is an amino protecting group; preferably Boc;

[0122] G 2 For NH;

[0123] G 1 L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (II).

[0124] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0125]

[0126] A compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction to yield a compound of general formula (III) or a pharmaceutically usable salt thereof; optionally, when R 6 When the group contains a protecting group, the removal of R is also included before or after the deprotection reaction. 6 The steps of using protecting groups on groups;

[0127] Where R is an amino protecting group; preferably Boc;

[0128] R 0 It is a hydroxyl protecting group; preferably MOM;

[0129] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 y, p, r and t are as defined in general formula (III).

[0130] Another aspect of this disclosure relates to a method for preparing a compound of general formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0131]

[0132] A compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction to yield a compound of general formula (III) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the removal of R is also included before, during, or after the deprotection reaction. 3 and / or R6 The steps of using protecting groups on groups;

[0133] Where R is an amino protecting group; preferably Boc;

[0134] R 0 It is a hydroxyl protecting group; preferably MOM;

[0135] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 y, p, r and t are as defined in general formula (III).

[0136] Another aspect of this disclosure relates to a pharmaceutical composition comprising a compound of formula (I), (II), (III) of this disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0137] This disclosure further relates to the use of compounds of general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for inhibiting KRAS G12D and / or KRAS G12V; wherein KRAS G12D and / or KRAS G12V is preferably KRAS G12D. This disclosure further relates to the use of compounds of general formulas (I), (II), (III) or Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising thereof, in the preparation of medicaments for treating and / or preventing diseases or conditions, wherein the disease or condition is cancer; wherein the disease or condition is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, and other cancers. Tubal cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, 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; further preferably selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0138] This disclosure further relates to a method of inhibiting KRAS G12D and / or KRAS G12V, comprising administering to a patient a therapeutically effective amount of a compound of general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof; wherein KRAS G12D and / or KRAS G12V is preferably KRAS G12D.

[0139] This disclosure further relates to a method of treating and / or preventing a disease or condition, comprising administering to a desired patient a therapeutically effective amount of a compound of general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the disease or condition is cancer; wherein the disease or condition 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, etc. Gallbladder cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, 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; further preferably selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0140] This disclosure further relates to a compound of general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicine.

[0141] This disclosure further relates to a compound of general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising thereof, which is used as a medicament for inhibiting KRAS G12D and / or KRAS G12V; wherein KRAS G12D and / or KRAS G12V is preferably KRAS G12D.

[0142] This disclosure further relates to a compound of general formula (I), (II), (III) or Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the thereof, used as a medicine for treating and / or preventing a disease or condition, wherein the disease or condition is cancer; the disease or condition is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, and bile duct cancer. Cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, 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; further preferably selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0143] The diseases or conditions described in this disclosure are those that are treated and / or prevented by inhibiting KRAS G12D and / or KRAS G12V; wherein KRAS G12D and / or KRAS G12V are preferably KRAS G12D.

[0144] Preferably, the brain cancer described in this 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's 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 known as bronchogenic carcinoma) is selected from non-small cell lung cancer (… NSCLC), small cell lung cancer (SCLC) and squamous cell carcinoma; renal cell carcinoma is selected from renal cell carcinoma, clear cell and renal eosinophilic tumor; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML); skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; multiple myeloma is preferred; colorectal cancer is preferred to be colon cancer or rectal cancer.

[0145] The active compounds can be formulated into forms suitable for administration via any appropriate route, using one or more pharmaceutically acceptable carriers through conventional methods. Therefore, the active compounds of this disclosure can be formulated into various dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of this disclosure can also be formulated into dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

[0146] As a general guideline, the active compound is preferably expressed in a unit dose manner, or in a manner that allows the patient to self-administer a single dose. The unit dose of the disclosed compound or composition may be expressed as a tablet, capsule, sachet, bottled liquid, powder, granule, lozenge, suppository, regenerated powder, or liquid formulation. Suitable unit doses may range from 0.1 to 1000 mg.

[0147] In addition to the active compound, the pharmaceutical compositions disclosed herein may contain one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, or excipients. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0148] Tablets contain an active ingredient and non-toxic, pharmaceutically acceptable excipients suitable for tablet preparation, used for mixing. These excipients may be inert excipients, granulating agents, disintegrants, binders, and lubricants. These tablets may be uncoated or coated using known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing sustained release over a longer period.

[0149] Oral formulations can also be provided using soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent or in which the active ingredient is mixed with a water-soluble carrier or an oil solvent.

[0150] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions, used for mixing. These excipients are suspending agents, dispersing agents, or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweeteners.

[0151] Oil suspensions are prepared by suspending the active ingredient in vegetable or mineral oil. Oil suspensions may contain thickeners. Sweeteners and flavoring agents mentioned above may be added to provide palatable formulations. These compositions may be preserved by adding antioxidants.

[0152] The pharmaceutical compositions disclosed herein may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, a mineral oil, or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsion may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such formulations may also contain modifiers, preservatives, colorants, and antioxidants.

[0153] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable solvents or media that can be used include water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase, which can be injected into the patient's bloodstream via local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds disclosed herein. To maintain such a constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS™ 5400 intravenous infusion pump.

[0154] The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous or oil suspensions for intramuscular and subcutaneous administration. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents as described above, according to known techniques. The sterile injectable formulations may also be sterile injectable solutions or suspensions prepared in parenteral-acceptable, non-toxic diluents or solvents. Furthermore, sterile fixative oils may be conveniently used as solvents or suspension media. For this purpose, any blended fixative oil may be used. Additionally, fatty acids may also be used to prepare injectable formulations.

[0155] The disclosed compounds can be administered in suppository form for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable, non-irritating excipient that is solid at normal temperatures but liquid in the rectum, and thus dissolves in the rectum to release the drug.

[0156] The compounds disclosed herein can be administered by adding water to prepare water-soluble dispersible powders and granules. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersant or wetting agent, a suspending agent, or one or more preservatives.

[0157] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to: the activity of the specific compound used, the severity of the disease, the patient's age, the patient's weight, the patient's health status, the patient's behavior, the patient's diet, the timing of administration, the route of administration, the rate of excretion, and the combination of drugs; in addition, the optimal treatment mode, such as the treatment regimen, the daily dosage of the compound, or the type of pharmaceutically acceptable salt, can be validated based on conventional treatment protocols.

[0158] Terminology Explanation

[0159] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0160] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched 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., C12). 1-12 Alkyl groups, more preferably alkyl groups having 1 to 6 carbon atoms (i.e., C1646-C ... 1-6Alkyl groups). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-Dimethylpentyl, 2,2-Dimethylpentyl, 3,3-Dimethylpentyl, 2-Ethylpentyl, 3-Ethylpentyl, n-Octyl, 2,3-Dimethylhexyl, 2,4-Dimethylhexyl, 2,5-Dimethylhexyl, 2,2-Dimethylhexyl, 3,3-Dimethylhexyl, 4,4-Dimethylhexyl, 2-Ethylhexyl, 3-Ethylhexyl, 4-Ethylhexyl, 2-Methyl-2-Ethylpentyl, 2-Methyl-3-Ethylpentyl, n-Nonyl, 2-Methyl-2-Ethylhexyl, 2-Methyl-3-Ethylhexyl, 2,2-Diethylpentyl, n-Decyl, 3,3-Diethylhexyl, 2,2-Diethylhexyl, and their various branched isomers, etc. More preferably, lower alkyl groups containing 1 to 6 carbon atoms are used. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups can be substituted or unsubstituted. When substituted, they can be substituted at any usable connection point. The substituents are preferably selected from one or more of the following: D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0161] The term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group, which is a residue derived from a parent alkane by removing two hydrogen atoms from the same carbon atom or two different carbon atoms. It is a straight-chain or branched group containing 1 to 20 carbon atoms, preferably having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C64). 1-12 Alkylenes, more preferably alkylenes having 1 to 6 carbon atoms (i.e., C16-164 ...1-6 Alkylenes. Non-limiting examples of alkylenes include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), etc. Alkylenes can be substituted or unsubstituted, and when substituted, they can be substituted at any usable linking point, wherein the substituent is preferably selected from one or more of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclic alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, and oxo.

[0162] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in a molecule, wherein the definition of alkyl 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., C2, C3, C4, C5, C6, C7, C8, C9, C9, C10, C11, and C12) carbon atoms. 2-12 Alkenyl), more preferably alkenyl groups having 2 to 6 carbon atoms (i.e., C14-C ... 2-6 Alkenyl). Non-limiting examples include vinyl, propenyl, isopropenyl, butenyl, etc. Alkenyl groups can be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0163] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in a molecule, as defined 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., C64). 2-12 Alkyne group), more preferably alkynyl group having 2 to 6 carbon atoms (i.e., C12-C6 ... 2-6 (Alynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. The alkynyl group can be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0164] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein 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), more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms (i.e., 3 to 8-membered cycloalkyl), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6-membered cycloalkyl). Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclohepttrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0165] The term "spirocycloalkyl" refers to a polycyclic group consisting of 5 to 20 quintiles, sharing a single carbon atom (called a spiro atom) between the rings, and may contain one or more double bonds. Preferably, it is 6 to 14 quintiles, more preferably 7 to 10 quintiles (e.g., 7, 8, 9, or 10 quintiles). Spirocycloalkyl groups are classified as monospirocycloalkyl or polyspirocycloalkyl (e.g., bispirocycloalkyl) based on the number of shared spiro atoms between the rings, with monospirocycloalkyl and bispirocycloalkyl being preferred. More preferably, it is a 3 / 4 quintile, 3 / 5 quintile, 3 / 6 quintile, 4 / 4 quintile, 4 / 5 quintile, 4 / 6 quintile, 5 / 3 quintile, 5 / 4 quintile, 5 / 5 quintile, 5 / 6 quintile, 5 / 7 quintile, 6 / 3 quintile, 6 / 4 quintile, 6 / 5 quintile, 6 / 6 quintile, 6 / 7 quintile, 7 / 5 quintile, or 7 / 6 quintile monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

[0166]

[0167] The term "fused cycloalkyl" refers to a 5- to 20-membered polycyclic aromatic hydrocarbon group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of constituent rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 3- / 4-membered, 3- / 5-membered, 3- / 6-membered, 4- / 4-membered, 4- / 5-membered, 4- / 6-membered, 5- / 3-membered, 5- / 4-membered, 5- / 5-membered, 5- / 6-membered, 5- / 7-membered, 6- / 3-membered, 6- / 4-membered, 6- / 5-membered, 6- / 6-membered, 6- / 7-membered, 7- / 5-membered, or 7- / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of fused cycloalkyl groups include:

[0168]

[0169] The term "bridged cycloalkyl" refers to a 5- to 20-membered polycyclic carbon group in which any two rings share two non-directly bonded carbon atoms, and may contain one or more double bonds. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered). Depending on the number of rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0170]

[0171] The cycloalkyl ring comprises a cycloalkyl group (including monocyclic, spirocyclic, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocyclic alkyl ring as described above, wherein the ring attached to the parent structure is a cycloalkyl group. Non-limiting examples include... etc.; preferably

[0172] The cycloalkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0173] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably selected from D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclic oxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0174] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic 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., 3 to 20 membered heterocyclic groups), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxides or sulfones), but does not include the -OO-, -OS-, or -SS- ring moiety, 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 heterocyclic groups), wherein 1 to 4 (e.g., 1, 2, 3, and 4) are heteroatoms; more preferably, it contains 3 to 8 ring atoms (e.g., 3, 4, 5, 6, 7, and 8) (i.e., 3 to 8-membered heterocyclic groups) or 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14), wherein 1 to 3 are heteroatoms (e.g., 1, 2, and 3); even more preferably, it contains 3 to 8 ring atoms, wherein 1 to 3 (e.g., 1, 2, and 3) are heteroatoms; most preferably, it contains 5 or 6 ring atoms (i.e., 5-membered or 6-membered heterocyclic groups), wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl. Polycyclic heterocyclic groups include spiroheterocyclic, fused heterocyclic, and bridged heterocyclic groups.

[0175] The term "spiroheterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which one or more ring atoms share a single atom (called a spiro atom), wherein the sulfur may optionally be oxidized (i.e., forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered spiroheterocyclic groups), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered spiroheterocyclic groups). Spiroheterocyclic groups are classified into monospiroheterocyclic groups or polyspiroheterocyclic groups (e.g., bispiroheterocyclic groups) according to the number of shared spiro atoms between the rings, with monospiroheterocyclic groups and bispiroheterocyclic groups being more preferred. More preferably, they are 3 / 4, 3 / 5, 3 / 6, 4 / 4, 4 / 5, 4 / 6, 5 / 3, 5 / 4, 5 / 5, 5 / 6, 5 / 7, 6 / 3, 6 / 4, 6 / 5, 6 / 6, 6 / 7, 7 / 5, or 7 / 6 monospirocyclic heterocyclic groups. Non-limiting examples of spirocyclic groups include:

[0176]

[0177] The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is a 6- to 14-membered group (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered group) (i.e., a 6- to 14-membered fused heterocyclic group), more preferably a 7- to 10-membered group (e.g., 7, 8, 9, or 10-membered group) (i.e., a 7- to 10-membered fused heterocyclic group). Based on the number of constituent rings, fused heterocyclic groups can be classified into bicyclic or multicyclic (e.g., tricyclic, tetracyclic) fused heterocyclic 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 heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0178]

[0179] The term "bridged heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which any two rings share two non-directly bonded atoms. It may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the sulfur may optionally be oxidized (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered (e.g., 6, 7, 8, 9, 10, 11, 12, 13, and 14-membered) (i.e., 6- to 14-membered bridged heterocyclic groups), more preferably 7- to 10-membered (e.g., 7, 8, 9, or 10-membered) (i.e., 7- to 10-membered bridged heterocyclic groups). Depending on the number of constituent rings, it can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0180]

[0181] The heterocyclic ring comprises a heterocyclic group (including monocyclic, spirocyclic, fused heterocyclic, and bridged heterocyclic rings) fused to an aryl, heteroaryl, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples include:

[0182] wait.

[0183] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0184] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic) group having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring comprises an aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0185]

[0186] The aryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0187] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably 5 to 10-membered (e.g., 5, 6, 7, 8, 9, or 10-membered) (i.e., 5 to 10-membered heteroaryl), more preferably 8 to 10-membered (e.g., 8, 9, or 10-membered), and more preferably 5 or 6-membered (i.e., 5 or 6-membered heteroaryl), such as furanyl, thiophene, pyridinyl, pyrroleyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring comprises a heteroaryl ring fused to an aryl, heterocyclic, or cycloalkyl ring as described above, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0188]

[0189] The heteroaryl group can be substituted or unsubstituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic oxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl.

[0190] The aforementioned cycloalkyl, heterocyclic, aryl, and heteroaryl residues include residues derived from removing one hydrogen atom from a parent ring atom, or residues derived from removing two hydrogen atoms from the same ring atom or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "aryl", and "heteroaryl".

[0191] The term "amino protecting group" is used to protect the amino group by a group that is easily removed, so that the amino group remains unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, allyl, p-toluenesulfonyl (Ts), and p-methoxybenzyl, etc. These groups may optionally be replaced by 1-3 substituents selected from halogens, alkoxy groups, or nitro groups; the amino protecting group is preferably Boc.

[0192] The term "hydroxyl protecting group" refers to a hydroxyl derivative that is typically used to block or protect a hydroxyl group from reacting on other functional groups of a compound. As an example, preferably, the hydroxyl protecting group can be triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, or p-nitrobenzoyl; the hydroxyl protecting group is preferably MOM.

[0193] The term “cycloalkyloxy” refers to cycloalkyl-O-, where the cycloalkyl group is as defined above.

[0194] The term “heterocyclic oxy group” refers to the heterocyclic group -O-, where the heterocyclic group is as defined above.

[0195] The term "aryloxy group" refers to aryl-O-, where the aryl group is as defined above.

[0196] The term “heteroaryloxy” refers to heteroaryl-O-, where the heteroaryl group is as defined above.

[0197] The term "alkylthio" refers to alkyl-S-, where the alkyl group is as defined above.

[0198] The term "halogenated alkyl" refers to an alkyl group that has been substituted with one or more halogens, wherein the alkyl group is as defined above.

[0199] The term "haloalkoxy" refers to an alkoxy group that is substituted by one or more halogens, wherein the alkoxy group is as defined above.

[0200] The term “deuterated alkyl” refers to an alkyl group that is replaced by one or more deuterium atoms, wherein the alkyl group is as defined above.

[0201] The term "hydroxyalkyl" refers to an alkyl group that is replaced by one or more hydroxyl groups, wherein the alkyl group is as defined above.

[0202] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0203] The term "hydroxyl group" refers to -OH.

[0204] The term "thiol" refers to -SH.

[0205] The term "amino" refers to -NH2.

[0206] The term "cyano" refers to -CN.

[0207] The term "nitro" refers to -NO2.

[0208] The term "oxo" or "oxo" refers to "=O".

[0209] The term "carbonyl" refers to C=O.

[0210] The term "carboxyl group" refers to -C(O)OH.

[0211] The term "carboxylic acid ester group" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, where alkyl and cycloalkyl are as defined above.

[0212] MOM refers to methyl oxymethyl.

[0213] Boc refers to tert-butyloxycarbonyl.

[0214] TIPS stands for triisopropylsilyl-based.

[0215] The compounds disclosed herein can exist in specific stereoisomer forms. The term "stereoisomer" refers to isomers with the same structure but different spatial arrangements of atoms. These include cis and trans (or Z and E) isomers, (-)- and (+)- isomers, (R)- and (S)- enantiomers, diastereomers, (D)- and (L)- isomers, tautomers, blocked isomers, conformational isomers, and mixtures thereof (such as racemic mixtures and mixtures of diastereomers). Substituents in the compounds disclosed herein may contain additional asymmetric atoms. All such stereoisomers and mixtures thereof are included within the scope of this disclosure. 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. This disclosure discloses an isomer of a compound, which can be prepared by asymmetric synthesis or with chiral auxiliaries, or, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), by forming a salt of the diastereomer with a suitable optically active acid or base, followed by diastereomer resolution using conventional methods known in the art to obtain the pure isomer. Furthermore, the separation of enantiomers and diastereomers is typically performed by chromatography.

[0216] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z-type and E-type are included.

[0217] The compounds and intermediates disclosed herein may also exist in different tautomer forms, and all such forms are included within the scope of this disclosure. The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that can interconvert via low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine, lactam-lactamimide isomerization.

[0218] All tautomers are within the scope of this disclosure. The nomenclature of compounds does not exclude any tautomers.

[0219] The compounds disclosed herein include all suitable isotopic derivatives thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that may be introduced into the compounds of this disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, […]. 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 Grade I, with deuterium as the preferred grade.

[0220] Compared to undeuterated drugs, deuterated drugs offer advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged biological half-life. All isotopic variations of the compounds disclosed herein, regardless of radioactivity, are included within the scope of this disclosure. Each available hydrogen atom bonded to a carbon atom can be independently replaced by a deuterium atom, wherein the deuterium substitution can be partial or complete; partial deuterium substitution refers to the replacement of at least one hydrogen atom with at least one deuterium atom.

[0221] "Optional" or "optional" means that the event or situation subsequently described may, but does not have to, occur; the description includes the possibility or possibility that the event or situation may or may not occur. For example, "optionally halogenated or cyano-substituted C..." 1-6 "Alkyl" means that halogens or cyano groups may or may not be present. This description includes cases where alkyl groups are substituted by halogens or cyano groups and cases where alkyl groups are not substituted by halogens or cyano groups.

[0222] "Substituted" refers to one or more hydrogen atoms in a group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, which are independently substituted by the corresponding number of substituents. Those skilled in the art can determine possible or impossible substitutions without much effort (through experimentation or theory). For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0223] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0224] "Pharmacologically acceptable salt" refers to the salt of the compounds disclosed herein, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and possess the expected biological activity. The salt can be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include both inorganic and organic acids.

[0225] For the purposes of pharmaceuticals or pharmacologically active agents, the term "therapeutic effective amount" refers to the amount of a drug or agent sufficient to achieve or at least partially achieve the intended effect. The determination of the therapeutic effective amount varies from person to person, depending on the recipient's age and general condition, as well as the specific active substance. The appropriate therapeutic effective amount in a given case can be determined by a person skilled in the art based on routine testing.

[0226] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions, and / or dosage forms are suitable for contact with patient tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, within reasonable medical judgment, have a reasonable benefit / risk ratio, and are effective for their intended use.

[0227] As used herein, the singular forms of “a,” “an,” and “the” include plural references, and vice versa, unless the context clearly indicates otherwise.

[0228] When the term "about" is applied to parameters such as pH, concentration, and temperature, it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0229] The method for synthesizing the compounds disclosed herein

[0230] In order to achieve the purpose of this disclosure, the following technical solution is adopted:

[0231] Option 1

[0232] This disclosure provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0233]

[0234] A compound of general formula (IA) or a salt thereof undergoes a deprotection reaction under acidic conditions to yield a compound of general formula (I) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the removal of R under acidic or basic conditions is also included before or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0235] Where R is an amino protecting group; preferably Boc;

[0236] G 2 For NH;

[0237] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (I).

[0238] Option 2

[0239] This disclosure provides a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0240]

[0241] A compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to yield a compound of general formula (II) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the removal of R under acidic or basic conditions is also included before or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0242] Where R is an amino protecting group; preferably Boc;

[0243] G 2 For NH;

[0244] G 1 L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (II).

[0245] Option 3

[0246] This disclosure provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0247]

[0248] A compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to yield a compound of general formula (III) or a pharmaceutically usable salt thereof; optionally, when R 6 When the group contains a protecting group, the removal of R under acidic or basic conditions is also included before or after the deprotection reaction. 6 The steps of using protecting groups on groups;

[0249] Where R is an amino protecting group; preferably Boc;

[0250] R 0 It is a hydroxyl protecting group; preferably MOM;

[0251] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 y, p, r and t are as defined in general formula (III).

[0252] Option 4

[0253] This disclosure provides a method for preparing a compound of general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0254]

[0255] A compound of general formula (IA) or a salt thereof undergoes a deprotection reaction under acidic conditions to yield a compound of general formula (I) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the deprotection reaction may include the removal of R under acidic or basic conditions before, during, or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0256] Where R is an amino protecting group; preferably Boc;

[0257] G 2 For NH;

[0258] G 1 Ring A, Ring B, L, R1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (I).

[0259] Option 5

[0260] This disclosure provides a method for preparing a compound of general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

[0261]

[0262] A compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to yield a compound of general formula (II) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the deprotection reaction may include the removal of R under acidic or basic conditions before, during, or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0263] Where R is an amino protecting group; preferably Boc;

[0264] G 2 For NH;

[0265] G 1 L, R 1 R 2 R 3 R 4 R 5 R 6 p, q, r and t are as defined in general formula (II).

[0266] Option Six

[0267] This disclosure provides a method for preparing a compound of formula (III) or a pharmaceutically acceptable salt thereof, the method comprising:

[0268]

[0269] A compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to yield a compound of general formula (III) or a pharmaceutically usable salt thereof; optionally, when R 3 and / or R 6 When the group contains a protecting group, the deprotection reaction may include the removal of R under acidic or basic conditions before, during, or after the deprotection reaction. 3 and / or R 6 The steps of using protecting groups on groups;

[0270] Where R is an amino protecting group; preferably Boc;

[0271] R 0 It is a hydroxyl protecting group; preferably MOM;

[0272] G 1 Ring A, Ring B, L, R 1 R 2 R 3 R 4 R 5 R 6 y, p, r and t are as defined in general formula (III).

[0273] The reagents providing acidic conditions in the above synthesis scheme include organic acids and inorganic acids. The organic acids include, but are not limited to, trifluoroacetic acid, formic acid, acetic acid, methanesulfonic acid, p-toluenesulfonic acid, Me3SiCl, and TMSOTf. The inorganic acids include, but are not limited to, hydrogen chloride, dioxane hydrochloride solution, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Dioxane hydrochloride solution is preferred.

[0274] The reagents providing alkaline conditions in the above synthesis scheme include organic and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylaminolithium, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride in tetrahydrofuran solution, or 1,8-diazabicycloundec-7-ene. The 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; preferably, tetrabutylammonium fluoride in tetrahydrofuran solution or cesium fluoride.

[0275] In the above synthesis scheme, when R 3 and / or R 6 When a terminal alkyne group is present, the terminal alkyne can be protected by TIPS. The reagent for removing TIPS is preferably a tetrahydrofuran solution of tetrabutylammonium fluoride or cesium fluoride.

[0276] The reactions described above are preferably carried out in a solvent, which may include, but is 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. Detailed Implementation

[0277] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure.

[0278] Example

[0279] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0280] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0281] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 liquid chromatograph.

[0282] Chiral HPLC analysis was performed using an Agilent 1260 DAD high-performance liquid chromatograph.

[0283] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0284] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0285] The CombiFlash rapid preparation system uses a CombiFlash Rf200 (TELEDYNE ISCO).

[0286] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0287] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0288] Mean inhibition rate of kinases and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG GmbH, Germany).

[0289] The known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, and Darui Chemicals.

[0290] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0291] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0292] A hydrogen atmosphere refers to a reaction vessel connected to a hydrogen balloon with a volume of approximately 1L.

[0293] The pressurized hydrogenation reaction was performed using a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0294] The hydrogenation reaction is usually carried out under vacuum, filled with hydrogen gas, and repeated 3 times.

[0295] The microwave reaction was performed using a CEM Discover-S 908860 microwave reactor.

[0296] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0297] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20℃~30℃.

[0298] The reaction process in the examples was monitored using thin-layer chromatography (TLC). The developing solvent used in the reaction, the eluent system for column chromatography used to purify the compounds, and the developing solvent system for TLC included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0299] Example 1

[0300] 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthyl-2-phenol

[0301]

[0302]

[0303] first step

[0304] 7-(2,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester 1c

[0305] 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine 1a (400 mg, 1.58 mol, prepared by the method disclosed in intermediate 4 on page 80 of patent application "WO2021 / 041671A1") and N,N-diisopropylethylamine (248 mg, 7.92 mmol) were dissolved in 10 mL of dichloromethane, and 3-oxa-7,9-diazabicyclo[3.3.1]nonane was added at -40 °C. 9-Tert-butyl carboxylate 1b (361 mg, 1.58 mmol, Nanjing Pharmaceutical Co., Ltd.) was reacted with stirring at the same temperature for 1 hour. Then, 10 mL of water was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL × 3). The organic phases were combined and washed with 2 M hydrochloric acid solution. The organic phases were dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to give the title compound 1c (500 mg, yield: 71%).

[0306] MS m / z(ESI):444.0[M+1].

[0307] Step 2

[0308] 7-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester 1e

[0309] Compound 1c (100 mg, 225 μmol) was dissolved in acetonitrile (2 mL), and ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol 1d (71 mg, 446 μmol, WuXi AppTec), N,N-diisopropylethylamine (108.5 mg, 839 μmol) and 4A molecular sieve (100 mg) were added. The mixture was stirred at 90 °C for 14 hours. 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 give title compound 1e (80 mg, yield: 62.6%).

[0310] MS m / z(ESI): 567.1 [M+1].

[0311] Step 3

[0312] 1 g of 7-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphth-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester

[0313] Compound 1e (50 mg, 88.1 μmol), 2-(8-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane 1f (50 mg, 150.5 μmol, prepared by the method disclosed in Example 282 on page 522 of patent application "WO2021 / 041671A1"), [1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloro(II) (10 mg, 15.3 μmol, adamas), and anhydrous potassium carbonate (30 mg, 217.0 μmol) were dissolved in 3 mL of a mixed solution of 1,4-dioxane and water (V:V = 5:1). The reaction was carried out at 100°C for 14 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give 1 g (25 mg, yield: 38.4%) of the title compound.

[0314] MS m / z(ESI): 737.2 [M+1].

[0315] Step 4

[0316] 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthyl-2-phenol

[0317] 1 g (20 mg, 27.1 μmol) of the compound was dissolved in acetonitrile (1 mL), and 1 mL of 4 M dioxane hydrochloride solution was added. The reaction was carried out at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30 mL / min) to obtain title compound 1 (2 mg, yield: 12.4%).

[0318] MS m / z(ESI): 593.2 [M+1].

[0319] 1 H NMR (500MHz, CD3OD): δ9.08(s,1H),7.58(d,1H),7.38(td,1H),7.32(t,1H),7.16(t,1H),6.91(dd,1 H),5.01(q,3H),4.35-4.21(m,2H),4.02-3.87(m,8H),3.02(s,4H),2.22-2.11(m,2H),2.01(q,4H).

[0320] Example 2

[0321] 7-(7-(8-ethynylnaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane 2

[0322]

[0323]

[0324] first step

[0325] Triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxoborhecyclopentan-2-yl)naphthyl)ethynyl)silane 2b

[0326] ((8-bromonaphthyl-1-yl)ethynyl)triisopropylsilane 2a (5 g, 12.9 mmol, prepared by the method disclosed in Example 179 on page 301 of patent application "WO2021 / 041671A1") was dissolved in 50 mL of 1,4-dioxane, and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronylcyclopentane) (6 g, 23.6 mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), potassium acetate (2.5 g, 25.47 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (1.05 g, 1.28 mmol) were added sequentially. The mixture was stirred at 80 °C for 16 hours under nitrogen protection. The solution was cooled, filtered through diatomaceous earth, concentrated, and purified by thin-layer chromatography using solvent system B to give title compound 2b (4 g, yield: 71.33%).

[0327] MS m / z(ESI):435.2[M+1].

[0328] Step 2

[0329] 7-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester 2c

[0330] Compound 1e (60 mg, 105.8 μmol), compound 2b (70 mg, 161.1 μmol), tetrakis(triphenylphosphine)palladium (24 mg, 20.7 μmol, adamas), and anhydrous cesium carbonate (68 mg, 208.7 μmol) were dissolved in 5 mL of a mixed solution of 1,4-dioxane and water (V:V = 5:1). The reaction was carried out at 100 °C for 14 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using eluent system A to give title compound 2c (80 mg, yield: 90.1%).

[0331] MS m / z(ESI): 839.2 [M+1].

[0332] Step 3

[0333] 7-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane 2d

[0334] Compound 2c (80 mg, 108.2 μmol) was dissolved in acetonitrile (2 mL), and 2 mL of 4 M dioxane hydrochloride solution was added. The reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain crude title compound 2d (70 mg, yield: 99.2%), which was used directly in the next reaction without purification.

[0335] MS m / z(ESI): 739.2 [M+1].

[0336] Step 4

[0337] 7-(7-(8-ethynylnaphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane 2

[0338] Compound 2d (80 mg, 108.2 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 2.4 mL of 1 M tetrabutylammonium fluoride tetrahydrofuran solution was added. The mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain title compound 2 (2 mg, yield: 3.1%).

[0339] MS m / z(ESI): 583.2 [M+1].

[0340] 1 H NMR (500MHz, CDCl3): δ9.07(s,1H),7.96(d,1H),7.77-7.73(m,1H),7.62(s ,1H),7.49(s,1H),7.46(s,1H),7.07(s,1H),5.35(d,2H),4.80(s,1H),4.3 0(d,2H),4.16(t,1H),3.95(d,3H),3.84(d,4H),3.18(s,2H),3.01-2.93(m ,1H),2.62(d,1H),2.26-2.20(m,3H),2.06-2.01(m,2H),1.96-1.90(m,2H).

[0341] Example 3

[0342] 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthol-2-phenol 3

[0343]

[0344]

[0345] first step

[0346] 7-(8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-7-(3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)pyridino[4,3-d]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester 3b

[0347] Compound 1e (30 mg, 52.9 μmol), triisopropyl((6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxoborhexacyclopentan-2-yl)naphth-1-yl)ethynyl)silane 3a (26.1 mg, 52.9 μmol, prepared by the method disclosed in intermediate 17 on page 103 of patent application "WO2021 / 041671A1"), tetra(triphenylphosphine)palladium (12.2 mg, 10.5 μmol, adamas) and anhydrous cesium carbonate (51.7 mg, 158.7 μmol) were dissolved in 3 mL of a mixed solution of 1,4-dioxane and water (V:V = 5:1). The reaction was carried out at 100°C for 3 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to give the title compound 3b (30 mg, yield: 38.4%).

[0348] MS m / z(ESI): 899.2 [M+1].

[0349] Step 2

[0350] 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-phenol 3c

[0351] Compound 3b (30 mg, 33.6 μmol) was dissolved in acetonitrile (1 mL), and 1 mL of 4 M dioxane hydrochloride solution was added. After reacting for 1 hour, the reaction solution was concentrated under reduced pressure to obtain crude title compound 3c (25 mg, yield: 99.5%). The product was used directly in the next reaction without purification.

[0352] MS m / z(ESI): 755.2 [M+1].

[0353] Step 3

[0354] 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthol-2-phenol 3

[0355] The crude compound 3c (25 mg, 33.1 μmol) was dissolved in N,N-dimethylformamide (1 mL), and cesium fluoride (25.2 mg, 165.5 μmol) was added. The mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to obtain the title compound 3 (5 mg, yield: 25.2%).

[0356] MS m / z(ESI): 599.2 [M+1].

[0357] 1 H NMR (500MHz, CDCl3): δ8.96(s,1H),8.79(s,1H),7.56(d,1H),7.49(s,1H) ,7.17(d,1H),7.09(d,1H),7.07(s,1H),5.32(d,1H),5.20(s,1H),4.81(m ,2H),4.73(m,2H),4.29(s,2H),4.25-4.20(m,2H),4.13-4.09(m,2H),3.8 9-3.8(m,3H),2.95(d,2H),2.19(dt,3H),2.00(d,2H),1.94-1.83(m,3H).

[0358] Example 4

[0359] 4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-phenol

[0360]

[0361] Using the synthetic route in Example 1, the starting compound 1f in the third step was replaced with 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronyl pentane (prepared by the method disclosed in intermediate 21 on page 111 of patent application "WO2021 / 041671A1") to obtain title compound 4 (5 mg, yield: 24.7%).

[0362] MS m / z(ESI): 603.2 [M+1].

[0363] 1 H NMR (500MHz, CDCl3): δ9.01(d,1H),7.57(d,1H),7.37-7.33(m,1H),7.23-7.21(m,1H),7.16 (m,1H),7.07(s,1H),6.99(s,1H),5.49-5.31(m,2H),5.24(s,1H),5.02-4.60(m,2H),4.30- 4.24(m,2H),3.94-3.83(m,3H),3.77-3.72(m,2H),3.33-3.30(m,2H),3.28-3.18(m,2H),3. 01-2.94(m,3H),2.37-2.29(m,3H),2.26-2.23(m,2H),2.20-2.17(m,1H),1.02-0.87(t,3H).

[0364] Example 5

[0365] 4-(4-(3,9-diazabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthyl-2-phenol 5

[0366]

[0367] Using the synthetic route in Example 1, the starting compound 1b of the first step was replaced with tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate to obtain title compound 5 (6 mg, yield: 24.8%).

[0368] MS m / z(ESI): 591.2 [M+1].

[0369] 1 H NMR (500MHz, CD3OD): δ9.12(s,1H),7.59(d,1H),7.39(td,1H),7.33(d,1H),7.17(d,1H),6.93(dd,1H),5.36(s,1H),4.34(dd,1H),4.27(d,1H),3. 87(s,1H),3.28(s,3H),3.26-3.18(m,4H),3.06-2.98(m,1H),2.31-2.11( m,4H),2.00(dd,4H),1.91(s,2H),1.59(s,1H),1.34(s,1H),1.29(s,1H).

[0370] Example 6

[0371] 4-(4-(3,9-diazabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthol-2-phenol 6

[0372]

[0373] first step

[0374] 3-(7-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester 6a

[0375] Using the first step of the synthetic route in Example 1, the starting compound 1b was replaced with tert-butyl 3,9-diazabicyclo[3.3.1]nonane-9-carboxylate to obtain title compound 6a (90 mg, yield: 70.4%).

[0376] MS m / z(ESI): 564.9 [M+1].

[0377] Step 2

[0378] 4-(4-(3,9-diazabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynylnaphthol-2-phenol 6

[0379] Using the synthetic route in Example 3, steps 1 to 3 were performed, with the starting material compound 1e replaced by compound 6a, to obtain title compound 6 (6 mg, yield: 25.2%).

[0380] MS m / z(ESI): 597.2 [M+1].

[0381] 1 H NMR (500MHz, CD3OD): δ9.06(s,1H),7.80(d,1H),7.48(d,1H),7.37(t,1H),7.30(d,1H),7.16(d,1H),5.36(s,1H),4.32(dd,1H),4.25(dd,1H),3.8 5(t,3H),3.28(s,3H),3.26-3.18(m,3H),2.99(dd,1H),2.30-2.16(m,4H) ,2.00(dt,4H),1.94-1.84(m,2H),1.60(s,1H),1.34(s,1H),1.29(d,1H).

[0382] Example 7

[0383] 4-(4-(3,9-diazabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-phenol 7

[0384]

[0385] first step

[0386] 3-(7-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester 7a

[0387] Compound 6a (30 mg, 53 μmol), 2-(8-ethyl-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (27 mg, 78.91 μmol), tetra(triphenylphosphine)palladium (9.1 mg, 7.8 μmol, adamas), and anhydrous cesium carbonate (51 mg, 156.5 μmol) were dissolved in 3 mL of a mixed solution of 1,4-dioxane and water (V:V = 5:1). The reaction was carried out at 100 °C for 14 hours under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and a mixed solution of dichloromethane and methanol (V:V = 10:1) was added to the residue. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 7a (15 mg, yield: 37.9%).

[0388] MS m / z(ESI): 745.2 [M+1].

[0389] Step 2

[0390] 4-(4-(3,9-diazabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethylnaphthyl-2-phenol 7

[0391] The crude compound 7a (15 mg, 20.1 μmol) was dissolved in ethyl acetate (3 mL), and 1 mL of 4 M dioxane hydrochloride solution was added. The mixture was reacted at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (Waters-2545, column: SharpSil-T C18, 30*150 mm, 5 μm; mobile phase: water (containing 10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 35%-45%, flow rate: 30 mL / min) to obtain the title compound 7 (3 mg, yield: 24.8%).

[0392] MS m / z(ESI): 601.2 [M+1].

[0393] 1H NMR (500MHz, CD3OD): δ9.12(s,1H),7.63(d,1H),7.40-7.33(m,1H),7.29(d,1H),7.16(d,1H),7.03(d,1H),5.36(s,1H),4.58(s,1H),4.36(d,1 H),4.29(d,1H),3.91(s,1H),3.86(d,1H),3.35(s,7H),3.05(d,1H),2. 35(d,2H),2.22(dd,4H),2.05-2.01(m,4H),1.92(q,3H),0.90(td,3H).

[0394] Example 8

[0395] 4-(4-(3-oxa7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthyl-2-phenol8

[0396]

[0397] Using the synthetic route in Example 1, the starting compound 1f in the third step was replaced with 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboronyl pentane (prepared by the method disclosed in intermediate 18 on page 104 of patent application "WO2021 / 041671") to obtain title compound 8 (5 mg, yield: 15.4%).

[0398] MS m / z(ESI): 621.2 [M+1].

[0399] 1 H NMR (500MHz, CDCl3): δ8.65(s,1H),8.33(s,1H),7.89(d,1H),7.65(s,1H),6.96(d ,1H),5.51-5.33(m,2H),5.26(s,1H),5.04-4.62(m,2H),4.32-4.27(m,2H),3.95- 3.85(m,3H),3.80-3.74(m,2H),3.33-3.32(m,2H),3.27-3.16(m,2H),3.02-2.95( m,3H),2.36-2.30(m,3H),2.27-2.24(m,2H),2.20-2.17(m,1H),1.03-0.86(t,3H).

[0400] Example 9 (Comparative Example 1)

[0401] 4-(4-(3,6-diazabicyclo[3.2.1]oct-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthyl-2-phenol 9

[0402]

[0403] Using the synthetic route in Example 1, the starting compound 1b of the first step was replaced with tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (Shanghai Bide) to obtain title compound 9 (4 mg, yield: 25%).

[0404] MS m / z(ESI): 577.2 [M+1].

[0405] 1 H NMR (500MHz, CD3OD): δ9.10(d,1H),7.61(d,1H),7.41(td,1H),7.35(d,1H),7.17(dd,1H ),6.93(dd,1H),5.37(dd,1H),4.61-4.51(m,2H),4.35(dd,1H),4.27(t,1H),3.88-3.79 (m,2H),3.68(s,1H),3.57(dd,2H),3.31-3.20(m,3H),3.07(s,2H),3.05-3.01(m,1H),2 .69(s,1H),2.27-2.18(m,1H),2.22-2.11(m,3H),2.07-1.99(m,2H),1.98-1.94(m,2H).

[0406] Example 10 (Comparative Example 2)

[0407] 4-(4-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthyl-2-phenol 10

[0408]

[0409] Using the synthetic route in Example 1, the starting compound 1b of the first step was replaced with tert-butyl 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate hydrochloride (Shanghai Bide) to prepare title compound 10 (5 mg, yield: 12.4%).

[0410] MS m / z(ESI): 593.2 [M+1].

[0411] 1 H NMR (500MHz, CD3OD): δ9.15(s,1H),7.60(d,1H),7.39(td,1H),7.33(t,1H),7.17(d,1H),6.92(dd,1H) ,4.76(d,4H),4.40-4.28(m,3H),4.04-3.92(m,5H),3.18-3.02(m,4H),2.32-2.12(m,4H),2.02(m,3H).

[0412] Example 11 (Comparative Example 3)

[0413] 4-(4-(2,5-diazabicyclo[2.2.1]hept-2-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-fluoronaphthyl-2-phenol 11

[0414]

[0415] Using the synthetic route in Example 1, the starting compound 1b of the first step was replaced with tert-butyl 2,5-azabicyclo[2.2.1]heptane-2-carboxylate (Shanghai Bide) to obtain title compound 11 (3.9 mg, yield: 13.9%).

[0416] MS m / z(ESI): 563.2 [M+1].

[0417] 1H NMR (500MHz, CD3OD): δ9.15(s,1H),7.61(d,1H),7.43-7.35(m,1H),7.35(s, 1H),7.22-7.13(m,1H),6.95-6.91(m,1H),5.52-5.39(m,2H),4.44-4.23(m, 4H),3.96-3.90(m,1H),3.25-3.14(m,2H),3.09-3.04(m,2H),2.39(dd,1H), 2.35-2.24(m,2H),2.23-2.13(m,3H),2.07-2.02(m,3H),1.99-1.93(m,3H).

[0418] Biological evaluation

[0419] Test Example 1: Biological Evaluation of ERK Phosphorylation Inhibition Experiment in AGS Cells (HTRF Method)

[0420] I. Purpose of the Test

[0421] This experiment investigated the inhibitory effect of compounds on cellular ERK phosphorylation, based on IC50 values. 50 The size of the compound was evaluated to assess its inhibitory effect on the KRAS target.

[0422] II. Experimental Methods

[0423] AGS cells (Nanjing Kebai, CBP60476) were cultured in RPMI 1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, AGS cells were seeded at a density of 40,000 cells / well in 96-well plates using complete medium, with 190 μL of cell suspension per well, and incubated overnight at 37°C in a 5% CO2 cell culture incubator.

[0424] On the second day, 10 μL of serially diluted test compounds prepared with complete culture medium were added to each well. The final concentration of the compound was determined by nine concentration points, starting from 10 μM and serially diluted 5-fold. A blank control containing 0.5% DMSO was included. The plate was incubated at 37°C in a cell culture incubator with 5% CO2 for 1 hour. After incubation, the 96-well cell culture plate was removed, the culture medium was aspirated, and each well was washed once with 200 μL of PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320). The PBS was then aspirated, and each well was added with 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC). The plate was then placed on a shaker and oscillated at room temperature for 40 minutes for lysis. After lysis, the lysis buffer was mixed by pipetting, and 16 μL of lysis buffer was transferred to each well into two HTRF 96-well detection plates (Cisbio, 66PL96100). Then, 4 μL of premixed phosphorylated ERK1 / 2 antibody solution (Cisbio, 64AERPEG) or 4 μL of premixed total ERK1 / 2 antibody solution (Cisbio, 64NRKPEG) was added to each plate. The microplates were sealed with sealing film, centrifuged for 1 minute, and incubated overnight at room temperature in the dark.

[0425] On the third day, the fluorescence values ​​of excitation at 337 nm and emission at 665 nm and 620 nm were read using the ENVISION multi-functional microplate reader (PerkinElmer, ENVISION).

[0426] III. Data Analysis

[0427] The IC50 of the compound's inhibitory activity was calculated using Graphpad Prism software based on the compound concentration and the ratio of phosphorylated ERK to total ERK. 50 The values ​​are shown in Table 1 below.

[0428] Table 1. Data on cellular ERK phosphorylation inhibition activity

[0429] 4 120 5 65.3 6 30.2 7 51.1 Comparative Example 1 >10000 Comparative Example 2 >10000

[0430] Conclusion: The compound disclosed herein has a good inhibitory effect on ERK phosphorylation in AGS cells.

[0431] Test Example 2: Biological Evaluation of GP2d Cell 3D Proliferation Inhibition Experiment

[0432] I. Purpose of the Test

[0433] The inhibitory effect of the disclosed compound on the KRAS target was evaluated by testing its 3D proliferation inhibition effect on GP2d cells.

[0434] II. Experimental Methods

[0435] GP2d cells (Nanjing Kebai, CBP60010) were cultured in complete medium, namely 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 at a density of 1000 cells / well in 96-well low-absorption plates (Corning, CLS7007-24EA) using complete medium, with 90 μL of cell suspension per well. After centrifugation at 2000 rpm for 5 minutes at room temperature, the cells were incubated overnight at 37°C in a 5% CO2 cell culture incubator.

[0436] On the second day, 10 μL of serially diluted test compound prepared with complete culture medium was added to each well. The final concentration of the compound in GP2d cells was determined by nine 3-fold serial dilutions starting from 1 μM. A blank control containing 0.5% DMSO was included. The plates were incubated at 37°C in a 5% CO2 incubator for 120 hours. On the seventh day, the 96-well cell culture plate was removed, and 50 μL of the test compound was added to each well. The 3D reagent (Promega, G9682) was shaken at room temperature for 25 minutes, then mixed by pipetting and aspiration. 50 μL was transferred to a white, opaque 96-well plate (PE, 6005290), and the luminescence signal value was read using a multi-functional microplate reader (PerkinElmer, ENVISION).

[0437] III. Data Analysis

[0438] The IC50 of the compound's inhibitory activity was calculated using Graphpad Prism software. 50 The values ​​are shown in Table 2 below.

[0439] Table 2 Data on cell 3D proliferation inhibition activity

[0440] 5 156 6 152 Comparative Example 1 >10000 Comparative Example 2 >10000 Comparative Example 3 >10000

[0441] Conclusion: The compound disclosed herein has a good inhibitory effect on the 3D proliferation of GP2d cells.

[0442] Test Example 3: SPR method for detecting the affinity of the disclosed compound for KRAS protein subtypes G12D or WT

[0443] Biotinylated Avi-KRAS-WT or Avi-KRAS-G12D was first diluted to 20 μg / mL with 1×HBS-P+ (Cat.#BR1006-71) buffer containing 100 mM MgCl2, and then flowed through channel 2 of the SA (Cat.#BR1005-31) biosensor chip for 420 s to obtain a coupling level of approximately 5000-7000 RU. Small molecule compound samples were then injected sequentially from low to high coupling levels for 120 s, followed by dissociation for 720 s. A single-cycle kinetic mode was used. The reaction signal was monitored in real time using a Biacore 8K instrument to obtain binding and dissociation curves. After the experiment, data analysis was performed using Biacore 8K evaluation software, and a 1:1 model was used to fit the data and obtain affinity data.

[0444] Table 3. Affinity data of compounds with KRAS protein subtypes G12D or WT

[0445]

[0446] Conclusion: The disclosed compound has good affinity for KRAS protein subtypes G12D or WT.

[0447] Test Example 4: Inhibitory effect of the disclosed compound on SW620 proliferation

[0448] I. Experimental Materials and Instruments

[0449] 1. SW620 cells (Nanjing Kebai Biotechnology)

[0450] 2. Leibovitz's L-15 medium (Gibco)

[0451] 3. Fetal bovine serum (FBS) (Gibco)

[0452] 4. 0.25% pancreatic enzyme (Gibco)

[0453] 5. Phosphate-buffered saline (PBS) (Shanghai Yuanpei Biotechnology Co., Ltd.)

[0454] 6.Cell Titer Glo(CTG)(Promega)

[0455] 7. T75 cell culture flasks (Corning)

[0456] 8. 15mL centrifuge tubes (Corning)

[0457] 9. 96-well preparation plate (Corning)

[0458] 10. 96-well flat-bottom cell culture plate (Corning)

[0459] 11. Thermo Scientific Cell Incubator

[0460] 12. Biosafety Cabinet (ESCO)

[0461] 13. Ultra-high-speed refrigerated centrifuge (Thermo Scientific)

[0462] 14. Multifunctional Plate Reader (PerkinElmer)

[0463] II. Experimental Procedure

[0464] SW620 cells are human colon cancer cells carrying the KRAS G12V mutation. This study evaluated the effect of a compound on the proliferation of SW620 cells. The addition of the compound inhibited SW620 cell proliferation; the inhibitory effect was assessed by measuring the relative luminescence unit value using CTG.

[0465] On day 0, SW620 cells that were growing well and reached 70%-80% confluence were harvested, digested, and then cultured in L-15 medium containing 10% FBS to adjust the cell density to 1.11*10⁻⁶ cells / year. 4 / mL. Add 90 μL of cell suspension to a 96-well cell culture plate, resulting in a final cell count of 1000 cells / well. Incubate the cells at 37°C in a CO2-free incubator for 24 hours. Day 1: Dilute the 20 mM test compound dissolved in 100% DMSO serially with 100% DMSO to 2000, 666.67, 222.22, 74.07, 24.69, 8.23, 2.74, 0.91, and 0.30 μM, respectively. For blank wells, use 100% DMSO. Then, dilute 20-fold in L-15 medium containing 10% FBS. Add 10 μL of the secondary diluted test compound to each well. The final concentrations of the test compounds were 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52 nM, respectively. DMSO wells served as blank wells, and test wells with only culture medium served as negative control wells. Cells were cultured at 37°C in a CO2-free incubator for 5 days. On day 6, the 96-well cell culture plate was removed, 50 μL of melted CTG was added, and the plate was incubated at room temperature for 20 minutes. The relative luminescence unit (RLU) value was read using a microplate reader. The inhibition rate was calculated using the following formula: Inhibition rate = [RLU(blank well) - RLU(test compound)] / [RLU(blank well) - RLU(negative control well)] * 100%. Inhibition curves were plotted using Graphpad Prism software based on the compound concentrations and corresponding inhibition rates. The concentration of the compound at which the inhibition rate reached 50% was calculated, i.e., the IC50 value. 50Value. The IC50 of the disclosed compound was determined by its inhibitory effect on the proliferation of human SW620 cells. 50 The values ​​are shown in Table 4.

[0466] Table 4. Data on the inhibitory activity of compounds on SW620 cell proliferation.

[0467] 1 1016 91 2 2795 96 4 667 86 7 1785 100 8 234 92 Comparative Example 1 >10000 14 Comparative Example 2 >10000 48

[0468] Conclusion: The compound disclosed herein has a good inhibitory effect on the proliferation of SW620 cells.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is: 、 。 2. A compound or a salt thereof, selected from the group consisting of: 、 。 3. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

4. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of a medicament for inhibiting KRAS G12D and / or KRAS G12V.

5. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is cancer.

6. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 3 in the preparation of a medicament for treating and / or preventing a disease or condition, wherein the disease or condition is selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, laryngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial carcinoma, 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.

7. The use according to claim 6, wherein, The diseases or conditions mentioned are selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

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