Condensed ring compound as well as preparation method and medical application thereof

Abstract

The invention relates to a fused ring compound, a preparation method thereof and application of the fused ring compound in medicine. Specifically, the invention relates to a fused ring compound as shown in a general formula (IN), a preparation method thereof, a pharmaceutical composition containing the compound and application of the fused ring compound as a therapeutic agent, in particular to application of the fused ring compound in preparation of drugs for inhibiting KRAS G12D. Wherein each group in the general formula (IN) is as defined in the specification. # imgabs0 #

Description

Technical Field

[0001] The present disclosure belongs to the field of medicine, and relates to a polycyclic compound, a preparation method thereof, and its application in medicine. In particular, the present disclosure relates to a polycyclic compound represented by the general formula (IN), a preparation method thereof, a pharmaceutical composition containing such a compound, and its use in the preparation of a drug for inhibiting KRAS G12D. Background Art

[0002] RAS is one of the oncogenes with the highest mutation rate in tumors, and about 30% of human malignancies are related to the mutation of the RAS gene. The RAS family includes KRAS, NRAS, and HRAS, among which the KRAS mutation is the most common, accounting for about 85%. The KRAS mutation is common in solid tumors, and there are high-frequency mutations in the three most lethal cancers in humans - lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Among the gene mutations of KRAS, 97% are mutations in the 12th or 13th amino acid residues, and G12D is an important mutation. Data analysis of the European and American populations shows that in pancreatic cancer, colorectal cancer, and non-small cell lung cancer, the G12D mutation accounts for 36%, 12%, and 4% of the patients, respectively.

[0003] After KRAS is activated, it regulates the functions of cell proliferation, survival, migration, and metabolism through many downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR, and TIAM1-RAc. After the KRAS gene mutates, the protein remains in an activated state continuously, resulting in the continuous activation of downstream signaling pathways and promoting tumorigenesis.

[0004] Since the surface of the KRAS protein lacks a small molecule binding site in the traditional sense and has an extremely high affinity for guanosine nucleotides and is extremely difficult to be inhibited, it has long been considered an undruggable drug target. However, due to the importance and universality of the abnormal activation of KRAS in cancer progression, KRAS has always been and still is a very concerned target for drug development. At present, except for KRAS G12C inhibitors, there is still a lack of effective KRAS inhibitors for other mutations, making most patients with KRAS mutations still have no drugs to treat. As a mutant that is widely highly expressed in a variety of tumors, developing an inhibitor against it has important clinical significance.

[0005] The related patent applications that have been publicly disclosed so far include WO2022268051, WO2022188729A1, WO2022194245A1, WO2022199587A1, WO2022206723A1, WO2023274383A1, WO2023001123A1, WO2023001141A1, WO2022173678A1, WO2023030385A1, WO2023103906A1, WO2023205719A1, WO2023225302A1, etc. Summary of the Invention

[0006] The purpose of the present disclosure is to provide a compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof:

[0007]

[0008] Wherein:

[0009] R d is selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, -C(O)R 17 , -C(O)OR 17 , -C(O)NR 18 R 19 , -(CR a R b ) v S(O) w R 17 , -(CR a R b ) v S(O) w NR 18 R 19 , a cycloalkyl group, a cycloalkylalkyl group, a heterocyclic group, and a heterocyclic alkyl group, and the alkyl group, cycloalkyl group, cycloalkylalkyl group, heterocyclic group, and heterocyclic alkyl group are each independently optionally substituted by one or more R 00 ;

[0010] Ring C is a heterocyclic group;

[0011] R x1 is a hydrogen atom or R x ;

[0012] R x is selected from =N-O-R 61 , =CR 62 R 63 and =N-R 64 ;

[0013] G 0 is selected from O, S, S(O), S(O)2, CRG0a R G0b and NR G0c ;

[0014] G 1 selected from CR G1a R G1b , CR G1a R G1b CR G1c R G1d , C=O and C(O)CR G1a R G1b ;

[0015] T is a chemical bond or selected from CR at R bt , NR T and O;

[0016] Q is N or CR 2a ;

[0017] Ring A is aryl or heteroaryl;

[0018] L is selected from a single bond, O, S and NR e ;

[0019] R at , R bt , R G0a , R G0b , R G1a , R G1b , R G1c and R G1d are the same or different and each independently selected from a hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic group, or R G0a , R G0b together with the adjacent carbon atom form a cycloalkyl, or R G1a , R G1b together with the adjacent carbon atom form a cycloalkyl, or R G1c , R G1d together with the adjacent carbon atom form a cycloalkyl, or R G0a , R G1a together with the adjacent carbon atom form a cycloalkyl, or R G0a , R G1c together with the adjacent carbon atom form a cycloalkyl, or R G1a , R G1c together with the adjacent carbon atom form a cycloalkyl, or R G0c , R G1a together with the adjacent atom form a heterocyclic group, or R G0c , R G1cTogether with the connected atoms, form a heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocyclic group are each independently optionally substituted by one or more R*;

[0020] Each R 1 is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-(CR a R b ) v S(O) w R 17 、-S(O) w NR 18 R 19 、-OC(O)R 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-NR 20 S(O) w R 17 、-OC(O)NR 18 R 19 、-(CR a R b ) v cycloalkyl, -(CR a R b ) v heterocyclic group, -(CR a R b ) v aryl and -(CR a R b ) v heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more R 01 substituted;

[0021] R 2a and R 4aSame or different, and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CR a R b ) v NR 18 R 19 , a hydroxyl group, a hydroxyalkyl group, and a cycloalkyl group;

[0022] Each R 3 Same or different, and each independently selected from a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CR a R b ) v NR 18 R 19 、-(CH2) w1 -(O) x1 -C(O)NR j1 R k1 、-(CH2) w2 -(O) x2 -C(O)OR j2 、nitro group, a hydroxyl group, a hydroxyalkyl group, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-(CR a R b ) v S(O) w R 17 、-S(O) w NR 18 R 19 、-OC(O)R 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-NR 20 S(O) w R 17 、-OC(O)NR 18 R 19 、-(CR a R b ) vCycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v Heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more R 01 Substituted;

[0023] Each R 6 Are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CR a R b ) v NR 18 R 19 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2 -(O) z2 -C(O)OR m2 、=N-O-R 61 、=CR 62 R 63 、=N-R 64 、nitro, hydroxy, hydroxyalkyl, oxo, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-(CR a R b ) v S(O) w R 17 、-S(O) w NR 18 R 19 、-OC(O)R 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR17 、 -NR 20 S(O) w R 17 、 -OC(O)NR 18 R 19 、 -(CR a R b ) v cycloalkyl, -(CR a R b ) v heterocyclic group, -(CR a R b ) v aryl and -(CR a R b ) v heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclic group, aryl and heteroaryl are each independently optionally substituted by one or more R 01 substituents;

[0024] R 61 、R 62 、R 63 and R 64 are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl, a haloalkyl, a hydroxyalkyl and -(CR a R b ) v cycloalkyl;

[0025] R 5a and R 5b are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl, a haloalkyl, a cyano, a hydroxy and a hydroxyalkyl; or

[0026] R 5a 、R 5b together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclic group, and the cycloalkyl or heterocyclic group is each independently optionally substituted by one or more identical or different substituents selected from a halogen, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a hydroxy and a hydroxyalkyl;

[0027] R G0c 、R T 、R e 、R a 、R b 、R j1 、R k1 、R j2 、R m1 、R n1 、R m2 、R 17 、R 18 、R 19 and R20 are the same or different and each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group, a cyano group, an amino group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, cycloalkyloxy group, heterocyclyloxy group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group are each independently optionally substituted with one or more R # substituents;

[0028] R 00 、R 01 、R*, and R # are the same or different and each independently selected from an oxo group, =S, a halogen, a hydroxyl group, an alkenyl group, an alkynyl group, a cyano group, a nitro group, an amino group, -NH-alkyl, -N(alkyl)2, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxy group, a haloalkoxy group, an alkoxyalkyl group, an aminoalkyl group, a cycloalkyl group, a cycloalkylalkyl group, a cycloalkyloxy group, a heterocyclic group, a heterocyclicalkyl group, a heterocyclyloxy group, an aryl group, an arylalkyl group, an aryloxy group, a heteroaryl group, a heteroarylalkyl group, a heteroaryloxy group, -C(O)alkyl, -C(O)OH, -C(O)NH2, -C(O)NH-alkyl, and -C(O)N(alkyl)2;

[0029] v, w1, w2, y1, and y2 are the same or different and each independently selected from 0, 1, 2, and 3;

[0030] w is 0, 1, or 2;

[0031] x1, x2, z1, and z2 are the same or different and each independently selected from 0 or 1;

[0032] r is 0, 1, 2, or 3;

[0033] p is 0, 1, 2, 3, 4, or 5;

[0034] q is 0, 1, 2, 3, 4, or 5; and

[0035] t1 is 0, 1, 2, 3, 4, or 5.

[0036] In some embodiments of the present disclosure, the compound of formula (IN) or a pharmaceutically acceptable salt thereof, wherein R d is selected from a hydrogen atom, C 1-6 alkyl, C 1-6 haloalkyl, and C(O)C 1-6 alkyl; in some embodiments, R d is selected from a hydrogen atom, C 1-6 alkyl, and C 1-6 haloalkyl; in some embodiments, R d is a hydrogen atom.

[0037] In some embodiments of the present disclosure, the compound of the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein selected from is in some embodiments T, G 0 , G 1 , R d , R 1 and p are as defined in the general formula (IN).

[0038] In some embodiments of the present disclosure, the compound of the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 0 is selected from O, CR G0a R G0b and NR G0c , R G0a and R G0b are the same or different and each independently selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl, R G0c is a hydrogen atom or C 1-6 alkyl; in some embodiments, G 0 is selected from O, CH2 and NH; in some embodiments, G 0 is O.

[0039] In some embodiments of the present disclosure, the compound of the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein G 1 is CR G1a R G1b , CR G1a R G1b CR G1c R G1d or C═O, R G1a , R G1b , R G1c and R G1d are the same or different and each independently selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano, a 3- to 8-membered cycloalkyl and a 3- to 8-membered cycloalkyl C 1-6 alkyl; in some embodiments, G 1 is CR G1a H, R G1a is as defined in the general formula (IN); in some embodiments, G 1 is CR G1a H, RG1a Selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl; in some embodiments, G 1 is CR G1a H, and R G1a is selected from a hydrogen atom, C 1-6 alkyl, and C 2-6 alkenyl; in some embodiments, G 1 is selected from CH2, C═O, and CH(CH3); in some embodiments, G 1 is CH(CH3).

[0040] In some embodiments of the present disclosure, the compound of the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein -G 0 -G 1 - is selected from -O-CH2-, -NH-C(O)-, -NH-CH2-, -CH2-CH2-, and -O-CH2-CH2-; in some embodiments, -G 0 -G 1 - is -O-CH2-; in some embodiments, -G 0 -G 1 - is -O-CH(CH3)-.

[0041] In some embodiments of the present disclosure, the compound of the general formula (IN) or a pharmaceutically acceptable salt thereof, wherein T is a chemical bond.

[0042] In some embodiments of the present disclosure, the compound of the general formula (IN) or a pharmaceutically acceptable salt thereof is the compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

[0043]

[0044] wherein

[0045] ring A, ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p, and q are as defined in the general formula (IN).

[0046] In some embodiments of the present disclosure, the compound of the general formula (I) or a pharmaceutically acceptable salt thereof, wherein is selected from

[0047]

[0048] R G1a 、R 1 and p are as defined in general formula (I); in some embodiments, is R G1a is selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocyclic group are each independently optionally substituted by one or more R*, and R*, R 1 and p are as defined in general formula (I).

[0049] In some embodiments of the present disclosure, the compound represented by general formula (IN), (I) or a pharmaceutically acceptable salt thereof is the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:

[0050]

[0051] wherein

[0052] ring A, ring C, R x1 、Q、L、R G1a 、R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、r, t1, p and q are as defined in general formula (I).

[0053] In some embodiments of the present disclosure, the compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, wherein when R G1a is a hydrogen atom, the configuration on the connected carbon atom does not exist.

[0054] In some embodiments of the present disclosure, the compound represented by general formula (IN), (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein Q is N or CH; in some embodiments, Q is N.

[0055] In some embodiments of the present disclosure, the compounds of the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein ring A is a 6- to 10-membered aryl or a 5- to 10-membered heteroaryl; in some embodiments, ring A is selected from naphthyl, phenyl, pyridyl, benzothienyl, benzothiazolyl and benzopyrazolyl; in some embodiments, ring A is selected from naphthyl, phenyl and benzothienyl; in some embodiments, ring A is phenyl or naphthyl.

[0056] In some embodiments of the present disclosure, the compounds of the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein selected from

[0057] q1 is 0, 1, 2, 3 or 4, R 3 as defined in the general formula (IN); in some embodiments, selected from

[0058] q1 is 2 or 3, R 3 are the same or different and each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and cyano; in some embodiments, selected from q1 is 2 or 3, R 3 are the same or different and each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and cyano; in some embodiments, selected from

[0059] In some embodiments, selected from

[0060] In some embodiments of the present disclosure, the compounds of the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein R 4a is selected from a hydrogen atom, halogen, C 1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R 4a is a hydrogen atom or halogen; in some embodiments, R 4a is halogen; in some embodiments, R 4a is F.

[0061] In some embodiments of the present disclosure, the compounds represented by the general formulas (IN), (I), (I-1) or pharmaceutically acceptable salts thereof, wherein R G1a is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano, a 3- to 8-membered cycloalkyl and a 3- to 8-membered cycloalkyl C 1-6 alkyl; in some embodiments, R G1a is selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 1-6 haloalkyl; in some embodiments, R G1a is selected from a hydrogen atom, C 1-6 alkyl and C 2-6 alkenyl; in some embodiments, R G1a is a hydrogen atom; in some embodiments, R G1a is a hydrogen atom or a methyl group; in some embodiments, R G1a is C 1-6 alkyl; in some embodiments, R G1a is a methyl group; in some embodiments, R G1a is an ethyl group; in some embodiments, R G1a is C 2-6 alkenyl; in some embodiments, R G1a is a vinyl group.

[0062] In some embodiments of the present disclosure, the compounds represented by the general formulas (IN), (I), (I-1) or pharmaceutically acceptable salts thereof, wherein L is selected from CH2, NH and O; in some embodiments, L is O.

[0063] In some embodiments of the present disclosure, the compounds represented by the general formulas (IN), (I), (I-1) or pharmaceutically acceptable salts thereof, wherein R 5a and R 5b are the same or different and each independently selected from a hydrogen atom, a halogen, C 1-6 alkyl, C 1-6 haloalkyl, a hydroxyl group and C 1-6 hydroxyalkyl, or R 5a , R 5b together with the carbon atom to which they are attached form a 3- to 8-membered cycloalkyl; in some embodiments, R 5a and R 5b are hydrogen atoms, or R 5a , R 5bforms a 3- to 6-membered cycloalkyl together with the attached carbon atom; in some embodiments, R 5a and R 5b are hydrogen atoms, or R 5a and R 5b form cyclopropyl together with the attached carbon atom.

[0064] In some embodiments of the present disclosure, for the compounds or their pharmaceutically acceptable salts represented by the general formulas (IN), (I), and (I-1), r is 1 or 3.

[0065] In some embodiments of the present disclosure, for the compounds or their pharmaceutically acceptable salts represented by the general formulas (IN), (I), and (I-1), where is -CH2- or In some embodiments, is In some embodiments, is -CH2-.

[0066] In some embodiments of the present disclosure, for the compounds or their pharmaceutically acceptable salts represented by the general formulas (IN), (I), and (I-1), where ring C is a 3- to 8-membered heterocyclic group; in some embodiments, ring C is selected from morpholinyl, pyrrolidinyl, piperidinyl,

[0067]

[0068] In some embodiments, ring C is selected from:

[0069] In some embodiments, ring C is selected from piperidinyl, morpholinyl and In some embodiments, ring C is selected from

[0070] In some embodiments of the present disclosure, for the compounds or their pharmaceutically acceptable salts represented by the general formulas (IN), (I), and (I-1), where is selected from:

[0071]

[0072]

[0073] In some embodiments, is In some embodiments, is In some embodiments,

[0074] is

[0075] In some embodiments of the present disclosure, the compounds represented by the general formulas (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein is selected from

[0076] R 61 、R 62 、R 63 and R 64 are as defined in general formula (IN); in some embodiments, is selected from

[0077] R 61 is C 1-6 alkyl, R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen, and R 64 is a hydrogen atom or C 1-6 alkyl; in some embodiments, is selected from

[0078] In some embodiments of the present disclosure, the compounds represented by the general formulas (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein is R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen; in some embodiments, is R 62 and R 63 are both halogens; in some embodiments, is R 62 is a halogen (preferably F), and R 63 is a hydrogen atom.

[0079] In some embodiments of the present disclosure, the compounds represented by the general formulas (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein R x1 is Rx , R x as defined in general formula (IN); in some embodiments, R x1 is selected from =N-O-R 61 , =CR 62 R 63 and =N-R 64 , R 61 is C 1-6 alkyl, R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen, R 64 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R x1 is =CR 62 R 63 , R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen; in some embodiments, R x1 is =CR 62 R 63 , R 62 and R 63 are different and are a hydrogen atom or a halogen.

[0080] In some embodiments of the present disclosure, the compounds represented by general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein t1 is 0 or 1; in some embodiments, t1 is 0.

[0081] In some embodiments of the present disclosure, the compounds represented by general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein each R 6 is the same or different and each independently is a halogen; in some embodiments, R 6 is F; in some embodiments, R 6 is F and t1 is 1.

[0082] In some embodiments of the present disclosure, the compounds represented by general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, each R 6 is the same or different and each independently is selected from =N-O-R 61 , =CR 62 R 63 , =N-R 64 and an oxo group, R 61 , R 62 , R 63 and R 64 are as defined in general formula (IN); in some embodiments, each R 6 is the same or different and each independently is selected from =N-O-R61 、 =CR 62 R 63 、 =N-R 64 and an oxo group, R 61 is C 1-6 alkyl, R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen, R 64 is a hydrogen atom or C 1-6 alkyl; in some embodiments, each R 6 is the same or different and each independently is =CR 62 R 63 or an oxo group, R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen.

[0083] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein R 61 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 61 is C 1-6 alkyl; in some embodiments, R 61 is methyl.

[0084] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein R 62 and R 63 are the same or different and each independently is a hydrogen atom or a halogen; in some embodiments, R 62 and R 63 are different and are a hydrogen atom or a halogen; in some embodiments, R 62 and R 63 are the same or different and each independently is a hydrogen atom or F; in some embodiments, R 62 is a hydrogen atom, R 63 is F.

[0085] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein R 64 is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 64 is a hydrogen atom or methyl.

[0086] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein R 2a is selected from a hydrogen atom, a halogen, C1-6 alkyl and C 1-6 haloalkyl; in some embodiments, R 2a is a hydrogen atom or C 1-6 alkyl; in some embodiments, R 2a is a hydrogen atom.

[0087] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or pharmaceutically acceptable salts thereof, wherein R e is a hydrogen atom or C 1-6 alkyl; in some embodiments, R e is a hydrogen atom.

[0088] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or pharmaceutically acceptable salts thereof, wherein each R 1 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, cyano, amino, hydroxy and C 1-6 hydroxyalkyl; in some embodiments, each R 1 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl and C 1-6 haloalkyl.

[0089] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or pharmaceutically acceptable salts thereof, wherein p is 0 or 1; in some embodiments, p is 0.

[0090] In some embodiments of the present disclosure, the compounds represented by the general formula (IN), (I), (I-1) or pharmaceutically acceptable salts thereof, wherein each R 3 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, cyano, amino, hydroxy, C 1-6 hydroxyalkyl and 3- to 8-membered cycloalkyl; in some embodiments, each R 3 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, hydroxy, -O-C(O)NHC 1-6Alkyl, amino, cyano, C 1-6 hydroxyalkyl and 3- to 8-membered cycloalkyl; in some embodiments, each R 3 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 haloalkyl, hydroxy, amino, and cyano; in some embodiments, each R 3 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and cyano; in some embodiments, each R 3 is the same or different and is independently selected from CF3, Cl, Me, F, cyano, and Et.

[0091] In some embodiments of the present disclosure, the compounds of the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein q is 2, 3 or 4; in some embodiments, q is 3 or 4; in some embodiments, q is 3.

[0092] In some embodiments of the present disclosure, the compounds of the general formula (IN), (I), (I-1) or their pharmaceutically acceptable salts, wherein q1 is 2 or 3; in some embodiments, q1 is 2.

[0093] In some embodiments of the present disclosure, the compounds of the general formula (I) or (I-1) or their pharmaceutically acceptable salts, wherein p is 0 or 1; R 1 is selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 haloalkyl; Selected from q1 is 2 or 3, R 3 is the same or different and is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and cyano; R 4a is halogen; is L is O; Q is N; R G1a is a hydrogen atom or methyl; is R 62 and R 63 are the same or different and are independently a hydrogen atom or halogen; or, is

[0094] In some embodiments of the present disclosure, the compounds of the general formula (I) or (I-1) or their pharmaceutically acceptable salts, wherein p is 0 or 1; R 1Selected from halogen, C 1-6 alkyl, C 2-6 alkenyl, and C 1-6 haloalkyl; Selected from q1 is 2 or 3, and R 3 are the same or different and each independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, and cyano; R 4a is halogen; is CH2; L is O; Q is N; R G1a is a hydrogen atom or methyl; is

[0095] Table A Typical compounds of the present disclosure include, but are not limited to:

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103] Another aspect of the present disclosure relates to a compound of formula (INA) or a salt thereof,

[0104]

[0105] wherein,

[0106] R y is a hydroxyl protecting group; preferably Bz;

[0107] Ring A, Ring C, R x1 , T, Q, L, G 0 , G 1 , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p, and q are as defined in formula (IN).

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

[0109]

[0110] Among them,

[0111] R y is a hydroxyl protecting group; preferably Bz;

[0112] Ring A, Ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p, and q are as defined in general formula (I).

[0113] Another aspect of the present disclosure relates to a compound represented by general formula (I-1A) or a salt thereof,

[0114]

[0115] Among them,

[0116] R y is a hydroxyl protecting group; preferably Bz;

[0117] Ring A, Ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p, and q are as defined in general formula (I).

[0118] In some embodiments of the present disclosure, for the compound represented by general formula (I-1A) or a salt thereof, when R G1a is a hydrogen atom, the configuration on the connected carbon atom does not exist.

[0119] Table B Typical intermediate compounds of the present disclosure include but are not limited to:

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129]

[0130]

[0131]

[0132]

[0133] Another aspect of the present disclosure relates to a method for preparing a compound of formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0134]

[0135] The compound of formula (INA) or a salt thereof is subjected to a deprotection reaction to obtain a compound of formula (IN) or a pharmaceutically acceptable salt thereof; optionally, when the R 3 group contains a protecting group, the step of removing the protecting group on the R 3 group is further included before, simultaneously or after the deprotection reaction;

[0136] Wherein,

[0137] R y is a hydroxyl protecting group; preferably Bz;

[0138] R d is a hydrogen atom;

[0139] Ring A, ring C, R x1 , T, Q, L, G 0 , G 1 , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q are as defined in formula (IN).

[0140] Another aspect of the present disclosure relates to a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0141]

[0142] The compound of general formula (IA) or its salt is subjected to a deprotection reaction to obtain the compound of general formula (I) or its pharmaceutically acceptable salt; optionally, when the R 3 group contains a protecting group, the step of removing the protecting group on the R 3 group is further included before, simultaneously or after the deprotection reaction;

[0143] wherein,

[0144] R y is a hydroxyl protecting group; preferably Bz;

[0145] Ring A, Ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q are as defined in general formula (I).

[0146] Another aspect of the present disclosure relates to a method for preparing the compound of general formula (I-1) or its pharmaceutically acceptable salt, the method comprising:

[0147]

[0148] The compound of general formula (I-1A) or its salt is subjected to a deprotection reaction to obtain the compound of general formula (I-1) or its pharmaceutically acceptable salt; optionally, when the R 3 group contains a protecting group, the step of removing the protecting group on the R 3 group is further included before, simultaneously or after the deprotection reaction;

[0149] wherein,

[0150] R y is a hydroxyl protecting group; preferably Bz;

[0151] Ring A, Ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q are as defined in general formula (I-1).

[0152] Another aspect of the present disclosure relates to a pharmaceutical composition, the pharmaceutical composition containing the compound of general formula (IN), (I), (I-1) or shown in Table A or its pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0153] The present disclosure further relates to the use of a compound of formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting KRAS G12D.

[0154] The present disclosure further relates to the use of a compound of formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by KRAS G12D.

[0155] The present disclosure further relates to the use of a compound of formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for treating and / or preventing tumors; the tumors are preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0156] The present disclosure further relates to a method for inhibiting KRAS G12D, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0157] The present disclosure further relates to a method for treating and / or preventing a disease or disorder mediated by KRAS G12D, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0158] The present disclosure further relates to a method for treating and / or preventing tumors, which comprises administering to a patient in need a therapeutically effective amount of a compound of general formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; the tumors are preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0159] The present disclosure further relates to a compound of general formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug.

[0160] The present disclosure further relates to a compound of general formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for inhibiting KRAS G12D.

[0161] The present disclosure further relates to a compound of general formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing a disease or disorder mediated by KRAS G12D.

[0162] The present disclosure further relates to a compound of general formula (IN), (I), (I-1) or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used for treating and / or preventing tumors; the tumors are preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

[0163] The disease or disorder described in the present disclosure is a disease or disorder that is treated and / or prevented by inhibiting KRAS G12D.

[0164] Preferably, the disease or disorder mediated by KRAS G12D according to the present disclosure is a tumor; the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma, and glioblastoma; more preferably selected from pancreatic cancer, colorectal cancer, and non-small cell lung cancer.

[0165] The colorectal cancer according to the present disclosure is preferably colon cancer or rectal cancer.

[0166] Preferably, the brain cancer in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyoma, leiomyosarcoma, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; lymphoma is selected from Hodgkin's disease and non-Hodgkin lymphoma (such as mantle cell lymphoma, diffuse large B-cell lymphoma, follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma, and peripheral T-cell lymphoma); liver cancer is preferably hepatocellular carcinoma; 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; kidney cancer is selected from renal cell carcinoma, clear cell, and renal oncocytoma; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myelogenous 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; myeloma is preferably multiple myeloma.

[0167] The active compound can be made into a form suitable for administration by any appropriate route, and the composition of the present disclosure is formulated by using one or more pharmaceutically acceptable carriers by conventional methods. Therefore, the active compound of the present disclosure can be formulated into various dosage forms for oral administration, injection (such as intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present 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.

[0168] As a general guidance, the active compounds of the present disclosure are preferably in the form of unit doses or in a form that allows the patient to self-administer a single dose. The unit dose of the compounds or compositions of the present disclosure can be expressed as tablets, capsules, cachets, vials of liquid medicine, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations. Suitable unit doses can be 0.1 to 1000 mg.

[0169] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg - 1000 mg.

[0170] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01 - 99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 0.1 - 99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 1% - 99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative. In certain embodiments, the pharmaceutical composition contains 2% - 98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopically substituted derivative.

[0171] In certain embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01% - 99.99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.1% - 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 0.5% - 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 1% - 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition contains 2% - 98% of a pharmaceutically acceptable excipient.

[0172] In addition to the active compound, the pharmaceutical compositions of the present disclosure may contain one or more excipients selected from the following components: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the mode of administration, the composition may contain 0.1 to 99% by weight of the active compound.

[0173] Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for mixing to prepare tablets. These excipients can be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets can be uncoated or coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.

[0174] Oral formulations can also be provided as 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.

[0175] The aqueous suspension contains the active substance and excipients suitable for the preparation of an aqueous suspension for mixing. Such excipients are suspending agents, dispersing agents or wetting agents. The aqueous suspension may also contain one or more preservatives, one or more colorants, one or more flavoring agents and one or more sweetening agents.

[0176] The oil suspension can be formulated by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickening agent. The above-mentioned sweetening agents and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

[0177] The pharmaceutical compositions of the present disclosure can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil, a mineral oil or a mixture thereof. Suitable emulsifying agents can be naturally occurring phospholipids. The emulsion can also contain sweetening agents, flavoring agents, preservatives and antioxidants. Such preparations can also contain emollients, preservatives, colorants and antioxidants.

[0178] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous solution. Acceptable solvents or vehicles that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation can be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection solution or microemulsion can be injected into the bloodstream of the patient by local large-volume injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. 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.TM.5400 type intravenous infusion pump.

[0179] The pharmaceutical compositions of the present disclosure can be in the form of a sterile injectable aqueous or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques with those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, a sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any compatible fixed oil can be used. In addition, fatty acids can also be used to prepare injectables.

[0180] The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperature but liquid in the rectum and thus will melt in the rectum to release the drug.

[0181] The compounds of the present disclosure can be administered as water-dispersible powders and granules in aqueous suspension, which can be prepared by adding water. 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.

[0182] 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 following: the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment regimen, such as the mode of treatment, the daily dosage of the compound, or the type of pharmaceutically acceptable salt, can be verified according to traditional treatment protocols.

[0183] Term Explanation

[0184] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0185] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight-chain or branched-chain group containing 1 to 20 carbon atoms, preferably an alkyl group having 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 1-12 alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C 1-6alkyl). 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 various branched isomers thereof. The alkyl group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of D atoms, halogens, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0186] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond, where the definition of the alkyl group is as described above, preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12 alkenyl), more preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C 2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group can be substituted or unsubstituted. When substituted, the substituents are preferably selected from one or more of alkoxy groups, halogens, haloalkyl groups, haloalkoxy groups, cycloalkyloxy groups, heterocyclyloxy groups, hydroxyl groups, hydroxyalkyl groups, cyano groups, amino groups, nitro groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups.

[0187] The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond, where the definition of the alkyl group is as described above. Preferably having 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms (i.e., C 2-12alkynyl), more preferably an alkynyl having 2 to 6 carbon atoms (i.e., C 2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. The alkynyl may be substituted or unsubstituted. When substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocycle, aryl, and heteroaryl.

[0188] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. 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 even 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, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyl includes spirocycloalkyl, fused cycloalkyl, and bridged cycloalkyl.

[0189] The term "spirocycloalkyl" refers to a polycyclic group having 5 to 20 members and sharing a single carbon atom (called a spiro atom) between monocyclic rings, which may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Spirocycloalkyl is classified into monospirocycloalkyl or polyspirocycloalkyl (e.g., dispirocycloalkyl) according to the number of spiro atoms shared between rings, preferably monospirocycloalkyl and dispirocycloalkyl. More preferably, it is 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 monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0190]

[0191] The term "fused cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 members, in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, and one or more of the rings may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). It can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused cycloalkyl according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 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 bicycloalkyl. Non-limiting examples of fused cycloalkyl include:

[0192]

[0193] The term "bridged cycloalkyl" refers to a fully carbon polycyclic group having 5 to 20 members, in which any two rings share two non-directly connected carbon atoms, and it may contain one or more double bonds. It is preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). It can be classified as bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged cycloalkyl according to the number of constituent rings, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0194]

[0195] The cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged) as described above fused to an aryl, heteroaryl, or heterocycloalkyl ring, where the ring connected to the parent structure is cycloalkyl. Non-limiting examples include etc.; preferably

[0196] Cycloalkyl can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0197] The term "alkoxy" refers to -O-(alkyl), where alkyl is defined as above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy can be optionally substituted or unsubstituted. When substituted, the substituents are preferably selected from D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

[0198] The term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic or polycyclic ring substituent containing 3 to 20 (such as 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 group), one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxidized (i.e., form sulfoxide or sulfone), but does not include ring moieties of -O-O-, -O-S- or -S-S-, and the remaining ring atoms are carbon. It preferably contains 3 to 14 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (i.e., 3- to 14-membered heterocyclic group), where 1 to 4 (such as 1, 2, 3 and 4) are heteroatoms; more preferably contains 3 to 8 ring atoms (such as 3, 4, 5, 6, 7 and 8) (i.e., 3- to 8-membered heterocyclic group) or 6 to 14 ring atoms (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14), where 1-3 are heteroatoms (such as 1, 2 and 3); more preferably contains 3 to 8 ring atoms, where 1-3 (such as 1, 2 and 3) are heteroatoms; most preferably contains 5 or 6 ring atoms (i.e., 5-membered or 6-membered heterocyclic group), where 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups.

[0199] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group with 5 to 20 members, where a single atom (called the spiro atom) is shared between monocyclic rings, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, and the sulfur may be optionally oxidized (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. It is preferably 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14) (i.e., 6- to 14-membered spiro heterocyclic group), more preferably 7 to 10 members (such as 7, 8, 9 or 10) (i.e., 7- to 10-membered spiro heterocyclic group). Spiro heterocyclic groups are classified into monospiro heterocyclic groups or polyspiro heterocyclic groups (such as dispiro heterocyclic groups) according to the number of spiro atoms shared between rings, preferably monospiro heterocyclic groups and dispiro heterocyclic groups. 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 monospiro heterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

[0200]

[0201] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein 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, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may optionally be oxidized (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6 to 14-membered fused heterocyclic group), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7 to 10-membered fused heterocyclic group). It can be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) fused heterocyclic groups according to the number of constituent rings, 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 the fused heterocyclic group include:

[0202]

[0203] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group having 5 to 20 members, wherein any two rings share two non-directly connected atoms, which may contain one or more double bonds, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may optionally be oxidized (i.e., form sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e., 6 to 14-membered bridged heterocyclic group), more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members) (i.e., 7 to 10-membered bridged heterocyclic group). It can be classified into bicyclic or polycyclic (e.g., tricyclic, tetracyclic) bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of the bridged heterocyclic group include:

[0204]

[0205] The heterocyclic group ring includes the above-mentioned heterocyclic groups (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, and non-limiting examples thereof include:

[0206] etc.

[0207] The heterocyclic group can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl, and heteroaryl.

[0208] The term "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic group (fused polycycles are rings sharing adjacent carbon atom pairs) having a conjugated π-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes the aryl ring fused to a heteroaryl, heterocyclic, or cycloalkyl ring as described above, where the ring connected to the parent structure is the aryl ring, and non-limiting examples thereof include:

[0209]

[0210] The aryl can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl, and heteroaryl.

[0211] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 (e.g., 1, 2, 3, and 4) heteroatoms and 5 to 14 ring atoms, where 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 even more preferably 5- or 6-membered (i.e., 5- or 6-membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes the heteroaryl fused to an aryl, heterocyclic, or cycloalkyl ring as described above, where the ring connected to the parent structure is the heteroaryl ring, and non-limiting examples thereof include:

[0212]

[0213]

[0214] The heteroaryl can be substituted or unsubstituted. When substituted, it can be substituted at any available attachment point, and the substituents are preferably selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl, and heteroaryl.

[0215] The above cycloalkyl, heterocyclic, aryl and heteroaryl groups include residues derived by removing one hydrogen atom from the parent ring atoms, or residues derived by removing two hydrogen atoms from the same or two different ring atoms of the parent, namely "divalent cycloalkyl", "divalent heterocyclic", "arylene" and "heteroarylene".

[0216] The term "amino protecting group" refers to a group that is used to protect the amino group with an easily removable group so that the amino group remains unchanged when reactions occur at other parts of the molecule. 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 substituted with 1-3 substituents selected from halogen, alkoxy and nitro; the amino protecting group is preferably Boc.

[0217] The term "hydroxy protecting group" refers to a hydroxy derivative that is usually used to block or protect the hydroxy group while reactions occur at other functional groups of the compound. As examples, preferably, the hydroxy protecting groups such as: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; the hydroxy protecting group is preferably MOM.

[0218] The term "alkynyl protecting group" refers to an easily removable group introduced on the alkynyl group so that the active hydrogen in acetylene or terminal alkyne remains unchanged when reactions occur at other parts of the molecule. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.; the alkynyl protecting group is preferably TIPS.

[0219] The term "cycloalkyloxy" means cycloalkyl-O-, where cycloalkyl is as defined above.

[0220] The term "heterocyclic oxy" means heterocyclic-O-, where heterocyclic is as defined above.

[0221] The term "aryloxy" means aryl-O-, where aryl is as defined above.

[0222] The term "heteroaryloxy" means heteroaryl-O-, where heteroaryl is as defined above.

[0223] The term "alkylthio" means alkyl-S-, where alkyl is as defined above.

[0224] The term "haloalkyl" means alkyl substituted with one or more halogen atoms, where alkyl is as defined above.

[0225] The term "haloalkoxy" means alkoxy substituted with one or more halogen atoms, where alkoxy is as defined above.

[0226] The term "deuterated alkyl" means alkyl substituted with one or more deuterium atoms, where alkyl is as defined above.

[0227] The term "hydroxyalkyl" means alkyl substituted with one or more hydroxyl groups, where alkyl is as defined above.

[0228] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0229] The term "hydroxyl" means -OH.

[0230] The term "mercapto" means -SH.

[0231] The term "amino" means -NH2.

[0232] The term "cyano" means -CN.

[0233] The term "nitro" means -NO2.

[0234] The term "oxo group" or "oxo" means "=O".

[0235] The term "carbonyl" means C=O.

[0236] The term "carboxyl" means -C(O)OH.

[0237] The term "carboxylate group" means -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.

[0238] MOM means methoxymethyl.

[0239] Boc means tert-butoxycarbonyl.

[0240] TIPS means triisopropylsilyl.

[0241] TBS means tert-butyldimethylsilyl.

[0242] Bz means benzoyl.

[0243] The compounds of the present disclosure may include all forms of their rotational isomers and conformationally restricted states. Also included are atropisomers, the term "atropisomer" referring to conformational stereoisomers resulting from restricted or greatly slowed rotation about a single bond in a molecule (due to steric interactions with other parts of the molecule and the asymmetry of the substituents at the two ends of the single bond), the interconversion of which is slow enough to allow separation and isolation under predetermined conditions. For example, certain compounds of the present disclosure may exist in the form of a mixture of atropisomers (such as an equimolar mixture, a mixture enriched in one atropisomer, etc.) or in the form of a purified atropisomer. The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. An example of the keto-enol equilibrium is shown below:

[0244]

[0245] All tautomeric forms are within the scope of the present disclosure. The naming of a compound does not exclude any tautomer.

[0246] The compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis- and trans- (or Z- and E-) isomers, (-)- and (+)-isomers, (R)- and (S)-enantiomers, diastereomers, (D)- and (L)-isomers, tautomers, atropisomers, conformational isomers, and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the compounds of the present disclosure may have additional asymmetric atoms. All such stereoisomers and their mixtures are included within the scope of the present disclosure. For all carbon-carbon double bonds, both the Z-form and the E-form are included even if only one configuration is named. 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. An isomer of a certain compound of the present disclosure can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, 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 diastereomeric salt with an appropriate optically active acid or base, and then separating the diastereomers by conventional methods well known in the art to obtain the pure isomer. In addition, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

[0247] In the chemical structure of the compounds described in the present disclosure, the bond represents an unspecified configuration, that is, if there are chiral isomers in the chemical structure, the bond can be or or can contain both and of the two configurations.

[0248] The compounds of the present disclosure include all suitable isotopic derivatives of the compounds. 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 can be introduced into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, iodine, etc., such as 2 H (deuterium, D), 3 H (tritium, T), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 p, 33 p, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, etc., preferably deuterium.

[0249] Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxicity and side effects, increasing drug stability, enhancing efficacy, and prolonging the biological half-life of the drug. All transformations of the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, where the replacement of deuterium can be partial or complete, and partial replacement of deuterium means that at least one hydrogen is replaced by at least one deuterium.

[0250] "Optionally" or "optional" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally substituted by halogen or cyano C 1-6 alkyl" means that halogen or cyano can but does not have to be present, and this description includes the cases where the alkyl is substituted by halogen or cyano and the cases where the alkyl is not substituted by halogen and cyano.

[0251] "Substituted" means that one or more, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group are independently replaced by the corresponding number of substituents. Those skilled in the art can determine what substitutions are possible or impossible without undue effort (by experiment or theory). For example, an amino or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (such as olefinic) bond.

[0252] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or pharmaceutically acceptable salts or prodrugs thereof and other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient and thus exert biological activity.

[0253] "Pharmaceutically acceptable salt" refers to salts of the compounds of the present disclosure, which can be selected from inorganic salts or organic salts. Such salts are safe and effective when used in mammals and have the appropriate biological activity. The salts can be prepared individually 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 inorganic acids and organic acids.

[0254] For a drug or pharmacological active agent, the term "therapeutically effective amount" refers to the amount of the drug or agent sufficient to achieve or at least partially achieve the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. In a particular case, the appropriate therapeutically effective amount can be determined by those skilled in the art according to routine tests.

[0255] As used herein, the term "pharmaceutically acceptable" means that these compounds, materials, compositions and / or dosage forms are suitable for contact with patient tissues within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, have a reasonable benefit / risk ratio, and are effective for the intended use.

[0256] As used herein, the singular forms "a", "an" and "the" include plural references and vice versa, unless the context clearly indicates otherwise.

[0257] When the term "about" is applied to parameters such as pH, concentration, temperature, etc., it indicates that the parameter can vary by ±10%, and sometimes more preferably within ±5%. As those skilled in the art will understand, when the parameter is not critical, numbers are usually given for illustrative purposes only and not for limitation.

[0258] Synthesis Method of the Compounds of the Present Disclosure

[0259] To achieve the objectives of the present disclosure, the following technical solutions are adopted in the present disclosure:

[0260] Solution 1

[0261] The present disclosure provides a method for preparing a compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising:

[0262]

[0263] The compound represented by general formula (INA) or a salt thereof undergoes a deprotection reaction under basic conditions to obtain the compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof; optionally, when the R 3 group contains a protecting group, before, simultaneously with, or after the deprotection reaction, it further includes a step of removing the protecting group on the R 3 group under acidic or basic conditions;

[0264] wherein

[0265] R y is a hydroxyl protecting group; preferably Bz;

[0266] R d is a hydrogen atom;

[0267] Ring A, Ring C, R x1 、T、Q、L、G 0 、G 1 、R 1 、R 3 、R 4a 、R 5a 、R 5b 、R 6 、r, t1, p and q are as defined in general formula (IN).

[0268] Solution 2

[0269] The present disclosure provides a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:

[0270]

[0271] The compound represented by general formula (IA) or a salt thereof undergoes a deprotection reaction under basic conditions to obtain the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof; optionally, when the R 3 group contains a protecting group, before, simultaneously with, or after the deprotection reaction, it further includes a step of removing the protecting group on the R 3 group under acidic or basic conditions;

[0272] wherein,

[0273] Ry is a hydroxyl protecting group; preferably Bz;

[0274] Ring A, Ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q are as defined in general formula (I).

[0275] Scheme III

[0276] The present disclosure provides a method for preparing a compound represented by general formula (I-1) or a pharmaceutically acceptable salt thereof, the method comprising:

[0277]

[0278] The compound of general formula (I-1A) or a salt thereof undergoes a deprotection reaction under basic conditions to obtain the compound of general formula (I-1) or a pharmaceutically acceptable salt thereof; optionally, when the R 3 group contains a protecting group, before, simultaneously or after the deprotection reaction, it further comprises the step of removing the protecting group on the R 3 group under acidic or basic conditions;

[0279] Wherein,

[0280] R y is a hydroxyl protecting group; preferably Bz;

[0281] Ring A, Ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q are as defined in general formula (I-1).

[0282] 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.

[0283] The reagents providing basic conditions in the above synthesis scheme include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, the tetrahydrofuran solution of tetrabutylammonium fluoride, 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, the reagent providing basic conditions is potassium carbonate.

[0284] In the above synthesis scheme, when R 3 contains a terminal alkyne group, the terminal alkyne can be protected by TIPS. The reagent for removing TIPS is preferably the tetrahydrofuran solution of tetrabutylammonium fluoride or cesium fluoride.

[0285] The reaction of the above steps is preferably carried out in a solvent. The solvents used include, but are not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane, and their mixtures. Detailed implementation mode

[0286] The following examples are used to further describe the present disclosure, but these examples do not limit the scope of the present disclosure.

[0287] Examples

[0288] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR chemical shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is carried out using a Bruker AVANCE-400 nuclear magnetic resonance spectrometer or a Bruker AVANCE NEO 500M. The solvents for measurement are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard is tetramethylsilane (TMS).

[0289] The MS measurement is carried out using an Agilent 1200 / 1290DAD-6110 / 6120Quadrupole MS liquid chromatography-mass spectrometry instrument (manufacturer: Agilent, MS model: 6110 / 6120Quadrupole MS).

[0290] waters ACQuity UPLC-QD / SQD (Manufacturer: waters, MS model: waters ACQuity QdaDetector / waters SQ Detector)

[0291] THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS model: THERMO QExactive)

[0292] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high pressure liquid chromatographs.

[0293] Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

[0294] High performance liquid chromatography for preparation was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0295] Chiral preparation was performed using a Shimadzu LC-20AP preparative chromatograph.

[0296] The CombiFlash rapid preparator used Combiflash Rf200 (TELEDYNE ISCO).

[0297] Thin layer chromatography silica gel plates used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) had a specification of 0.15 mm - 0.2 mm, and the silica gel plates used for thin layer chromatography separation and purification of products had a specification of 0.4 mm - 0.5 mm.

[0298] Silica gel column chromatography generally used Yantai Huanghai silica gel with a mesh size of 200 - 300 as the carrier.

[0299] Average kinase inhibition rate and IC 50 The value was measured using a NovoStar microplate reader (BMG Labtech, Germany).

[0300] The known starting materials of the present invention can be adopted, synthesized according to methods known in the art, or purchased from companies such as ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, etc.

[0301] Unless otherwise specified in the examples, the reactions can all be carried out under an argon or nitrogen atmosphere.

[0302] An argon or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1 L.

[0303] A hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1 L.

[0304] The pressure hydrogenation reaction uses a Parr 3916EKX type hydrogenator and a Qinglan QL-500 type hydrogen gas generator or an HC2-SS type hydrogenator.

[0305] The hydrogenation reaction usually involves evacuating, filling with hydrogen, and repeating the operation 3 times.

[0306] The microwave reaction uses a CEM Discover-S 908860 type microwave reactor.

[0307] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0308] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.

[0309] The progress of the reactions in the examples was monitored by thin layer chromatography (TLC). The eluent systems for column chromatography used to purify the compounds and the developing agent systems for thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate. The volume ratio of the solvents was adjusted according to the polarity of the compounds, and a small amount of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0310] Example 1

[0311] (5S,5aS,6S,9R)-2-(5-Amino-3-chloro-2-(trifluoromethyl)phenyl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol

[0314]

[0315] The first step

[0316] tert-Butyl 4-(difluoromethylene)piperidine-1-carboxylate 1b

[0317] Dissolve (difluoromethyl)triphenylphosphonium tetrafluoroborate (30.2 g, 79 mmol, Shanghai Bide) in tetrahydrofuran (200 mL). Add a 1 M solution of potassium bis(trimethylsilyl)amide in tetrahydrofuran (75.3 mL) at -70 °C. Stir the reaction mixture at this temperature for 1 hour. Then add N-Boc-4-piperidone 1a (15 g, 75.3 mmol, Shanghai Bide). Stir the reaction mixture at -70 °C for 1 hour and then allow it to warm to room temperature naturally and stir for 16 hours. Quench the reaction mixture by adding saturated ammonium chloride solution. Extract with ethyl acetate (100 mL × 3). Combine the organic phases, dry over anhydrous sodium sulfate, filter off the desiccant, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography using eluent system B to obtain the title compound 1b (13.7 g, yield: 84.3%).

[0318] MS m / z (ESI): 234.1 [M+1].

[0319] The second step

[0320] 4-(Difluoromethylene)piperidine hydrochloride 1c

[0321] Under an ice bath, dissolve compound 1b (13.7 g, 63.5 mmol) in a 4.0 M solution of hydrogen chloride in 1,4-dioxane (80 mL). Allow it to warm to room temperature naturally and stir for 2 hours. Concentrate the reaction mixture under reduced pressure to obtain the crude title compound 1c (9.6 g). The product is used directly in the next step without purification.

[0322] MS m / z (ESI): 134.1 [M+1].

[0323] The third step

[0324] Methyl 1-(4-(difluoromethylene)piperidine-1-carbonyl)cyclopropane-1-carboxylate 1d

[0325] Dissolve monomethyl 1,1-cyclopropanedicarboxylate (22 g, 152.6 mmol, Shanghai Leyan) in dichloromethane (400 mL). Flush with nitrogen three times. At 0 °C, add oxalyl chloride (77.5 g, 610.4 mmol) and N,N-dimethylformamide (DMF) (391 mg, 5.3 mmol). Allow it to warm to room temperature naturally and stir for 3 hours. Concentrate the reaction mixture under reduced pressure and dissolve it in dichloromethane (80 mL) for later use.

[0326] The crude compound 1c (23.1 g, 152.6 mmol) was dissolved in dichloromethane (400 mL). At 0 °C, triethylamine (61.8 g, 610.4 mmol) was added, and the above-prepared solution was added dropwise. The mixture was stirred and reacted for 1 hour. Saturated sodium bicarbonate solution was added to the reaction solution. After liquid separation, the organic phase was washed with saturated sodium chloride solution and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1d (27.3 g, yield: 74.2%). MS m / z (ESI): 260.1 [M+1].

[0327] The fourth step

[0328] (1-((4-(Difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methanol 1e

[0329] Compound 1d (14.3 g, 59.34 mmol) was dissolved in tetrahydrofuran (300 mL). At 0 °C, a 1.0 M solution of lithium aluminum hydride in tetrahydrofuran (118.8 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. Water and saturated sodium potassium tartrate solution were successively added to the reaction solution. The mixture was extracted with ethyl acetate (300 mL × 3). The combined organic phases were dried over 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 obtain the title compound 1e (10.8 g, yield: 91.3%).

[0330] MS m / z (ESI): 218.1 [M+1].

[0331] The fifth step

[0332] 2,5,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-ol 1g

[0333] The crude compound 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidin-2,4-ol 1f (2 g, 8 mmol, prepared by the method disclosed in Example 4 on page 117 of patent application "WO2022268051A1") was dissolved in phosphorus oxychloride (25 mL). N,N-Diisopropylethylamine (5.16 g, 40 mmol) was added, and the mixture was stirred and reacted at 110 °C for 14 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and 20% potassium carbonate solution was added dropwise to adjust the pH to 2-3. After stirring for 2 hours, the mixture was filtered. The filter cake was washed with water and dried to obtain the crude title compound 1g (1.5 g). The product was used directly in the next step without purification.

[0334] MS m / z (ESI): 267.8 [M+1].

[0335] The sixth step

[0336] (R)-Methyl 5-methoxy-3,4-dihydro-2H-pyrrole-2-carboxylate 1i

[0337] (R)-Methyl 2-pyrrolidone-5-carboxylate 1h (20 g, 139.7 mmol, Shanghai Bide) and dimethyl sulfate (22.1 g, 175.2 mmol) were mixed and reacted at 60 °C for 22 h. The reaction solution was cooled to room temperature and poured into a solution of triethylamine (20 g) and water (100 mL) under ice bath. After extraction with methyl tert-butyl ether (60 mL×6), the crude product of the title compound 1i (16.3 g, yield: 74.2%) was obtained by concentration under reduced pressure. The crude product was directly used in the next step without purification.

[0338] MS m / z (ESI): 158.1 [M+1].

[0339] The seventh step

[0340] (R,Z)-Methyl 5-(2-methoxy-1-nitro-2-oxoethylidene)pyrrolidine-2-carboxylate 1j

[0341] The crude product of compound 1i (16.3 g, 103.7 mmol) and methyl nitroacetate (13.6 g, 114.2 mmol, Shanghai Shaoyuan) were mixed and heated to 60 °C with stirring for 24 h. 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 B to obtain the title compound 1j (8.37 g, yield: 33%).

[0342] MS m / z (ESI): 245.1 [M+1].

[0343] The eighth step

[0344] (1S,2S,5R)-Methyl 4-oxo-3,8-diazabicyclo[3.2.1]octane-2-carboxylate 1k

[0345] Compound 1j (7.5 g, 30.7 mmol) was dissolved in 150 mL of methanol, 10% palladium on carbon catalyst (wet) (1.5 g) was added, and the mixture was purged with hydrogen three times. Then it was heated to 50 °C and stirred for 24 h. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure to obtain the crude product of the title compound 1k (5.6 g). The product was directly used in the next step without purification.

[0346] MS m / z (ESI): 185.2 [M+1].

[0347] The ninth step

[0348] 8-(tert-Butyl) 2-methyl (1S,2S,5R)-4-oxo-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate 1l

[0349] The crude compound 1k (5.65 g, 30.4 mmol) was dissolved in 60 mL of dichloromethane. Triethylamine (6.2 g, 61.27 mmol) and di-tert-butyl dicarbonate (6.6 g, 30.24 mmol) were added under an ice bath, and the mixture was stirred for 14 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1l (3 g, yield: 34.7%).

[0350] MS m / z (ESI): 285.2 [M+1].

[0351] The tenth step

[0352] (1S,2S,5R)-2-(Hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1m

[0353] Compound 1l (3 g, 10.55 mmol) was dissolved in 30 mL of tetrahydrofuran. 32 mL of 1 M lithium aluminum hydride in tetrahydrofuran solution was added dropwise under an ice bath, and the mixture was stirred at room temperature for 4 h. 1.05 mL of water, 1.05 mL of 15% sodium hydroxide solution and 3.15 mL of water were added successively under an ice bath, and the mixture was stirred at room temperature for 15 min. Anhydrous magnesium sulfate (1 g) was added, and the mixture was stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound 1m (2.4 g). The product was used directly in the next step without purification.

[0354] MS m / z (ESI): 243.2 [M+1].

[0355] The eleventh step

[0356] (1S,2S,5R)-2-(Hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid di-tert-butyl ester 1n

[0357] Compound 1m (940 mg, 3.88 mmol) was dissolved in 10 mL of absolute ethanol. Di-tert-butyl dicarbonate (890 mg, 4.08 mmol) was added, and the mixture was stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure, diluted with dichloromethane, washed successively with 2% aqueous citric acid solution, water, 5% aqueous sodium bicarbonate solution, dried, and concentrated under reduced pressure to obtain the crude title compound 1n (1.15 g). The product was used directly in the next step without purification.

[0358] MS m / z (ESI): 343.2 [M+1].

[0359] The twelfth step

[0360] (1S,2S,5R)-Di-tert-butyl 2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate 1o

[0361] Oxalyl chloride (1.15 g, 3.36 mmol) was dissolved in 9 mL of dry dichloromethane. A solution of DMSO (630 mg, 8.06 mmol) in dichloromethane (1.2 mL) was added under protection at -60 °C. After stirring at -60 °C for 5 min, a solution of compound 1n (1.15 g, 3.36 mmol) in dichloromethane (3.5 mL) was added. After stirring at -60 °C for 15 min, triethylamine (1.70 g, 16.80 mmol) was added, and the mixture was gradually warmed to room temperature and stirred for 1 hour. The reaction was quenched with water and washed successively with 2% aqueous citric acid solution, water, and 5% aqueous sodium bicarbonate solution, dried, and concentrated under reduced pressure to obtain the crude title compound 1o (1.13 g). The product was used directly in the next step without purification. MS m / z (ESI): 341.2 [M+1].

[0362] Step 13: (1S,6S,9R,9aS)-tert-Butyl 1-methyl-3-oxohexahydro-1H,3H-6,9-methanobisoxazolo[3,4-a]azepine-10-carboxylate 1p

[0363] Compound 1o (400 mg, 1.17 mmol) was dissolved in 5 mL of tetrahydrofuran. 1M Methylmagnesium bromide (1.7 mL, 1.76 mmol) was added at -40 °C. After gradually warming to room temperature and stirring for 1 hour, the temperature was raised to 50 °C and the reaction was carried out for 2 hours. The reaction was quenched with water, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 1p (160 mg, 46%).

[0364] MS m / z (ESI): 283.2 [M+1].

[0365] Step 14

[0366] (1S,2S,5R)-2-((S)-1-Hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1q

[0367] Compound 1p (160 mg, 0.54 mmol) was dissolved in 3 mL of tetrahydrofuran and 1 mL of water. Sodium hydroxide (215 mg, 5.4 mmol) was added, and the mixture was stirred at 80 °C for 2 hours and then returned to room temperature. Water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound 1q (145 mg, 99%). The product was used directly in the next step without purification.

[0368] MS m / z (ESI): 257.2 [M+1].

[0369] The fifteenth step

[0370] (1S,2S,5R)-2-((S)-1-((2,7-dichloro-8-fluoro-4-hydroxypyrido[4,3-d]pyrimidin-5-yl)oxy)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 1r

[0372] Dissolve compound 1q (370 mg, 1.44 mmol) in tetrahydrofuran (10 mL). Add sodium hydride (201 mg, 5.2 mmol, 60% purity) under ice bath. After reacting for 30 minutes, add compound 1g (353 mg, 1.31 mmol), stir and react for 2 hours. Quench the reaction mixture with water and then concentrate it under reduced pressure to obtain the crude title compound 1r (600 mg). The product is used directly in the next step without purification.

[0373] MS m / z (ESI): 488.2 [M+1].

[0374] The sixteenth step

[0375] (5S,5aS,6S,9R)-2,12-dichloro-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-carboxylic acid tert-butyl ester 1s

[0377] Dissolve compound 1r (300 mg, 0.60 mmol) in chloroform (10 mL). Add N,N-diisopropylethylamine (154 mg, 1.20 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (198 mg, 0.78 mmol). Stir and react at 70 °C for 2 hours. Filter to remove the desiccant and then concentrate it under reduced pressure. Purify it with column chromatography system A to obtain the title compound 1s (160 mg, 55%).

[0378] MS m / z (ESI): 470.2 [M+1].

[0379] The seventeenth step

[0380] (5S,5aS,6S,9R)-2-chloro-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-carboxylic acid tert-butyl ester 1t

[0382] Compound 1s (160 mg, 0.34 mmol) and compound 1e (92 mg, 0.42 mmol) were dissolved in tetrahydrofuran (5 mL). Under protection of an ice-water bath, 2 M sodium bis(trimethylsilyl)amide (0.25 mL, 0.50 mmol) was added, and the mixture was stirred at 0 °C for 1 hour. The reaction was quenched by adding methanol, and the mixture was concentrated under reduced pressure and purified by column chromatography system B to obtain the title compound 1t (100 mg, 45%).

[0383] MS m / z (ESI): 651.3 [M+1].

[0384] The eighteenth step

[0385] (5S,5aS,6S,9R)-2-(5-Amino-3-chloro-2-(trifluoromethyl)phenyl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-yl tert-butyl carbonate 1u

[0387] Compound 1t (100 mg, 0.15 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (62 mg, 194.6 μmol, prepared by the method disclosed in Example 80 on page 257 of the specification of patent application "WO2022148422") (74 mg, 0.23 mmol), tetrakis(triphenylphosphine)palladium (35.4 mg, 0.03 mol), and cesium carbonate (150 mg, 0.46 mmol) were mixed in 1,4-dioxane (3 mL) and water (0.5 mL). The mixture was purged with nitrogen and reacted at 100 °C for 16 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure after filtering off the desiccant to obtain the crude title compound 1u (120 mg). The product was used directly in the next step without purification.

[0388] MS m / z (ESI): 810.2 [M+1].

[0389] The nineteenth step

[0390] 3-Chloro-5-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-2-yl)-4-(trifluoromethyl)aniline 1v

[0392] The crude compound 1u (100 mg, 0.12 mmol) was dissolved in dichloromethane (1 mL), 1 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 1 hour. Then it was concentrated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to obtain the title compound 1v (40 mg, yield: 45%).

[0393] MS m / z (ESI): 710.2 [M+1].

[0394] The Twentieth Step

[0395] (5S,5aS,6S,9R)-2-(5-Amino-3-chloro-2-(trifluoromethyl)phenyl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-yl benzoate 1wUnder nitrogen protection, dipotassium hydrogen phosphate trihydrate was suspended in 5 mL of DMF, and then benzoyl peroxide (240 mg, 0.99 mmol) was added; a solution of compound 1v (441 mg, 0.62 mmol) in DMF (5 mL) was added under ice-water bath protection. The reaction was carried out overnight at room temperature, water was added, and the mixture was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and then concentrated under reduced pressure to obtain the crude title compound 1w (460 mg). The product was used directly in the next step without purification.

[0398] MS m / z (ESI): 830.2 [M+1].

[0399] The Twenty-First Step

[0400] (5S,5aS,6S,9R)-2-(5-Amino-3-chloro-2-(trifluoromethyl)phenyl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol 1

[0402] Compound 1w (100 mg, 0.138 mmol) was dissolved in 8 mL of methanol, and then anhydrous potassium carbonate (153 mg, 1.10 mmol) was added. The reaction was carried out at room temperature for 1 hour, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-2545, column: YMC Triart-Exrs C18, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mmol / L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-45%, flow rate: 30 mL / min) to obtain the title compound 1 (100 mg, yield: 24.8%).

[0403] MS m / z (ESI): 726.2 [M+1]. 1 1H NMR (500 MHz, CD3OD) δ 6.90 (d, 1H), 6.49 (d, 1H), 5.42 (dd, 1H), 4.64 - 4.35 (m, 3H), 4.11 (t, 1H), 3.70 (d, 1H), 3.59 (d, 1H), 3.43 (dd, 1H), 3.22 (t, 2H), 2.61 - 2.35 (m, 5H), 2.29 - 1.91 (m, 6H), 1.72 - 1.46 (m, 4H), 0.74 (s, 2H), 0.51 (s, 2H).

[0404] Example 2

[0405] (5S,5aS,6S,9R)-2-(5-Amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol 2

[0408]

[0409] The first step

[0410] tert-Butyl 4-(fluoromethylene)piperidine-1-carboxylate 2b

[0411] Dissolve 2-((fluoromethyl)sulfonyl)pyridine (4.2 g, 23.97 mmol) in tetrahydrofuran (50 mL). Add a solution of 1 M potassium bis(trimethylsilyl)amide in tetrahydrofuran (30 mL) at -78 °C. After maintaining the temperature for 30 minutes, add N-tert-butoxycarbonyl-4-piperidone 2a (5 g, 25.09 mmol, from Shanghai Shaoyuan). React at this temperature for 3 hours, then restore to room temperature and react for 1 hour. Quench the reaction mixture by adding saturated ammonium chloride solution, add 3 N hydrochloric acid (100 mL), stir for 1 hour, and then extract with ethyl acetate (50 mL × 3). Combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter to remove the desiccant, and then concentrate under reduced pressure. Purify the residue by silica gel column chromatography using eluent system B to obtain the title compound 2b (2 g, yield: 37%).

[0412] The second step

[0413] 4-(fluoromethylene)piperidine hydrochloride 2c

[0414] Dissolve compound 2b (1 g, 4.64 mmol) in a 4 M hydrogen chloride in 1,4-dioxane solution (20 mL), stir and react for 1 hour. Concentrate the reaction mixture under reduced pressure to obtain the crude title compound 2c (700 mg). The product is used directly in the next step without purification.

[0415] MS m / z (ESI): 116.1 [M+1].

[0416] The third step

[0417] (5S,5aS,6S,9R)-2-(5-amino-3-chloro-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol 2

[0418] Using the synthetic route in Example 1, replace the starting material 4-(difluoromethylene)piperidine hydrochloride in the third step with the crude compound 2c to obtain the title compound 2 (900 mg, yield: 58.6%).

[0419] MS m / z (ESI): 708.2 [M+1].

[0420] 11H NMR (500 MHz, CD3OD) δ 6.89 (s, 1H), 6.59 (s, 0.5H), 6.55 (s, 0.6H), 6.43 (s, 0.4H), 6.41 (s, 0.5H), 5.41 (dd, 1H), 4.58 - 4.51 (m, 1H), 4.46 (d, 1H), 4.41 (d, 1H), 4.10 (dd, 1H), 3.69 (d, 1H), 3.59 (d, 1H), 3.25 - 3.19 (m, 1H), 2.55 - 2.47 (m, 4H), 2.47 - 2.39 (m, 2H), 2.32 (d, 2H), 2.15 (tt, 1H), 2.10 - 2.03 (m, 3H), 2.03 - 1.93 (m, 1H), 1.63 (m, 1H), 1.57 (d, 3H), 0.73 (d, 2H), 0.51 (d, 2H).

[0421] Example 3

[0422] (5S, 5aS, 6S, 9R)-2-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol 3

[0424]

[0425] Using the synthetic route of Example 1, replace 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline in the eighteenth step with (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (prepared by the method disclosed in Intermediate 20 on page 170 of the patent application "WO2023225302A1") to obtain the title compound 3.

[0426] MS m / z (ESI): 724.3 [M + 1].[[]END]]

[0427] Example 4

[0428] (5S,5aS,6S,9R)-2-(5-Amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-1-fluoro-12-((1-((4-(fluoromethylene))piperidin-1-yl)methyl)cyclopropyl)methoxy)-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol 4

[0430]

[0431] Using the synthetic route of Example 2, the starting material 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline was replaced with (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (prepared by the method disclosed in Intermediate 20 on page 170 of the patent application "WO2023225302A1") to obtain the title compound 4.

[0432] MS m / z(ESI): 706.3[M+1].

[0433] Example 5

[0434] 2-Amino-4-((5S,5aS,6S,9R)-12-((1-((4-(difluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-1-fluoro-14-hydroxy-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-2-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 5

[0436]

[0437] Using the synthetic route of Example 1, the 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline in the eighteenth step was replaced with tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (prepared by the method disclosed in Preparation 15 on page 50 of the patent application "WO2021118877A1") to obtain the title compound 5.

[0438] MS m / z(ESI): 723.2[M+1].

[0439] Example 6

[0440] 2-Amino-7-fluoro-4-((5S,5aS,6S,9R)-1-fluoro-12-((1-((4-(fluoromethylene)piperidin-1-yl)methyl)cyclopropyl)methoxy)-14-hydroxy-5-methyl-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaazaphenanthro[1,8-ab]azulen-2-yl)benzo[b]thiophene-3-carbonitrile 6

[0442]

[0443] Using the synthetic route of Example 2, the raw material 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline was replaced with tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (prepared by the method disclosed in Preparation 15 on page 50 of the specification of patent application "WO2021118877A1"), to obtain the title compound 6.

[0444] MS m / z(ESI): 705.3 [M+1].

[0445] Example 7

[0446] (5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaazaphenanthro[1,8-ab]azulen-14-ol 7

[0448]

[0449] Using the synthetic route of Example 1, the raw material 1v was replaced with compound 7a (prepared by the method disclosed in Example 9-p1 on page 125 of patent application "WO2022268051A1"), to obtain the title compound 7.

[0450] MS m / z(ESI): 648.7 [M+1].

[0451] Example 8

[0452] (5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol 8

[0453]

[0454] The first step

[0455] (1-(Morpholinomethyl)cyclopropyl)methanol 8b

[0456] 1-Aminomethylcyclopropanemethanol 8a (1 g, 9.89 mmol, Shanghai Shaoyuan), bis(2-bromoethyl) ether (2.3 g, 9.91 mmol, Shanghai Bide) were dissolved in acetonitrile (60 mL), anhydrous sodium carbonate (3.1 g, 29.52 mmol) was added, and the reaction solution was refluxed for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with eluent system A to obtain the title compound 8b (1.3 g, yield: 76.7%).

[0457] MS m / z (ESI): 172.2 [M+1].

[0458] The second step

[0459] (5S,5aS,6S,9R)-2-(8-Ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-5-methyl-12-((1-(morpholinomethyl)cyclopropyl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano-naphtho[1,8-ab]azulen-14-ol 8

[0461] Using the synthetic route of Example 1, compound 1e in the seventeenth step was replaced with compound 8b, and 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline in the eighteenth step was replaced with 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (195 mg, 540 μmol, prepared by the method disclosed in Intermediate 18 on page 104 of the specification of patent application "WO2021 / 041671") to obtain the title compound 8 (11.8 mg, yield: 3.3%).

[0462] MS m / z (ESI): 674.8 [M+1].

[0463] Biological evaluation

[0464] Test Example 1: Biological evaluation of 3D proliferation inhibition experiment of AsPC-1 cells

[0465] On the first day of the experiment, after digesting AsPC-1 cells with good growth and 70%-80% confluence, resuspend them with RPMI 1640 (Hyclone, SH30809.01) medium containing 10% FBS, and adjust the cell density to the required density. Add 90 μL of cell suspension to each well of a U-bottom low-attachment 96-well plate (Corning, CLS7007-24EA), with a cell density of 1500 cells / well. After centrifuging the cell plate at 2500 rpm for 5 minutes, place it in an incubator at 37°C and 5% CO2 overnight. On the second day, dilute the 20 mM test compound dissolved in DMSO to the initial concentration of 2 mM with DMSO, and then further dilute it in a 5-fold gradient, with a total of 9 concentration points. The control well is DMSO. Then further dilute the gradient-diluted compound 20-fold with the medium. Add 10 μL of the test compound diluted with the medium to each well of the cell plate, and the final concentration of the compound is the initial concentration of 10 μM, with 9 concentration points in a 5-fold gradient dilution. Set the cell wells containing 0.5% DMSO as the solvent control wells, and the wells with only the medium and 0.5% DMSO as the blank control wells. Each concentration of the compound and the control wells are set up in duplicate, and the final concentration of DMSO in each well is 0.5%. After centrifuging the cell plate at 2500 rpm for 3 minutes, place it in an incubator at 37°C and 5% CO2 for 5 days. On the seventh day, take out the 96-well cell culture plate, add 50 μL of the luminescent cell viability detection reagent 3D Cell Viability Assay (Promega, G9683), shake it in the dark at room temperature for 25 minutes, mix well by pipetting up and down, and then transfer 100 μL from each well to a white opaque-bottom OptiPlate TM -96-well plate (PerkinElmer, 6005290), and use a multi-functional microplate reader (PerkinElmer, EnVision2105) to read the luminescence signal value

[0466] Use the following formula to calculate the inhibition rate: Inhibition rate = (luminescence value 溶媒对照孔 - luminescence value 受试化合物 ) / (luminescence value 溶媒对照孔 - luminescence value 空白对照孔 ) × 100%. Use GraphPad Prism software to plot a curve based on the concentration of each compound and the corresponding inhibition rate, and calculate the IC 50 value of the compound

[0467] Table 1. Data of 3D proliferation inhibition activity of AsPC-1 cells

[0468] Example Number <![CDATA[AsPC-1 / IC 50 (nM)]]> 2 4.5

[0469] Conclusion: The compounds of the present disclosure have good inhibitory effects on the 3D proliferation of AsPC-1 cells.

Claims

1. A compound represented by the general formula (IN) or a pharmaceutically acceptable salt thereof: in: R d Selected from hydrogen atom, alkyl, haloalkyl, hydroxyalkyl, -C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-(CR a R b ) v S(O) w R 17 、-(CR a R b ) v S(O) w NR 18 R 19 , cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, wherein the alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl are each independently optionally substituted by one or more R 00 replace; Ring C is a heterocyclic group; R x1 is a hydrogen atom or R x ; R x Selected from = NOR 61 , =CR 62 R 63 Sum = NR 64 ; G 0 Selected from O, S, S(O), S(O)2, CR G0a R G0b and NR G0c ; G 1 selected from CR G1a R G1b 、CR G1a R G1b CR G1c R G1d 、C=O and C(O)CR G1a R G1b ; T is a chemical bond or selected from CR at R bt NR T and O; Q is N or CR 2a ; Ring A is an aryl group or a heteroaryl group; L is selected from a single bond, O, S and NR e ; R at , R bt , R G0a , R G0b , R G1a , R G1b , R G1c and R G1d are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, a nitro group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group, or R G0a , R G0b Together with the attached carbon atom, it forms a cycloalkyl group, or R G1a , R G1b Together with the attached carbon atom, it forms a cycloalkyl group, or R G1c , R G1d Together with the attached carbon atom, it forms a cycloalkyl group, or R G0a , R G1a Together with the attached carbon atom, it forms a cycloalkyl group, or R G0a , R G1c Together with the attached carbon atom, it forms a cycloalkyl group, or R G1a , R G1c Together with the attached carbon atom, it forms a cycloalkyl group, or R G0c , R G1a Together with the atoms to which they are attached, they form a heterocyclic group, or R G0c , R G1c Together with the atoms to which they are attached, they form a heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl and heterocyclic groups are each independently optionally substituted with one or more R*; Each R 1 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-(CR a R b ) v S(O) w R 17 、-S(O) w NR 18 R 19 、-OC(O)R 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-NR 20 S(O) w R 17 、-OC(O)NR 18 R 19 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v Heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace; R 2a and R 4a are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CR a R b ) v NR 18 R 19 , hydroxy, hydroxyalkyl, and cycloalkyl; Each R 3 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CR a R b ) v NR 18 R 19 、-(CH2) w1 -(O) x1 -C(O)NR j1 R k1 、-(CH2) w2 -(O) x2 -C(O)OR j2 , nitro, hydroxy, hydroxyalkyl, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-(CR a R b ) v S(O) w R 17 、-S(O) w NR 18 R 19 、-OC(O)R 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-NR 20 S(O) w R 17 、-OC(O)NR 18 R 19 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v Heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace; Each R 6 are the same or different and are each independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CR a R b ) v NR 18 R 19 、-(CH2) y1 -(O) z1 -C(O)NR m1 R n1 、-(CH2) y2 -(O) z2 -C(O)OR m2 , =NOR 61 , =CR 62 R 63 , =NR 64 , nitro, hydroxy, hydroxyalkyl, oxo, -(CR a R b ) v OR 17 、-(CR a R b ) v NR 18 R 19 、-C(O)R 17 、-C(O)OR 17 、-C(O)NR 18 R 19 、-(CR a R b ) v S(O) w R 17 、-S(O) w NR 18 R 19 、-OC(O)R 17 、-NR 20 C(O)R 17 、-NR 20 C(O)OR 17 、-NR 20 S(O) w R 17 、-OC(O)NR 18 R 19 、-(CR a R b ) v Cycloalkyl, -(CR a R b ) v Heterocyclic group, -(CR a R b ) v Aryl and -(CR a R b ) v Heteroaryl, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted by one or more R 01 replace; R 61 , R 62 , R 63 and R 64 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and -(CR a R b ) v Cycloalkyl; R 5a and R 5b are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; or R 5a , R 5b Together with the carbon atom to which it is attached, it forms a cycloalkyl or heterocyclic group, wherein the cycloalkyl or heterocyclic group is independently substituted by one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; R G0c , R T , R e , R a , R b , R j1 , R k1 , R j2 , R m1 , R n1 , R m2 , R 17 , R 18 , R 19 and R 20 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, a hydroxyl, an alkoxy, a haloalkoxy, a cyano, an amino, a cycloalkyloxy, a heterocyclyloxy, a hydroxyalkyl, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyloxy, a heterocyclyloxy, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl are each independently optionally replaced by one or more R # replace; R 00 , R 01 , R* and R # are the same or different and are each independently selected from the group consisting of oxo, =S, halogen, hydroxy, alkenyl, alkynyl, cyano, nitro, amino, -NHalkyl, -N(alkyl), alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, aryl, arylalkyl, aryloxy, heteroaryl, heteroarylalkyl, heteroaryloxy, -C(O)alkyl, -C(O)OH, -C(O)NH, -C(O)NHalkyl, and -C(O)N(alkyl); v, w1, w2, y1 and y2 are the same or different and are each independently selected from 0, 1, 2 and 3; w is 0, 1, or 2; x1, x2, z1 and z2 are the same or different and are each independently selected from 0 or 1; r is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4 or 5; and t1 is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R d is a hydrogen atom; and / or G 0 is O; and / or G 1 CR G1a H, R G1a As defined in claim 1; and / or T is a chemical bond.

3. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, which is a compound or pharmaceutically acceptable salt thereof represented by general formula (I): in, Ring A, Ring C, R x1 , Q, L, R G1a , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Q is N; and / or Ring A is selected from naphthyl, phenyl, pyridyl, benzothienyl, benzothiazolyl and benzopyrazolyl; and / or R 4a is a hydrogen atom or a halogen; and / or R G1a is a hydrogen atom or a methyl group; and / or L is O; and / or -CH2- or and / or each R 3 are the same or different and are each independently selected from halogen, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Haloalkyl, hydroxy, amino and cyano.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, which is the following compound:

6. A compound represented by the general formula (INA) or a salt thereof: in, R y is a hydroxyl protecting group; preferably Bz; Ring A, Ring C, R x1 , T, Q, L, G 0 , G 1 , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q as defined in claim 1; Preferred are the following compounds:

7. A method for preparing a compound represented by general formula (IN) or a pharmaceutically acceptable salt thereof, the method comprising: The compound of the general formula (INA) or its salt is subjected to a deprotection reaction to obtain a compound of the general formula (IN) or its pharmaceutically acceptable salt; optionally, when R 3 When the group contains a protecting group, the deprotection reaction also includes removing R 3 Steps for protecting groups on radicals; in, R y is a hydroxyl protecting group; preferably Bz; R d is a hydrogen atom; Ring A, Ring C, R x1 , T, Q, L, G 0 , G 1 , R 1 , R 3 , R 4a , R 5a , R 5b , R 6 , r, t1, p and q are as defined in claim 1.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

9. Use of the compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 8 in the preparation of a medicament for inhibiting KRAS G12D.

10. Use of a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a tumor; the tumor is preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, colorectal cancer, small intestine 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; more preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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