WO2024208305A1 - Fused tetracyclic compound and preparation method therefor and use thereof in medicine - Google Patents

Abstract

The present disclosure relates to a fused tetracyclic compound and a preparation method therefor and a use thereof in medicine. Specifically, the present disclosure relates to a fused tetracyclic compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing same, and a use thereof as a therapeutic agent, particularly a use thereof in the preparation of a drug for inhibiting KRAS G12D. The groups in general formula (I) are as defined in the description.

Description

Condensed tetracyclic compound, preparation method thereof and application thereof in medicine Technical Field

The present disclosure belongs to the field of medicine and relates to a fused tetracyclic compound, a preparation method thereof and its application in medicine. In particular, the present disclosure relates to a fused tetracyclic compound represented by general formula (I), a preparation method thereof and a pharmaceutical composition containing the compound, and its use in the preparation of a drug for inhibiting KRAS G12D.

Background Art

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

After KRAS is activated, it regulates cell proliferation, survival, migration, metabolism and other functions through numerous 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, resulting in continuous activation of downstream signaling pathways and promoting tumorigenesis.

Since the KRAS protein lacks small molecule binding sites in the traditional sense on its surface and has an extremely high affinity with guanosine, it is extremely difficult to inhibit. It has long been considered an undruggable drug target. However, due to the importance and prevalence of abnormal KRAS activation in cancer progression, KRAS has always been and remains a target of great interest in drug development. At present, in addition to KRAS G12C inhibitors, there is still a lack of KRAS inhibitors that are effective for other mutations, leaving most patients with KRAS mutations untreatable. G12D, as a mutant that is widely and highly expressed in a variety of tumors, has important clinical significance for the development of inhibitors against it.

The related patent applications that have been published so far include WO2023001141A1, WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1, WO2021000885A1, WO2022188729A1, WO2022268051A1, WO2023274383A1 and WO2023046135A1, etc.

Summary of the invention

The purpose of the present disclosure is to provide a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof:

in:

^G0 is selected from O, S, S(O), S(O) ₂ , CR ^G0a , R ^G0b and NR ^G0c ;

G ¹ is selected from CR ^{G1a RG1b} , CR ^{G1a RG1b} CR ^{G1c RG1d} , C=O and C(O)CR ^{G1a RG1b} ;

R ^P is selected from -C(O) ^RP1 , -(CR ^x1 R ^x2 -O) _x3 -C(O)OR ^P3 , -C(O)NR ^P3 R ^P4 , -C(O)OCR ^P11 R ^P12 OC (O)Z, -C(O)CR ^P11 R ^P12 NR ^P3 R ^P4 , -C(O)NR ^P13 CR ^P11 R ^P12 C(O)OR ^P3 , -S(O) ₂ R ^P1 , -S(O ) ₂ OR ^P3 and -S(O) ₂ NR ^P3 R ^P4 ;

R ^Q is a hydrogen atom or R ^P ;

^Rx1 , ^Rx2 , ^Rp1 , ^Rp11 , ^Rp12 , ^Rp3 , ^Rp4 , ^Rp13 and Z are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -C(O) ^Rp20 , a cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl group, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl group are each independently selected from a halogen, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -OC(O) ^Rp21 , cycloalkyl, heterocyclyl, aryl and heteroaryl, which are substituted by one or more substituents which are the same or different;

R ^P20 and R ^P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl;

T is a chemical bond or is selected from CR ^a R ^b , NR ^T and O;

Q is N or CR ^2a ;

Ring A is an aryl group or a heteroaryl group;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

L is selected from a single bond, O and NR ^e ;

^Ra , ^Rb , 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 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 ^G1a , R ^G1b and the carbon atom to which they are connected form a cycloalkyl group; or, R ^G1c , R ^G1d and the carbon atom to which they are connected form a cycloalkyl group;

Each R ¹ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _u -NR ^f R ^g , hydroxy, and hydroxyalkyl;

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, -(CH ₂ ) _v -NR ^h R ⁱ , a hydroxyl group, a hydroxyalkyl group and a cycloalkyl group;

each R ³ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _w -NR ^j R ^k , -(CH ₂ ) _w1 -(O) _z1 -C(O)NR ^j1 R ^k1 , -(CH ₂ ) _w2 -(O) _z2 -C(O)OR ^j2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R ⁶ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _w5 -NR ^m R ⁿ , -(CH ₂ ) _w3 -(O) _z3 -C(O)NR ^m1 R ⁿ¹ , -(CH ₂ ) _w4 -(O) _z4 -C(O)OR ^m2 , =NOR ⁶¹ , =CR ⁶² R ⁶³ , =NR ⁶⁴ , nitro, hydroxyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl; R ⁶¹ , R ⁶² , R ⁶³ and R ⁶⁴ are the same or different and are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

R ^5a and R ^5b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxyl group and a hydroxyalkyl group; or

R ^5a , R ^5b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group or the heterocyclic group are each independently substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl;

R ^G0c , ^RT , ^Re , R ^f , R ^g , R ^h , R ⁱ , R ^m , R ⁿ , R ^{m1 , R n1} , R ^m2 , R ^j , R ^k , R ^j1 , R ^k1 and R ^j2 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl ^group ;

u, v, w, w1, w2, w3, w4 and w5 are the same or different and are each independently selected from 0, 1, 2 and 3;

z1 is 0 or 1;

z2 is 0 or 1;

z3 is 0 or 1;

z4 is 0 or 1;

x3 is 0, 1, or 2;

r is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4 or 5;

y is 0, 1, 2, 3, 4, or 5; and

t is 0, 1, 2, 3, 4, or 5.

The purpose of the present disclosure is to provide a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof:

in:

^G0 is selected from O, S, S(O), S(O) ₂ , CR ^G0a , R ^G0b and NR ^G0c ;

G ¹ is selected from CR ^{G1a RG1b} , CR ^{G1a RG1b} CR ^{G1c RG1d} , C=O and C(O)CR ^{G1a RG1b} ;

R ^P is selected from -C(O) ^RP1 , -C(O)OR ^P3 , -C(O)NR ^P3 R ^P4 , -C(O)OCR ^P11 R ^P12 OC(O)Z, -C(O) CR ^P11 R ^P12 NR ^P3 R ^P4 , -C(O)NR ^P13 CR ^P11 R ^P12 C(O)OR ^P3 , -S(O) ₂ R ^P1 , -S(O) ₂ OR ^P3 and -S(O) _2NR ^P3 R ^P4 ;

R ^Q is a hydrogen atom or R ^P ;

R ^P1 , R ^P11 , R ^P12 , R ^P3 , R ^P4 , R ^P13 and Z are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -C(O)R ^P20 , a cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -OC(O)R ^P21 , a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl;

R ^P20 and R ^P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl;

T is a chemical bond or is selected from CR ^a R ^b , NR ^T and O;

Q is N or CR ^2a ;

Ring A is an aryl group or a heteroaryl group;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

L is selected from a single bond, O and NR ^e ;

^Ra , ^Rb , 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 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 ^G1a , R ^G1b and the carbon atom to which they are connected form a cycloalkyl group; or, R ^G1c , R ^G1d and the carbon atom to which they are connected form a cycloalkyl group;

Each R ¹ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _u -NR ^f R ^g , hydroxy, and hydroxyalkyl;

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, -(CH ₂ ) _v -NR ^h R ⁱ , a hydroxyl group, a hydroxyalkyl group and a cycloalkyl group;

each R ³ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _w -NR ^j R ^k , -(CH ₂ ) _w1 -(O) _z1 -C(O)NR ^j1 R ^k1 , -(CH ₂ ) _w2 -(O) _z2 -C(O)OR ^j2 , nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

each R ⁶ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _w5 -NR ^m R ⁿ , -(CH ₂ ) _w3 -(O) _z3 -C(O)NR ^m1 R ⁿ¹ , -(CH ₂ ) _w4 -(O) _z4 -C(O)OR ^m2 , =NOR ⁶¹ , =CR ⁶² R ⁶³ , =NR ⁶⁴ , nitro, hydroxyl, hydroxyalkyl, oxo, cycloalkyl, heterocyclic, aryl and heteroaryl; R ⁶¹ , R ⁶² , R ⁶³ and R ⁶⁴ are the same or different and are independently selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl and cycloalkyl;

R ^5a and R ^5b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxyl group and a hydroxyalkyl group; or

R ^5a , R ^5b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group or the heterocyclic group are each independently substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl;

R ^G0c , ^RT , ^Re , R ^f , R ^g , R ^h , R ⁱ , R ^m , R ⁿ , R ^{m1 , R n1} , R ^m2 , R ^j , R ^k , R ^j1 , R ^k1 and R ^j2 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl ^group ;

u, v, w, w1, w2, w3, w4 and w5 are the same or different and are each independently selected from 0, 1, 2 and 3;

z1 is 0 or 1;

z2 is 0 or 1;

z3 is 0 or 1;

z4 is 0 or 1;

r is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4 or 5;

y is 0, 1, 2, 3, 4, or 5; and

t is 0, 1, 2, 3, 4, or 5.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein ^G0 is selected from O, CR ^G0a R ^G0b and NR ^G0c , R ^G0a and R ^G0b are the same or different and are each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 haloalkyl group, and R ^G0c is a hydrogen atom or a C _1-6 alkyl group; preferably, ^G0 is selected from O, CH ₂ and NH; further preferably, ^G0 is O.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein ^G1 is CR ^{G1a RG1b} , CR ^{G1a RG1b} CR ^{G1c RG1d} or C=O, ^RG1a , ^RG1b , ^RG1c and ^RG1d are the same or different, and are each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 haloalkyl group; preferably, G ¹ is CH ₂ or CHCH ₃ ; further preferably, G ¹ is CH ₂ .

In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein ^-G0 - ^G1- is selected from -O- _CH2- , -NH-C( _O )-, _-NH -CH2-, -CH2- _CH2- and -O- _CH2 - _CH2- ; preferably -O- _CH2- or -O- _CHCH3- ; further preferably -O- _CH2- .

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

In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein Q is N or CH; preferably N.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein ring A is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; preferably, ring A is phenyl or naphthyl; further preferably, naphthyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein 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, hydroxyl, C _1-6 hydroxyalkyl and 3 to 8 membered cycloalkyl; preferably, 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, hydroxyl and cyclopropyl; further preferably, each R ³ is halogen or C _1-6 alkyl; most preferably, each R ³ is F or ethyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I’) or a pharmaceutically acceptable salt thereof, wherein y is 2.

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

in

R ^P is selected from -C(O) ^RP1 , -(CR ^x1 R ^x2 -O) _x3 -C(O)OR ^P3 , -C(O)NR ^P3 R ^P4 , -C(O)OCR ^P11 R ^P12 OC (O)Z, -C(O)CR ^P11 R ^P12 NR ^P3 R ^P4 , -C(O)NR ^P13 CR ^P11 R ^P12 C(O)OR ^P3 , -S(O) ₂ R ^P1 , -S(O ) ₂ OR ^P3 and -S(O) ₂ NR ^P3 R ^P4 ;

R ^Q is a hydrogen atom or R ^P ;

^Rx1 , ^Rx2 , ^Rp1 , ^Rp11 , ^Rp12 , ^Rp3 , ^Rp4 , ^Rp13 and Z are the same or different and are each independently selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino alkyl, -C(O)R ^P20 , cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, -OC(O)R ^P21 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^P20 and R ^P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

L is selected from a single bond, O and NR ^e ;

R ^G1a is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

each R ¹ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _u -NR ^f R ^g , hydroxyl and hydroxyalkyl;

R ^3a and R ^3b 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 hydroxyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R ^4a is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH ₂ ) _v -NR ^h R ⁱ , a hydroxyl group, a hydroxyalkyl group and a cycloalkyl group;

each R ⁶ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _w5 -NR ^m R ⁿ , -(CH ₂ ) _w3 -(O) _z3 -C(O)NR ^m1 R ⁿ¹ , -(CH ₂ ) _w4 -(O) _z4 -C(O)OR ^m2 , =NOR ⁶¹ , =CR ⁶² R ⁶³ , =NR ⁶⁴ , nitro, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁶¹ , R ⁶² , R ⁶³ and R ⁶⁴ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group and a cycloalkyl group;

R ^5a and R ^5b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxyl group and a hydroxyalkyl group; or

R ^5a , R ^5b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group or the heterocyclic group are each independently substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl;

^Re , ^Rf , ^Rg , ^Rh , ^Ri , Rm, ^Rn , ^Rm1 , ^Rn1 and ^Rm2 are the same or different and are each independently selected ^from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

u, v, w3, w4 and w5 are the same or different and are each independently selected from 0, 1, 2 and 3;

z3 is 0 or 1;

z4 is 0 or 1;

x3 is 0, 1, or 2;

r is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4 or 5; and

t is 0, 1, 2, 3, 4, or 5.

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

in

R ^P is selected from -C(O) ^RP1 , -C(O)OR ^P3 , -C(O)NR ^P3 R ^P4 , -C(O)OCR ^P11 R ^P12 OC(O)Z, -C(O) CR ^P11 R ^P12 NR ^P3 R ^P4 , -C(O)NR ^P13 CR ^P11 R ^P12 C(O)OR ^P3 , -S(O) ₂ R ^P1 , -S(O) ₂ OR ^P3 and -S(O) _2NR ^P3 R ^P4 ;

R ^Q is a hydrogen atom or R ^P ;

R ^P1 , R ^P11 , R ^P12 , R ^P3 , R ^P4 , R ^P13 and Z are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -C(O)R ^P20 , a cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl are each independently optionally substituted with one or more identical or different substituents selected from a halogen, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -OC(O)R ^P21 , a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl;

R ^P20 and R ^P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

L is selected from a single bond, O and NR ^e ;

R ^G1a is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups;

each R ¹ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _u -NR ^f R ^g , hydroxyl and hydroxyalkyl;

R ^3a and R ^3b 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 hydroxyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group;

R ^4a is selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an amino group, -(CH ₂ ) _v -NR ^h R ⁱ , a hydroxyl group, a hydroxyalkyl group and a cycloalkyl group;

each R ⁶ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _w5 -NR ^m R ⁿ , -(CH ₂ ) _w3 -(O) _z3 -C(O)NR ^m1 R ⁿ¹ , -(CH ₂ ) _w4 -(O) _z4 -C(O)OR ^m2 , =NOR ⁶¹ , =CR ⁶² R ⁶³ , =NR ⁶⁴ , nitro, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁶¹ , R ⁶² , R ⁶³ and R ⁶⁴ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group and a cycloalkyl group;

R ^5a and R ^5b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxyl group and a hydroxyalkyl group; or

R ^5a , R ^5b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group or the heterocyclic group are each independently substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl;

^Re , ^Rf , ^Rg , ^Rh , ^Ri , Rm, ^Rn , ^Rm1 , ^Rn1 and ^Rm2 are the same or different and are each independently selected ^from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

u, v, w3, w4 and w5 are the same or different and are each independently selected from 0, 1, 2 and 3;

z3 is 0 or 1;

z4 is 0 or 1;

r is 0, 1, 2, or 3;

p is 0, 1, 2, 3, 4 or 5; and

t is 0, 1, 2, 3, 4, or 5.

In some embodiments of the present disclosure, in the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, R ^G1a is a hydrogen atom or a C _1-6 alkyl group; preferably, R ^G1a is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 7- to 10-membered fused heterocyclic group, and R ⁶ can be substituted at any position of the ring B; preferably, ring B is R ⁶ may be substituted at any position of the ring B.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3- to 8-membered heterocyclic group.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, in for R ⁶ is as defined in general formula (I); preferably, for R ⁶ is halogen; further preferably, for R ⁶ is halogen; R ⁶ is more preferably F.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein for Preferably

In some embodiments of the present disclosure, in the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, L is selected from CH ₂ , NH and O; preferably O.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein ^Re is a hydrogen atom or a C _1-6 alkyl group; preferably, ^Re is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein each R ¹ is the same or different and is independently selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, cyano, amino, -(CH ₂ ) _u -NR ^f R ^g , hydroxyl and C _1-6 hydroxyalkyl, R ^f and R ^g are the same or different and are independently hydrogen atom or C _1-6 alkyl, and u is 0 or 1; preferably, each R ¹ is the same or different and is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein p is 0 or 1; preferably 0.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein R ^5a and R ^5b are the same or different and are each independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a hydroxyl group and a C _1-6 hydroxyalkyl group; preferably, R ^5a and R ^5b are the same or different and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, a hydroxyl group and a C _1-6 hydroxyalkyl group; further preferably, R ^5a and R ^5b are hydrogen atoms.

In some embodiments of the present disclosure, in the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, R ^5a and R ^5b are hydrogen atoms; or R ^5a , R ^5b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl group; preferably, R ^5a and R ^5b are hydrogen atoms; or R ^5a , R ^5b together with the carbon atom to which they are attached form a cyclopropyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein each R ⁶ is the same or different and is independently selected from halogen, C _1-6 alkyl and C _1-6 haloalkyl; further preferably halogen; more preferably F.

In some embodiments of the present disclosure, in the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, r is 0 or 1, preferably 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I’) or (I) or a pharmaceutically acceptable salt thereof, wherein r is 1 or 3.

In some embodiments of the present disclosure, in the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, r is 1; and/or R ^5a and R ^5b are hydrogen atoms.

In some embodiments of the present disclosure, the compound represented by the general formula (I’) or (I) or a pharmaceutically acceptable salt thereof, wherein t is 1 or 2, preferably 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I’) or (I) or a pharmaceutically acceptable salt thereof, wherein u is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I’) or (I) or a pharmaceutically acceptable salt thereof, wherein v is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or a pharmaceutically acceptable salt thereof, wherein w is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I’) or a pharmaceutically acceptable salt thereof, wherein w1 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I’) or a pharmaceutically acceptable salt thereof, wherein w2 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein w3 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein w4 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I') or (I) or a pharmaceutically acceptable salt thereof, wherein w5 is 0 or 1.

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

in

R ^P , R ^Q , R ^3a , R ^3b and R ^4a are as defined in the general formula (I); preferably, R ^3b is a C _1-6 alkyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein ^RP is -C(O)NR ^{P3 RP4} or -(CR ^x1 R ^x2 -O) _x3 -C(O)OR ^P3 , x3, R ^x1 , R ^x2 , ^RP3 and ^RP4 is as defined in the general formula (I); preferably, ^RP is selected from -C(O)NR ^{P3 RP4} , -C(O)OR ^P3 and -CR ^x1 R ^x2 -OC(O)OR ^P3 , R ^x1 , R ^x2 , ^RP3 and ^RP4 are the same or different and each independently a hydrogen atom or a C _1-6 alkyl group; preferably, ^RP is selected from -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)OCH ₂ CH ₃ and -CH(CH ₃ )-OC(O)OCH ₂ CH ₃ .

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein ^RP is -C(O)NR ^{P3 RP4} , ^RP3 and ^RP4 are as defined in the general formula (I); preferably, ^RP is -C(O)NR ^{P3 RP4} , ^RP3 and ^RP4 are the same or different and each independently is a hydrogen atom or a C _1-6 alkyl group; preferably, ^RP is -C(O)NHCH ₃ or -C(O)N(CH ₃ ) ₂ .

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein R ^P3 and R ^P4 are the same or different and are each independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ^P3 and R ^P4 are the same or different and are each independently a hydrogen atom or a methyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein R ^x1 and R ^x2 are the same or different and are each independently a hydrogen atom or a C _1-6 alkyl group; preferably, R ^x1 and R ^x2 are the same or different and are each independently a hydrogen atom or a methyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I’) or (II) or a pharmaceutically acceptable salt thereof, wherein x3 is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein R ^Q is a hydrogen atom or -C(O)OCR ^P11 R ^P12 OC(O)Z, R ^P11 , R ^P12 and Z are as defined in the general formula (I'); preferably, R ^Q is a hydrogen atom or -C(O)OCHR ^P12 OC(O)Z, R ^P12 and Z are C _1-6 alkyl groups; more preferably, R ^Q is a hydrogen atom or -C(O)OCHCH ₃ OC(O)CH ₂ CH ₂ CH ₃ .

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein R ^P11 and R ^P12 are the same or different and are each independently a hydrogen atom, a halogen, a C _1-6 alkyl group and a C _1-6 haloalkyl group; preferably, R ^P11 and R ^P12 are the same or different and are each independently a hydrogen atom or a C _1-6 alkyl group; further preferably, R ^P11 and R ^P12 are the same or different and are each independently a hydrogen atom or a methyl group; more preferably, R ^P11 is a hydrogen atom and R ^P12 is a methyl group.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein Z is selected from _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl and _C1-6 haloalkyl; preferably, Z is _C1-6 alkyl; more preferably, Z is n-propyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein R ^3a is selected from a hydrogen atom, a halogen, a C _1-6 alkyl, a C _2-6 alkynyl, a C _1-6 haloalkyl, a C _1-6 hydroxyalkyl and a 3 to 8 membered cycloalkyl; preferably, R ^3a is selected from a hydrogen atom, a halogen and a C _1-6 alkyl; further preferably, R ^3a is a halogen; more preferably, R ^3a is F.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein R ^3b is selected from a hydrogen atom, a halogen, a C _1-6 alkyl, a C _2-6 alkynyl, a C _1-6 haloalkyl, a C _1-6 hydroxyalkyl and a 3 to 8 membered cycloalkyl; preferably, R ^3b is selected from a hydrogen atom, a halogen and a C _1-6 alkyl; further preferably, R ^3b is a C _1-6 alkyl; more preferably, R ^3b is an ethyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (I') or (II) or a pharmaceutically acceptable salt thereof, wherein R ^4a is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; preferably halogen; more preferably F.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ^RP is -C(O)NR ^{P3 RP4} or -(CR ^x1 R ^x2 -O) _x3 -C(O)OR ^P3 , R ^x1 , R ^x2 , ^RP3 and ^RP4 are the same or different and each independently is a hydrogen atom or a C _1-6 alkyl group; R ^Q is a hydrogen atom or -C(O)OCHR ^P12 OC(O)Z, ^RP12 and Z are C _1-6 alkyl groups; R ^3a is a halogen; R ^3b is a C _1-6 alkyl group; x3 is 0 or 1; and R ^4a is a halogen.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein ^RP is -C(O)NR ^{P3 RP4} , ^RP3 and ^RP4 are the same or different and are independently a hydrogen atom or a C _1-6 alkyl group; R ^Q is a hydrogen atom or -C(O)OCHR ^P12 OC(O)Z, ^RP12 and Z are C _1-6 alkyl groups; R ^3a is a halogen; R ^3b is a C _1-6 alkyl group; and R ^4a is a halogen.

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

Another aspect of the present disclosure relates to a compound represented by general formula (I'A) or a salt thereof,

in,

R is an amino protecting group; preferably Boc;

^RP , ^G0 , ^G1 , T, Ring A, Ring B, Q, L, ^R1 , ^R3 , ^R4a , ^R5a , ^R5b , ^R6 , p, y, r and t are as defined in the general formula (I').

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

in,

R is an amino protecting group; preferably Boc;

^RP , ^RG1a , Ring B, L, ^R1 , ^R3a , ^R3b , ^R4a , ^R5a , ^R5b , ^R6 , p, r and t are as defined in the general formula (I).

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

in,

R is an amino protecting group; preferably Boc;

R ^P , R ^3a , R ^3b and R ^4a are as defined in the general formula (II).

Table B Typical intermediate compounds disclosed herein include but are not limited to:

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I') or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of the general formula (I'A) or its salt is subjected to a deprotection reaction to obtain a compound of the general formula (I') or its pharmaceutically acceptable salt, wherein R is an amino protecting group, preferably Boc, and R ^Q is H;

Optionally, further comprising subjecting a compound of the general formula (I') wherein R ^Q is H or a pharmaceutically acceptable salt thereof to a substitution reaction with R ^P -R ^L to obtain a compound of the general formula (I') wherein R ^Q is R ^P or a pharmaceutically acceptable salt thereof, wherein R ^L is a leaving group, preferably 4-nitrophenoxy;

^RP , ^G0 , ^G1 , T, Ring A, Ring B, Q, L, ^R1 , ^R3 , ^R4a , ^R5a , ^R5b , ^R6 , p, y, r and t are as defined in the general formula (I').

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, The method includes:

The compound of the general formula (IA) or its salt is subjected to a deprotection reaction to obtain a compound of the general formula (I) or its pharmaceutically acceptable salt, wherein R is an amino protecting group, preferably Boc, and R ^Q is H;

Optionally, further comprising subjecting a compound of the general formula (I) wherein R ^Q is H or a pharmaceutically acceptable salt thereof to a substitution reaction with R ^P -R ^L to obtain a compound of the general formula (I) wherein R ^Q is R ^P or a pharmaceutically acceptable salt thereof, wherein R ^L is a leaving group, preferably 4-nitrophenoxy;

^RP , ^RG1a , Ring B, L, ^R1 , ^R3a , ^R3b , ^R4a , ^R5a , ^R5b , ^R6 , p, r and t are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIA) or its salt is subjected to a deprotection reaction to obtain a compound of general formula (II) or its pharmaceutically acceptable salt, wherein R is an amino protecting group, preferably Boc, and R ^Q is H;

Optionally, further comprising subjecting a compound of the general formula (II) wherein R ^Q is H or a pharmaceutically acceptable salt thereof to a substitution reaction with R ^P -R ^L to obtain a compound of the general formula (II) wherein R ^Q is R ^P or a pharmaceutically acceptable salt thereof, wherein R ^L is a leaving group, preferably 4-nitrophenoxy;

R ^P , R ^3a , R ^3b and R ^4a are as defined in the general formula (II).

Another aspect of the disclosure relates to a pharmaceutical composition comprising a compound of the general formula (I), (I'), (II), or shown in Table A of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to compounds shown in general formula (I), (I'), (II), Table A or pharmaceutically acceptable salts thereof, Or use of a pharmaceutical composition comprising the same in preparing a drug for inhibiting KRAS G12D.

The present disclosure further relates to the use of the compounds shown in general formula (I), (I'), (II), Table A or their pharmaceutically acceptable salts, or pharmaceutical compositions comprising the same in the preparation of drugs for treating and/or preventing diseases or conditions, wherein the diseases or conditions are cancers; the diseases or conditions are preferably selected from brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, pharyngeal cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, Preferably, the present invention is selected from the group consisting of pancreatic cancer, colorectal cancer, small intestinal cancer, gastrointestinal stromal tumor, urothelial carcinoma, urethral cancer, bladder cancer, anal cancer, joint cancer, breast cancer, vaginal cancer, ovarian cancer, endometrial cancer, cervical cancer, fallopian tube cancer, testicular cancer, prostate cancer, hemangioma, leukemia, lymphoma, myeloma, skin cancer, melanoma, lipoma, bone cancer, soft tissue sarcoma, neurofibroma, glioma, neuroblastoma and glioblastoma; further preferably, the present invention is selected from the group consisting of pancreatic cancer, colorectal cancer and non-small cell lung cancer.

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 (I), (I'), (II), or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

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

The present disclosure further relates to a compound of formula (I), (I'), (II), or shown in Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a medicine.

The present disclosure further relates to a compound shown in the general formula (I), (I’), (II), Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, which is used as a drug for inhibiting KRAS G12D.

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

The diseases or conditions described in the present disclosure are diseases or conditions that are treated and/or prevented by inhibiting KRAS G12D.

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

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyomas, leiomyosarcomas, dedifferentiated liposarcoma, pleomorphic liposarcoma, malignant fibrous histiocytoma, round cell sarcoma and synovial sarcoma; lymphoma is selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, follicle 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 bronchial lung cancer) is selected from Non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and squamous cell carcinoma; renal cancer is selected from renal cell carcinoma, clear cell and renal oncocytoma; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myeloid leukemia, acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML); skin cancer is selected from malignant melanoma, squamous cell carcinoma, basal cell carcinoma and angiosarcoma; myeloma is preferably multiple myeloma.

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

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

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

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

In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable excipient based on the total weight of the composition. 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. Pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of a pharmaceutically acceptable excipient.

The pharmaceutical composition of the present disclosure may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for preparing tablets. These excipients may be inert excipients, granulating agents, disintegrants, binders and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.

Oral preparations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water-soluble carrier or an oily vehicle.

Aqueous suspensions contain the active substance and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents.

Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil, or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

Pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Such preparations may also contain a demulcent, a preservative, a coloring agent, and an antioxidant.

The pharmaceutical compositions disclosed herein may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injectable solution or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, it is preferred that the solution and microemulsion be administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be prepared by known techniques with the above-mentioned suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable non-toxic diluents or solvents. In addition, sterile fixed oils can be conveniently used as solvents or suspension media. For this purpose, any blended fixed oils can be used. In addition, fatty acids can also be used to prepare injections.

The disclosed compounds may 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 which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

The compounds of the present disclosure can be administered by preparing water-suspended dispersible powders and granules by adding water. These pharmaceutical compositions can be prepared by mixing the active ingredient with a dispersing or wetting agent, a suspending agent, or one or more preservatives.

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 factors: 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 method 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 regimens.

Terminology

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

The term "alkyl" refers to a saturated straight or branched aliphatic hydrocarbon group having 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., _C1-20 alkyl). The alkyl group is preferably an alkyl group having 1 to ₁₂ carbon atoms (i.e., _C1-12 alkyl), and more preferably an alkyl group having 1 to 6 carbon atoms (i.e., _C1-6 alkyl). 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 chain isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituent is preferably selected from one or more of a D atom, a halogen, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyloxy group, a heterocyclyloxy group, a hydroxyl group, a hydroxyalkyl group, a cyano group, an amino group, a nitro group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group.

The term "alkylene" refers to a divalent alkyl group, wherein the alkyl group is as defined above, and has 1 to 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., _C1-20 alkylene). The alkylene group is preferably an alkylene group having 1 to _{12 carbon atoms (i.e., C1-12 alkylene} ), and more preferably an alkylene group having 1 to 6 carbon atoms (i.e., _C1-6 alkylene). Non-limiting examples include: _-CH2- , -CH( _CH3 )-, _-C ( _CH3 ) _2- , _-CH2CH2- , -CH(CH2CH3)-, _-CH2CH (CH3) _- , _-CH2C ( _CH3 ) _2- , _{-CH2CH2CH2- , -CH2CH2CH2- ,} -CH2CH2CH2CH2-, _etc. Alkylene _can be substituted or _{unsubstituted} . When substituted, it _can be substituted at any available point of attachment. The substituents are _preferably selected from the D atom, One or more of halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., C2-12 _alkenyl ). The alkenyl group preferably has an alkenyl group of 2 to 6 carbon atoms (i.e., _C2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, etc. The alkenyl group can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above, and it has 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12) carbon atoms (i.e., _C2-12 alkynyl). The alkynyl group preferably has an alkynyl group of 2 to 6 carbon atoms (i.e., _C2-6 alkynyl). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Alkynyl can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment, and the substituent is preferably selected from one or more of D atoms, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to -O-(alkyl), wherein alkyl is as defined above. Non-limiting examples include methoxy, ethoxy, propoxy and butoxy, etc. Alkoxy can be substituted or unsubstituted, and when substituted, it can be substituted at any usable point of attachment, and the substituent is preferably selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic all-carbon ring (i.e., monocyclic cycloalkyl) or polycyclic ring system (i.e., polycyclic cycloalkyl) having 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 3 to 20-membered cycloalkyl). The cycloalkyl is preferably a cycloalkyl having 3 to 12 ring atoms (i.e., 3 to 12-membered cycloalkyl), more preferably a cycloalkyl having 3 to 8 ring atoms (i.e., 3 to 8-membered cycloalkyl), and most preferably a cycloalkyl having 3 to 6 ring atoms (i.e., 3 to 6-membered cycloalkyl).

Non-limiting examples of the monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl and cyclooctyl.

The polycyclic cycloalkyl group includes: spirocycloalkyl group, fused cycloalkyl group and bridged cycloalkyl group.

The term "spirocycloalkyl" refers to a polycyclic system in which the rings share a carbon atom (called a spiro atom), which may contain one or more double bonds in the ring, or one or more heteroatoms selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), provided that it contains at least one all-carbon ring and the point of attachment is on the all-carbon ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, The spirocycloalkyl group preferably has 6 to 14 ring atoms (i.e., 6 to 14 ring atoms), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10 ring atoms). The spirocycloalkyl group includes monospirocycloalkyl and polyspirocycloalkyl (such as bispirocycloalkyl, etc.), preferably monospirocycloalkyl or bispirocycloalkyl, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan monospirocycloalkyl. Non-limiting examples include:

Its connection point can be at any position;

wait.

The term "fused cycloalkyl" refers to a polycyclic system in which two adjacent carbon atoms are shared between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyls, or a monocyclic cycloalkyl fused to one or more heterocyclyls, aryls or heteroaryls, wherein the point of attachment is on the monocyclic cycloalkyl, which may contain one or more double bonds within the ring, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., 5 to 20-membered fused cycloalkyl). The fused cycloalkyl preferably has 6 to 14 ring atoms (i.e., 6 to 14-membered fused cycloalkyl), and more preferably has 7 to 10 ring atoms (i.e., 7 to 10-membered fused cycloalkyl). The condensed cycloalkyl includes bicyclic condensed cycloalkyl and polycyclic condensed cycloalkyl (such as tricyclic condensed cycloalkyl, tetracyclic condensed cycloalkyl, etc.), preferably bicyclic condensed cycloalkyl or tricyclic condensed cycloalkyl, more preferably 3 yuan/4 yuan, 3 yuan/5 yuan, 3 yuan/6 yuan, 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/3 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 5 yuan/7 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 yuan/5 yuan, 6 yuan/6 yuan, 6 yuan/7 yuan, 7 yuan/5 yuan or 7 yuan/6 yuan bicyclic condensed cycloalkyl. Non-limiting examples include:

, whose connection points can be at any position; wait.

The term "bridged cycloalkyl" refers to a full carbon polycyclic system that shares two carbon atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) carbon atoms (i.e., 5 to 20-membered bridged cycloalkyl). The bridged cycloalkyl preferably has a bridged cycloalkyl of 6 to 14 carbon atoms (i.e., 6 to 14-membered bridged cycloalkyl), and more preferably has a bridged cycloalkyl of 7 to 10 carbon atoms (i.e., 7 to 10-membered bridged cycloalkyl). The bridged cycloalkyl includes bicyclic bridged cycloalkyl and polycyclic bridged cycloalkyl (e.g., tricyclic bridged cycloalkyl, tetracyclic bridged cycloalkyl, etc.), preferably bicyclic bridged cycloalkyl or tricyclic bridged cycloalkyl. Non-limiting examples include:

Its connection point can be at any position.

The cycloalkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic heterocycle (i.e., a monocyclic heterocyclyl) or a polycyclic heterocyclic ring system (i.e., a polycyclic heterocyclyl), which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S- or -S-S-), and has 3 to 20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 3- to 20-membered heterocyclyl). The heterocyclic group is preferably a heterocyclic group having 3 to 12 ring atoms (i.e., a 3- to 12-membered heterocyclic group); further preferably a heterocyclic group having 3 to 8 ring atoms (i.e., a 3- to 8-membered heterocyclic group); more preferably a heterocyclic group having 3 to 6 ring atoms (i.e., a 3- to 6-membered heterocyclic group); and most preferably a heterocyclic group having 5 or 6 ring atoms (i.e., a 5- or 6-membered heterocyclic group).

The monocyclic heterocyclic group includes, but is not limited to, pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyranyl, pyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and homopiperazinyl, etc.

The polycyclic heterocyclic group includes a spiro heterocyclic group, a fused heterocyclic group and a bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic ring system in which the rings share one atom (called a spiro atom), which may contain one or more double bonds in the ring and at least one (e.g., 1, 2, 3 or 4) heteroatom selected from nitrogen, oxygen and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone, but does not include -O-O-, -O-S- or -S-S-), provided that it contains at least one monocyclic heterocyclic group and the point of attachment is on the monocyclic heterocyclic group, which has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered spiroheterocyclyl). The spiro heterocyclic radical preferably has a spiro heterocyclic radical of 6 to 14 ring atoms (i.e., a 6 to 14-membered spiro heterocyclic radical), and more preferably has a spiro heterocyclic radical of 7 to 10 ring atoms (i.e., a 7 to 10-membered spiro heterocyclic radical). The spiro heterocyclic radical includes a monospiro heterocyclic radical and a polyspiro heterocyclic radical (such as a bispiro heterocyclic radical, etc.), preferably a monospiro heterocyclic radical or a bispiro heterocyclic radical, more preferably a 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 7-yuan/5-yuan or 7-yuan/6-yuan monospiro heterocyclic radical. Non-limiting examples include:

wait.

The term "fused heterocyclyl" refers to a polycyclic heterocyclic ring system which shares two adjacent atoms between the rings, which may contain one or more double bonds within the ring, and which contains at least one (e.g., 1, 2, 3 or 4) heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -OO-, -OS- or -SS-), which is a monocyclic heterocyclyl fused to one or more monocyclic heterocyclyls, or a monocyclic heterocyclyl fused to one or more of cycloalkyl, aryl or heteroaryl, wherein the point of attachment is on the monocyclic heterocyclyl, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) ring atoms (i.e., a 5- to 20-membered fused heterocyclyl). The fused heterocyclic group preferably has a fused heterocyclic group of 6 to 14 ring atoms (i.e., a 6 to 14-membered fused heterocyclic group), and more preferably has a fused heterocyclic group of 7 to 10 ring atoms (i.e., a 7 to 10-membered fused heterocyclic group). The fused heterocyclic group includes bicyclic and polycyclic fused heterocyclic groups (such as tricyclic fused heterocyclic groups, tetracyclic fused heterocyclic groups, etc.), preferably a bicyclic fused heterocyclic group or a tricyclic fused heterocyclic group, more preferably a 3-yuan/4-yuan, 3-yuan/5-yuan, 3-yuan/6-yuan, 4-yuan/4-yuan, 4-yuan/5-yuan, 4-yuan/6-yuan, 5-yuan/3-yuan, 5-yuan/4-yuan, 5-yuan/5-yuan, 5-yuan/6-yuan, 5-yuan/7-yuan, 6-yuan/3-yuan, 6-yuan/4-yuan, 6-yuan/5-yuan, 6-yuan/6-yuan, 6-yuan/7-yuan, 7-yuan/5-yuan or 7-yuan/6-yuan bicyclic fused heterocyclic group. Non-limiting examples include:

wait.

The term "bridged heterocyclic group" refers to a polycyclic heterocyclic ring system that shares two atoms that are not directly connected between the rings, which may contain one or more double bonds in the ring, and which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S-, or -S-S-), and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., 5 to 20-membered bridged heterocyclic groups). The bridged heterocyclic group is preferably a bridged heterocyclic group having 6 to 14 ring atoms (i.e., 6 to 14-membered bridged heterocyclic groups), and more preferably a bridged heterocyclic group having 7 to 10 ring atoms (i.e., 7 to 10-membered bridged heterocyclic groups). According to the number of constituent rings, it can be divided into bicyclic bridged heterocyclic groups and polycyclic bridged heterocyclic groups (such as tricyclic bridged heterocyclic groups, tetracyclic bridged heterocyclic groups, etc.), preferably bicyclic bridged heterocyclic groups or tricyclic bridged heterocyclic groups. Non-limiting examples include:

wait.

The heterocyclic group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclic groupoxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclic group, aryl and heteroaryl.

The term "aryl" refers to a monocyclic all-carbon aromatic ring (i.e., monocyclic aromatic group) or a polycyclic aromatic ring system (i.e., polycyclic aromatic group) having a conjugated π electron system, which has 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 or 14) ring atoms (i.e., 6 to 14-membered aromatic group). The aryl group is preferably an aromatic group having 6 to 10 ring atoms (i.e., 6 to 10-membered aromatic group). The monocyclic aromatic group is, for example, phenyl. The polycyclic aromatic group is The polycyclic aromatic group also includes phenyl fused to one or more heterocyclic or cycloalkyl groups, or naphthyl fused to one or more heterocyclic or cycloalkyl groups, wherein the connection point is on the phenyl or naphthyl group, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic aromatic ring system, and non-limiting examples include:

wait.

The aryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, oxo, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a monocyclic heteroaromatic ring (i.e., a monocyclic heteroaryl) or a polycyclic heteroaromatic ring system (i.e., a polycyclic heteroaryl) having a conjugated π electron system, which contains at least one (e.g., 1, 2, 3, or 4) heteroatoms selected from nitrogen, oxygen, and sulfur in the ring (the nitrogen may be optionally oxidized, i.e., to form nitrogen oxides; the sulfur may be optionally oxidized, i.e., to form sulfoxides or sulfones, but does not include -O-O-, -O-S-, or -S-S-), and has 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) ring atoms (i.e., a 5- to 14-membered heteroaryl). The heteroaryl is preferably a heteroaryl having 5 to 10 ring atoms (i.e., a 5- to 10-membered heteroaryl), and more preferably a heteroaryl having 5 or 6 ring atoms (i.e., a 5- or 6-membered heteroaryl).

The monocyclic heteroaryl group includes, but is not limited to, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furazanyl, pyrrolyl, N-alkylpyrrolyl, pyridyl, pyrimidinyl, pyridonyl, N-alkylpyridone (e.g. etc.), pyrazinyl, pyridazinyl, etc.

The polycyclic heteroaryl, non-limiting examples include: indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, phthalazinyl, benzimidazolyl, benzothiophenyl, quinazolinyl, benzothiazolyl, carbazolyl, etc. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more aromatic groups, wherein the connection point is on the aromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. The polycyclic heteroaryl also includes a monocyclic heteroaryl fused with one or more cycloalkyl or heterocyclic groups, wherein the connection point is on the monocyclic heteroaromatic ring, and in this case, the number of ring atoms continues to represent the number of ring atoms in the polycyclic heteroaromatic ring system. Non-limiting examples include:

wait.

The heteroaryl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment, and the substituents are preferably selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "amino protecting group" refers to a group that is easily removed and introduced on the amino group in order to keep the amino group unchanged when other parts of the molecule react. Non-limiting examples include: (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), methyloxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilylethoxycarbonyl (Teoc), methoxycarbonyl, ethoxycarbonyl, phthaloyl (Pht), p-toluenesulfonyl (Tos), trifluoroacetyl (Tfa), trityl (Trt), 2,4-dimethoxybenzyl (DMB), acetyl, benzyl, allyl, p-methoxybenzyl, etc.; the amino protecting group is preferably Boc.

The term "hydroxy protecting group" refers to a group that is easily removed and introduced on a hydroxyl group, and is used to block or protect the hydroxyl group while reacting on other functional groups of the compound. Non-limiting examples include: trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBS), tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS), methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzoyl, p-nitrobenzoyl, etc.

The term "alkynyl protecting group" refers to a group that is easily removed and introduced into the alkynyl group in order to keep the active hydrogen in acetylene or terminal alkyne unchanged when other parts of the molecule are reacted. 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 term "cycloalkyloxy" refers to a cycloalkyl-O- group wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to an aryl-O- group in which aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S- group in which alkyl is as defined above.

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

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

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

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

The term "methylidene" refers to = _CH2 .

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

The term "hydroxy" refers to -OH.

The term "thiol" refers to -SH.

The term "amino" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "oxo" or "oxo" refers to "=0".

The term "carbonyl" refers to C=O.

The term "carboxy" refers to -C(O)OH.

The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O)O-, wherein alkyl and cycloalkyl are as defined above.

MOM stands for methoxymethyl.

Boc refers to tert-butyloxycarbonyl.

TIPS refers to triisopropylsilyl.

TBS refers to tert-butyldimethylsilyl.

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers with identical structures 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, conformers and mixtures thereof (such as racemates, mixtures of diastereomers). Substituents in the disclosed compounds may have additional asymmetric atoms. All of these stereoisomers and their mixtures are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, (R)- and (S)-enantiomers and (D)- and (L)-isomers may be prepared by chiral synthesis, chiral reagents or other conventional techniques. An isomer of a compound disclosed herein can be prepared by asymmetric synthesis or 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), a diastereoisomer salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereomers is usually completed by chromatography.

In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond Can be or include both In the chemical structure of the compounds disclosed in the present invention, the bond The configuration is not specified, i.e., it can be Z, E, or both. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E configurations are included.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is easily converted from one isomeric form to another isomeric form. It includes all possible tautomers, that is, in the form of a single isomer or in the form of a mixture of any proportions of the tautomers. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, etc. An example of a lactam-lactim equilibrium is shown below:

For example, when referring to pyrazolyl, it is understood to include either or a mixture of two tautomers of the following two structures:

All tautomeric forms are within the scope of the present disclosure, and the naming of compounds does not exclude any tautomer.

The compounds of the present disclosure may contain atropisomers. The term "atropisomer" is a conformational stereoisomer produced due to hindered or greatly slowed rotation around a single bond in a molecule (this is due to steric interactions with other parts of the molecule and the result of asymmetry of the substituents at both ends of the single bond), and its interconversion is slow enough to allow separation and separation under predetermined conditions. For example, some of the compounds of the present disclosure may exist in the form of a mixture of atropisomers (such as an equal proportion mixture, a mixture enriched in one atropisomer, etc.) or a purified atropisomer. Non-limiting examples include: wait.

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

Compared with non-deuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds disclosed herein, whether radioactive or not, are included in the scope of the present disclosure. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom, wherein the replacement of deuterium can be partial or complete, and partial deuterium replacement means that at least one hydrogen is replaced by at least one deuterium.

Compounds of the present disclosure, when a position is specifically designated as "deuterium" or "D", the position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 1000 times greater than the natural abundance of deuterium (i.e., at least 15% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 2000 times greater than the natural abundance of deuterium (i.e., at least 30% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3000 times greater than the natural abundance of deuterium (i.e., at least 45% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3340 times greater than the natural abundance of deuterium (i.e., at least 50.1% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 3500 times greater than the natural abundance of deuterium (i.e., at least 52.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4000 times greater than the natural abundance of deuterium (i.e., at least 60% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 4500 times greater than the natural abundance of deuterium (i.e., at least 67.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5000 times greater than the natural abundance of deuterium (i.e., at least 75% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 5500 times greater than the natural abundance of deuterium (i.e., at least 82.5% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6000 times greater than the natural abundance of deuterium (i.e., at least 90% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6333.3 times greater than the natural abundance of deuterium (i.e., at least 95% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6466.7 times greater than the natural abundance of deuterium (i.e., at least 97% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6600 times greater than the natural abundance of deuterium (i.e., at least 99% deuterium incorporation). In some embodiments, the abundance of deuterium for each designated deuterium atom is at least 6633.3 times greater than the natural abundance of deuterium (ie, at least 99.5% deuterium incorporation).

"Optionally" or "optionally" means that the event or environment described later can but does not necessarily occur, and includes two situations in which the event or environment occurs or does not occur. For example, "alkyl optionally (optionally) substituted with halogen or cyano" includes the situation in which alkyl is substituted with halogen or cyano and the situation in which alkyl is not substituted with halogen and cyano.

"Substitution" or "substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms in a group are independently replaced by a corresponding number of substituents. It is not possible to determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond (such as an alkene).

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

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which may be selected from inorganic or organic salts. Such salts are safe and effective when used in mammals and have the desired biological activity. They may be prepared separately during the final isolation and purification of the compound, or by reacting a suitable group with a suitable base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids and organic acids.

With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to an 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 on the specific active substance, and the appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art based on routine experiments.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular form of "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

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

Synthesis method of the disclosed compound

In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

Solution 1

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

The compound of general formula (I'A) or its salt is subjected to a deprotection reaction under acidic conditions to obtain a compound of general formula (I') or its pharmaceutically acceptable salt, wherein R is an amino protecting group, preferably Boc, and R ^Q is H;

Optionally, further comprising subjecting a compound of the general formula (I') wherein R ^Q is H or a pharmaceutically acceptable salt thereof to a substitution reaction with R ^P -R ^L under alkaline conditions and in the presence of an optional catalyst to obtain a compound of the general formula (I') wherein R ^Q is R ^P or a pharmaceutically acceptable salt thereof, wherein R ^L is a leaving group, preferably 4-nitrophenoxy;

^RP , ^G0 , ^G1 , T, Ring A, Ring B, Q, L, ^R1 , ^R3 , ^R4a , ^R5a , ^R5b , ^R6 , p, y, r and t are as defined in the general formula (I').

Solution 2

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

The compound of the general formula (IA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain a compound of the general formula (I) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, and R ^Q is H;

Optionally, further comprising subjecting a compound of the general formula (I) wherein R ^Q is H or a pharmaceutically acceptable salt thereof to a substitution reaction with R ^P -R ^L under alkaline conditions and optionally in the presence of a catalyst to obtain a compound of the general formula (I) wherein R ^Q is R ^P or a pharmaceutically acceptable salt thereof, wherein R ^L is a leaving group, preferably 4-nitrophenoxy;

^RP , ^RG1a , Ring B, L, ^R1 , ^R3a , ^R3b , ^R4a , ^R5a , ^R5b , ^R6 , p, r and t are as defined in the general formula (I).

Option 3

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

The compound of general formula (IIA) or its salt is subjected to a deprotection reaction under acidic conditions to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof, wherein R is an amino protecting group, preferably Boc, and R ^Q is H;

Optionally, further comprising subjecting a compound of the general formula (II) wherein R ^Q is H or a pharmaceutically acceptable salt thereof to a substitution reaction with R ^P -R ^L under alkaline conditions and optionally in the presence of a catalyst to obtain a compound of the general formula (II) wherein R ^Q is R ^P or a pharmaceutically acceptable salt thereof, wherein R ^L is a leaving group, preferably 4-nitrophenoxy;

R ^P , R ^3a , R ^3b and R ^4a are as defined in the general formula (II).

In some embodiments of the present disclosure, the ^RL is selected from hydrogen atom, halogen, -OTs, 4-nitrophenoxy and -OTf; preferably, ^RL is 4-nitrophenoxy.

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, Me ₃ SiCl and TMSOTf; the inorganic acids include but are not limited to hydrogen chloride, a 1,4-dioxane solution of hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably a 1,4-dioxane solution of hydrogen chloride.

The base providing alkaline conditions includes organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide; the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide monohydrate, lithium hydroxide and potassium hydroxide; preferably N,N-diisopropylethylamine.

The catalyst includes but is not limited to 4-dimethylaminopyridine and N,N-dimethylformamide; preferably 4-dimethylaminopyridine.

The reaction in the above steps is preferably carried out in a solvent, and the solvent used includes but is not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2-dibromoethane and a mixture thereof.

DETAILED DESCRIPTION

The following embodiments are used to further describe the present disclosure, but these embodiments are not intended to limit the scope of the present disclosure.

Example

The structures of the compounds were determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

MS was determined using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC-MS/MS instrument (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS).

waters ACQuity UPLC-QD/SQD (Manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector)

THERMO Ultimate 3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive

High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC instruments.

Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

HPLC preparation was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

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

The CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

The average kinase inhibition rate and _IC50 value were determined using NovoStar microplate reader (BMG, Germany).

The known starting materials disclosed in the present invention can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals and other companies.

Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clear Blue QL-500 hydrogen generator or a HC2-SS hydrogenator.

The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.

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

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

The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

Example 1

5-Ethyl-6-fluoro-4-((5aS,6S,9R)-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-pentaaza-6,9-methano[1,8-ab]heptyl)naphthalen-2-ylmethylcarbamate 1

first step

(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-pentaaza-6,9-methano[1,8-ab]heptyl-4-carboxylic acid tert-butyl ester 1b

5-Ethyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl)naphthalen-2-ol (1.3 g, 2.05 mmol, prepared by the method of the first embodiment of the specification of patent application "WO2022268051") 25) was dissolved in dichloromethane (50 mL), and triethylamine (624 mg, 6.17 mmol) and di-tert-butyl dicarbonate (673 mg, 3.08 mmol) were added. The reaction was stirred for 3 hours, and saturated sodium bicarbonate solution was added to the reaction solution. The mixture was extracted with dichloromethane (30 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system A to obtain the title compound 1b (1.33 g, yield: 88.3%).

MS m/z(ESI):733.4[M+1].

Step 2

(5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-((methylcarbamoyl)oxy)naphthalen-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-pentaaza-6,9-methanaphtho[1,8-ab]heptyl-4-carboxylic acid tert-butyl ester 1c

Compound 1b (300 mg, 409.4 μmol) was dissolved in dichloromethane (15 mL), and triethylamine (207 mg, 2.05mmol), methylaminoformyl chloride (115mg, 1.23mmol, Anaiji), stirred for 16 hours, added saturated sodium bicarbonate solution to the reaction solution, extracted with dichloromethane (10mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure. The residue was purified with eluent system A to obtain the title compound 1c (270mg, yield 83.4%).

MS m/z(ESI):789.9[M+1].

Step 3

5-Ethyl-6-fluoro-4-((5aS,6S,9R)-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-pentaaza-6,9-methano[1,8-ab]heptyl)naphthalen-2-ylmethylcarbamate 1

Compound 1c (270 mg, 341.84 μmol) was dissolved in dichloromethane (10 mL), and 4 M hydrogen chloride solution in 1,4-dioxane (15 mL) was added. The reaction mixture was stirred for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by 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 35%-45%, flow rate: 30 mL/min) to give the title compound 1 (100 mg, yield: 42.4%).

MS m/z(ESI):690.3[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.99-7.96(m,1H),7.85-7.84(m,1H),7.79-7.73(m,1H),7.52-7.47(m,1H), 7.30-7.19(m,1H),5.33-5.22(m,1H),4.83-4.80(m,1H),4.56-4.52(m,1H),4.46-4. 35(m,1H),4.13-4.11(m,1H),4.04-3.99(m,2H),3.64-3.53(m,2H),3.12-3.03(m,4H),2.85-2.80(m,1H ),2.69-2.67(m,3H),2.43-1.54(m,13H),0.89-0.73(m,3H).

Example 2

5-Ethyl-6-fluoro-4-((5aS,6S,9R)-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-pentaaza-6,9-methano[1,8-ab]heptyl)naphthalen-2-yl dimethylcarbamate 2

The title compound 2 was prepared by using the synthetic route in Example 1, replacing the second step raw material methylaminoformyl chloride with dimethylaminoformyl chloride.

MS m/z(ESI):704.3[M+1].

¹ H NMR (500MHz, CD ₃ OD): δ7.89(ddd,1H),7.80(t,1H),7.44–7.28(m,2H),5.31(d,1H),5.06(ddd,1H), 4.62(td,1H),4.48(ddd,1H),4.30(d,1H),4.23(d,1H),4.14(dd,1H),3.73(dd,1H),3.64(p,1H),3.30 –3.13(m,7H),3.03(d,4H),2.56(dtd,1H), 2.39–2.12(m,4H),2.08–1.78(m,7H),0.89(dt,3H).

Example 3

1-(Butyryloxy)ethyl(5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-((methylcarbamoyl)oxy)naphthalen-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-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 3 (mixture of two isomers)

Compound 1 (104 mg, 150.7 μmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (97 mg, 603 μmol), 4-dimethylaminopyridine (2 mg, 16 μmol), 1-(((4-nitrophenoxy)carbonyl)oxy)butyric acid ethyl ester (179 mg, 1.23 mmol, prepared by the method disclosed in the literature "ACS Omega 2023, 8, 7211-7221" were added. The reaction mixture was stirred at 40 °C for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified by HPLC (Waters-2545, chromatographic column: YMC Triart-Exrs C18, 30*150mm, 5μm; mobile phase: aqueous phase (10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 30%-40%, flow rate: 30mL/min) to give the title compound 3 (25mg, yield 19.5%).

MS m/z(ESI):848.3[M+1].

¹ H NMR (500MHz, CD ₃ OD): δ7.88(ddd,1H),7.79(d,1H),7.43–7.25(m,2H),6.90–6.79(m,1H),5.39–5.11(m ,2H),4.69(d,1H),4.54(t,3H),4.37–4.16(m,3H),3.22(dd,3H),3.08–2.95(m,1H),2.86–2.44(m,4H ),2.39–2.13(m,6H),2.09–1.89(m,7H),1.64(s,2H),1.54(t,3H),0.89(dt,7H).

Example 4

1-(Butyryloxy)ethyl(5aS,6S,9R)-2-(3-((dimethylcarbamoyl)oxy)-8-ethyl-7-fluoronaphthalen-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-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 4 (mixture of two isomers)

The title compound 4 was prepared by adopting the synthetic route in Example 3 and replacing compound 1 with compound 2.

MS m/z(ESI):862.1[M+1].

Embodiment 5, 6

1-(Butyryloxy)ethyl(5aS,6S,9R)-2-(3-(1-((ethoxycarbonyl)oxy)ethoxy)-8-ethyl-7-fluoronaphthalen-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-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 5 (mixture of four isomers)

1-(Butyryloxy)ethyl(5aS,6S,9R)-2-(3-((ethoxycarbonyl)oxy)-8-ethyl-7-fluoronaphthalen-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-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 6 (mixture of two isomers)

first step

(5aS,6S,9R)-2-Chloro-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-pentaaza-6,9-methano[1,8-ab]heptyl)-1 ... 5b

Compound 5a (0.6 g, 1.03 mmol, prepared by the method disclosed in intermediate 4i-1 in Example 4 on page 117 of the specification of patent application "WO2022268051") was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added, and the reaction was stirred for 1 hour, concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure after filtering to remove the desiccant. The crude product was used directly in the next step without purification (500 mg, yield: 99%).

MS m/z(ESI):479.2[M+1].

Step 2

(5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-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-pentaaza-6,9-methano[1,8-ab]heptanol 5c

Compound 5b (500 mg, 1.04 mmol), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (564 mg, 1.56 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (132 mg, 0.156 mmol), cesium carbonate (1.02 g, 3.13 mmol) were mixed in 1,4-dioxane (10 mL) and water (2 mL). The mixture was stirred at 100°C for 3 hours under nitrogen atmosphere, cooled to room temperature, concentrated under reduced pressure, and the residue was purified with eluent system B to give the title compound 5c (500 mg, yield: 70.1%).

MS m/z(ESI):677.3[M+1].

Step 3

1-(Butyryloxy)ethyl (5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-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-pentaaza-6,9-methano[1,8-ab]heptyl-4-carboxylate 5d (mixture of two isomers)

Compound 5c (500 mg, 739 μmol) was dissolved in dichloromethane (5 mL), and triethylamine (239 mg, 1.85 mmol), 4-dimethylaminopyridine (18 mg, 148 μmol), and ethyl 1-(((4-nitrophenoxy)carbonyl)oxy)butyrate (395 mg, 1.33 mmol, prepared by the method disclosed in the document "ACS Omega 2023, 8, 7211-7221") were added. The reaction was stirred at 40°C for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was purified with eluent system B to give the title compound 5d (a mixture of two isomers) (150 mg, yield: 24.3%).

MS m/z(ESI):835.4[M+1].

Step 4

1-(Butyryloxy)ethyl((5aS,6S,9R)-2-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 5e (mixture of two isomers)

Compound 5d (150 mg, 0.18 mmol) was dissolved in methanol (3.0 mL), and 4 M hydrochloric acid/1,4-dioxane (1 mL) was added under ice-water bath protection. After stirring for 15 minutes, the mixture was concentrated under reduced pressure, and saturated sodium bicarbonate solution was added. The solution was extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure after filtering to remove the desiccant, and the crude product was used directly in the next step without purification (140 mg, yield: 99%).

MS m/z(ESI):791.3[M+1].

Step 5

1-(Butyryloxy)ethyl(5aS,6S,9R)-2-(3-(1-((ethoxycarbonyl)oxy)ethoxy)-8-ethyl-7-fluoronaphthalen-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-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 5 (mixture of four isomers)

1-(Butyryloxy)ethyl(5aS,6S,9R)-2-(3-((ethoxycarbonyl)oxy)-8-ethyl-7-fluoronaphthalen-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-pentaaza-6,9-methano[1,8-ab]heptyl-14-carboxylate 6 (mixture of two isomers)

Compound 5e (200 mg, 0.252 mmol) was dissolved in acetone (5 mL), and ethyl (1-iodoethyl) carboxylate (186 mg, 0.758 mmol, prepared by the method disclosed in Intermediate 2 in Example 3 on page 15 of the specification of patent application "WO2009118580A2") and anhydrous potassium carbonate (175 mg, 1.26 mmol) were added in sequence. The mixture was stirred at 60°C for 2 hours, returned to room temperature, filtered, and the reaction solution was concentrated under reduced pressure. The residue was purified by high performance liquid preparative chromatography (Waters-2545, chromatographic 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%-40%, flow rate: 30 mL/min) to obtain the title compound 5 (a mixture of four isomers) and compound 6 (a mixture of two isomers).

Compound 5: (30 mg, yield 13.1%)

MS m/z(ESI):907.4[M+1].

¹ H NMR (500 MHz, CD ₃ OD): δ7.91(dd,1H),7.72–7.67(m,1H),7.48(td,1H),7.29–7.09(m,1H),6.75(dq,1H),6.58(ddd,1H),5.30(d,1H),4.99(d,1H),4.81–4.35(m,5H),4 .20–3.97(m,6H),3.32(s,3H),3.07(d,3H),2.85(s,1H),2.40–2.24(m,2H),2.14–1.74(m,10H),1.63(dt,3H),1.48(dd,4H),1.17(q,3H),0.87(d ,3H),0.77(t,2H).

Compound 6: (15 mg, yield 6.9%)

MS m/z(ESI):863.4[M+1].

¹ H NMR (500MHz, CD ₃ OD): δ8.09–7.95(m,2H),7.55(td,1H),7.50–7.31(m,1H),6.75(q,1H),5.29(d,1H ),4.99(d,1H),4.78–4.38(m,6H),4.29(p,3H),4.22–3.98(m,4H),3.30(s,3H),3.06(d,3H),2.84( d,1H),2.30(t,2H),2.18–1.70(m,8H),1.57–1.44(m,4H),1.31(q,3H),0.87(dt,3H),0.78(d,2H) .

Biological evaluation

Test Example 1: Biological evaluation of ERK phosphorylation inhibition experiment in AGS cells (HTRF method)

1. Test Purpose

In this experiment, the inhibitory effect of the compounds on cellular ERK phosphorylation was detected, and the inhibitory effect of the disclosed compounds on the KRAS target was evaluated according to the IC ₅₀ value.

2. Experimental Methods

AGS cells (Nanjing Kebai, CBP60476) were cultured in RPMI1640 (Gibco, 11875093) complete medium containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, AGS cells were seeded in a 96-well plate at a density of 30,000 cells/well using complete medium, with 190 μL of cell suspension per well, and placed in a 37°C, 5% _CO2 cell culture incubator for overnight culture.

On the second day, 10 μL of the compound to be tested prepared with complete medium was added to each well. The final concentration of the compound was 9 concentration points of 6-fold gradient dilution starting from 10 μM. A blank control containing 0.5% DMSO was set, and the well plate was placed in a cell culture incubator at 37°C and 5% _CO2 for 1 hour. After the incubation was completed, the 96-well cell culture plate was taken out, the medium was sucked off, and 200 μL PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) was added to each well to wash once. PBS was sucked off, and 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well. The well plate was placed on an oscillator for 40 minutes of shaking at room temperature and then centrifuged at 2400 rpm for 10 minutes. After lysis, pipette to mix, transfer 16 μL of lysate to each well into two HTRF 96-well detection plates (Cisbio, 66PL96100), and then add 4 μL of premixed phosphorylated ERK1/2 antibody solution (Cisbio, 64AERPEH) or 4 μL of premixed total ERK1/2 antibody solution (Cisbio, 64NRKPEH) to the two plates. The microplate was sealed with a sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark.

On the third day, the fluorescence values with excitation at 337 nm and emission at 665 nm and 620 nm were read using a PHERAstar FS multifunctional microplate reader.

3. Data Analysis

Graphpad Prism software was used to calculate the _IC50 value of the inhibitory activity of the compound based on the compound concentration and the ratio of phosphorylated ERK/total ERK.

Test Example 2: Biological evaluation of GP2d and AGS cell 3D proliferation inhibition experiment

1. Test Purpose

The inhibitory effect of the disclosed compounds on the KRAS target was evaluated by testing the 3D proliferation inhibitory effect of the disclosed compounds on GP2d and AGS cells.

2. Experimental Methods

GP2d cells (Nanjing Kebai, CBP60010) were cultured with complete medium, i.e., DMEM/high glucose medium (Hyclone, SH30243.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, GP2d cells were seeded in a 96-well low-adsorption plate (Corning, CLS7007-24EA) at a density of 1000 cells/well using complete medium, 90 μL of cell suspension per well, centrifuged at 2000 rpm at room temperature for 5 minutes, and then placed in a 37°C, 5% _CO2 cell culture incubator for overnight culture.

AGS cells (Nanjing Kebai, CBP60476) were cultured with complete medium containing 10% fetal bovine serum (Corning, 35-076-CV) RPMI1640 medium (Hyclone, SH30809.01). On the first day of the experiment, AGS cells were seeded in a 96-well low-adhesion plate (Corning, CLS7007-24EA) at a density of 1000 cells/well using complete medium, 90 μL of cell suspension per well, centrifuged at 2000 rpm for 5 minutes at room temperature, and then placed in a 37°C, 5% _CO2 cell culture incubator for overnight culture.

On the second day, 10 μL of the compound to be tested prepared with complete medium was added to each well. The final concentration of the compound for GP2d cells was 9 concentration points of 5-fold gradient dilution starting from 1 μM, and the final concentration of the compound for AGS cells was 9 concentration points of 5-fold gradient dilution starting from 10 μM. A blank control containing 0.5% DMSO was set. The well plate was placed in a cell culture incubator at 37°C and 5% CO ₂ for 120 hours. On the seventh day, the 96-well cell culture plate was removed and 50 μL of the compound to be tested was added to each well. 3D reagent (Promega, G9682) was shaken at room temperature for 25 minutes, then pipetted to mix and 100 μL was transferred to a white opaque 96-well plate (PE, 6005290), and the luminescent signal value was read using a multi-function microplate reader (PerkinElmer, EnVision).

3. Data Analysis

The _IC50 values of the inhibitory activity of the compounds were calculated using Graphpad Prism software. The results are shown in Table 1 below.

Table 1 GP2d cell 3D proliferation inhibitory activity data

Conclusion: The disclosed compounds have a good inhibitory effect on GP2d cell 3D proliferation.

Test Example 3: Pharmacokinetic Evaluation

1. SD rat experiment

1. Summary

SD rats were used as test animals, and the drug concentrations in plasma at different times after i.g. administration of the example compounds to SD rats were determined by LC/MS/MS. The pharmacokinetic behavior of the disclosed compounds in SD rats was studied, and their pharmacokinetic characteristics were evaluated.

2. Experimental plan

2.1 Trial Drugs

Example 1 Compound.

2.2 Experimental animals

Four SD rats, half male and half female, were provided by Weitonglihua Experimental Animal Technology Co., Ltd.

2.3 Drug preparation

A certain amount of the example compounds were weighed respectively, and 5% DMF + 45% PG + 50% (10% HS15-pH7.4 buffer) + 400mpk SNAC were added to prepare a 6.541 mg/mL colorless, clear solution.

2.4 Administration

The dosage was 65.41 mg/kg and the administration volume was 10.0 mL/kg.

3. Operation

Rats were fed overnight and given HM30181ASD-F (5 mpk) 30 minutes before administration. At 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration, 0.2 mL of blood was collected from the eye sockets and placed in EDTA-K2 tubes. The blood was centrifuged at 10,000 rpm for 1 minute (4°C), and the plasma was separated within 1 hour and stored at -20°C for testing.

Determine the content of the test compound in the plasma of SD rats after administration of different drug concentrations: take 20 μL of SD rat plasma samples at each time after administration, add 20 ng/mL internal standard (verapamil), then add 200 μL acetonitrile precipitation, vortex mix for 5 minutes, and centrifuge at 4000 rpm for 15 minutes, 75 μl water + 75 μl supernatant, vortex mix for 5 minutes, and take 3 μL of supernatant for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

Table 2 Pharmacokinetic parameters of the disclosed compounds in SD rats

Conclusion: The disclosed compounds have high exposure in SD rats and have obvious pharmacokinetic advantages.

Claims (19)

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof:
in: R ^P is selected from -C(O) ^RP1 , -(CR ^x1 R ^x2 -O) _x3 -C(O)OR ^P3 , -C(O)NR ^P3 R ^P4 , -C(O)OCR ^P11 R ^P12 OC (O)Z, -C(O)CR ^P11 R ^P12 NR ^P3 R ^P4 , -C(O)NR ^P13 CR ^P11 R ^P12 C(O)OR ^P3 , -S(O) ₂ R ^P1 , -S(O ) ₂ OR ^P3 and -S(O) ₂ NR ^P3 R ^P4 ; R ^Q is a hydrogen atom or R ^P ; ^Rx1 , ^Rx2 , ^Rp1 , ^Rp11 , ^Rp12 , ^Rp3 , ^Rp4 , ^Rp13 and Z are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl, an alkenyl, an alkynyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -C(O) ^Rp20 , a cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl group, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkylalkyl-, a heterocyclylalkyl-, an arylalkyl-, a heteroarylalkyl-, a cycloalkyl, a heterocyclyl, an aryl and a heteroaryl group are each independently selected from a halogen, an alkyl, a haloalkyl, an alkoxy, a haloalkoxy, a cyano, an amino, a nitro, a hydroxyl, a hydroxyalkyl, -OC(O) ^Rp21 , cycloalkyl, heterocyclyl, aryl and heteroaryl, which are substituted by one or more substituents which are the same or different; R ^P20 and R ^P21 are the same or different and are each independently selected from alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkylalkyl-, heterocyclylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; L is selected from a single bond, O and NR ^e ; R ^G1a is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl and heterocyclic groups; each R ¹ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _u -NR ^f R ^g , hydroxyl and hydroxyalkyl; R ^3a and R ^3b 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 hydroxyl group, a hydroxyalkyl group, a cycloalkyl group and a heterocyclic group; R ^4a is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _v -NR ^h R ⁱ , hydroxy, hydroxyalkyl, and cycloalkyl; each R ⁶ is the same or different and is independently selected from halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, -(CH ₂ ) _w5 -NR ^m R ⁿ , -(CH ₂ ) _w3 -(O) _z3 -C(O)NR ^m1 R ⁿ¹ , -(CH ₂ ) _w4 -(O) _z4 -C(O)OR ^m2 , =NOR ⁶¹ , =CR ⁶² R ⁶³ , =NR ⁶⁴ , nitro, hydroxy, hydroxyalkyl, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁶¹ , R ⁶² , R ⁶³ and R ⁶⁴ are the same or different, and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group and a cycloalkyl group; R ^5a and R ^5b are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a cyano group, a hydroxyl group and a hydroxyalkyl group; or R ^5a , R ^5b together with the carbon atom to which they are attached form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group or the heterocyclic group are each independently substituted with one or more identical or different substituents selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, hydroxyl and hydroxyalkyl; ^Re , ^Rf , ^Rg , ^Rh , ^Ri , Rm, ^Rn , ^Rm1 , ^Rn1 and ^Rm2 are the same or different and are each independently selected ^from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; u, v, w3, w4 and w5 are the same or different and are each independently selected from 0, 1, 2 and 3; z3 is 0 or 1; z4 is 0 or 1; x3 is 0, 1, or 2; r is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4 or 5; and t is 0, 1, 2, 3, 4, or 5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ^G1a is a hydrogen atom. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein for R ⁶ is as defined in claim 1. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein L is O. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein r is 1; and/or R ^5a and R ^5b are hydrogen atoms. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:
wherein R ^P , R ^Q , R ^3a , R ^3b and R ^4a are as defined in claim 1. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ^RP is -C(O)NR ^{P3 RP4} or -(CR ^x1 R ^x2 -O) _x3 -C(O)OR ^P3 , and x3, R ^x1 , R ^x2 , ^RP3 and ^RP4 are as defined in claim 1. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ^Q is a hydrogen atom or -C(O)OCR ^P11 R ^P12 OC(O)Z, and R ^P11 , R ^P12 and Z are as defined in claim 1. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R ^3a is halogen. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ^3b is C _1-6 alkyl. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R ^4a is halogen. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, which is the following compound:

A compound represented by general formula (IA) or a salt thereof:
in, R is an amino protecting group; preferably Boc; ^RP , ^RG1a , Ring B, L, ^R1 , ^R3a , ^R3b , ^R4a , ^R5a , ^R5b , ^R6 , p, r and t are as defined in claim 1. A compound or a pharmaceutically acceptable salt thereof, which is the following compound:
A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, the method comprising:
The compound of the general formula (IA) or its salt is subjected to a deprotection reaction to obtain a compound of the general formula (I) or its pharmaceutically acceptable salt, wherein R is an amino protecting group, preferably Boc, and R ^Q is H; Optionally, further comprising subjecting a compound of the general formula (I) wherein R ^Q is H or a pharmaceutically acceptable salt thereof to a substitution reaction with R ^P -R ^L to obtain a compound of the general formula (I) wherein R ^Q is R ^P or a pharmaceutically acceptable salt thereof, wherein R ^L is a leaving group, preferably 4-nitrophenoxy; ^RP , ^RG1a , Ring B, L, ^R1 , ^R3a , ^R3b , ^R4a , ^R5a , ^R5b , ^R6 , p, r and t are as defined in claim 1. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the preparation of a medicament for inhibiting KRAS G12D. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the preparation of a medicament for treating and/or preventing a disease or condition, wherein the disease or condition is cancer. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the preparation of a medicament for treating and/or preventing a disease or condition 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 tumors, 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; preferably selected from pancreatic cancer, colorectal cancer and non-small cell lung cancer.