TW202337890A - Bridged ring compounds, preparation method and medical use thereof - Google Patents

Abstract

The present disclosure relates to bridged ring compounds, preparation method and medical use thereof. Specifically, the present disclosure relates to a bridged ring compound represented by the general formula (I), its preparation method thereof, a pharmaceutical composition comprising the same, and its use as a therapeutic agent, especially its use in the preparation of drugs for inhibiting KRAS G12D and/or KRAS G12V. Wherein each group in the general formula (I) is as defined in the specification.

Description

Bridged ring compounds, their preparation methods and their applications in medicine

The present disclosure belongs to the field of medicine and relates to a bridged ring compound, its preparation method and its application in medicine. In particular, the present disclosure relates to bridged ring compounds represented by general formula (I), their preparation methods and pharmaceutical compositions containing such compounds, as well as their use in the preparation of drugs for inhibiting KRAS G12D and/or KRAS G12V. use.

RAS is one of the oncogenes with the highest mutation rate in tumors. About 30% of human malignant tumors are related to mutations in the RAS gene. The RAS family includes KRAS, NRAS and HRAS, of which KRAS mutations are the most common, accounting for about 85%. KRAS mutations are common in solid tumors, with high frequency mutations found in the three most lethal cancers in humans: lung cancer (17%), colorectal cancer (33%), and pancreatic cancer (61%). Among KRAS gene mutations, 97% are mutations in amino acid residue No. 12 or No. 13, among which G12D and G12V are important mutations. 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 and metabolism through numerous downstream signaling pathways represented by RAF-MEK-ERK, PI3K-AKT-mTOR and TIAM1-RAc. Functionality in many aspects. After the KRAS gene is mutated, the protein remains in an activated state, resulting in continued activation of downstream signaling pathways and promoting tumorigenesis.

Because the surface of KRAS protein lacks small molecule binding sites in the traditional sense and has ultra-high affinity to guanylate, making it extremely difficult to inhibit, it has long been considered an undruggable drug target. However, based on the importance and prevalence of abnormal activation of KRAS in cancer progression, KRAS has been and remains a target of great concern for drug development. Currently, in addition to KRAS G12C inhibitors, there is still a lack of KRAS inhibitors that are effective against other mutations, leaving most patients with KRAS mutations still untreatable. G12D and/or G12V, as a mutant that is widely expressed in a variety of tumors, has important clinical significance in developing inhibitors against it.

The relevant patent applications that have been published so far include WO2021041671A1, WO2020146613A1, WO2017172979A1, WO2020238791A1 and WO2021000885A1, etc.

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

in,

G ¹ is selected from O, NR ^a and CR ^b R ^c ;

G ² is NR ^d ;

Ring A is aryl or heteroaryl;

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

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

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

R ² and R ⁴ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, -( CH ₂ ) _v -NR ^h R ⁱ , hydroxyl, hydroxyalkyl and cycloalkyl;

R ³ and R ⁶ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, -( CH ₂ ) _w -NR ^j R ^k , nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl;

R ^b and R ^c are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, -( CH ₂ ) _x -NR ^m R ⁿ , nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^a , R ^d , Re , R ^f , R ^g , Rh , R ⁱ , R ^j , R ^k , R ^m and R ⁿ are the same or different, and are each independently ^selected from hydrogen atoms, alkyl groups, and ^alkenyl groups. , alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

u, v, w and x are the same or different, and are each independently selected from 0, 1, 2 and 3;

r is 0, 1 or 2;

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

q 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 G ¹ is O or CR ^b R ^c , R ^b and R ^c are as in the general formula (I) Definition; Preferably, G ¹ is O or CH ₂ ; More preferably, G ¹ is O.

，R⁶可取代在該環B任意位置。 In some embodiments of the present disclosure, the compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a naphthalene ring; and/or ring B is

, R ⁶ can be substituted at any position of ring B.

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

in

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

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

Another aspect of the present disclosure relates to a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

in,

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

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

為

，環C為6員芳基或5-6員雜芳基，z為 0、1或2，R³如通式(III)中所定義；較佳地，

為

，R³如通式 (III)中所定義。 In some embodiments of the present disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein

for

, ring C is a 6-membered aryl group or a 5-6-membered heteroaryl group, z is 0, 1 or 2, R ³ is as defined in the general formula (III); preferably,

for

, R ³ is as defined in general formula (III).

為

，R^3a和R^3b相同或不同，且各自獨立地選自氫 原子、鹵素、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6烷氧基、C_1-6鹵烷基、C_1-6鹵烷 氧基、氰基、胺基、-(CH₂)_w-NR^jR^k和C_1-6羥烷基，R^j和R^k相同或不同，且各自 獨立地為氫原子或C_1-6烷基，w為0或1；較佳地，

為

，R^3a 和R^3b相同或不同，且各自獨立地選自氫原子、鹵素、C_1-6烷基、C_2-6炔基、C_1-6 鹵烷基和C_1-6羥烷基；更佳地，

為

，R^3a為氫原子或鹵素， R^3b選自鹵素、C_1-6烷基和C_2-6炔基；最佳地，

為

，R^3a為氫 原子或F，R^3b選自F、乙基和乙炔基。 In some embodiments of the present disclosure, the compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, wherein

for

, R ^3a and R ^3b are the same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, cyano group, amine group, -(CH ₂ ) _w -NR ^j R ^k and C _1-6 hydroxyalkyl group, R ^j and R ^k are the same or Different, and each independently a hydrogen atom or a C _1-6 alkyl group, w is 0 or 1; preferably,

for

, R ^3a and R ^3b are the same or different, and are each independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 haloalkyl and C _1-6 hydroxyalkyl ;Better still,

for

, R ^3a is a hydrogen atom or halogen, R ^3b is selected from halogen, C _1-6 alkyl and C _2-6 alkynyl; optimally,

for

, R ^3a is a hydrogen atom or F, R ^3b is selected from F, ethyl and ethynyl.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or (III) or a pharmaceutically acceptable salt thereof, wherein G ¹ is O or CR ^b R ^c , R ^b and R ^c are as in the general formula ( As defined in I); preferably, G ¹ is O or CH ₂ ; more preferably, G ¹ is O.

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

In some embodiments of the present disclosure, the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof, wherein ring A is a bicyclic aryl group or a bicyclic heteroaryl group; preferably, ring A is 8-10 membered bicyclic aryl group or 8-10 membered bicyclic heteroaryl group; more preferably, it is naphthyl group.

；R⁶可取代在該環 B任意位置。 In some embodiments of the present disclosure, the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof, wherein ring B is a 3-8 membered heterocyclyl; preferably, ring B is

; R ⁶ can be substituted at any position of ring B.

為

，R⁶如通式(I)中所定義；較佳地，

為

或

，R⁶為鹵素；進一步佳地，

為

，R⁶為鹵素；R⁶進一步佳為F。 In some embodiments of the present disclosure, the compound represented by general formula (I) or (III) or a pharmaceutically acceptable salt thereof, wherein

for

, R ⁶ is as defined in general formula (I); preferably,

for

or

, R ⁶ is halogen; further preferably,

for

, R ⁶ is halogen; R ⁶ is further preferably F.

為

或

；較佳為

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

for

or

; Preferably

.

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

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

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

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen atom, halogen, C _1-6 alkyl group , C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, cyano group, amino group, -(CH ₂ ) _v -NR ^h R ⁱ , hydroxyl group and C _1-6 Hydroxyalkyl, R ^h and R ⁱ are the same or different, and each is independently a hydrogen atom or C _1-6 alkyl group, v is 0 or 1; preferably, R ² is selected from hydrogen atom, halogen, C _{1- 6} alkyl and C _1-6 haloalkyl; further preferably, R ² is a hydrogen atom.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R ³ is the same or different, and each is independently selected from a hydrogen atom, Halogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano , amino group, -(CH ₂ ) _w -NR ^j R ^k , hydroxyl group and C _1-6 hydroxyalkyl group, R ^j and R ^k are the same or different, and each is independently a hydrogen atom or C _1-6 alkyl group, w is 0 or 1; preferably, R ³ is the same or different, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl; further preferably, R ³ is the same or different, and each is independently selected from a hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkynyl and hydroxyl; most preferably, ^R3 is the same or different, and each is independently selected from halogen, ethyl, ethynyl and hydroxyl.

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl group , C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, cyano group, amino group, -(CH ₂ ) _v -NR ^h R ⁱ , hydroxyl group and C _1-6 Hydroxyalkyl, R ^h and R ⁱ are the same or different, and each is independently a hydrogen atom or C _1-6 alkyl group, v is 0 or 1; preferably, R ⁴ is selected from hydrogen atom, halogen, C _{1- 6} alkyl and C _1-6 haloalkyl; further preferably, R ⁴ is halogen; most preferably, R ⁴ is F.

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

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is the same or different, and each is independently selected from a hydrogen atom, Halogen, C _1-6 alkyl, C 1-6 alkoxy, ^C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amino, -(CH ₂ ) _w -NR _j R ^k , hydroxyl and C _1-6 hydroxyalkyl, R ^j and R ^k are the same or different, and each is independently a hydrogen atom or C _1-6 alkyl, w is 0 or 1; preferably, R ⁶ is the same or Different, and each is independently selected from hydrogen atoms, halogen, C _1-6 alkyl and C _1-6 haloalkyl; further preferably, R ⁶ is halogen; most preferably, R ⁶ is F.

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

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

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

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

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

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

In some embodiments of the present disclosure, the compound represented by the general formula (I), (II) or (III) 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), (II) or (III) 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), (II) or (III) 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), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein x 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 G ¹ is O or CH ₂ ; G ² is NH; L is selected from single bonds, O and NR ^e ; R ^e is a hydrogen atom or C _1-6 alkyl group; Ring A is an 8-10-membered bicyclic aryl group or an 8-10-membered bicyclic heteroaryl group; Ring B is a 3-8-membered heterocyclyl group; p is 0 or 1 ; R ¹ is selected from hydrogen atom, halogen, C _1-6 alkyl group, C _1-6 haloalkyl group, cyano group, amino group, -(CH ₂ ) _u -NR ^f R ^g , hydroxyl group and C _1-6 hydroxyl group Alkyl group, R ^f and R ^g are the same or different, and are each independently a hydrogen atom or C _1-6 alkyl group, u is 0 or 1; R ² is selected from hydrogen atom, halogen, C _1-6 alkyl group, C _1-6 alkoxy, C _1-6 haloalkyl, C _1-6 haloalkoxy, cyano, amine, -(CH ₂ ) _v -NR ^h R ⁱ , hydroxyl and C _1-6 hydroxyalkyl group, R ^h and R ⁱ are the same or different, and each is independently a hydrogen atom or a C _1-6 alkyl group, v is 0 or 1; q is 1 or 2; R ³ is the same or different, and each is independently selected from Hydrogen atom, halogen, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group , cyano group, amino group, -(CH ₂ ) _w -NR ^j R ^k , hydroxyl group and C _1-6 hydroxyalkyl group, R ^j and R ^k are the same or different, and each is independently a hydrogen atom or C _1-6 Alkyl group, w is 0 or 1; R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, Cyano group, amino group, -(CH ₂ ) _v -NR ^h R ⁱ , hydroxyl group and C _1-6 hydroxyalkyl group, R ^h and R ⁱ are the same or different, and each is independently a hydrogen atom or C _1-6 alkane Base, v is 0 or 1; r is 0 or 1; R ⁵ is selected from hydrogen atom, halogen, C _1-6 alkyl, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl; t is 0 or 1; R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 haloalkyl group, C _1-6 haloalkoxy group, cyano group, amino group , -(CH ₂ ) _w -NR ^j R ^k , hydroxyl group and C _1-6 hydroxyalkyl group, R ^j and R ^k are the same or different, and each is independently a hydrogen atom or C _1-6 alkyl group, w is 0 or 1.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G ¹ is O or CH ₂ ; G ² is NH; L is O; p is 1; R ¹ Selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; R ² is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; q is 1 or 2; R ³ is the same or different, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl ; R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; r is 0 or 1; R ⁵ is selected from hydrogen atom, C _1-6 alkyl, hydroxyl and C _{1- 6hydroxyalkyl} ; t is 1; and R ⁶ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl.

In some embodiments of the present disclosure, the compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, wherein G ¹ is O or CH ₂ ; G ² is NH; L is O; p is 0; R ² is a hydrogen atom; q is 1, 2 or 3; R ³ is the same or different, and each is independently selected from hydrogen atoms, halogen, C _1-6 alkyl, C _2-6 alkynyl and hydroxyl; R ⁴ is halogen; r is 1; R ⁵ is a hydrogen atom; t is 1; and R ⁶ is halogen.

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

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

in,

R is an amino protecting group; preferably Boc;

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

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

in,

R is an amino protecting group; preferably Boc;

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

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

in,

R is an amino protecting group; preferably Boc;

R ⁰ is a hydroxyl protecting group; preferably MOM;

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

Typical intermediate compounds of the present disclosure 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 general formula (IA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups contain a protective group , before or after the deprotection reaction, it also includes the step of removing the protecting group on the R ³ and/or R ⁶ groups;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

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 general formula (IA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups contain a protective group , before, at the same time or after the deprotection reaction, it also includes the step of removing the protecting group on the R ³ and/or R ⁶ group;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

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, which method includes:

The compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups contain a protective group , before or after the deprotection reaction, it also includes the step of removing the protecting group on the R ³ and/or R ⁶ groups;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

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, which method includes:

The compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups contain a protective group , before, at the same time or after the deprotection reaction, it also includes the step of removing the protecting group on the R ³ and/or R ⁶ group;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

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

The compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; optionally, when the ^R group contains a protecting group, the deprotection step Before or after the reaction, a step of removing the protecting group on the R ⁶ group is also included;

Among them, R is an amino protecting group; preferably Boc;

R ⁰ is a hydroxyl protecting group; preferably MOM;

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

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

The compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups contain a protective group , before, at the same time or after the deprotection reaction, it also includes the step of removing the protecting group on the R ³ and/or R ⁶ groups;

Among them, R is an amino protecting group; preferably Boc;

R ⁰ is a hydroxyl protecting group; preferably MOM;

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

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

The present disclosure further relates to the preparation of compounds shown in general formula (I), (II), (III) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including the same for inhibiting KRAS G12D and/or The use of KRAS G12V in medicine; wherein KRAS G12D and/or KRAS G12V is preferably KRAS G12D. The present disclosure further relates to the preparation of compounds shown in general formula (I), (II), (III) or Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions including the same for the treatment and/or prevention of diseases. Or use in medicine for a disease, the disease or disease is cancer; the disease or disease is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, Lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer Cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colorectal cancer, small intestine cancer, gastrointestinal stromal tumor, urothelial cancer, urethra 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 method for inhibiting KRAS G12D and/or KRAS G12V, which includes administering to a patient in need a therapeutically effective amount of a compound represented by general formula (I), (II), (III) or Table A or a drug thereof The salt used, or the pharmaceutical composition including the same; among them, KRAS G12D and/or KRAS G12V is preferably KRAS G12D.

The present disclosure further relates to a method for treating and/or preventing a disease or condition, which includes administering to a patient in need a therapeutically effective amount of a compound represented by formula (I), (II), (III) or Table A or a medicament thereof The salt used, or the pharmaceutical composition including 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, throat cancer, oral cancer, salivary gland cancer, Esophageal cancer, stomach cancer, lung cancer, liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urethra 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 represented by general formula (I), (II), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used as a medicine.

The present disclosure further relates to a compound represented by general formula (I), (II), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used to inhibit KRAS G12D and/or The drug of KRAS G12V; among them KRAS G12D and/or KRAS G12V is preferably KRAS G12D.

The present disclosure further relates to a compound represented by general formula (I), (II), (III) or Table A or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including the same, which is used to treat and/or prevent diseases. Or a medicine for a condition, wherein the disease or condition is cancer; the disease or condition is preferably selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, Liver cancer, kidney cancer, pleural cancer, peritoneal cancer, pancreatic cancer, gallbladder cancer, cholangiocarcinoma, colorectal cancer, small intestinal cancer, gastrointestinal stromal tumor, urothelial cancer, urethra 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 and/or KRAS G12V; wherein KRAS G12D and/or KRAS G12V is preferably KRAS G12D.

Preferably, the brain cancer described in the present disclosure is selected from glioblastoma multiforme or neuroblastoma; the soft tissue cancer is selected from fibrosarcoma, gastrointestinal sarcoma, rhabdomyosarcoma, leiomyosarcoma, dedifferentiated liposarcoma, multiple liposarcoma, malignant fibrous histiocytoma, round cell sarcoma, and synovial sarcoma; lymphoma selected from Hodgkin's disease and non-Hodgkin's lymphoma (e.g., mantle cell lymphoma, diffuse large B-cell lymphoma, Follicular center lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); 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; kidney cancer is selected from renal cell carcinoma, clear cell and renal oncocytoma; leukemia is selected from chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia , acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), and acute myelogenous leukemia (AML); skin cancer selected from malignant melanoma , squamous cell carcinoma, basal cell carcinoma and angiosarcoma; myeloma is preferably multiple myeloma; colorectal cancer is preferably colon cancer or rectal cancer.

The active compounds may be prepared in a form suitable for administration by any appropriate route. The compositions of the present disclosure may be formulated by conventional methods using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the present disclosure may be formulated in various dosage forms for oral administration, injection (eg, intravenous, intramuscular or subcutaneous) administration, inhalation or insufflation administration. The compounds of the present disclosure may also be formulated in 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 are preferably in unit dosage form, or in such form that the patient may self-administer a single dose. The unit dose of the compound or composition of the present disclosure may be expressed as a tablet, capsule, cachet, bottled solution, powder, granule, lozenge, suppository, reconstituted powder or liquid preparation. Suitable unit dosage can be 0.1~1000mg.

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

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

Oral formulations may also be presented in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier or oil vehicle.

Aqueous suspensions contain the active substances and excipients suitable for the preparation of aqueous suspensions for mixing. Such excipients are suspending, dispersing 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 formulated by suspending the active ingredient in vegetable oil, or mineral oil. Oil suspensions may contain thickening agents. Sweetening and flavoring agents as described above may be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oil phase may be vegetable oil, or mineral oil or mixtures 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 demulcents, preservatives, coloring agents and antioxidants.

The pharmaceutical compositions of the present disclosure 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. Sterile injectable preparations can be sterile injectable oil-in-water microemulsions in which the active ingredient is dissolved in the oil phase. Injectable solutions or microemulsions can be injected into the patient's bloodstream by local large-volume injection. Alternatively, solutions and microemulsions are preferably administered in a manner that maintains constant circulating concentrations of the disclosed compounds. To maintain this constant concentration, continuous intravenous drug delivery devices can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oily suspensions for intramuscular and subcutaneous administration. Suitable dispersing or wetting agents and suspending agents such as those mentioned above may be used according to known techniques. Prepare this suspension. The sterile injectable preparation may also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent. In addition, sterile fixed oil can be conveniently used as the solvent or suspending medium. For this purpose, any blend of fixed oils can be used. In addition, fatty acids are also prepared as injectables.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions may 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 dissolve in the rectum to release the drug.

Compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may 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 of ordinary skill in the art, the dosage of a drug depends on a variety of factors, including, but not limited to, the activity of the specific compound used, the severity of the disease, the age of the patient, the weight of the patient, the patient's The health status of the patient, the patient's behavior, the patient's diet, administration time, administration method, excretion rate, drug combination, etc.; in addition, the best treatment method such as treatment mode, daily dosage of the compound or pharmaceutically acceptable The type of salt can be verified according to the traditional treatment plan.

[Explanation of terminology]

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

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups of carbon atoms (i.e. C _1-12 alkyl), more preferably alkyl groups with 1 to 6 carbon atoms (i.e. C _1-6 alkyl base). 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-di Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl base, 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-methyl Pentyl, 2,3-dimethylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkyl. One or more of oxygen, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl .

The term "(alkylene)" refers to a saturated linear or branched aliphatic hydrocarbon group, which is a residue derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, which It is a linear or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 ) carbon atom (i.e., C _1-12 (alkylene) group), more preferably an alkylene group having 1 to 6 carbon atoms (i.e., C _1-6 (alkylene) group). Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH ₂ -), 1,1-ethylene (-CH(CH ₃ )-), 1,2-ethylidene (-CH ₂ CH ₂ )-, 1,1-propylene (-CH(CH ₂ CH ₃ )-), 1,2-propylene (-CH ₂ CH(CH ₃ )-), 1,3-propylene (-CH ₂ CH ₂ CH ₂ -), 1,4-butyl (-CH ₂ CH ₂ CH ₂ CH ₂ -), etc. The (alkylene) group may be substituted or unsubstituted. When substituted, it may be substituted at any available point of attachment. The substituent is preferably selected from the group consisting of alkenyl, alkynyl, alkoxy, Haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, hetero One or more of aryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio and pendant oxy.

The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above, preferably having 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C _2-12 alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e. C _2-6 alkenyl). Non-limiting examples include: vinyl, propenyl, isopropenyl, butenyl, and the like. Alkenyl can be substituted or unsubstituted. When substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl , one or more of 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, where alkyl is as defined above. Preferably it has 2 to 12 (such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e. C _2-12 alkynyl), more preferably it has 2 to 6 Alkynyl group with carbon atoms (i.e. C _2-6 alkynyl group). Non-limiting examples include: ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. The alkynyl group may be substituted or unsubstituted. When substituted, the substituent is preferably selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl , one or more of hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

The term "spirocycloalkyl" refers to a polycyclic group with 5 to 20 members, sharing one carbon atom (called a spiro atom) between the single rings, and which may contain one or more double bonds. Preferably, there are 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). According to the number of shared spiro atoms between the rings, spirocycloalkyl groups are divided into single spirocycloalkyl groups or polyspirocycloalkyl groups (such as double spirocycloalkyl groups). The preferred ones are single spirocycloalkyl groups and double spirocycloalkyl groups. Cycloalkyl. Better to be 3 members/4 members, 3 members/5 members, 3 members/6 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/3 members, 5 members/4 members , 5 members/5 members, 5 members/6 members, 5 members/7 members, 6 members/3 members, 6 members/4 members, 6 members/5 members, 6 members/6 members, 6 members/7 members, 7 Member/5-member or 7-member/6-member monospirocyclic alkyl group. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more rings. Multiple double bonds. Preferably, there are 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (such as tricyclic, tetracyclic) fused ring alkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, or 3-membered. /6 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/3 members, 5 members/4 members, 5 members/5 members, 5 members/6 members, 5 members/7 members, 6 members/3 members, 6 members/4 members, 6 members/5 members, 6 members /6-member, 6-member/7-member, 7-member/5-member or 7-member/6-member bicyclic fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, with any two rings sharing two carbon atoms that are not directly connected, and which may contain one or more double bonds. Preferably, there are 6 to 14 members, more preferably 7 to 10 members (for example, 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (such as tricyclic, tetracyclic) bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

、

、

等；較佳為

或

The cycloalkyl ring includes a cycloalkyl group (including a monocyclic ring, a spiro ring, a condensed ring and a bridged ring) as described above fused to an aryl, heteroaryl or heterocycloalkyl ring, where it is connected to the parent structure at The rings together are cycloalkyl, non-limiting examples include

,

,

etc; preferably

or

Cycloalkyl can be substituted or unsubstituted. When substituted, it can be substituted at any available point of attachment. The substituent is preferably selected from halogen, alkyl, alkoxy, haloalkyl, haloalkane One or more of oxygen, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl .

The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably selected from the group consisting of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, hetero Cycloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent, which contains 3 to 20 (for example, 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 heterocyclyl), one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, the Sulfur can be oxidized (i.e., to form sulfur or sulfur) if desired, but does not include the -O-O-, -O-S- or -S-S- ring portion, and the remaining ring atoms are carbon. Preferably, it contains 3 to 14 (such as 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (ie, 3 to 14 membered heterocyclyl), wherein 1~ 4 (such as 1, 2, 3 and 4) are heteroatoms; more preferably, 3 to 8 ring atoms (such as 3, 4, 5, 6, 7 and 8) are included (i.e. 3 to 8 membered heterocyclyl ) or 6 to 14 ring atoms (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14), of which 1-3 are heteroatoms (such as 1, 2 and 3); more preferably 3 to 8 ring atoms, of which 1-3 (e.g., 1, 2, and 3) are heteroatoms; optimally contains 5 or 6 ring atoms (i.e., 5- or 6-membered heterocyclyl), of which 1-3 One is a heteroatom. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazine base, etc. Polycyclic heterocyclyl groups include spiroheterocyclyl groups, fused heterocyclyl groups and bridged heterocyclyl groups.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, sharing one atom (called a spiro atom) between the single rings, in which one or more ring atoms are heterocyclic groups selected from nitrogen, oxygen and sulfur. atoms, the sulfur may be oxidized if desired (i.e., to form sulfur or sulfur), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 members (such as 7 , 8, 9 or 10 members) (i.e. 7 to 10 membered spiroheterocyclyl). According to the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into a single spiroheterocyclyl group or a polyspiroheterocyclyl group (such as a double spiroheterocyclyl group), and the preferred ones are a single spiroheterocyclyl group and a double spiroheterocyclyl group. ring base. Better to be 3 members/4 members, 3 members/5 members, 3 members/6 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/3 members, 5 members/4 members , 5 members/5 members, 5 members/6 members, 5 members/7 members, 6 members/3 members, 6 members/4 members, 6 members/5 members, 6 members/6 members, 6 members/7 members, 7 Member/5-member or 7-member/6-member single spiroheterocyclic group. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members. Each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur being optionally oxidized (i.e. forming sulfur or sulfur) and the remaining ring atoms being carbon. Preferably it is 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e. 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 members (such as 7 , 8, 9 or 10 members) (i.e. 7 to 10 membered fused heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (such as tricyclic, tetracyclic) fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, or 3-membered. /6 members, 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/3 members, 5 members/4 members, 5 members/5 members, 5 members /6 members, 5 members/7 members, 6 members/3 members, 6 members/4 members, 6 members/5 members, 6 members/6 members, 6 members/7 members, 7 members/5 members or 7 members/6 Member bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, the sulfur being optionally oxidized (i.e., forming sulfur or sulfur), and the remaining ring atoms are carbon. Preferably it is 6 to 14 members (such as 6, 7, 8, 9, 10, 11, 12, 13 and 14 members) (i.e. 6 to 14 membered bridged heterocyclyl group), more preferably 7 to 10 members (such as 7 , 8, 9 or 10 members) (i.e. 7 to 10 membered bridged heterocyclyl). According to the number of constituent rings, it can be divided into bicyclic or polycyclic (such as tricyclic or tetracyclic) bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

The heterocyclyl ring includes a heterocyclyl group (including a monocyclic ring, a spiroheterocyclic ring, a fused heterocyclic ring and a bridged heterocyclic ring) as described above, fused to an aryl, heteroaryl or cycloalkyl ring, which is identical to the parent structure. The rings linked together are heterocyclyl, non-limiting examples of which include:

和

等。

and

wait.

Heterocyclyl may be substituted or unsubstituted. When substituted, it may be substituted at any available attachment point. The substituent is preferably selected from halogen, alkyl, alkoxy, haloalkyl, One of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or Multiple.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares pairs of adjacent carbon atoms) group with a conjugated π electron system, preferably 6 to 10 members such as phenyl and naphthyl. The aryl ring includes the aryl ring fused to a heteroaryl, heterocyclyl or cycloalkyl ring as above, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, halo One or more of alkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl Piece.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 (eg, 1, 2, 3, and 4) heteroatoms, and from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 members (such as 5, 6, 7, 8, 9 or 10 members) (i.e. 5 to 10 membered heteroaryl), more preferably 8 to 10 members (such as 8, 9 or 10 members), more preferably 5 members Or 6-membered (i.e. 5-membered or 6-membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyridyl Azolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes the above-mentioned heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include:

Heteroaryl groups may be substituted or unsubstituted. When substituted, they may be substituted at any available point of attachment. The substituents are preferably selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, One of haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amine, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl or Multiple.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogens from the same ring atom or two different ring atoms of the parent The residues derived from the atoms are "bivalent cycloalkyl", "bivalent heterocyclyl", "(ex)arylene" and "(ex)heteroaryl".

The term "amine protecting group" is used to protect the amine group with an easily removable group in order to keep the amine group unchanged when other parts of the molecule react. Non-limiting examples include (trimethylsilyl)ethoxymethyl (SEM), tetrahydropyranyl, tert-butoxycarbonyl (Boc), acetyl, benzyl, allyl, p-methyl Benzenesulfonyl (Ts) and p-methoxybenzyl, etc. These groups are optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro; the amino protecting group is preferably Boc.

The term "hydroxyl protecting group" refers to hydroxyl derivatives commonly used to block or protect hydroxyl groups while reactions proceed on other functional groups of the compound. As an example, preferably, the hydroxyl protecting group can be triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl (TBS), tert-butyldiphenylsilyl, methyl base, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-tetrahydropyranyl (THP), formyl, acetyl, benzyl Cyl group, p-nitrobenzoyl group; the hydroxyl protective group is preferably MOM.

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

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

The term "aryloxy" refers to aryl-O-, where aryl is as defined above.

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

The term "alkylthio" refers to alkyl-S-, where alkyl is as defined above.

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

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

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

The term "hydroxy" refers to -OH.

The term "mercapto" refers to -SH.

The term "amine" refers to _-NH2 .

The term "cyano" refers to -CN.

The term "nitro" refers to _-NO2 .

The term "pendant oxy" or "pendant oxygen" refers to "=O".

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-, where alkyl and cycloalkyl are as defined above.

MOM methoxymethyl.

Boc refers to tertiary butoxycarbonyl.

TIPS refers to triisopropylsilyl.

Compounds of the present disclosure may exist in specific stereoisomeric forms. The term "stereoisomer" refers to isomers that have the same structure but different arrangements of atoms in space. It includes cis and trans (or Z and E ) isomers, (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, diastereomers body, (D )- and ( L )-isomers, tautomers, atropisomers, conformational isomers and their mixtures (such as racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in the substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-)- and (+)-isomers, ( R )- and ( S )-enantiomers, and (D )- can be prepared by chiral synthesis, chiral reagents, or other conventional techniques and ( L )-isomer. An isomer of a compound disclosed in this disclosure can be prepared through asymmetric synthesis or chiral auxiliaries, or when the molecule contains a basic functional group (such as an amine group) or an acidic functional group (such as a carboxyl group), it can be prepared with appropriate Optically active acids or bases form diastereomeric salts, and then the diastereoisomers are resolved by conventional methods known in the art to obtain pure isomers. In addition, the separation of enantiomers and diastereomers is usually accomplished by chromatography.

”表示未指定構型，即如果化學結構中存在手性異構體，鍵“

”可以為“

”或“

”，或者同時包含“

”和“

”兩種構型。對於所有的碳-碳雙鍵，即使僅命名了一個構型，Z型和E型均包括在內。 In the chemical structure of the compounds described in this disclosure, the bond "

"Indicates that the configuration is not specified, i.e. if there are chiral isomers in the chemical structure, the bond"

"can be"

"or"

”, or both “

"and"

"Two configurations. For all carbon-carbon double bonds, even if only one configuration is named, both the Z and E forms are included.

The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include tautomers via proton migration, such as keto-enol and imine-enamine, lactam-lactam imine isomerizations.

All tautomeric forms are within the scope of the present disclosure. The naming of the compounds does not exclude any tautomers.

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 with the same atomic number but a different atomic mass. Examples of isotopes that may be incorporated into the compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as ² H (deuterium, D), respectively. ³ H (tritium, T), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N ^{, 17} O, 18 O, ³² p, ³³ p, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I, ¹²⁹ I and ¹³¹ I, etc., preferably deuterium.

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

"Optionally" or "as appropriate" is meant to mean that the subsequently described event or circumstances may but need not occur, and that the description includes instances where the event or circumstances do or do not occur. For example, "C _1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but does not have to be present. This description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen. and the case of cyano substitution.

"Substituted" means that one or more hydrogen atoms in the group, preferably 1 to 6, more preferably 1 to 3 hydrogen atoms, are independently substituted by a corresponding number of substituents. A person of ordinary skill in the art can determine possible or impossible substitutions without undue effort (by experiment or theory). For example, an amine or hydroxyl group with a free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other ingredients such as pharmaceutically acceptable carriers and excipients. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

"Pharmaceutically acceptable salts" refer to salts of compounds of the present disclosure, which may be selected from inorganic salts or organic salts. This type of salt is safe and effective when used in mammals, and has due biological activity. Can Salts are prepared separately during the final isolation and purification of the compounds, 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 amines. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent 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, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate therapeutically effective amount in an individual case can be determined by a person with ordinary knowledge in the art based on routine experiments.

The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and/or dosage forms which, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reaction or other problems or complications, has a reasonable benefit/risk ratio, and is effective for the intended use.

As used herein, the singular forms "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 means that the parameter can vary by ±10%, and sometimes preferably within ±5%. As those skilled in the art will appreciate, when a parameter is not critical, numbers are generally given for purposes of illustration only and not limitation.

Synthetic methods of the disclosed compounds

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

Option One

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

The compound of general formula (IA) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups When containing a protecting group, before or after the deprotection reaction, a step of removing the protecting group on the R ³ and/or R ⁶ groups under acidic or alkaline conditions is also included;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

Option II

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

The compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups When containing a protecting group, before or after the deprotection reaction, a step of removing the protecting group on the R ³ and/or R ⁶ groups under acidic or alkaline conditions is also included;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

third solution

The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which method includes:

The compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; optionally, when the R ⁶ group contains a protective group, Before or after the deprotection reaction, a step of removing the protecting group on the R ⁶ group under acidic or alkaline conditions is also included;

Among them, R is an amino protecting group; preferably Boc;

R ⁰ is a hydroxyl protecting group; preferably MOM;

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

Option 4

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

The compound of general formula (IA) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups When containing a protecting group, the step of removing the protecting group on the R ³ and/or R ⁶ groups under acidic or alkaline conditions is also included before, simultaneously or after the deprotection reaction;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

Option five

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

The compound of general formula (IIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain a compound of general formula (II) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups When containing a protecting group, the step of removing the protecting group on the R ³ and/or R ⁶ groups under acidic or alkaline conditions is also included before, simultaneously or after the deprotection reaction;

Among them, R is an amino protecting group; preferably Boc;

G ² is NH;

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

Option six

The present disclosure provides a method for preparing a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof, which method includes:

The compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction under acidic conditions to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups When containing a protecting group, the step of removing the protecting group on the R ³ and/or R ⁶ groups under acidic or alkaline conditions is also included before, simultaneously or after the deprotection reaction;

Among them, R is an amino protecting group; preferably Boc;

R ⁰ is a hydroxyl protecting group; preferably MOM;

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

The reagents that provide 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 it is not limited to hydrogen chloride, dioxane hydrochloride solution, hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; preferably it is dioxane hydrochloride solution.

The reagents that provide alkaline conditions in the above synthesis scheme include organic bases and inorganic bases. The organic bases include but are not limited to triethylamine, N,N-diisopropylethylamine, n-butyllithium, and diisopropyl amine. Lithium amide, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium fluoride solution in tetrahydrofuran or 1,8-diazabicyclounde-7 -ene, the inorganic bases include but are not limited to sodium hydride, potassium phosphate, sodium carbonate, sodium acetate, potassium acetate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, cesium fluoride and potassium hydroxide; preferably It is a solution of tetrabutylammonium fluoride in tetrahydrofuran or cesium fluoride.

In the above synthesis scheme, when R ³ and/or R ⁶ contain a terminal alkyne group, the terminal alkyne can be protected by TIPS, and the reagent for removing TIPS is preferably a tetrabutylammonium fluoride solution in tetrahydrofuran or cesium fluoride.

The reaction of the above steps is preferably carried out in a solvent. The solvents used include but are not limited to: pyridine, glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, n-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether , Ethyl acetate, n-hexane, dimethylstyrene, 1,4-dioxane, water, N,N-dimethylformamide, N,N-dimethylacetamide, 1,2- Dibromoethane and its mixtures.

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

[Example]

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR was measured using a Bruker AVANCE NEO 500M nuclear magnetic instrument. The measurement solvents were deuterated dimethyl styrene (DMSO- d ₆ ), deuterated chloroform (CDCl ₃ ), and deuterated methanol (CD ₃ OD). The internal standard was tetrahydrofuran. Methylsilane (TMS).

MS was measured using Agilent 1200/1290 DAD-6110/6120 Quadrupole MS (manufacturer: Agilent, MS model: 6110/6120 Quadrupole 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 used Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 liquid chromatographs.

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

High performance liquid phase preparation used Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson-281 preparative chromatographs.

Chiral preparation uses Shimadzu LC-20AP preparative chromatograph.

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

Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used in thin layer chromatography (TLC) are 0.15mm~0.2mm. The specifications used for thin layer chromatography separation and purification products are 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 IC ₅₀ value were measured using NovoStar microplate reader (BMG Company, Germany).

The known starting materials of the present disclosure 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.

There are no special instructions in the examples, and 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 volume of about 1L.

The hydrogen atmosphere refers to the reaction bottle connected to a hydrogen balloon with a volume of about 1L.

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

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

The microwave reaction uses CEM Discover-S 908860 microwave reactor.

There is no special explanation in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples. The reaction temperature is room temperature, which is 20°C to 30°C.

The reaction process in the embodiment is monitored by thin layer chromatography (TLC). The developing agent used in the reaction, the eluent system of column chromatography and the developing agent system of thin layer chromatography used to purify the compound include: A : Dichloromethane/methanol system, B: n-hexane/ethyl acetate, the volume ratio of the solvent can be 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

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

first step

7-(2,7-Dichloro-8-fluoropyrido[4,3- d ]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane- 9-tert-butylcarboxylate 1c

2,4,7-Trichloro-8-fluoropyrido[4,3- d ]pyrimidine 1a (400 mg, 1.58 mol, using the method disclosed in Intermediate 4 on page 80 of the specification in the patent application "WO2021/041671A1" Prepared), N , N -diisopropylethylamine (248 mg, 7.92 mmol) was dissolved in 10 mL dichloromethane, and 3-oxa-7,9-diazabicyclo [3.3.1 ] Nonane-9-carboxylic acid tert-butyl ester 1b (361 mg, 1.58 mmol, Nanjing Yaoshi), keep the temperature and stir the reaction for 1 hour, add 10 mL water to the reaction solution, extract with dichloromethane (10 mL × 3), organic The phases were combined, washed with 2M hydrochloric acid solution, the organic phase was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 1c (500 mg, product rate: 71%).

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

Step 2

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

Compound 1c (100 mg, 225 μmol) was dissolved in acetonitrile (2 mL), and ((2 R ,7 aS )-2-fluorotetrahydro-1 H -pyrrolizin-7 a (5 H )-yl)methanol 1d (71 mg , 446 μmol, WuXi), N , N -diisopropylethylamine (108.5 mg, 839 μmol) and 4A molecular sieve (100 mg), stir and react at 90°C for 14 hours, cool the reaction solution to room temperature and then concentrate under reduced pressure, and the residue Purification using silica gel column chromatography with eluent system A gave the title compound 1e (80 mg, yield: 62.6%).

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

third step

7-(8-fluoro-7-(8-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-2-(((2 R ,7 aS )-2-fluorotetrahydro-1 H -Pyrrozine-7 a (5 H )-yl)methoxy)pyrido[4,3- d ]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3. 1] Nonane-9-carboxylic acid tert-butyl ester 1g

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

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

the fourth step

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

Dissolve 1g of compound (20mg, 27.1μmol) in acetonitrile (1mL), add 1mL of 4M hydrochloric acid dioxane solution, react at room temperature for 0.5 hours, concentrate the reaction solution under reduced pressure and use high performance liquid chromatography (Waters-2545, Chromatography column: SharpSil-T C18, 30*150mm, 5μm; mobile phase: water (containing 10mmol/L ammonium bicarbonate) and acetonitrile, gradient ratio: acetonitrile 38%-45%, flow rate: 30mL/min) purified Title compound 1 (2 mg, yield: 12.4%).

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

¹ H NMR (500MHz, CD ₃ OD): δ 9.08 (s, 1H), 7.58 (d, 1H), 7.38 (td, 1H), 7.32 (t, 1H), 7.16 (t, 1H), 6.91 (dd ,1H),5.01(q,3H),4.35-4.21(m,2H),4.02-3.87(m,8H),3.02(s,4H),2.22-2.11(m,2H),2.01(q,4H ).

Example 2

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

first step

Triisopropyl((8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphth-1-yl)ethynyl)silane 2b

((8-bromonaphth-1-yl)ethynyl)triisopropylsilane 2a (5g, 12.9mmol, prepared by the method disclosed in Example 179 on page 301 of the patent application "WO2021/041671A1" ) was dissolved in 50 mL of 1,4-dioxane, and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3, 2-dioxaborolane) (6g, 23.6mmol, Shaoyuan Technology (Shanghai) Co., Ltd.), potassium acetate (2.5g, 25.47mmol) and [1,1'-bis(diphenylphosphine) ) Ferrocene]palladium dichloride dichloromethane complex (1.05g, 1.28mmol), stir at 80°C for 16 hours under nitrogen protection. Cool, filter through diatomaceous earth, concentrate the filtrate, and purify by thin layer chromatography using developer system B to obtain the title compound 2b (4 g, yield: 71.33%).

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

Step 2

7-(8-fluoro-2-(((2 R ,7 aS )-2-fluorotetrahydro-1 H -pyrrozine-7 a (5 H )-yl)methoxy)-7-(8- ((Triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3- d ]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3. 1] Nonane-9-carboxylic acid tert-butyl ester 2c

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

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

third step

7-(8-fluoro-2-(((2 R ,7 aS )-2-fluorotetrahydro-1 H -pyrrozine-7 a (5 H )-yl)methoxy)-7-(8- ((Triisopropylsilyl)ethynyl)naphth-1-yl)pyrido[4,3- d ]pyrimidin-4-yl)-3-oxa-7,9-diazabicyclo[3.3. 1] Nonane 2d

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

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

the fourth step

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

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

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

¹ H NMR (500MHz, CDCl ₃ ): δ 9.07 (s, 1H), 7.96 (d, 1H), 7.77-7.73 (m, 1H), 7.62 (s, 1H), 7.49 (s, 1H), 7.46 ( s,1H),7.07(s,1H),5.35(d,2H),4.80(s,1H),4.30(d,2H),4.16(t,1H),3.95(d,3H),3.84(d ,4H),3.18(s,2H),3.01-2.93(m,1H),2.62(d,1H),2.26-2.20(m,3H),2.06-2.01(m,2H),1.96-1.90(m ,2H).

Example 3

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

first step

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

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

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

Step 2

4-(4-(3-oxa-7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2 R ,7 aS )-2-fluoro Tetrahydro-1 H -pyrrozine-7 a (5 H )-yl)methoxy)pyrido[4,3- d ]pyrimidin-7-yl)-5-((triisopropylsilyl)acetylene base) naphthalene-2-phenol 3c

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

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

third step

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

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

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

¹ H NMR (500MHz, CDCl ₃ ): δ 8.96 (s, 1H), 8.79 (s, 1H), 7.56 (d, 1H), 7.49 (s, 1H), 7.17 (d, 1H), 7.09 (d, 1H),7.07(s,1H),5.32(d,1H),5.20(s,1H),4.81(m,2H),4.73(m,2H),4.29(s,2H),4.25-4.20(m ,2H),4.13-4.09(m,2H),3.89-3.8(m,3H),2.95(d,2H),2.19(dt,3H),2.00(d,2H),1.94-1.83(m,3H ).

Example 4

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

Adopt the synthetic route in Example 1, and replace the third step raw material compound 1f with 2-(8-ethyl-3-(methoxymethoxy)naphthalene-1-yl)-4,4,5,5 - Tetramethyl-1,3,2-dioxaborolane (prepared by the method disclosed in Intermediate 21 on page 111 of the specification in the patent application "WO2021/041671A1") to prepare the title compound 4 (5mg, yield: 24.7%).

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

¹ H NMR (500MHz, CDCl ₃ ): δ 9.01(d,1H),7.57(d,1H),7.37-7.33(m,1H),7.23-7.21(m,1H),7.16(m,1H), 7.07(s,1H),6.99(s,1H),5.49-5.31(m,2H),5.24(s,1H),5.02-4.60(m,2H),4.30-4.24(m,2H),3.94- 3.83(m,3H),3.77-3.72(m,2H),3.33-3.30(m,2H),3.28-3.18(m,2H),3.01-2.94(m,3H),2.37-2.29(m,3H ),2.26-2.23(m,2H),2.20-2.17(m,1H),1.02-0.87(t,3H).

Example 5

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

Adopting the synthetic route in Example 1, the first step raw material compound 1b was replaced with 3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester to obtain the title compound 5 (6mg, Yield: 24.8%).

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

¹ H NMR (500MHz, CD ₃ OD): δ 9.12(s,1H),7.59(d,1H),7.39(td,1H),7.33(d,1H),7.17(d,1H),6.93(dd ,1H),5.36(s,1H),4.34(dd,1H),4.27(d,1H),3.87(s,1H),3.28(s,3H),3.26-3.18(m,4H),3.06- 2.98(m,1H),2.31-2.11(m,4H),2.00(dd,4H),1.91(s,2H),1.59(s,1H),1.34(s,1H),1.29(s,1H) .

Example 6

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

first step

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

The first step of the synthetic route in Example 1 was adopted, and the first step raw material compound 1b was replaced with 3,9-diazabicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester to prepare the title compound 6a (90mg, yield: 70.4%).

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

Step 2

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

The first to third steps of the synthetic route in Example 3 were adopted, and the raw material compound 1e in the first step was replaced by compound 6a to obtain the title compound 6 (6 mg, yield: 25.2%).

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

¹ H NMR (500MHz, CD ₃ OD): δ 9.06 (s, 1H), 7.80 (d, 1H), 7.48 (d, 1H), 7.37 (t, 1H), 7.30 (d, 1H), 7.16 (d ,1H),5.36(s,1H),4.32(dd,1H),4.25(dd,1H),3.85(t,3H),3.28(s,3H),3.26-3.18(m,3H),2.99( dd,1H),2.30-2.16(m,4H),2.00(dt,4H),1.94-1.84(m,2H),1.60(s,1H),1.34(s,1H),1.29(d,1H) .

Example 7

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

first step

3-(7-(8-ethyl-3-(methoxymethoxy)naphthyl-1-yl)-8-fluoro-2-(((2 R ,7 aS )-2-fluorotetrahydro- 1 H -Pyrrozine-7 a (5 H )-yl)methoxy)pyrido[4,3- d ]pyrimidin-4-yl)-3,9-diazabicyclo[3.3.1]nonane -9-tert-butylcarboxylate 7a

Compound 6a (30 mg, 53 μmol), 2-(8-ethyl-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3, 2-dioxaborolane (27 mg, 78.91 μmol), tetrakis(triphenylphosphine)palladium (9.1 mg, 7.8 μmol, adamas) and anhydrous cesium carbonate (51 mg, 156.5 μmol) were dissolved in 3 mL 1,4 -In a mixed solution of dioxane and water (V:V=5:1). Under nitrogen atmosphere, react at 100°C for 14 hours. The reaction solution is concentrated under reduced pressure. A mixed solution of methylene chloride and methanol (V: V=10:1) is added to the residue, filtered, and the filtrate is concentrated under reduced pressure to obtain the crude title compound 7a ( 15mg, yield: 37.9%).

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

Step 2

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

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

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

¹ H NMR (500MHz, CD ₃ OD): δ 9.12 (s, 1H), 7.63 (d, 1H), 7.40-7.33 (m, 1H), 7.29 (d, 1H), 7.16 (d, 1H), 7.03 (d,1H),5.36(s,1H),4.58(s,1H),4.36(d,1H),4.29(d,1H),3.91(s,1H),3.86(d,1H),3.35( s,7H),3.05(d,1H),2.35(d,2H),2.22(dd,4H),2.05-2.01(m,4H),1.92(q,3H),0.90(td,3H).

Example 8

4-(4-(3-oxa7,9-diazabicyclo[3.3.1]non-7-yl)-8-fluoro-2-(((2 R ,7 aS )-2-fluorotetra Hydro-1 H -pyrrolazine-7 a (5 H )-yl)methoxy)pyrido[4,3- d ]pyrimidin-7-yl)-5-ethyl-6-fluoronaphthalene-2-phenol 8

Adopt the synthetic route in Example 1, and replace the third step raw material compound 1f with 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-yl)-4,4 , 5,5-Tetramethyl-1,3,2-dioxaborolane (prepared by the method disclosed in Intermediate 18 on page 104 of the specification in the patent application "WO2021/041671"), prepared The title compound 8 was obtained (5 mg, yield: 15.4%).

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

¹ H NMR (500MHz, CDCl ₃ ): δ 8.65(s,1H),8.33(s,1H),7.89(d,1H),7.65(s,1H),6.96(d,1H),5.51-5.33( m,2H),5.26(s,1H),5.04-4.62(m,2H),4.32-4.27(m,2H),3.95-3.85(m,3H),3.80-3.74(m,2H),3.33- 3.32(m,2H),3.27-3.16(m,2H),3.02-2.95(m,3H),2.36-2.30(m,3H),2.27-2.24(m,2H),2.20-2.17(m,1H ),1.03-0.86(t,3H).

Example 9 (Comparative Example 1)

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

Adopt the synthetic route in Example 1, replace the first step raw material compound 1b with 3,6-diazabicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (Shanghai Bide) to obtain the title Compound 9 (4 mg, yield: 25%).

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

¹ H NMR (500MHz, CD ₃ OD): δ 9.10(d,1H),7.61(d,1H),7.41(td,1H),7.35(d,1H),7.17(dd,1H),6.93(dd ,1H),5.37(dd,1H),4.61-4.51(m,2H),4.35(dd,1H),4.27(t,1H),3.88-3.79(m,2H),3.68(s,1H), 3.57(dd,2H),3.31-3.20(m,3H),3.07(s,2H),3.05-3.01(m,1H),2.69(s,1H),2.27-2.18(m,1H),2.22- 2.11(m,3H),2.07-1.99(m,2H),1.98-1.94(m,2H).

Example 10 (Comparative Example 2)

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

Adopting the synthetic route in Example 1, the first step raw material compound 1b is replaced with 9-oxa-3,7-diazabicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester hydrochloride ( Shanghai BiDe), the title compound 10 (5 mg, yield: 12.4%) was obtained.

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

¹ H NMR (500MHz, CD ₃ OD): δ 9.15 (s, 1H), 7.60 (d, 1H), 7.39 (td, 1H), 7.33 (t, 1H), 7.17 (d, 1H), 6.92 (dd ,1H),4.76(d,4H),4.40-4.28(m,3H),4.04-3.92(m,5H),3.18-3.02(m,4H),2.32-2.12(m,4H),2.02(m ,3H).

Example 11 (Comparative Example 3)

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

Adopt the synthetic route in Example 1, replace the first step raw material compound 1b with 2,5-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Shanghai Bide) to prepare the title compound 11 (3.9 mg, yield: 13.9%).

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

¹ H NMR (500MHz, CD ₃ OD): δ 9.15 (s, 1H), 7.61 (d, 1H), 7.43-7.35 (m, 1H), 7.35 (s, 1H), 7.22-7.13 (m, 1H) ,6.95-6.91(m,1H),5.52-5.39(m,2H),4.44-4.23(m,4H),3.96-3.90(m,1H),3.25-3.14(m,2H),3.09-3.04( m,2H),2.39(dd,1H),2.35-2.24(m,2H),2.23-2.13(m,3H),2.07-2.02(m,3H),1.99-1.93(m,3H).

biological evaluation

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

1. Test purpose

This experiment detects the inhibitory effect of compounds on cellular ERK phosphorylation, and evaluates the inhibitory effect of the disclosed compounds on the KRAS target based on the IC ₅₀ size.

2. Experimental methods

AGS cells (Nanjing Kebai, CBP60476) were cultured in RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal calf serum. On the first day of the experiment, AGS cells were seeded in a 96-well plate at a density of 40,000 cells/well using complete culture medium, with 190 μL of cell suspension in each well, and cultured overnight in a 37°C, 5% CO ₂ cell incubator.

The next day, add 10 μL of a gradient dilution of the compound to be tested prepared in complete culture medium to each well. The final concentration of the compound is 9 concentration points of 5-fold gradient dilution starting from 10 μM. Set a blank control containing 0.5% DMSO. The well plate Place in a 37°C, 5% _CO2 cell culture incubator and incubate for 1 hour. After the incubation is completed, take out the 96-well cell culture plate, aspirate the culture medium, add 200 μL PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) to each well and wash it once. Aspirate the PBS, add 50 μL of lysis buffer (lysis buffer, Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) to each well, and place the well plate on a shaker at room temperature for 40 minutes of shaking and lysis. After lysis, use a pipette to mix evenly. Transfer 16 μL of lysis solution to each well into two HTRF 96-well detection plates (Cisbio, 66PL96100). Then add 4 μL of premixed phosphorylated ERK1/2 antibody solution to the two plates. (Cisbio, 64AERPEG) or 4 μL of premixed total ERK1/2 antibody solution (Cisbio, 64NRKPEG). The microplate was sealed with sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight at room temperature in the dark.

On the third day, use an ENVISION multifunctional microplate reader (PerkinElmer, ENVISION) to read the fluorescence values of 337 nm wavelength excitation, 665 nm and 620 nm wavelength emission.

3. Data analysis

Use Graphpad Prism software to calculate the IC ₅₀ value of the compound's inhibitory activity based on the compound concentration and the ratio of phosphorylated ERK/total ERK. The results are shown in Table 1 below.

結論：本揭露化合物對AGS細胞ERK磷酸化具有較好的抑制作用。

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

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

1. Test purpose

By testing the 3D proliferation inhibitory effect of the disclosed compound on GP2d cells, the inhibitory effect of the disclosed compound on the KRAS target was evaluated.

2. Experimental methods

GP2d cells (Nanjing Kebai, CBP60010) were cultured in complete medium, that is, DMEM/high glucose medium (Hyclone, SH30243.01) containing 10% fetal calf 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) using complete culture medium at a density of 1,000 cells/well, with 90 μL of cell suspension in each well, centrifuged at room temperature at 2,000 rpm for 5 minutes, and then placed for 37 °C, 5% _CO2 cell culture incubator overnight.

The next day, add 10 μL of a gradient dilution of the test compound prepared in complete culture medium to each well. The final concentration of the compound in GP2d cells is 9 concentration points starting from 1 μM and 3-fold gradient dilution, and a blank control containing 0.5% DMSO is set. The well plate was placed in a cell culture incubator at 37°C and 5% _CO2 for 120 hours. On the seventh day, take out the 96-well cell culture plate, add 50 μL of CellTiter-Glo® 3D reagent (Promega, G9682) to each well, shake at room temperature for 25 minutes, mix by pipetting and transfer 50 μL to a white 96-well plate with opaque bottom. (PE, 6005290), a multifunctional microplate reader (PerkinElmer, ENVISION) was used to read the luminescence signal value.

3. Data analysis

Use Graphpad Prism software to calculate the IC ₅₀ value of the compound's inhibitory activity. The results are shown in Table 2 below.

結論：本揭露化合物對GP2d細胞3D增殖具有較好的抑制作用。

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

Test Example 3: SPR method to detect the affinity of the disclosed compound to KRAS protein isoform G12D or WT

Biotinylated Avi-KRAS-WT or Avi-KRAS-G12D was first diluted to 20 μg/mL with ₁ ×HBS-P+ (Cat.# BR1006-71) buffer containing 100mM MgCl, and then flowed through SA (Cat. .# BR1005-31) Biosensor chip channel 2, lasting 420s, obtaining a coupling level of approximately 5000-7000RU. Then small molecule compound samples were injected sequentially from low to high for 120 s, and then dissociated for 720 s. The experiment adopts single cycle kinetic mode. The Biacore 8K instrument detects the reaction signal in real time to obtain the binding and dissociation curve. After the test, Biacore 8K evaluation software was used for data analysis, and a 1:1 model was used to fit the data and obtain affinity data.

結論：本揭露化合物與KRAS蛋白亞型G12D或WT具有較好的親和力。

Conclusion: The disclosed compound has good affinity to KRAS protein isoform G12D or WT.

Test Example 4 Inhibitory Effect of the Disclosed Compound on SW620 Proliferation

1. Experimental materials and instruments

1.SW620 cells (Nanjing Kebai Biotechnology)

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

3. Fetal bovine serum (FBS) (Gibco)

4.0.25% trypsin (Gibco)

5. Phosphate buffer saline (PBS) (Shanghai Yuanpei Biotechnology Co., Ltd.)

6.Cell Titer Glo(CTG)(Promega)

7.T75 cell culture flask (Corning)

8.15mL centrifuge tube (Corning)

9.96-well dispensing plate (Corning)

10.96-well flat bottom cell culture plate (Corning)

11. Constant temperature cell culture incubator (Thermo scientific)

12. Biological safety cabinet (ESCO)

13. Ultra-high speed refrigerated centrifuge (Thermo scientific)

14. Multifunctional plate reader (PerkinElmer)

2. Experimental steps

SW620 cells are human colon cancer cells carrying the KRAS G12V mutation. The proliferation effects of compounds on SW620 cells were evaluated. Adding the compound will inhibit the proliferation of SW620 cells. The relative luminescence unit value is measured by CTG to evaluate the inhibitory effect of the compound on SW620 cell proliferation.

On day 0, take SW620 cells that have grown well and reached 70%-80% confluence. After digestion, culture the cells with L-15 containing 10% FBS and adjust the cell density to 1.11*10 ⁴ /mL. Add 90 μL of cell suspension to the 96-well cell culture plate, and the final number of cells per well is 1000/well. Place the cells in a 37°C, _CO2 -free incubator for 24 hours. Day 1: 20mM test compound dissolved in 100% DMSO was serially diluted with 100% DMSO to 2000, 666.67, 222.22, 74.07, 24.69, 8.23, 2.74, 0.91, 0.30μM. The blank well was 100% DMSO, and then 20 Diluted twice in L-15 medium containing 10% FBS. Add 10 μL of the test compound after secondary dilution to each well. The final concentrations of the test compound are 10000, 3333.33, 1111.11, 370.37, 123.46, 41.15, 13.72, 4.57, and 1.52nM; the DMSO wells are blank wells, and only the culture medium is added. The test wells are negative control wells. The cells were cultured in a 37°C, _CO2 -free incubator for 5 days. On the 6th day, take out the 96-well cell culture plate, add 50 μL of melted CTG, incubate at room temperature for 20 minutes, and read the relative luminescence unit (RLU) value with a microplate reader. Use the following formula to calculate the inhibition rate: Inhibition rate = [RLU (blank well) - RLU (test compound)] / [RLU (blank well) - RLU (negative control well)] * 100%, and use Graphpad Prism software to calculate each compound. Draw an inhibition curve between the concentration and the corresponding inhibition rate, and calculate the concentration of the compound when the inhibition rate reaches 50%, that is, the IC ₅₀ value. The IC ₅₀ values of the disclosed compounds measured by inhibiting the proliferation of human SW620 are shown in Table 4.

結論：本揭露化合物對SW620細胞增殖具有較好的抑制作用。

Conclusion: The disclosed compound has a good inhibitory effect on SW620 cell proliferation.

Claims (22)

A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

in, G ¹ is selected from O, NR ^a and CR ^b R ^c ; G ² is NR ^d ; Ring A is aryl or heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; L is selected from single bonds, O and NR ^e ; R ¹ is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, -(CH ₂ ) _u -NR ^f R ^g , hydroxyl and hydroxyalkyl; R ² and R ⁴ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, -( CH ₂ ) _v -NR ^h R ⁱ , hydroxyl, hydroxyalkyl and cycloalkyl; R ³ and R ⁶ are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, -( CH ₂ ) _w -NR ^j R ^k , nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ⁵ is the same or different, and each is independently selected from hydrogen atom, halogen, alkyl, haloalkyl, cyano, hydroxyl and hydroxyalkyl; R ^b and R ^c are the same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, cyano, amine, -( CH ₂ ) _x -NR ^m R ⁿ , nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ^a , R ^d , Re , R ^f , R ^g , Rh , R ⁱ , R ^j , R ^k , R ^m and R ⁿ are the same or different, and are each independently ^selected from hydrogen atoms, alkyl groups, and ^alkenyl groups. , alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; u, v, w and x are the same or different, and are each independently selected from 0, 1, 2 and 3; r is 0, 1 or 2; p is 0, 1, 2, 3, 4 or 5; q is 0, 1, 2, 3, 4, or 5; and t is 0, 1, 2, 3, 4 or 5. The compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, wherein G ¹ is O or CR ^b R ^c , R ^b and R ^c are as defined in claim 1 . The compound as described in claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is a naphthalene ring; and/or ring B is

, R ⁶ can be substituted at any position of ring B. The compound or pharmaceutically acceptable salt thereof as described in claim 1 or 3, which is a compound represented by general formula (II) or a pharmaceutically acceptable salt thereof:

Wherein G ¹ , G ² , L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , p, q, r and t are as defined in claim 1. The compound or pharmaceutically acceptable salt thereof as described in claim 1, which is a compound represented by general formula (III) or a pharmaceutically acceptable salt thereof:

in, y is 0, 1, 2, 3 or 4; G ¹ , Ring A, Ring B, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , p, r and t are as defined in claim 1. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein ^G2 is NH. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein L is O. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ¹ is the same or different, and each is independently selected from a hydrogen atom, halogen, C _1-6 alkyl and C _{1- 6} haloalkyl; preferably, R ¹ is a hydrogen atom. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R ² is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; preferably , R ² is a hydrogen atom. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein R ³ is the same or different, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl, C _{2- 6} alkynyl, C _1-6 haloalkyl, hydroxyl and C _1-6 hydroxyalkyl; preferably, R ³ is the same or different, and each is independently selected from halogen, ethyl, ethynyl and hydroxyl. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ⁴ is selected from hydrogen atom, halogen, C _1-6 alkyl and C _1-6 haloalkyl; preferably , R ⁴ is halogen. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ⁵ is the same or different, and each is independently selected from a hydrogen atom, a C _1-6 alkyl group, a hydroxyl group and a C _{1- 6hydroxyalkyl} ; preferably, R ⁵ is a hydrogen atom. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ⁶ is the same or different, and each is independently selected from hydrogen atom, halogen, C _1-6 alkyl and C _{1- 6} haloalkyl; preferably, R ⁶ is halogen. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, which is the following compound:

A compound represented by general formula (IIIA) or a salt thereof,

in, R is an amino protecting group; preferably Boc; R ⁰ is a hydroxyl protecting group; preferably MOM; G ¹ , ring A, ring B, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , y, p, r and t are as defined in claim 5. A compound selected from,

A method for preparing the compound represented by general formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (I) or a pharmaceutically acceptable salt thereof; optionally, when the R ³ and/or R ⁶ groups contain a protective group , before, at the same time or after the deprotection reaction, it also includes the step of removing the protecting group on the R ³ and/or R ⁶ group; Among them, R is an amino protecting group; preferably Boc; G ² is NH; G ¹ , Ring A, Ring B, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , p, q, r and t are as defined in claim 1. A method for preparing the compound represented by general formula (III) as described in claim 5 or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIIA) or a salt thereof undergoes a deprotection reaction to obtain a compound of general formula (III) or a pharmaceutically acceptable salt thereof; Among them, R is an amino protecting group; preferably Boc; R ⁰ is a hydroxyl protecting group; preferably MOM; G ¹ , ring A, ring B, L, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , y, p, r and t are as defined in claim 5. A pharmaceutical composition containing a compound as described in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. Use of a compound as described in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 19 in the preparation of a drug for inhibiting KRAS G12D and/or KRAS G12V . Use of a compound as described in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 19 in the preparation of a medicament for the treatment and/or prevention of diseases or conditions , the disease or condition is cancer. Use of a compound as described in any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 19 in the preparation of a medicament for the treatment and/or prevention of diseases or conditions , the disease or condition is selected from the group consisting of brain cancer, thyroid cancer, head and neck cancer, nasopharyngeal cancer, throat cancer, oral cancer, salivary gland cancer, esophageal cancer, gastric cancer, lung cancer, liver cancer, kidney cancer, pancreatic cancer, gallbladder cancer, bile duct cancer, Colorectal cancer, small bowel cancer, gastrointestinal stromal tumor, urothelial cancer, urethra 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 cancer and non-small cell lung cancer.