Targeting protein degradation agents with kras inhibitory effects

Abstract

The present application relates to a compound having KRas inhibiting effect represented by formula (I), or a pharmaceutically acceptable salt thereof, or an isomer thereof, and application thereof in preparing a medicine for treating KRas related diseases.[B-L]n-KRAS ligand (I)

Description

Targeted protein degradation agents with KRas inhibitory effect TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and relates to a kind of compound with KRas inhibitory effect, or its pharmaceutically acceptable salt, or its isomer, and its application in preparing drug for treating KRas related diseases. BACKGROUND

[0002] KRAS gene, i.e., Kirsten rat sarcoma 2 virus oncogene homolog, encodes a small GTPase, which belongs to the RAS superfamily of proteins. Under normal circumstances, KRAS can regulate the path of cell growth, and its gene mutation will lead to tumor growth.

[0003] Currently, there are two KRAS G12C inhibitors successfully used in clinical practice, but G12C mutation accounts for only a small part of KRAS mutations, and there is still a lack of satisfactory effective inhibitor compounds for KRAS mutations at other sites (such as G12D, G12V, G13D, G12R, G12S, G12A, Q61H, etc.). Based on the importance of KRAS abnormal activation in cancer progression and the universality of KRAS gene mutations in human cancer, there is still a great unmet clinical need for the development of safe and effective pan-KRAS inhibitors.

[0004] Drug development targeting KRAS mutants is one of the important means to intervene or treat the above-mentioned cancers. For a long time, KRAS has been crowned with the curse of "undruggable" and "no drug targeting" due to its extremely high affinity with guanosine triphosphate GTP and the "smooth" surface of KRAS protein, which is difficult to target.

[0005] One of the biggest advantages of PROTAC technology is that it can change the target from "undruggable" to "druggable". Most traditional small molecule drugs or monoclonal antibodies need to bind to the active site of enzymes or receptors to function, however, PROTACs can grab target proteins through any corner or gap.

[0006] Therefore, a small molecule therapeutic agent capable of selectively binding to Kras and inhibiting its function will be very useful. And the KRAS-PROTAC chimeric compound of the present application is an attractive drug for this mutant cancer. SUMMARY

[0007] An object of the present application is to provide a protein degradation targeting chimeric compound having good KRAS inhibition / degradation activity and capable of inducing KRAS degradation, and a pharmaceutically acceptable salt or stereoisomer thereof, and their application in treating diseases such as tumors, immunity or inflammation.

[0008] The present application provides a compound represented by the following formula (I):

[0009] [B-L]n-KRAS ligand (I),

[0010] and a pharmaceutically acceptable salt or isomer thereof,

[0011] wherein:

[0012] The KRAS ligand is, for example, a KRAS inhibitor, further a Pan KRAS inhibitor,

[0013] B is a degradation tag, such as an E3 ligase ligand,

[0014] L is a linker between B and the KRAS ligand,

[0015] n is the number of the degradation tag connected on the KRAS ligand, selected from 1, 2 or 3.

[0016] The selection of the connection site of the group binding to the E3 ligase, the connection number, and the connection site on the KRAS inhibitor will affect the activity of the compound.

[0017] S1. KRAS ligand

[0018] In a first aspect, the present application provides the KRAS ligand in the formula (I), which is a compound represented by the following formula (KI):

[0019] or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0020] wherein:

[0021] X1is nitrogen or carbon;

[0022] R a is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -CN, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2- 8alkynyl, -CONR 1a R 1b, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, C 1- 3alkoxy, C 1-3 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0023] R a may optionally form a ring cycB with its adjacent substituent, atom or structural unit, where said cycB is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, and 9-14 membered fused heterocyclyl, and wherein the heteroatoms of said 5-8 membered heterocyclyl and 9-14 membered fused heterocyclyl are 1-4 atoms optionally selected from N, O, or S;

[0024] R1is selected from hydrogen, halogen, amino, oxo, hydroxyl, -C 1-8 alkyl, -S-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1a , -SO2R 1a , -COR 1a , -CO2R 1a , -CONR 1a R 1b , -CH2C(=O)NR 1a R 1b , -C 2-8 alkynyl (NR 1a )2, -C(=NR 1a )NR 1b R 1c , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CONR 1b R 1c , -NR 1a CO2R 1b , -NR 1a SONR 1b R 1c , -NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1bwherein each of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, -C 1-8 alkoxy, -C(O)NR 1d R 1e , -NR 1d R 1e , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0025] each R 1a , R 1b , and R 1c is independently hydrogen, deuterium, halogen, cyano, amino, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2- 8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl is each optionally substituted with at least one substituent R 1d ; or

[0026] (R 1a and R 1b ), (R 1b and R 1c ), or (R 1c and R 1a ) together with the atom(s) to which they are attached form cycA, wherein the cycA is a 3 to 10 membered ring, wherein the ring comprises 0, 1, 2, or 3 heteroatoms independently selected from N, O, or optionally oxidized S as a ring member(s), and the ring is optionally substituted with at least one substituent R 1e ;

[0027] R 1d and R 1e are each independently hydrogen, oxo, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1f , -SO2R 1f , -COR 1f , -CO2R 1f , -CONR 1f R 1g , -C(=NR 1f )NR 1gR 1h , -NR 1f R 1g , -NR 1f COR 1g , -NR 1f CONR 1g R 1h , -NR 1f CO2R 1g , -NR 1f SONR 1g R 1h , -NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from the group consisting of halo, -C 1-8 alkyl, -OR 1i , -NR 1i R 1j , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0028] R 1f , R 1g , R 1h , R 1i , and R 1j are each independently hydrogen, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 5-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0029] R2is selected from

[0030] R3and R4are each independently hydrogen, halo, cyano, -OC 1-8 alkyl, C 1-8 alkyl, or cycloalkyl, wherein each of said -C 1-8 alkyl, -OC 1-8 alkyl, and cycloalkyl is optionally substituted with deuterium, halo, cyano, hydroxyl, amino, -OC 1-8 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, provided that at least one of R3or R4is F, Cl, -NO2, or -CN;

[0031] m is selected from 0, 1, 2, or 3.

[0032] The compound of formula (KI) above is a compound of formula (KI-1) below:

[0033] or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0034] wherein:

[0035] R a , R2, cycB, m, R3, and R4 are as defined above;

[0036] R0is independently selected from hydrogen, oxo, cyano, hydroxyl, C 1-3 alkyl, C 1-3 alkyl-hydroxy, halo, C 1-3 haloalkyl, -C(O)NR 1d R 1e , -NR 1d R 1e , or -C 1-3 alkoxy; wherein R 1d and R 1e are as defined above;

[0037] n is selected from 1 or 2;

[0038] cycA is selected from wherein said cycA is optionally substituted from 1 to 3 times with R 1e ;

[0039] is selected from

[0040] In some embodiments, is selected from

[0041] The compound of formula (KI) above is a compound of formula (KI-2) below:

[0042] or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0043] wherein:

[0044] R a , R2, cycB, m, n, R3, and R4 are as defined above;

[0045] R5is independently selected from hydrogen, C 1-3 alkyl, halo, C 1-3 haloalkyl, -C(O)NR 1d R 1e, -NR 1d R 1e , or -C 1-3 alkyl; wherein R 1d and R 1e are as previously defined.

[0046] The present application also includes embodiments that are the result of any combination of the above variables.

[0047] In some embodiments, X1is N, CH, or C. In some embodiments, X1is CH. In some preferred embodiments, X1is N.

[0048] In some embodiments, R a is independently selected from hydrogen, halogen, hydroxyl, amino, cyano, -C 1-8 alkyl, -OC 1-8 alkyl, or 3-8 membered cycloalkyl, preferably hydrogen, halogen, cyano, -OC 1-3 alkyl, or 3-8 membered cycloalkyl, more preferably H, F, Cl, and cyclopropyl;

[0049] In some embodiments, R3and R4are each independently hydrogen, halogen, cyano, -OC 1-8 alkyl, -C 1-8 alkyl, or cycloalkyl, each of which -C 1-8 alkyl, -OC 1-8 alkyl, and cycloalkyl is optionally substituted with deuterium, halogen, cyano, hydroxyl, amino, -OC 1-8 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, provided that at least one of R3or R4is F, Cl, -NO2, or -CN;

[0050] In some embodiments, R3and R4are independently selected from halogen, hydrogen, C 1-6 alkyl, cyano, -NO2, provided that at least one of R3or R4is F, Cl, -NO2, or -CN;

[0051] In some preferred embodiments, at least one of R3or R4is F, more preferably one of R3or R4is F; further more preferably one of R3or R4is F, and the other is preferably H.

[0052] In some embodiments, R1is selected from C 4-11 heterocyclyl, or C 4-10 heteroaryl, said heterocyclyl or heteroaryl comprising 1 to 3 heteroatoms independently selected from N, O, or optionally oxidized S as a ring member or members, said heterocyclyl or heteroaryl optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, -C 1-8 alkyl, -C 1-8alkyl, -C(O)NR 1d R 1e , -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0053] In some embodiments, R1is selected from hydrogen, amino, -CN, -NO2, -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CONR 1b R 1c , -NR 1a CO2R 1b , -NR 1a SONR 1b R 1c , -NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b ;

[0054] In some embodiments, R 1a , R 1b are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, -C 1-8 alkyl;

[0055] In some embodiments, R1is selected from

[0056] Additionally or alternatively, R1is selected from

[0057] In some embodiments, cycB is selected from 7-8 membered cycloalkyl, 7-8 membered heterocyclyl, and 9-14 membered fused heterocyclyl, the heteroatoms of which are 1-4 optionally selected from N, O, or S;

[0058] In some embodiments, cycB is selected from

[0059] In some embodiments, structural unit is selected from

[0060] In some embodiments, structural unit is selected from

[0061] The present application provides a KRAS ligand compound as described above, or a pharmaceutically acceptable salt or a stereoisomer thereof, selected from:

[0062] Accordingly, the present application provides the following embodiments according to the first aspect:

[0063] Embodiment E1. A KRAS ligand which is a compound according to Formula (KI):

[0064] or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0065] wherein:

[0066] X1is nitrogen or carbon;

[0067] R a is independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -CN, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2- alkynyl, -CONR 1a R 1b , 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, C 1- 3alkoxy, C 1-3 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;

[0068] R a may optionally form a ring cycB with its adjacent substituents, atoms or structural units, where said cycB is selected from 5-8 membered cycloalkyl, 5-8 membered heterocyclyl and 9-14 membered fused heterocyclyl, and wherein the heteroatoms of said 5-8 membered heterocyclyl and 9-14 membered fused heterocyclyl are 1-4 atoms optionally selected from N, O or S;

[0069] R1is selected from hydrogen, halogen, amino, oxo, hydroxyl, -C 1-8 alkyl, -S-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1a , -SO2R 1a , -COR 1a, -CO2R 1a , -CONR 1a R 1b , -CH2C(=O)NR 1a R 1b , -C 2-8 alkenyl(NR 1a )2, -C(=NR 1a )NR 1b R 1c , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CONR 1b R 1c , -NR 1a CO2R 1b , -NR 1a SONR 1b R 1c , -NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b , wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, -C 1-8 alkoxy, -C(O)NR 1d R 1e , -NR 1d R 1e , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0070] each R 1a , R 1b , and R 1c is independently hydrogen, deuterium, halogen, cyano, amino, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2- alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl is optionally substituted with at least one substituent R 1d ; or

[0071] (R 1a and R 1b ), (R 1b and R 1c), or (R 1c and R 1a ) together with the atom to which they are attached form cycA, wherein the cycA is a 3- to 10-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from N, O, or optionally oxidized S as a ring member(s), and the ring is optionally substituted with at least one substituent R 1e ;

[0072] R 1d and R 1e are each independently hydrogen, oxo, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1f , -SO2R 1f , -COR 1f , -CO2R 1f , -CONR 1f R 1g , -C(=NR 1f )NR 1g R 1h , -NR 1f R 1g , -NR 1f COR 1g , -NR 1f CONR 1g R 1h , -NR 1f CO2R 1g , -NR 1f SONR 1g R 1h , -NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is each optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 1i , -NR 1i R 1j , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0073] R 1f , R 1g , R 1h , R 1i and R 1j are each independently hydrogen, -C1-3 Alkyl, -C 1-3 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkynyl, 3-8 membered cycloalkyl, 5-6 membered heterocyclic, aryl or 5-6 membered heteroaryl;

[0074] R2 is selected from

[0075] R3 and R4 are independently hydrogen, halogen, cyano, and -OC groups. 1-8 Alkyl, C 1-8 Alkyl or cycloalkyl, wherein the -C 1-8 Alkyl, -OC 1-8 Alkyl and cycloalkyl groups are each optionally replaced by deuterium, halogen, cyano, hydroxyl, amino, -OC 1-8 Alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclic, aryl or 5-6 membered heteroaryl substitution, provided that at least one of R3 or R4 is F, Cl, -NO2 or -CN;

[0076] m is selected from 0, 1, 2 or 3.

[0077] Implementation Scheme E2. The compound according to Implementation Scheme E1, wherein the compound of formula (KI) is the compound shown in formula (KI-1):

[0078] Or its pharmaceutically acceptable salt, or its isomer.

[0079] in:

[0080] R a R2, cycB, m, R3, and R4 are as defined in implementation scheme E1;

[0081] R0 is independently selected from hydrogen, oxo, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkyl-hydroxyl, halogen, C 1-3 Haloalkyl, -C(O)NR 1d R 1e -NR 1d R 1e 、or -C 1-3 Alkoxy; wherein R 1d and R 1e The definition is the same as that described in implementation scheme E1;

[0082] n is selected from 1 or 2;

[0083] cycA is selected from

[0084] said cycA is optionally substituted 1 to 3 times with R 1e ; and

[0085] selected from the group consisting of

[0086] Embodiment E3. The compound according to Embodiment E1, wherein the compound of Formula (KI) is a compound represented by the following Formula (KI-2):

[0087] or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0088] wherein:

[0089] R a , R2, cycB, m, n, R3, and R4 are as defined in Embodiment E1;

[0090] R5is independently selected from the group consisting of hydrogen, C 1-3 alkyl, halogen, C 1-3 haloalkyl, -C(O)NR 1d R 1e , -NR 1d R 1e , or -C 1-3 alkoxy; wherein R 1d and R 1e are as defined in Embodiment E1.

[0091] Embodiment E4. The compound according to Embodiment E1, wherein:

[0092] X1is N, CH, or C; and / or

[0093] R a is independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, -C 1-8 alkyl, -OC 1-8 alkyl, or 3-8 membered cycloalkyl, preferably hydrogen, halogen, cyano, -OC 1-3 alkyl, or 3-8 membered cycloalkyl, more preferably H, F, Cl, and cyclopropyl; and / or

[0094] R3and R4are each independently hydrogen, halogen, cyano, -OC 1-8 alkyl, -C 1-8 alkyl, or cycloalkyl, wherein said -C 1-8 alkyl, -OC 1-8 alkyl, and cycloalkyl are each optionally substituted with deuterium, halogen, cyano, hydroxyl, amino, -OC 1-8alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, provided that at least one of R3or R4is F, Cl, -NO2, or -CN; and / or

[0095] R3and R4are independently selected from halogen, hydrogen, C 1-6 alkyl, cyano, -NO2, provided that at least one of R3or R4is F, Cl, -NO2, or -CN; and / or

[0096] R1is selected from C 4-11 heterocyclyl, or C 4-10 heteroaryl, wherein said heterocyclyl or heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O, or optionally oxidized S as a ring member or members, said heterocyclyl or heteroaryl is optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, -C 1-8 alkyl, -C 1-8 alkoxy, -C(O)NR 1d R 1e , -NR 1d R 1e , cycloalkyl, heterocyclyl, aryl, or heteroaryl; and / or

[0097] R1is selected from hydrogen, amino, -CN, -NO2, -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CONR 1b R 1c , -NR 1a CO2R 1b , -NR 1a SONR 1b R 1c , -NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b ; and / or

[0098] R 1a , R 1b are each independently hydrogen, deuterium, halogen, cyano, hydroxyl, -C 1-8 alkyl; and / or

[0099] R1is selected from and / or

[0100] cycB is selected from the group consisting of 7-8 membered cycloalkyl, 7-8 membered heterocyclyl, and 9-14 membered fused heterocyclyl, wherein the heteroatoms of said 7-8 membered heterocyclyl and 9-14 membered fused heterocyclyl are 1-4 atoms optionally selected from N, O, or S; and / or

[0101] cycB is selected from the group consisting of and / or

[0102] structural unit is selected from the group consisting of and / or

[0103] structural unit is selected from the group consisting of

[0104] In a second aspect, the present application provides a KRAS ligand of formula (I) which is a compound of formula (KII):

[0105] In a second aspect, the present application provides a KRAS ligand of formula (I) which is a compound of formula (KII):

[0106] or a pharmaceutically acceptable salt thereof, or an isomer thereof,

[0107] wherein:

[0108] X1is N or CH;

[0109] R1’is -NR 1a R 1b , or a ring CyAof formula

[0110] R 1a is -C 1-8 alkyl optionally substituted with halogen, hydroxyl, cyano, or amino;

[0111] R 1b is selected from a ring CyB, wherein said CyB is 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl, and wherein said 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl is optionally substituted with halogen, hydroxyl, cyano, amino, oxo, -C 1-8 alkyl, -C 1-8 haloalkyl, -OC 1-8 alkyl, -OC 1-8 haloalkyl, -C(O)NR 1d R 1e , or -NR 1d R 1e ​substituted, and one available ring atom of the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl is attached to one available ring atom of the six-membered aromatic ring having X1such that the moiety of formula has the structure of formula ,

[0112] L 1 is selected from O, S, NH, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -CH2-NH-, -O-CH2-, -S-CH2-, and -NH-CH2-; and

[0113] ring CyCis optionally substituted with 1-4 R a2 ;

[0114] R a1 and R a2 are independently hydrogen, or -C 1-8 alkyl optionally substituted with halo, hydroxyl, cyano, or amino;

[0115] said ring CyAis selected from:

[0116] (1) a 3-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl,

[0117] wherein said 3-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl has 1, 2, or 3 N and 0, 1, or 2 O or S in the ring, and is optionally fused to 1 ring CyDwhich is 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, and said 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, when present, are each optionally substituted with 1, 2, or 3 substituents independently selected from halo, hydroxyl, cyano, oxo, -C 1- 8alkyl, -C 1-8 haloalkyl, -OC 1-8 alkyl, -OC 1-8 haloalkoxy, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e ;

[0118] (2) a 6-10 membered spiro nitrogen heterocycloalkyl,

[0119] wherein said 6-10 membered spiro nitrogen heterocycloalkyl has 1, 2, or 3 N and 0, 1, or 2 O or S in the ring, and is optionally substituted with 1, 2, or 3 substituents independently selected from halo, hydroxyl, cyano, oxo, -C 1-8 8alkyl, -C 1-8haloalkyl, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e ; and

[0120] (3) which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, hydroxyl, cyano, -C 1-8 alkyl, -C 1-8 haloalkyl, -OC 1-8 alkyl, -OC 1-8 haloalkoxy, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e ;

[0121] when R1’ is said ring CyA and said ring CyA is selected from said 3-7 membered nitrogen-containing monocyclic cycloalkyl or heterocycloalkenyl, then one available ring atom of said ring CyA is optionally annelated with one available ring atom of a six-membered aromatic ring having X1, such that the moiety of formula has the structure of formula

[0122] L 2 is selected from O, S, NH, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -CH2-NH-, -O-CH2-, -S-CH2-, and -NH-CH2-; and

[0123] ring CyE is optionally substituted with 1-4 R a3 ;

[0124] each R a3 is independently selected from -C 1-8 alkyl optionally substituted with halo, hydroxyl, cyano, or amino;

[0125] R a is independently hydrogen, deuterium, halo, hydroxyl, cyano, amino, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -CONR 1a’ R 1b’ , 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 ​The alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-6 membered heteroaryl groups are each optionally bound by one or more deuterium, halogen, cyano, hydroxyl, C 1-3 Alkoxy, C 1-3 Alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclic, aryl, or 5-6 membered heteroaryl substitution;

[0126] R 1a’ and R 1b’ Each is independently hydrogen, deuterium, and -C. 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, 3-8 membered cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-6 membered heteroaryl, wherein the -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 The alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclic, aryl, or 5-6 membered heteroaryl groups are each optionally surrounded by at least one R 1d replace;

[0127] R 1d and R 1e Each is independently hydrogen, oxo, halogen, -C 1-8 Alkyl, -C 2-8 alkenyl, -C 2-8 Alkyne, 3-8 membered cycloalkyl, 3-10 membered heterocyclic, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1f -SO2R 1f -COR 1f -CO2R 1f -CONR 1f R 1g -C(=NR) 1f )NR 1g R 1h -NR 1f R 1g -NR 1f COR 1g -NR 1f CONR 1g R 1h -NR 1f CO2R 1g -NR 1f SONR 1g R 1h -NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g Wherein -C 1-8 Alkyl, -C2-8 alkyl, -OR 2-8 alkenyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, each optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 1i , -NR 1i R 1j , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0128] R 1f , R 1g , R 1h , R 1i and R 1j are each independently hydrogen, -C 1-3 alkyl, -C 1-3 alkoxy, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 5-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl;

[0129] R2is selected from

[0130] R3and R4are each independently hydrogen, halogen, cyano, -OC 1-8 alkyl, C 1-8 alkyl, or 3-8 membered cycloalkyl, said -C 1-8 alkyl, -OC 1-8 alkyl, and 3-8 membered cycloalkyl, each optionally substituted with deuterium, halogen, cyano, hydroxyl, amino, -OC 1-8 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, provided that at least one of R3or R4is F, CI, -NO2, or -CN; and

[0131] m is selected from 0, 1, 2, or 3.

[0132] In some embodiments, at least one of R3or R4is F. In some such embodiments, one of R3or R4is F. More preferably, one of R3or R4is F, and the other is preferably H.

[0133] In some embodiments, X1is CH. In preferred embodiments, X1is N.

[0134] In some embodiments, R 1f , R 1g , R 1h , R 1i and R 1j are each independently hydrogen or -C 1-3 alkyl.

[0135] In some implementation schemes, R 1d and R 1e Each is independently hydrogen or -C 1-3 alkyl.

[0136] In some implementation schemes, R 1a’ and R 1b’ Each is independently hydrogen, deuterium, and -C. 1-3 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic, aryl, or 5-6 membered heteroaryl, wherein the -C 1-3 Alkyl, 3-6 membered cycloalkyl, 3-7 membered heterocyclic, aryl, or 5-6 membered heteroaryl are each optionally bound by at least one R 1d Replacement. Preferably, R 1a’ and R 1b’ Each is independently hydrogen, deuterium, and -C. 1-3 Alkyl or -C 1-3 Halogenated alkyl, more preferably hydrogen, methyl, ethyl or isopropyl.

[0137] In some implementations, R1' is -NR 1a R 1b .

[0138] In some such implementations, R 1a -C is optionally substituted with F, Cl, hydroxyl, cyano or amino groups. 1-3 Alkyl groups, preferably methyl or ethyl groups optionally substituted with F, Cl, hydroxyl, cyano or amino groups.

[0139] In some implementation schemes, R 1b Selected from cycloCyB, wherein the CyB is a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, and wherein the 3-7 membered cycloalkyl or the 3-7 membered heterocycloalkyl is optionally converted by F, Cl, hydroxyl, cyano, amino, oxo, or -C. 1-3 Alkyl, -C 1-3 Halogenated alkyl groups, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl groups, -NH(C 1-3 alkyl), -N(C) 1-3 Alkyl)2, -C(O)NH2, -C(O)NH(C 1-3 alkyl) or -C(O)N(C 1-3 Alkyl)2-substituted.

[0140] In some preferred embodiments, the CyB is a 5, 6, or 7-membered cycloalkyl or a 5, 6, or 7-membered heterocycloalkyl, preferably cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, oxetylheptyl, pyrrolidinyl, piperidinyl, or azirheptanyl.

[0141] In some embodiments, the compound of formula (KII) has the structure of formula (KII-1):

[0142] In some embodiments, the CyB is a 5-, 6-, or 7-membered cycloalkyl, or a 5-, 6-, or 7-membered heterocycloalkyl, preferably cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, pyrrolidinyl, piperidinyl, or azepanyl.

[0143] In some embodiments, L 1 is selected from O, S, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -O-CH2-, and -CH2-S-, preferably O, -CH2-O-, and -O-CH2-.

[0144] In some embodiments, R a1 and R a2 are independently hydrogen, or -C 1- 3alkyl, preferably hydrogen, methyl, or ethyl.

[0145] In some such embodiments, the moiety in formula (KII-1) is, for example, preferably

[0146] In other embodiments, R1’ is the ring CyA.

[0147] In some preferred embodiments, the ring CyA is a 4-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, wherein the 4-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl has 1 or 2 N and 0 or 1 O or S in the ring, and is optionally fused to 1 ring CyD, which is a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5 or 6 membered heteroaryl, wherein the 4-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, and the 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, or 5 or 6 membered heteroaryl, when present, are optionally substituted with 1, 2, or 3 groups independently selected from halogen, hydroxyl, cyano, oxo, -C 1-3 alkyl, -C 1-3 haloalkyl, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1esubstituted with 1 or 2 substituents independently selected from F, CI, hydroxyl, cyano, amino, oxo, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)CH3, -C(O)NH2, -C(O)NH(C 1-3 alkyl), and -C(O)N(C 1-3 alkyl)2.

[0148] In some such embodiments, R1’is selected from (preferably ), (preferably ), (preferably ), (preferably ),

[0149] In other embodiments, the compound of Formula (KII) has the structure of Formula (KII-2):

[0150] In some such embodiments, the ring CyA is preferably a 6- or 7-membered nitrogen- containing monocyclic heterocycloalkyl, wherein the 6- or 7-membered nitrogen-containing monocyclic heterocycloalkyl has 1 or 2 N and 0 or 1 O or S in the ring, wherein the 6- or 7-membered nitrogen-containing monocyclic heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CI, hydroxyl, cyano, amino, oxo, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)CH3, -C(O)NH2, -C(O)NH(C 1-3 alkyl), and -C(O)N(C 1-3 alkyl)2.

[0151] In some embodiments, L 2 is selected from O, S, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -O-CH2-, and -CH2-S-, preferably O, -CH2-O-, and -O-CH2-.

[0152] In some such embodiments, the moiety of formula in (KII-2) is, for example, (preferably More preferably

[0153] In some embodiments, each R a3 is independently selected from -C 1-3 alkyl, preferably methyl or ethyl.

[0154] In other embodiments, R1' is a 6-10 membered spiroazacycloalkyl.

[0155] In some embodiments, the 6-10 membered spiroazacycloalkyl has 1, 2, or 3 N and 0 or 1 O or S in the ring and is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxyl, cyano, oxo, -C 1-3 alkyl, -C 1-3 haloalkyl, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e , more preferably optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, hydroxyl, cyano, amino, oxo, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)CH3, -C(O)NH2, -C(O)NH(C 1-3 alkyl), and -C(O)N(C 1-3 alkyl)2.

[0156] In some such embodiments, R1' is preferably

[0157] In other embodiments, R1' is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxyl, cyano, -C 1-3 alkyl, -C 1-3 haloalkyl, -OC 1-3 alkyl, -OC 1-3 haloalkoxy, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e , more preferably optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, hydroxyl, cyano, amino, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3alkyl), -N(C 1-3 alkyl), -C(O)CH3, -C(O)NH2, -C(O)NH(C 1- alkyl), and -C(O)N(C 1-3 alkyl)2.

[0158] In some such embodiments, R1’is preferably

[0159] In some embodiments, R a independently selected from hydrogen, halogen, hydroxyl, amino, cyano, -C 1-8 alkyl, -OC 1-8 alkyl, or 3-8 membered cycloalkyl, preferably hydrogen, halogen, cyano, -OC 1-3 alkyl, or 3-8 membered cycloalkyl, more preferably H, F, CI, methoxy, and cyclopropyl.

[0160] In some embodiments, m is selected from 0, 1, or 2, preferably 0 or 1.

[0161] In some embodiments, R2is selected from In some preferred embodiments, R2is selected from

[0162] In some preferred embodiments, the compound of formula (KII) is selected from: (including ) (including ) (including ) (including ) (including ) (including ) (including ) (including )

[0163] S2. Degradation tag B

[0164] In some embodiments, B is a group that binds an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon (CRBN), XIAP, E3A, MDM2, anaphase promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNX p80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP (pan), ITCH / AIP4, KAP1, MARCH8, MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3.

[0165] Further, B is a group that binds an E3 ligase selected from VHL, CRBN, MDM2, or cIAP. Preferably, B is a group that binds CRBN.

[0166] In some embodiments, B is selected from: and

[0167] V1is selected from a single bond, -O-, -CH2-, -CH=CH-, -C(O)-NH-, or -NH-.

[0168] In some embodiments, said B is selected from: Additionally or alternatively, said B is selected from:

[0169] In some embodiments, said B is preferably: Additionally or alternatively, said B is preferably

[0170] In some more preferred embodiments, said B is

[0171] S3. Linker L

[0172] L is a linker between B and the KRAS ligand.

[0173] In some embodiments, said L is (LNK) u wherein:

[0174] u is 1, 2, 3, 4, 5 or 6;

[0175] each LNK is independently absent, or selected from:

[0176] (1) C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene, wherein said C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene are optionally substituted with 1 or more substituents independently selected from halogen, OH and -OC 1-4 alkyl; -N(C 1- 8alkyl)-, -CON(C 1-8 alkyl)-, -N(C 1-8 alkyl)CO-;

[0177] preferably C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene, wherein said C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene are optionally substituted with 1 or more substituents independently selected from F, Cl, OH and -OC 1-3 alkyl; -N(C 1-8 alkyl)-, -CON(C 1-8 alkyl)-, -N(C 1-8 alkyl)CO-;

[0178] More preferably, C 1-8 alkylene (preferably C 1-3 alkylene, more preferably alkylene), C 2-8 alkenylene (preferably C 2-3 alkenylene), C 2-8 alkynylene (preferably C 2-3 alkynylene), haloC 1-8 alkylene (preferably haloC 1-3 alkylene, more preferably alkylene), C 1-3 alkoxy-substituted C 1-8 alkylene (preferably C 1-3 alkoxy-substituted C 1-3 alkylene, more preferably alkylene), or

[0179] (2) optionally substituted by 1 or more halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylhydroxy, cyano, amino, oxo, C 1-4 alkoxy-substituted 4- to 8-membered heteromonocyclic, 4- to 10-membered heteroannellated cyclic, 5- to 12-membered heterospirocyclic, 7- to 10-membered heterobridged cyclic, 3- to 7-membered monocyclic alkyl, 4- to 10-membered annellated alkyl, 5- to 12-membered spiroalkyl, 7- to 10-membered bridged alkyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, wherein said plurality of halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylhydroxy, cyano, amino, oxo, C 1-4 alkoxy for substitution can form a 3- to 5-membered carbocyclic or heterocyclic ring, and said heteroaryl, heteromonocyclic, heteroannellated cyclic, heterospirocyclic, heterobridged cyclic contains 1 to 4 heteroatoms independently selected from O, S, N; wherein said monocyclic alkyl is preferably said heteromonocyclic is preferably said heterospirocyclic is preferably said spiroalkyl is preferably The heteroaromatic group is preferably The heteroaromatic group is preferably The heteroaromatic group is preferably The aryl group is preferably

[0180] In some embodiments, the L is (LNK) u wherein:

[0181] u is 1, 2, 3, 4, 5, or 6; and

[0182] each LNK is independently absent, or selected from C 1-8 alkylene (preferably C 1-3 alkylene, more preferably alkylene, more preferably 2-8 alkylene, more preferably 2-8 alkylene, more preferably 1-8 alkylene, more preferably 1-3 alkylene, more preferably alkylene, more preferably 1-3 alkylene, more preferably 1-3 alkylene, more preferably ,

[0183] In some preferred embodiments, all LNK are not simultaneously absent.

[0184] In the above embodiments, u is preferably 1, 2, 3, 4, or 5. In some embodiments, u is 1, 2, 3, or 4. In some embodiments, u is 1, 2, or 3. In some embodiments, u is preferably 1 or 2. In some embodiments, u is 1.

[0185] In some embodiments, the L or (LNK) u is selected from:

[0186] In some embodiments, the L or (LNK) u is selected from:

[0187] In more preferred embodiments, the L or (LNK) u is selected from

[0188] In some embodiments, the compound of formula (I) is a compound of formula (V):

[0189] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0190] wherein X1, R1, R2, R3, R4, R a and m are defined as in the first aspect of the section "S1. KRAS Ligands" above, u, LNK and B are defined as above. Further, at least one of said R3and R4is F, Cl, -NO2or -CN.

[0191] In some embodiments, the compound of formula (I) is a compound of formula (V-1):

[0192] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0193] wherein R0, R2, R3, R4, R a and m and n are defined as in the first aspect of the section "S1. KRAS Ligands" above, u, LNK and B are defined as above. Further, at least one of said R3and R4is F, Cl, -NO2or -CN.

[0194] In some embodiments, the compound of formula (I) is a compound of formula (V-2):

[0195] or a pharmaceutically acceptable salt or stereoisomer thereof,

[0196] wherein R2, R3, R4, R5, R a and m and n are defined as in the first aspect of the section "S1. KRAS Ligands" above, u, LNK and B are defined as above. Further, at least one of said R3and R4is F, Cl, -NO2or -CN.

[0197] In other embodiments, the compound of formula (I) is a compound of formula (VI):

[0198] preferably a compound of formula (VI'):

[0199] wherein R1', R2, R3, R4, R a and m are defined as in the second aspect of the section "S1. KRAS Ligands" above, u, LNK and B are defined as above.

[0200] In some preferred embodiments, the compound of formula (I) is a compound of formula (VI-1):

[0201] preferably a compound of formula (VI-1’):

[0202] wherein CyB, CyC, L 1 , R a1 , R2, R3, R4, R a and m are as defined above in the second aspect of the section “S1. KRAS Ligands”, u, LNK and B are as defined above.

[0203] The compound of formula (I) is a compound of formula (VI-2):

[0204] preferably a compound of formula (VI-2’):

[0205] wherein the ring CyA, R2, R3, R4, R a and m are as defined above in the second aspect of the section “S1. KRAS Ligands”, u, LNK and B are as defined above.

[0206] In some embodiments, the ring CyA in formula (VI-2) or (VI-2’) is a 5-, 6- or 7- membered nitrogen-containing monocyclic heterocycloalkyl having 1 N and 1 O in the ring, wherein the nitrogen-containing monocyclic heterocycloalkyl is fused to 1 3-6 membered cycloalkyl. In some embodiments, the ring CyA in formula (VI-2) or (VI-2’) is In some embodiments, R2in formula (VI-2) or (VI-2’) is selected from In some embodiments, R2is In some embodiments, R2is In some embodiments, R a is independently selected from halogen, preferably F or Cl, more preferably F. In some embodiments, m in formula (VI-2) is 1. In some embodiments, one of R3or R4in formula (VI-2) or (VI-2’) is F and the other is H. In some embodiments, (LNK) u is In some embodiments, B in formula (VI-2) or (VI-2’) is preferably

[0207] In some embodiments, the compound of formula (I) is a compound of formula (VI-3):

[0208] preferably a compound of formula (VI-3’):

[0209] wherein ring CyA, CyE, L 2 , R2, R3, R4, R a and m are as defined above in the second aspect of the section “S1. KRAS Ligands”, u, LNK and B are as defined above.

[0210] In some embodiments, the ring CyA in the compound of formula (VI-3) or (VI-3’) is a 6- or 7-membered nitrogen-containing monocyclic heterocycloalkyl having 1 N and 1 O in the ring, and L 2 is selected from -CH2-O- and -O-CH2-. In some embodiments, the moiety of the compound of formula (VI-3) or (VI-3’) is preferably more preferably In some embodiments, R2 in the compound of formula (VI-3) or (VI-3’) is selected from In some embodiments, R2 is In some embodiments, R2 is In some embodiments, R in the compound of formula (VI-3) or (VI-3’) is a is independently selected from halogen, preferably F or Cl, more preferably F. In some embodiments, m in the compound of formula (VI-3) is 1. In some embodiments, one of R3 or R4 in the compound of formula (VI-3) or (VI-3’) is F and the other is H. In some embodiments, (LNK) u is In some embodiments, B in the compound of formula (VI-3) or (VI-3’) is preferably

[0211] The present application also includes embodiments resulting from any combination of the above embodiments, unless mutually contradictory.

[0212] In some embodiments, the present application provides a compound of formula (I) and pharmaceutically acceptable salts thereof or isomers thereof, selected from: preferably preferably preferably preferably preferably preferably preferably preferably

[0213] preferably preferably preferably preferably

[0214] preferably preferably

[0215] In some embodiments, the present application provides a compound of Formula (I) and pharmaceutically acceptable salts thereof or isomers thereof, selected from:

[0216] In some embodiments, the present application provides a compound of Formula (I) and pharmaceutically acceptable salts thereof or isomers thereof, selected from:

[0217] Pharmaceutical compositions and uses

[0218] The present application provides a composition comprising a compound of the present application, or a pharmaceutically acceptable salt thereof, or an isomer thereof, and a pharmaceutically acceptable carrier. In some embodiments, the composition is a pharmaceutical composition.

[0219] The present application also provides use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for inhibiting or degrading Pan-KRas.

[0220] The present application also provides use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or an isomer thereof, in the preparation of a medicament for inhibiting Pan-KRas.

[0221] The present application also provides use of the above-mentioned compound, or a pharmaceutically acceptable salt thereof, or an isomer thereof in the preparation of a medicament for treating and / or preventing a disease or disorder mediated by KRas wild type and / or mutant.

[0222] The KRas mutant according to the present application is selected from KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13C and Q61H.

[0223] In some embodiments of the present application, in the above-mentioned use, the Pan-KRas inhibitor related medicament is a medicament for treating or preventing a KRas mutant protein related disease, including but not limited to pancreatic cancer, colorectal cancer, lung cancer, endometrial cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0224] The present application provides a method for treating or preventing a KRas mutant protein related disease, comprising administering to a patient in need thereof an effective amount of a compound of the present application, or a pharmaceutically acceptable salt thereof, or an isomer thereof. The disease includes but is not limited to pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer. In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0225] In some embodiments of the present application, the KRas mediated disease or related disease is cancer. In some preferred embodiments, the cancer is selected from lung cancer, breast cancer, multiple myeloma, bladder cancer, endometrial cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, large intestine cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, lung cancer of pleomorphic, ovarian cancer, esophageal cancer, esophageal cancer, melanoma, lymphoma, blood cancer, brain tumor, gastrointestinal stromal tumor, small intestine cancer, urothelial cancer, bladder cancer, breast cancer, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer, colorectal cancer, hepatocellular carcinoma, head and neck tumor, hepatobiliary cancer, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, keratosis lichenoides, synovial sarcoma, testicular cancer or liposarcoma.

[0226] Definitions and Descriptions

[0227] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be construed as being indefinite or unclear unless specifically defined, but should be interpreted in accordance with the ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0228] The term "pharmaceutically acceptable" as used herein pertains to compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0229] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the application which are acid or base addition salts.

[0230] Herein, when a third group (or moiety) interposed between a first group and a second group (or moiety) is defined to be "absent", it is meant that the third group is a single bond, i.e., the first group and the second group are connected by a single bond.

[0231] Unless otherwise specified, the term "C 1-3 "alkyl" is used to denote a straight or branched saturated carbon hydride group consisting of from 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 , C 2-3 alkyl groups, and the like; which can be monovalent, divalent, or multivalent. The C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like. Unless otherwise specified, "C 2-8 "alkenyl" is used to denote a straight or branched carbon hydride group consisting of from 2 to 8 carbon atoms containing at least one carbon-carbon double bond, which can be located in any position on the group. The C 2-8 alkenyl group includes C 2-6 , C 2-4 , C 2-3 , C4, C3, and C2 alkenyl groups, and the like; which can be monovalent, divalent, or multivalent. The C 2-8 Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, and the like.

[0232] Unless otherwise specified, the term "C 1-3 "alkoxy" and "-OC 1-3 alkyl" are interchangeable and denote those alkyl groups containing from 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C3, and C2 alkoxy groups, and the like. The C 1-3 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propyloxy (including n-propyloxy and isopropoxy), and the like.

[0233] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated cyclic hydrocarbon groups, including monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups, including fused cycloalkyl, bridged cycloalkyl, or spirocycloalkyl groups.

[0234] The term "spirocycloalkyl" refers to a cyclic structure containing carbon atoms and formed from at least two rings that share one atom. As used herein, 7- to 12-membered spirocycloalkyl refers to a cyclic structure containing 7 to 12 carbon atoms and formed from at least two rings that share one atom.

[0235] The terms "fused cycloalkyl" and "annelated cycloalkyl" are used interchangeably herein to mean a fused ring containing carbon atoms and formed from two or more rings that share two adjacent atoms. As used herein, 4- to 10-membered fused cycloalkyl refers to a fused ring containing 4 to 10 ring carbon atoms and formed from two or more rings that share two adjacent atoms.

[0236] The term "aryl," used alone or in combination with other terms, refers to a group selected from:

[0237] - 5- and 6-membered carbocyclic aromatic rings, such as phenyl;

[0238] - bicyclic ring systems, such as 7- to 12-membered bicyclic ring systems, wherein at least one ring is carbocyclic and aromatic, such as naphthyl and indanyl;

[0239] - tricyclic ring systems, such as 10- to 15-membered tricyclic ring systems, wherein at least one ring is carbocyclic and aromatic, such as fluorenyl.

[0240] The terms "aromatic hydrocarbon ring" and "aryl" are used interchangeably throughout the disclosure herein. In some embodiments, a monocyclic or bicyclic aromatic hydrocarbon ring has 5 to 10 ring-forming carbon atoms (i.e., C5-10 aryl). Examples of monocyclic or bicyclic aromatic hydrocarbon rings include, but are not limited to, phenyl, naphth-1-yl, naphth-2-yl, anthryl, phenanthryl, and the like.

[0241] The term "heteroaryl" refers to a group selected from:

[0242] - 5-, 6-, or 7-membered aromatic monocyclic ring comprising at least one heteroatom, such as 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, in some embodiments 1 to 2 heteroatoms, the heteroatoms being selected from nitrogen (N), sulfur (S), and oxygen (O), the remaining ring atoms being carbon;

[0243] - 7- to 12-membered bicyclic ring comprising at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the heteroatoms being selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and

[0244] - 11- to 14-membered tricyclic ring comprising at least one heteroatom, for example 1 to 4 heteroatoms, or in some embodiments 1 to 3 heteroatoms, or in other embodiments 1 or 2 heteroatoms, the heteroatoms being selected from N, O, and S, the remaining ring atoms being carbon, and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring.

[0245] When the total number of S and O atoms in a heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in a heteroaryl group is no more than 2. In some embodiments, the total number of S and O atoms in an aromatic heterocycle is no more than 1. When a heteroaryl group contains more than one heteroatom ring member, the heteroatoms can be the same or different.

[0246] In some embodiments, a monocyclic or bicyclic aromatic heterocycle has 5, 6, 7, 8, 9, or 10 ring members, wherein 1, 2, 3, or 4 heteroatom ring members are independently selected from nitrogen (N), sulfur (S), and oxygen (O), and the remaining ring members are carbon. In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a monocyclic or bicyclic ring comprising 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is a 5- to 6-membered heteroaryl ring that is monocyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen (N), sulfur (S), and oxygen (O). In some embodiments, a monocyclic or bicyclic aromatic heterocycle is an 8- to 10-membered heteroaryl ring that is bicyclic and has 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen.

[0247] "Heterocyclyl," "heterocycle," or "heterocyclic" are interchangeable and refer to a non-aromatic heterocyclyl group comprising one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members and the remaining ring members are carbon, including monocyclic rings, fused rings, bridged rings, and spiro rings, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclyl groups. The term "optionally oxidized sulfur" as used herein refers to S, SO, or SO2.

[0248] The term "monocyclic heterocyclyl" refers to a monocyclic group in which at least one ring member is a heteroatom selected from nitrogen, oxygen, or optionally oxidized sulfur. The heterocycle can be saturated or partially saturated.

[0249] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclyl group having a ring connected through a common carbon atom (referred to as a spiro atom), containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remainder of the ring members being carbon. One or more rings of the spiroheterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the spiroheterocyclyl group is 6- to 14-membered, and more preferably 7- to 12-membered. Depending on the number of common spiro atoms, the spiroheterocyclyl group is classified as a mono-, bi-, or polyspiroheterocyclyl, and preferably refers to a monosprioheterocyclyl or a bispiroheterocyclyl, and more preferably a 4-membered / 4-membered, 3-membered / 5-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monosprioheterocyclyl.

[0250] The terms "fused heterocyclyl" and "heteroannelated ring" are used interchangeably in the art to mean a 5- to 20-membered polycyclic heterocyclyl group in which each ring in the system shares an adjacent pair of atoms (a carbon and carbon atom or a carbon and nitrogen atom) with another ring, containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remainder of the ring members being carbon. One or more rings of the fused heterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the fused heterocyclyl is 6- to 14-membered, preferably 7- to 12-membered and more preferably 7- to 10-membered. Depending on the number of member rings, the fused heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably refers to a bicyclic or tricyclic fused heterocyclyl, and more preferably a 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused heterocyclyl.

[0251] The terms "bridged heterocyclyl" or "heterobridged ring" refer to a 5- to 14-membered polycyclic heterocyclyl group in which each two rings in the system share two non-adjacent atoms, containing one or more heteroatoms selected from nitrogen, oxygen, or optionally oxidized sulfur as ring members, with the remainder of the ring members being carbon. One or more rings of the bridged heterocyclyl group can contain one or more double bonds, but no ring has a fully conjugated pi-electron system. Preferably, the bridged heterocyclyl is 6- to 14-membered, and more preferably 7- to 10-membered. Depending on the number of member rings, the bridged heterocyclyl is classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, and preferably refers to a bicyclic, tricyclic, or tetracyclic bridged heterocyclyl, and more preferably a bicyclic or tricyclic bridged heterocyclyl.

[0252] Unless otherwise specified, the term "halo" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine, or iodine atom.

[0253] Unless otherwise indicated, the term "isomers" is intended to include geometric isomers, cis / trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers, and tautomers.

[0254] The compounds of the present application can exist in particular geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as the racemic mixtures and other mixtures thereof, such as those that are enantiomeric or diastereomeric mixtures. Additional asymmetric carbon atoms can be present in a substituent group. All such isomers, as well as mixtures thereof, are included within the scope of the present application.

[0255] The term "enantiomeric" or "optical isomer" means a stereoisomer that is a mirror image of the other and is not superimposable.

[0256] The term "cis" or "geometric isomer" means a stereoisomer that results from the restriction of free rotation about a single bond due to the presence of adjacent groups.

[0257] The term "diastereomeric" means a stereoisomer that has two or more chiral centers and is not a mirror image of the other.

[0258] "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic, unless otherwise indicated.

[0259] Unless otherwise indicated, a solid wedge and a dashed wedge indicate the absolute configuration of a stereogenic center, and a wavy line indicates the cis or trans configuration of a geometric isomer, such as in the compound The wavy line indicates that the compound can be either and so on.

[0260] Unless otherwise indicated, the term "enriched in an isomer," "isomer-enriched," "enriched in an enantiomer," or "enantiomer-enriched" means that the content of one isomer or enantiomer is less than 100% and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0261] The term "enantiomeric excess" or "diastereomeric excess" means the difference between the relative percentages of the two isomers or the two diastereomers, unless otherwise indicated. For example, where one isomer or enantiomer is present in an amount of 90% and the other isomer or enantiomer is present in an amount of 10%, the enantiomeric or diastereomeric excess (the ee value) is 80%.

[0262] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomeric isomer. Alternatively, when a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group) is present in the molecule, diastereomeric salts with an appropriate optically active acid or base are formed, and the diastereomeric salt is separated by conventional means, and the desired enantiomer is recovered by conventional means. In addition, separation of the enantiomers and diastereomers is typically accomplished by chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of a carbamate from an amine).

[0263] The compounds of the application can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as for example deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For example, deuterium can be substituted for hydrogen to form deuterated drugs, which have advantages over non-deuterated drugs, such as reduced toxicity, increased stability, increased efficacy, increased biological half-life, etc. All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0264] The term "optionally" or "optionally" means that the subsequently described event or circumstance can or can not occur and this description includes instances where the described event or circumstance occurs and instances where it does not.

[0265] The term "substituted" means that any one or more hydrogen atoms in a given atom are replaced with a substituent group, can include heavy hydrogen and variations of hydrogen, as long as the valency of the given atom is normal and the resulting compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that the group can or can not be substituted, and unless otherwise specified, the kinds and number of substituents can be any that are chemically possible.

[0266] When any variable (e.g., R) occurs more than one time in a compound or substituent, its definition in each instance is independent of the definition of the other. Thus, for example, if a group is substituted with 0-2 R groups, then the group is optionally substituted with up to two R groups, and the R groups are independently selected at each occurrence. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0267] When the number of occurrences of a linking group is zero, such as -(L1)0-, it means that the linking group is a single bond.

[0268] When the number of occurrences of a substituent is zero, it means that the substituent is absent, such as -A-(R)0means that the structure is actually -A.

[0269] When a substituent is null, it means that the substituent is absent, such as X is null in A-X means that the structure is actually A.

[0270] When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, such as L represents a single bond in A-L-Z means that the structure is actually A-Z.

[0271] When a substituent can bond to more than two atoms on a ring, it can bond to any atom on the ring, for example, the structural element means that the substituent R can be on any of the atoms of the cyclohexyl or cyclohexadiene ring. When a listed substituent is not designated by which atom it is attached to the substituted group, it can be bonded through any of its atoms, for example, a pyridyl group as a substituent can be bonded to the substituted group through any of the carbon atoms of the pyridine ring.

[0272] When a listed linking group is not designated by its direction of attachment, its direction of attachment is arbitrary, for example, where the linking group L is -M-W-, then -M-W- can attach ring A and ring B to form Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0273] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight solid line key with * or wavy line This indicates that the two forms can be used interchangeably. For example, the straight solid line bond in -OCH3 indicates that the oxygen atom in the group is connected to other groups; The wavy line in the text indicates that the phenyl group is connected to other groups through the carbon atom at position #1 of the phenyl group. The asterisk (*) indicates that the phenyl group is linked to other groups through the carbon atom at position #1.

[0274] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a "3-9 elemental ring" refers to a "ring" with 3 to 9 atoms arranged around it.

[0275] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, the terms "administration," "administering," "treating," and "treatment" mean contact between an exogenous agent, therapeutic agent, diagnostic agent, or composition and the animal, human, subject, cell, tissue, organ, or biological fluid. Treatment of cells encompasses contact between the reagent and the cell, as well as contact between the reagent and a fluid, wherein the fluid contacts the cell. The terms "administration" and "treatment" also mean in vitro and ex vivo treatment of, for example, cells by means of a reagent, diagnostic agent, conjugated compound, or another cell. The term "patient" as used herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit), and most preferably a human.

[0276] The term “effective amount” or “therapeutic effective amount” refers to an amount of an active ingredient (such as a compound) that is sufficient to affect such treatment of a disease or at least one clinical symptom of a disease or disorder when the compound is given to a subject.

[0277] The term "disease" refers to any illness, ailment, sickness, condition, or indication, and can be used interchangeably with the term "disorder" or "impairment."

[0278] Throughout the specification and the following aspects, the term "C n-m " indicates a range inclusive of the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 , C 1-3 , and the like.

[0279] Unless specifically defined otherwise herein, all other technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0280] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by the combination of the embodiments set forth below with other chemical synthetic methods well known in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including, but not limited to, the examples of the present application.

[0281] Solvents used in the present application are commercially available.

[0282] Compounds are named according to the principles of nomenclature conventionally used in the art or using Ariad Nomenclature software, and commercially available compounds are named using the vendor catalog name. Examples

[0283] The present application will be further described with reference to the following examples, but these examples are not intended to limit the scope of the present application. The following examples are used to understand the method and core idea of the present application, and any possible changes or replacements made by those skilled in the art without departing from the concept of the present application shall fall within the scope of the present application. The experimental methods not specified in the examples of the present application are usually conventional conditions, or according to the conditions suggested by the raw material or commodity manufacturers; reagents not specified by the source are usually conventional reagents that can be purchased through commercial channels.

[0284] Preparation Examples

[0285] Preparation of Intermediate A:

[0286] Step 1: Synthesis of A-2

[0287] The starting material, 1,3-dihydroxy-2-propanone, A-1 (50 g, 0.56 mol, 1 eq), was placed in a 1 L clean three-necked flask, 500 mL of N,N-dimethylformamide was added, and the temperature was lowered to 0 °C. Imidazole (38 g, 0.56 mol, 1 eq) and tert-butyldiphenylsilyl chloride (107 g, 0.39 mol, 0.7 eq) were added portionwise. After the addition was completed, the reaction was allowed to recover to room temperature and was allowed to react for 18 h. TLC monitoring showed that the starting material was completely consumed. The reaction solution was extracted with water and ethyl acetate. The organic phase was concentrated and separated by column chromatography to obtain compound A-2.

[0288] Step 2: Synthesis of A-3

[0289] The starting material A-2 (30 g, 0.09 mol, 1 eq) was placed in a 1 L clean three-necked flask, 300 mL of dichloromethane was added, and the temperature was lowered to 0 °C. Imidazole (9.5 g, 0.14 mol, 1.5 eq) and tert-butyldimethylsilyl chloride (13.5 g, 0.09 mol, 1 eq) were added portionwise. After the addition was completed, the reaction was allowed to recover to room temperature and was allowed to react for 18 h. TLC monitoring showed that the starting material was completely consumed. The reaction solution was extracted with water and ethyl acetate. The organic phase was concentrated and purified by column chromatography to obtain compound A-3.

[0290] Step 3: Synthesis of A-5

[0291] The starting material A-4 (33 g, 87 mmol, 1.2 eq) was placed in a 1 L clean three-necked flask, 300 mL of THF was added, and the temperature was lowered to -78 °C. Sodium bis(trimethylsilyl)amide (54 mL, 108 mmol, 1.5 eq) was added dropwise. After the addition was completed, the reaction was allowed to react at -78 °C for 1 h. A-3 (32 g, 72 mmol, 1 eq) dissolved in 100 mL of THF was added dropwise. After the addition was completed, the reaction was allowed to recover to room temperature and was allowed to react for 2 h. TLC monitoring showed that the starting material was completely consumed. The reaction solution was extracted with water and ethyl acetate. The organic phase was concentrated and separated by column chromatography to obtain compound A-5.

[0292] Step 4: Synthesis of intermediate A

[0293] The starting material A-5 (20 g, 46 mmol, 1 eq) was placed in a 1 L clean three-necked flask, 200 mL of THF was added, and HCl / dioxane (117 mL, 460 mmol, 10 eq) was added. The reaction was allowed to react at room temperature for 3 h. TLC monitoring showed that the starting material was completely consumed. The reaction solution was extracted with water and ethyl acetate. The organic phase was concentrated and separated by column chromatography to obtain compounds A (1) and A (2). LCMS (ESI) m / z: 345.2 (M+H) + .

[0294] Example 1: Synthesis of P001

[0295] Step 1: Synthesis of P1-2

[0296] To a solution of 6-bromo-3-iodo-1H-indazole, P1-1 (30.0 g, 92.900 mmol) in acetone (300 mL) was added potassium hydroxide (13.0 g, 232.250 mmol) at room temperature and stirred at room temperature. To the reaction mixture was added iodomethane (33.0 g, 232.250 mmol) dropwise. After the addition was completed, the reaction mixture was stirred at room temperature for 16 hours. TLC monitoring showed that the starting material was completely consumed. The reaction mixture was filtered through celite and concentrated. The residue was extracted with ethyl acetate and water. The organic phase was concentrated and purified by column chromatography to give compound P1-2.

[0297] Step 2: Synthesis of P1-4

[0298] To a solution of P1-2 (15.0 g, 44.516 mmol) in tetrahydrofuran / water (150 mL / 25 mL) was added P1-3 (22.3 g, 53.419 mmol), cesium carbonate (43.9 g, 133.548 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.8 g, 2.226 mmol) sequentially at room temperature. The mixture was stirred at 80 °C for 16 hours. TLC monitoring showed that the starting material was completely consumed. The reaction mixture was extracted with ethyl acetate and water. The organic phase was concentrated and purified by column chromatography to give compound P1-4.

[0299] Step 3: Synthesis of P1-6

[0300] To a solution of P1-4 (10.5 g, 20.983 mmol) in 1,4-dioxane / water (105 mL / 21 mL) was added N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester, P1-5 (9.7 g, 31.475 mmol), potassium carbonate (8.7 g, 62.950 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (1.7 g, 2.098 mmol) sequentially at room temperature. The mixture was stirred at 85 °C for 16 hours. TLC monitoring showed that the starting material was completely consumed. The reaction mixture was diluted with ethyl acetate and filtered through celite. The filtrate was extracted with brine and ethyl acetate. The organic phase was combined, filtered and concentrated. The residue was purified by column chromatography to give compound P1-6.

[0301] Step 4: Synthesis of P1-7

[0302] To a solution of P1-6 (5 g) in ethyl acetate / ethanol (100 mL / 100 mL) was added Pd / C (2 g) at room temperature, and the reaction mixture was stirred at 30 °C for 16 h under hydrogen atmosphere. The reaction mixture was filtered through celite, concentrated and purified by column chromatography to give compound P1-7. MS m / z (ESI): 427.2 [M+H] + .

[0303] Step 5: Synthesis of P1-8

[0304] To a solution of P1-7 (5 g) in dichloromethane (50 mL) was added trifluoroacetic acid (13 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Concentrated, a small amount of dichloromethane was added, and the pH was adjusted to 11-12 with saturated potassium carbonate solution. Dichloromethane / methanol (5 / 1) and brine were added, and the organic phase was extracted with dichloromethane / methanol (5 / 1) (500 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give compound P1-8. MS m / z (ESI): 327.2 [M+H] + .

[0305] Step 6: Synthesis of P1-10

[0306] Compound 1-8 (600 mg, 1.0 eq) was added to DMSO (10 ml), P1-9 (659 mg, 1.5 eq) and acetic acid (110 mg, 1.0 eq) were added at room temperature, and sodium triacetoxyborohydride (1.94 g, 5 eq) was added after stirring at room temperature for 15 min, and stirred at room temperature for 16 h, and then water and EA were added and extracted, and the organic phase was filtered, concentrated and purified by silica gel column to give intermediate P1-10. MS m / z (ESI): 411.2 [M+H] + .

[0307] Step 7: Synthesis of P1-13

[0308] P1-11 (8.3 g, 33 mmol) was dissolved in 1,4-dioxane (90 mL) at room temperature, N,N-diisopropyl ethylamine (17 ml, 99 mmol) was added, and P1-12 (5 g, 33 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h under nitrogen protection. The reaction mixture was diluted with ethyl acetate, and the organic phase was washed with saturated brine, and then concentrated and purified by silica gel column chromatography to give compound P1-13. LCMS (ESI) m / z: 331.1 (M+H) + .

[0309] Step 8: Synthesis of P1-14

[0310] P1-13 (9 g, 27.2 mmol) was added to tetrahydrofuran (90 mL) at room temperature, and the reaction mixture was added to sodium thiomethoxide (2.6 g, 32.6 mmol) in batches at -10 °C. The reaction mixture was reacted at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography to obtain compound P1-14. LCMS (ESI) m / z: 343.0 (M+H) + .

[0311] Step 9: Synthesis of P1-16

[0312] P1-14 (7 g, 20.3 mmol) was added to 1,4-dioxane (140 mL) and water (35 mL) at room temperature, and then potassium phosphate (12.9 g, 60.9 mmol), [n-butylbis(1-adamantyl)phosphine]methanesulfonic acid (2-amino-1,1-biphenyl-2-yl)palladium(II) (2.9 g, 4.06 mmol), and P1-15 (10.4 g, 20.3 mmol) were sequentially added. The reaction solution was reacted for 3 hours under nitrogen protection. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography to obtain compound P1-16. LCMS (ESI) m / z: 693.3 (M+H) + .

[0313] Step 10: Synthesis of 1-17

[0314] Compound 1-16 (7.5 g, 10.8 mmol) was added to dichloromethane (80 mL) at room temperature, and then meta-chloroperoxybenzoic acid (2.2 g, 12.9 mmol) was added. LCMS detection showed no starting material, and the reaction solution was diluted with dichloromethane. The organic phase was washed with saturated brine, and the organic phase was concentrated and purified by silica gel column chromatography to obtain compound P1-17.

[0315] LCMS (ESI) m / z: 709.3 (M+H) + .

[0316] Step 11: Synthesis of compound P1-18

[0317] Intermediate A (1) (2.1 g, 6.2 mmol) was added to toluene (30 mL), and sodium tert-butoxide (894 mg, 9.3 mmol) was added to the reaction solution, which was stirred at room temperature for 10 minutes. Compound P1-17 (2.5 g, 3.1 mmol) was added to the above reaction solution, and the reaction mixture was reacted at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated brine. The organic phase was concentrated and purified by silica gel column chromatography to obtain compound P1-18. LCMS (ESI) m / z: 989.6 (M+H)+ .

[0318] Step 12: Synthesis of compound P1-19

[0319] Compound P1-18 (1.16 g, 1.6 mmol), ammonium fluoride (1.2 g, 30 mmol) were dissolved in 50 mL clean three-necked flask, 16 mL methanol was added, and the reaction was carried out at room temperature for 16 hours. The reaction solution was directly rotary dried. 50 mL ethyl acetate was added, filtered, and the filtrate was concentrated and separated by silica gel column chromatography to obtain compound P1-19. LCMS (ESI) m / z: 751.3 (M+H) + .

[0320] Step 13: Synthesis of compound P1-20

[0321] Compound P1-19 (700 mg, 0.93 mmol) was dissolved in dichloromethane (3 mL) at room temperature, triethylamine (282 mg, 2.79 mmol) was added, and methyl sulfonyl chloride (160 mg, 1.40 mmol) was added at 0 degrees. The reaction mixture was reacted at 0 degrees for 1 hour. The reaction solution was directly column chromatography to obtain compound P1-20. LCMS (ESI) m / z: 829.4 (M+H) +

[0322] Step 14: Synthesis of compound P1-21

[0323] P1-20 (370 mg, 0.44 mmol), potassium carbonate (150 mg, 1.78 mmol), P1-10 (180 mg, 0.44 mmol), sodium iodide (80 mg, 0.22 mmol) were dissolved in super dry N,N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted at room temperature for 16 hours. Ethyl acetate (30 mL) was added for dilution and water (30 mL) was added for extraction. The organic phase was concentrated and purified by silica gel column chromatography to obtain compound P1-21. LCMS (ESI) m / z: 1182.2 (M+H) +

[0324] Step 15: Synthesis of compound P1-22

[0325] Cesium fluoride (162 mg, 1.06 mmol) was added to P1-21 (120 mg, 0.10 mmol) in N,N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was reacted at 25 degrees for 1 hour. The reaction solution was extracted with ethyl acetate and water, and the organic phase was concentrated and purified by silica gel column chromatography to obtain compound P1-22. LCMS m / z (ESI): 1025.1 (M+H) +

[0326] Step 16: Preparation of P001A

[0327] Trifluoroacetic acid (2 mL) was added to P1-22 (103 mg, 0.10 mmol) in dichloromethane (6 mL) at room temperature. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed most of the product. The reaction was concentrated at low temperature to remove trifluoroacetic acid. The crude product was purified by reverse phase preparative chromatography to give compound P001A.

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.18 (s, 1H), 9.15 (d, J = 63.7 Hz, 1H), 7.98 (dd, J = 9.2, 6.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.27 (s, 0.5H), 7.21 (d, J = 20.3 Hz, 1H), 7.05 (d, J = 5.6 Hz, 1H), 7.02 (s, 0.6H), 4.85 (s, 2H), 4.75 (d, J = 26.2 Hz, 1H), 4.37 (s, 1H), 4.34 - 4.31 (m, 1H), 4.12 - 4.10 (m, 1H), 3.95 (d, J = 5.5 Hz, 4H), 3.65 - 3.52 (m, 5H), 3.03 (s, 2H), 2.90 (s, 2H), 2.61 (s, 6H), 2.33 (s, 4H), 2.18 (s, 3H), 1.90 (s, 3H), 1.69 - 1.65 (m, 4H), 1.47 - 1.44 (m, 7H), 1.17 - 1.15 (m, 3H). LCMS (ESI) m / z: 982.3 (M+H) + .

[0329] P001B was synthesized similarly to P001A, with A(1) replaced by A(2).

[0330] 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.15 (d, J = 66.5 Hz, 1H), 8.18 (s, 1H), 7.98 (dd, J = 9.2, 5.9 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.48 - 7.49 (m, 3H), 7.21 (dd, J = 18.2, 2.3 Hz, 1H), 7.04 (s, 1H), 7.02 (s, 0.5H), 6.84 (s, 0.5H), 4.96 (s, 2H), 4.71 (s, 1H), 4.45 - 4.26 (m, 2H), 4.11 (d, J = 13.5 Hz, 1H), 4.00 (s, 1H), 3.96 (s, 3H), 3.95 (s, 1H), 3.60 (s, 1H), 3.34 (d, J = 13.3 Hz, 1H), 3.06 (d, J = 10.6 Hz, 2H), 2.91 (s, 1H), 2.70 - 2.61 (m, 3H), 2.39 - 2.30 (m, 3H), 2.24 - 2.14 (m, 3H), 2.08 (d, J = 9.3 Hz, 2H), 1.95 (s, 2H), 1.87 - 1.75 (m, 4H), 1.70 - 1.61 (m, 6H), 1.49 - 1.42 (m, 5H), 1.19 (s, 1H), 1.14 (s, 3H). LCMS (ESI) m / z: 982.5 (M+H) + .

[0331] Example 2: Synthesis of P002

[0332] Step 1: Synthesis of P2-2

[0333] P1-14 (633 mg, 1.85 mmol) was added to 1,4-dioxane (6 mL) and water (1.2 mL) at room temperature, followed by potassium phosphate (1.178 g, 5.55 mmol), [n- butyldi(1-adamantyl)phosphine]methanesulfonic acid (2-amino-1,1- biphenyl-2-yl)palladium(II) (407.8 mg, 0.56 mmol), P2-1 (800 mg, 2.22 mmol) successively. The reaction was carried out for 3 hours under nitrogen protection. LCMS showed that the starting material was not detected and most of it was converted into the desired product. The reaction was diluted with ethyl acetate, and the organic phase was washed with saturated brine. After the organic phase was separated, dried over anhydrous sodium sulfate and concentrated, the compound P2-2 (720 mg, 71.8%) was separated by column chromatography (petroleum ether / ethyl acetate = 3:1). LCMS (ESI) m / z: 541.1 (M+H) + .

[0334] Step 2: Synthesis of P2-3

[0335] P2-2 (800 mg, 1.48 mmol) was added to dichloromethane (8 mL) at room temperature, followed by addition of m-chloroperoxybenzoic acid (332.1 mg, 1.92 mmol). LCMS showed no starting material and most of the starting material was converted to the desired product. The reaction solution was diluted with dichloromethane, and the organic phase was washed with saturated brine. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was separated by column chromatography (petroleum ether / ethyl acetate = 1:2) to give compound P2-3 (620 mg, 75.3%). LCMS (ESI) m / z: 557.7 (M+H)+.

[0336] Step 3: Synthesis of P2-4

[0337] P2-3 (500 mg, 0.899 mmol) was added to a pre-stirred solution of A (1) (619.4 mg, 1.798 mmol) and sodium tert-butoxide (259 mg, 2.697 mmol) in toluene (5 mL) at room temperature in batches. The reaction mixture was stirred at room temperature for 0.5 h. Ethyl acetate (10 mL) was added to the reaction mixture, and the organic phase was washed with saturated sodium chloride solution. The organic phase was separated, dried, and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / ethyl acetate = 2:1) to give compound P2-4 (360 mg, 48.1%).

[0338] Step 4: Synthesis of P2-5

[0339] P2-4 (380 mg, 0.454 mmol) was dissolved in methanol (6 mL) at room temperature, and ammonium fluoride (168 mg, 4.54 mmol) was added. The reaction mixture was stirred at 60 °C for 16 h. The reaction solution was concentrated by rotary evaporation, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:1) to give compound P2-5 (190 mg, 70.1%). LCMS (ESI) m / z: 599.7 (M+H)+.

[0340] Step 5: Synthesis of compound P2-6

[0341] Triethylamine (80 mg, 0.794 mmol) and methylsulfonyl chloride (115 mg, 0.794 mmol) were separately diluted with dichloromethane (0.5 ml), and then added dropwise to a solution of P2-5 (80 mg, 0.138 mmol) in dichloromethane (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 to 1 h. The reaction solution was directly purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1:2) to give compound P2-6 (45 mg, 49%). LCMS (ESI) m / z: 676.9 (M+H) + .

[0342] Step 6: Synthesis of P2-7

[0343] P2-6 (70 mg, 0.103 mmol) and P1-10 (93.06 mg, 0.207 mmol) were dissolved in N,N-dimethylformamide (2 mL) at room temperature, potassium carbonate (71.55 mg, 0.5177 mmol) was added, and the reaction mixture was reacted at 25 degrees for 2 hours. Ethyl acetate (5 mL) was added to the reaction solution, and the organic phase was washed with saturated sodium chloride solution, dried, and concentrated to obtain a residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 9:1) to obtain compound P2-7 (80 mg, 75.4%).

[0344] Step 7: Synthesis of P002A

[0345] Trifluoroacetic acid (0.4 mL) was added to P2-7 (80 mg) in dichloromethane (1.2 mL) at 0°C, and the reaction mixture was reacted at 25 degrees for 1 hour. Most of the product was detected by LCMS. The product was precipitated by adding 10 mL of ethyl ether, and the obtained crude compound was purified by preparative chromatography to obtain compound P002A (24.61 mg, 31%). 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.98 (d, J = 2.7 Hz, 1H), 9.25 (s, 1H), 7.77 (dd, J = 9.0, 6.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.42 - 7.32 (m, 3.5H), 7.04-7.02 (m, 2.5H), 4.92 (s, 2H), 4.74 (d, J = 8.0 Hz, 1H), 4.34 (dd, J = 9.8, 5.1 Hz, 2H), 4.08 (dd, J = 20.9, 13.9 Hz, 1H), 3.98 (s, 3H), 3.61-3.57 (m, 3H), 3.42 (s, 3H), 2.93-2.85 (m, 4H), 2.74-2.52 (m, 4H), 2.41-2.27 (m, 4H), 2.16 (dd, J = 13.3, 5.1 Hz, 4H), 2.07 (s, 2H), 1.93 (s, 4H), 1.76 (s, 2H), 1.68 (d, J = 10.7 Hz, 4H), 1.62-1.47 (m, 2H), 1.17 (d, J = 10.1 Hz, 3H), 0.74 (q, J = 7.2 Hz, 3H). LCMS (ESI) m / z: 986.8 (M+H) + .

[0346] P002B was synthesized in the same way as P002A, except that A(1) was replaced by A(2).

[0347] 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.23 (s, 1H), 8.17 (s, 1H), 7.77 (d, J = 8.0, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.37 - 7.33 (m, 2H), 7.04 (s, 1H), 7.02 (s, 0.5H), 6.82 (s, 0.5H),, 4.99 (s, 2H), 4.75 - 4.73 (m, 1H), 4.35 - 4.33 (m, 2H), 4.09 - 4.01 (m, 1H), 3.96 (s, 3H), 3.62 - 3.52 (m, 4H), 2.92 - 2.87 (m, 4H), 2.62 - 2.50 (m, 5H), 2.34 - 2.13 (m, 7H), 1.87 - 1.50 (m, 11H), 1.45 - 1.37 (m, 6H), 1.17 (d, J = 10.1 Hz, 3H), 0.74 - 0.73 (m, 3H). LCMS (ESI) m / z: 986.8 (M+H) + .

[0348] Example 3: Synthesis of P003

[0349] The synthetic method was the same as P001 except P1-10 was replaced by P3-2.

[0350] P003A: 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.23 (s, 0.5H), 9.07 (s, 0.5H), 8.36 (s, 2H), 7.99-7.96 (m, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.47-7.45 (m, 2H), 7.39 (s, 1H), 7.28 (s, 0.5H), 7.24-7.22 (m, 1H), 7.09-6.99 (m, 1.5H), 4.86 (s, 2H), 4.33-4.31 (m, 2H), 4.11 (d, J = 13.2 Hz, 1H), 4.02-3.91 (m, 5H), 3.59-3.57 (m, 3H), 3.07 (s, 3H), 2.94 (d, J = 8.6 Hz, 2H), 2.81 (d, J = 9.9 Hz, 2H), 2.68-2.64 (m, 5H), 2.34 (d, J = 10.0 Hz, 1H), 2.17 (s, 1H), 1.99 (s, 5H), 1.87-1.61 (m, 10H), 1.51-1.47 (m, 10H), 1.36 (s, 1H), 1.19-1.15 (m, 3H). LCMS (ESI) m / z: 1093.9 (M+H) + .

[0351] P003B: 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.22 (s, 0.5H), 9.06 (s, 0.5H), 7.97-7.94 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.45-7.43 (m, 2H), 7.37 (s, 1H), 7.22 (dd, J = 19.8, 2.3 Hz, 1H), 7.05-7.03 (m, 1.5H), 6.84 (s, 0.5H), 4.96 (s, 2H), 4.79-4.75 (m, 1H), 4.33-4.31 (m, 2H), 4.12-4.10 (m, 1H), 3.59 (dd, J = 13.1, 8.5 Hz, 1H), 3.40 (s, 3H), 2.92 (s, 4H), 2.80 (s, 2H), 2.72-2.58 (m, 4H), 2.34 (d, J = 9.8 Hz, 1H), 2.17-2.15 (m, 1H), 2.00 (d, J = 7.8 Hz, 3H), 1.91 (s, 2H), 1.75-1.70 (m, 10H), 1.52 (s, 10H), 1.36 (s, 2H), 1.19-1.16 (m, 4H), 0.85 (s, 3H). LCMS (ESI) m / z: 1093.3 (M+H) + .

[0352] Synthesis of P3-2:

[0353] Step 1: Synthesis of P3-1

[0354] P1-10 (20 mg, 1.0 eq) was dissolved in DMF (2 ml), 3-1 (11 mg, 1.1 eq) and DIPEA (29 mg, 5.0 eq) were added, and finally HATU (34 mg, 2.0 eq) was added, and stirred at room temperature overnight. Then, water and EA were added, and the solution was divided, the water layer was extracted with EA, the combined organic phase was washed with saturated brine once, dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated to dryness to obtain the crude product, which was separated by TLC preparation plate to obtain compound P3-1. LCMS (ESI) m / z: 661.4 (M+H) + .

[0355] Step 2: Synthesis of P3-2:

[0356] Intermediate P3-1 (20 mg) was dissolved in 3 ml of DCM, 1 ml of TFA was added at room temperature, and the reaction was carried out at room temperature for 1 h, and LCMS was used to monitor the complete disappearance of the raw material. The reaction solution was rotary evaporated to obtain the crude compound P3-2, which was directly used in the next step. LCMS (ESI) m / z: 561.3 (M+H) + .

[0357] Example 4: Synthesis of P004A

[0358] The synthesis method is the same as P001A, except that is replaced by

[0359] P004A: 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.15 (s, 1H), 8.21 (s, 2H), 7.98 (dd, J = 9.2, 5.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.44 (s, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.26 (s, 0.5H), 7.19 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H), 7.02 (s, 0.5H), 4.84 (s, 2H), 4.74 - 4.71 (m, 1H), 4.56 - 4.54 (m, 1H), 4.33 - 4.30 (m, 1H), 4.21 (s, 2H), 3.99 (s, 1H), 3.96 (s, 3H), 3.02 (s, 1H), 2.96 (d, J = 10.0 Hz, 2H), 2.72 (d, J = 6.8 Hz, 1H), 2.65 - 2.61 (m, 2H), 2.56 (s, 2H), 2.26 - 2.23 (m, 4H), 2.02 (s, 2H), 1.96 - 1.69 (m, 12H), 1.55 - 1.47 (m, 4H), 1.41 (s, 2H). LCMS (ESI) m / z: 980.4 (M+H) + .

[0360] Example 5: Synthesis of P005

[0361] Synthetic procedure was same as P001 except was replaced by

[0362] P005A: LCMS (ESI) m / z: 966.7 (M+H) + .

[0363] P005B: LCMS (ESI) m / z: 966.7 (M+H) + .

[0364] Example 6: Synthesis of P006

[0365] Synthetic procedure was same as P001 except was replaced by

[0366] P006A: 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.26 (d, J = 9.6 Hz, 1H), 10.08 (s, 1H), 9.44 (d, J = 16.0 Hz, 1H), 9.29 (s, 1H), 7.98 (dd, J = 9.0, 6.0 Hz, 1H), 7.69 - 7.63 (m, 1.5H), 7.50 - 7.41 (m, 3.5H), 7.21 - 7.19 (m, 1H), 7.04 (d, J = 8.6 Hz, 1H), 5.06 - 4.88 (m, 2H), 4.50 (s, 1H), 4.35 (dd, J = 9.8, 5.0 Hz, 1H), 4.12 (s, 1H), 3.98 (s, 5H), 3.94 - 3.84 (m, 2H), 3.83 - 3.54 (m, 6H), 2.99-2.94 (m, 8H), 2.77 - 2.55 (m, 3H), 2.36 (d, J = 9.2 Hz, 2H), 2.26 - 2.04 (m, 8H), 2.00 - 1.70 (m, 7H), 1.35 - 1.33 (m, 1H), 0.79 - 0.76 (m, 1H). LCMS (ESI) m / z: 980.8 (M+H) + .

[0367] P006B: 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.15 (s, 1H), 9.41 (d, J = 19.6 Hz, 1H), 8.14 (s, 1H), 7.98 (dd, J = 9.2, 5.8 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 9.0 Hz, 1H), 7.42 (s, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.06 (s, 0.5H), 7.04 (d, J = 8.4 Hz, 1H), 6.85 (s, 0.5H), 4.96 (s, 2H), 4.50 (s, 1H), 4.33 (dd, J = 9.8, 5.0 Hz, 1H), 4.16 (s, 1H), 3.97 (s, 3H), 3.89 (s, 1H), 3.77 - 3.75 (m, 2H), 3.63 - 3.60 (m, 1H), 3.45 (s, 2H), 3.24 - 3.19 (m, 1H), 2.94 (s, 3H), 2.65 - 2.61 (m, 3H), 2.27 - 2.25 (m, 8H), 2.08 - 1.68 (m, 10H), 1.50 - 1.45 (m, 4H), 1.36 - 1.20 (m, 1H), 0.83 - 0.80 (m, 1H). LCMS (ESI) m / z: 980.8 (M+H)+ .

[0368] P006AA and P006AB were obtained by following the synthetic procedure of P001. P006AA and P006AB were obtained by following the synthetic procedure of P001. Referring to the synthetic procedure of P1-19, 6-1A was obtained. Then chiral column resolution was carried out to obtain 6-1AA and 6-1AB. Then chiral column resolution was carried out to obtain 6-1AA and 6-1AB. Then P006AA and P006AB were obtained by following the synthetic procedure of P001.

[0369] P006AA: 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.40 (d, J = 16.0 Hz, 1H), 7.92-7.90 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45-7.40 (m, 2H), 7.32 (s, 1H), 7.27 (s, 0.5H), 7.16-7.15 (m, 1H), 7.06-7.02 (m, 1.5H), 4.85 (s, 2H), 4.52-4.49 (m, 1H), 4.32-4.30 (m, 1H), 4.14 (s, 1H), 3.95 (s, 3H), 3.92–3.84 (m, 1H), 3.75–3.70 (m, 2H), 3.62-3.59 (m, 1H), 3.44-3.39 (m, 2H), 3.03 (s, 2H), 2.85 (s, 2H), 2.62-2.59 (m, 4H), 2.30-2.15 (m, 6H), 1.90 (s, 3H), 1.75-1.72 (m, 6H), 1.49-1.25 (m, 7H), 0.79-0.76 (m, 1H). LCMS (ESI) m / z: 980.8 (M+H) + .

[0370] P006AB: 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.15 (s, 1H), 9.43-9.38 (m, 1H), 7.99-7.96 (m, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.49-7.45 (m, 2H), 7.39 (s, 1H), 7.27 (s, 0.5H), 7.18 (s, 1H), 7.06-7.02 (m, 1.5H), 4.86 (s, 2H), 4.52-4.49 (m, 1H), 4.34-4.30 (m, 1H), 4.17 (s, 1H), 3.96 (s, 3H), 3.88-3.61 (m, 4H), 3.44-3.39 (m, 2H), 3.03 (s, 2H), 2.85 (s, 2H), 2.67-2.61 (m, 3H), 2.33-2.18 (m, 7H), 1.90 (s, 3H), 1.79-1.73 (m, 5H), 1.50-1.24 (m, 7H), 0.81-0.73 (m, 1H). LCMS (ESI) m / z: 980.8 (M+H) + .

[0371] Example 7: Synthesis of P007

[0372] Step 1: Synthesis of P7-3

[0373] The starting material P7-1 (1.3 g, 4.7 mmol,) and P7-2 (1.1 g, 4.7 mmol) were placed in a 50 mL clean three-necked flask, 15 mL of tetrahydrofuran was added, and the temperature was lowered to -5 °C. Sodium hydride (451 mg, 18.8 mmol) was added in batches, and stirred at -5 °C for 2 h. LCMS monitoring showed that the starting material was completely reacted. The reaction solution was quenched with 1 N hydrochloric acid aqueous solution, and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine, and then separated. The organic phase was dried over anhydrous sodium sulfate and concentrated. Column chromatography (petroleum ether / ethyl acetate = 4:1) gave the product P7-3 (1.2 g, 54.5%). + .

[0374] Step 2: Synthesis of P7-4

[0375] The starting material P7-3 (1.2 g, 2.5 mmol) was placed in a 50 mL clean three-necked flask, 12 mL of acetonitrile and 11 mL of 4M hydrochloric acid dioxane were added, and stirred at room temperature for 1 h. LCMS monitoring showed that the starting material was completely reacted. The reaction solution was concentrated to give the product P7-4 (900 mg, 95%). + .

[0376] Step 3: Synthesis of P7-5

[0377] The starting material P7-4 (900 mg, 2.4 mmol, 1 eq), N, N diisopropyl amine (4.2 mL, 24 mmol) were placed in a 50 mL clean three-necked flask, 10 mL of toluene was added, and phosphorus oxychloride (1.1 mL, 12 mmol) was added. The reaction was stirred at room temperature for 1 h. LCMS monitoring showed that the starting material was completely consumed. The reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL x 3), and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 10:1) to give the product P7-5 (380 mg, 44.3%). LCMS (ESI) m / z: 357.0 (M+H) + .

[0378] Step 4: Synthesis of P7-6

[0379] P7-5 (380 mg, 1.1 mmol) was added to 1,4-dioxane (10 mL) and water (2 mL) at room temperature, followed by the addition of potassium phosphate (700 mg, 3.3 mmol), [n-butylbis(1-adamantyl)phosphine]methanesulfonic acid (2-amino-1,1-biphenyl-2-yl)palladium(II) (80 mg, 0.11 mmol), and P1-15 (655 mg, 1.3 mmol). The reaction was carried out at 95 °C under nitrogen protection for 3 h. LCMS detection showed that the starting material was completely consumed and most of it was converted into the desired product. The reaction was diluted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 15:1) to give compound P7-6 (380 mg, 50.4%). LCMS (ESI) m / z: 706.9 (M+H) + .

[0380] Step 5: Synthesis of P7-7

[0381] P7-6 (380 mg, 0.54 mmol) was added to dichloromethane (5 mL) at room temperature, followed by the addition of meta-chloroperoxybenzoic acid (111 mg, 0.65 mmol). LCMS detection showed that the starting material was completely consumed. The reaction was diluted with dichloromethane, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane / methanol = 10:1) to give compound P7-7 (340 mg, 87.4%). LCMS (ESI) m / z: 723.1 (M+H) + .

[0382] Step 6: Synthesis of compound P7-8

[0383] P7-8 (430 mg, 0.428 mmol) was dissolved in methanol (5 mL) at room temperature, ammonium fluoride (476 mg, 12.8 mmol) was added, and the reaction mixture was reacted at 60 °C for 16 hours. The reaction mixture was concentrated by rotary evaporation, washed with ethyl acetate (10 mL), filtered, and concentrated by rotary evaporation to obtain compound P7-9 (280 mg, 85.4%). LCMS (ESI) m / z: 765.5 [M+H] + .

[0384] Step 7: Synthesis of compound P7-9

[0385] P7-8 (430 mg, 0.428 mmol) was dissolved in methanol (5 mL) at room temperature, ammonium fluoride (476 mg, 12.8 mmol) was added, and the reaction mixture was reacted at 60 °C for 16 hours. The reaction mixture was concentrated by rotary evaporation, washed with ethyl acetate (10 mL), filtered, and concentrated by rotary evaporation to obtain compound P7-9 (280 mg, 85.4%). LCMS (ESI) m / z: 765.5 [M+H] + .

[0386] Step 8: Synthesis of compound P7-10

[0387] P7-9 (280 mg, 0.366 mmol) was dissolved in tetrahydrofuran (3 mL) at room temperature, and tetrabutylammonium fluoride (0.73 mL, 0.732 mmol) was added, and the reaction mixture was reacted at room temperature for 10 minutes. Ethyl acetate (5 mL) was added to the reaction mixture, the organic phase was washed with saturated sodium chloride solution, the organic phase was separated, dried, and concentrated to obtain a residue, which was purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound P7-10 (200 mg, 89.7%). LCMS (ESI) m / z: 609.3 [M+H] + .

[0388] Step 9: Synthesis of compound P7-11

[0389] To a solution of P7-10 (200 mg, 0.328 mmol) in dichloromethane (2 mL) was added triethylamine (100 mg, 0.985 mmol), methylsulfonyl chloride (113 mg, 0.985 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 0.5 to 1 h. The reaction mixture was directly purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:2) to give compound P7-11 (150 mg, 66.7%). LCMS (ESI) m / z: 687.3 [M+H] + .

[0390] Step 10: Synthesis of compound P7-12

[0391] P7-11 (75 mg, 0.109 mmol) and P1-10 (98 mg, 0.218 mmol) were dissolved in N,N- dimethylformamide (1 mL) at room temperature, and potassium carbonate (45 mg, 0.327 mmol) was added. The reaction mixture was stirred at 25 °C for 2 h. Ethyl acetate (5 mL) was added to the reaction mixture, and the organic phase was washed with saturated sodium chloride solution. The organic phase was separated, dried, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 9:1) to give compound P7-12 (70 mg, 61.9%). LCMS (ESI) m / z: 1040.3 [M+H] + .

[0392] Step 11: Synthesis of compound P007A

[0393] Trifluoroacetic acid (0.4 mL) was added to P7-12 (70 mg) in dichloromethane (1.2 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS showed most of the product. The product was precipitated by adding 10 mL of ethyl ether. The crude compound obtained after filtration and drying was purified by preparative chromatography to give compound P007A (5.16 mg, 7.7%).

[0394] 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.14 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 9.0, 5.7 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.46 (dd, J = 11.4, 6.6 Hz, 2H), 7.37 (s, 1H), 7.25 (s, 0.5H), 7.20 - 7.12 (m, 1H), 7.04 (s, 0.5H), 7.03 - 7.01 (m, 1H), 5.00 (s, 1H), 4.85 (s, 2H), 4.66 (d, J = 13.0 Hz, 1H), 4.50 (d, J = 12.9 Hz, 1H), 4.32 (dd, J = 9.7, 5.1 Hz, 2H), 4.13 (m, 1H), 3.95 - 3.92 (m, 4H), 3.59 (m, 3H), 3.04 (s, 2H), 2.91 (s, 2H), 2.65 - 2.62 (m, 4H), 2.20 - 2.17 (m, 8H), 1.91 (s, 3H), 1.76 (s, 6H), 1.49 - 1.45 (m, 6H). LCMS (ESI) m / z: 996.8 [M+H] + .

[0395] P007B was synthesized in the same manner as P007A except that A(l) was replaced by A(2).

[0396] P007B: 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.14 (s, 1H), 7.96 (dd, J = 9.1, 6.1 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.47 - 7.45 (m, 2H), 7.37 (s, 1H), 7.20 - 7.12 (m, 1H), 7.04 (s, 1H), 7.02 (s, 0.5H), 6.83 (s, 0.5H), 4.98 (d, J = 18.1 Hz, 3H), 4.66 (d, J = 12.4 Hz, 1H), 4.50 (d, J = 13.5 Hz, 1H), 4.32 (dd, J = 9.6, 5.2 Hz, 2H), 4.13 (m, 1H), 3.93 (m, 4H), 3.55 (m, 3H), 2.89 (s, 4H), 2.64 - 2.62 (m, 4H), 2.19 (m, 8H), 1.89 (s, 3H), 1.74 (m, 6H), 1.47 - 1.44 (m, 6H). LCMS (ESI) m / z: 996.8 [M+H] + .

[0397] Example 8: Synthesis of P008

[0398] Synthetic procedure was same as P007 except P1-15 was changed to P2-1

[0399] P008A: 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.94 (s, 1H), 7.75 (dd, J = 9.0, 6.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.36 - 7.29 (m, 2H), 7.27 (s, 0.5H), 7.05 (d, J = 5.9 Hz, 1H), 7.02 (s, 1H), 6.99 (s, 0.5H), 5.01 (s, 1H), 4.89 (s, 2H), 4.67 (d, J = 9.1 Hz, 1H), 4.53 (dd, J = 13.1, 5.2 Hz, 1H), 4.32 (dd, J = 9.6, 5.2 Hz, 2H), 4.11 (s, 1H), 3.90 (s, 1H), 3.69 - 3.53 (m, 1H), 3.45 (s, 2H), 3.03 (s, 2H), 2.90 (s, 2H), 2.69 - 2.56 (m, 4H), 2.37 - 2.10 (m, 7H), 2.02 (s, 1H), 1.89 (s, 3H), 1.74 (d, J = 8.6 Hz, 6H), 1.45-1.43 (m, 6H), 0.83-0.81 (m, 3H). LCMS (ESI) m / z: 1000.3 [M+H] + .

[0400] P008B: 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.94 (s, 1H), 7.75 (dd, J = 9.1, 6.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.44 (s, 1H), 7.37 - 7.29 (m, 2H), 7.04 (dd, J = 9.8, 5.4 Hz, 2H), 6.98 (s, 0.5H), 6.83 (s, 0.5H), 5.01 (s, 3H), 4.67 (d, J = 10.2 Hz, 1H), 4.53 (dd, J = 12.9, 8.1 Hz, 1H), 4.34 - 4.31 (m, 2H), 4.16 - 4.06 (m, 1H), 3.96 (s, 3H), 3.90 (s, 1H), 3.60 - 3.58 (m, 1H), 3.47 - 3.45 (m, 2H), 2.90 - 2.88 (m 4H), 2.69 - 2.57 (m, 4H), 2.34 - 2.31 (m, 5H), 2.21 - 2.11 (m, 3H), 2.03 (s, 1H), 1.88 (s, 3H), 1.79 (s, 1H), 1.76 (s, 4H), 1.47 (s, 4H), 1.38 (s, 2H), 0.86 - 0.77 (m, 3H). LCMS (ESI) m / z: 1000.3 [M+H] + .

[0401] Example 9: Synthesis of P009

[0402] The synthetic method was the same as P001, except that was replaced by

[0403] P009A: 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.16 (d, J = 20.0 Hz, 1H), 8.25 (s, 1H), 8.04 - 7.91 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.39 (s, 1H), 7.27 (s, 0.5H), 7.18 (d, J = 8.2 Hz, 1H), 7.05 (d, J = 6.2 Hz, 1H), 7.02 (s, 0.5H), 5.13 (d, J = 43.4 Hz, 1H), 4.87 (s, 2H), 4.48 - 4.37 (m, 1H), 4.34 - 4.23 (m, 2H), 4.10 (s, 1H), 3.97 (d, J = 6.2 Hz, 4H), 3.03 (s, 3H), 2.92 (d, J = 7.8 Hz, 3H), 2.63 (m, 6H), 2.33 (m, 3H), 2.18 (m, 3H), 2.00 (m, 3H), 1.90 (m, 3H), 1.77 (m, 5H), 1.49 (s, 4H), 1.41 (s, 2H). LCMS: MS m / z (ESI): 984.9 [M+H] + .

[0404] P009B: 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 10.17 (s, 1H), 9.16 (d, J = 20.8 Hz, 1H), 8.14 (s, 1H), 8.02 - 7.94 (m, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 6.0 Hz, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.04 (s, 1H), 7.02 (s, 0.5H), 6.84 (s, 0.5H), 5.20 - 5.18 (m, 1H), 5.08 - 5.06 (m, 1H), 4.98 (s, 2H), 4.45 - 4.43 (m, 1H), 4.34 - 4.31 (m, 2H), 4.11 (m, 1H), 3.98 (d, J = 5.8 Hz, 4H), 2.90 (s, 6H), 2.61 (m, 6H), 2.33 (s, 3H), 2.18 (m, 3H), 1.99 (m, 6H), 1.81 (m, 5H), 1.68 - 1.60 (m, 1H), 1.49 (m, 3H), 1.43 (m, 2H). LCMS: MS m / z (ESI): 984.9 [M+H] + .

[0405] Example 10: Synthesis of P010

[0406] Synthetic procedure was same as P001 except was replaced by

[0407] P010A: 1 HNMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.19 (s, 1H), 9.12 (s, 1H), 7.98 (dd, J = 9.0, 6.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.49 - 7.44 (m, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.27 (s, 0.5H), 7.18 (d, J = 2.4 Hz, 1H), 7.04-7.03 (m, 1H), 7.02 (s, 0.5H), 4.86 (s, 2H), 4.31 (dd, J = 9.5, 5.0 Hz, 1H), 4.15-4.14 (m, 4H), 4.00 (s, 1H), 3.94 (d, J = 7.4 Hz, 5H), 3.75 (s, 2H), 3.03 (s, 2H), 2.90-2.88 (m, 2H), 2.68 - 2.58 (m, 4H), 2.35-2.10 (m, 8H), 1.88-1.87 (m, 2H), 1.75-1.74 (m 6H), 1.47-1.45 (m, 4H), 1.39 (s, 2H). LCMS (ESI) m / z: 968.8 [M+H] + .

[0408] P010B: 1HNMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 10.15 (s, 1H), 9.11 (s, 1H), 7.98 (dd, J = 9.0, 6.0 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H), 7.02 (s, 0.5H), 6.83 (s, 0.5H), 4.96 (s, 2H), 4.32 (dd, J = 9.7, 5.0 Hz, 1H), 4.14 (d, J = 6.7 Hz, 4H), 4.01 (s, 1H), 3.95 (d, J = 7.4 Hz, 5H), 3.76 (s, 2H), 2.89 (d, J = 9.8 Hz, 4H), 2.68 - 2.58 (m, 4H), 2.33 (s, 2H), 2.27 (s, 2H), 2.15-2.12 (m, 5H), 1.88 (s, 2H), 1.74-1.73 (m, 6H), 1.47 (s, 4H), 1.39 (s, 2H). LCMS (ESI) m / z: 968.8 [M+H] + .

[0409] Example 11: Synthesis of P011

[0410] The synthesis method is the same as P011, except that P1-7 is replaced by P11-5.

[0411] P011A: LCMS (ESI) m / z: 997.4 [M+H] + .

[0412] P011B: LCMS (ESI) m / z: 997.4 [M+H] + .

[0413] Synthesis of P11-5:

[0414] Step 1: Synthesis of P11-2

[0415] Compound P11-1 (2.0 g, 1.0 eq) was added to 20 ml of hydrochloric acid (2N), heated to 55°C, and acrylic acid (0.96 g, 1.5 eq) and TBAB (0.29 g, 0.1 eq) were added and reacted at 100°C overnight. LCMS showed that the raw material disappeared, and the main peak was the product. After cooling to room temperature, the pH was adjusted to about 5 with sodium bicarbonate solution, and precipitation was obtained. After filtration and washing with water, the filter cake was dried to obtain compound P11-2. LCMS: [M+1] = 298.1. + .

[0416] Step 2: Synthesis of P11-3:

[0417] Intermediate P11-2 (2.1 g, 1.0 eq) was dissolved in 21 ml of glacial acetic acid, NaOCN (0.92 g, 2.0 eq) was added at 60 °C overnight, 21 ml of hydrochloric acid (6N) was continuously added, and the reaction was continued at this temperature for 2 h, precipitated, cooled to room temperature, and filtered, and the filter cake was washed with water and dried to give P11-3. LCMS: [M+1] 323.1. + .

[0418] Step 3: Synthesis of P11-4

[0419] P11-3 (1.5 g, 4.6 mmol) was dissolved in 1,4-dioxane (14 mL) and H2O (1.4 mL), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.1 g, 6.9 mmol), K3CO4 (2.9 g, 13.8 mmol), and XPhos Pd G3 (389 mg, 0.46 mmol) were added. The mixture was stirred at 60 °C under nitrogen protection for 3 h. After TLC detection of the end of the reaction, the reaction was diluted with DCM, washed with water and brine, concentrated, and then column chromatography (DCM:MeOH = 20:1) to give P11-4.

[0420] Step 4: Synthesis of P11-5

[0421] P11-4 (1.2 g, 2.8 mmol) was dissolved in CH3OH (26 mL), and palladium on carbon (894 mg, 0.84 mmol) was added. The reaction was stirred at room temperature under hydrogen for 36 h. After LCMS detection of the end of the reaction, the reaction mixture was filtered through a celite pad, washed with a mixture of DCM / CH3OH (1:1), and concentrated, and column chromatography (DCM:MeOH = 20:1) to give P11-5. MS m / z (ESI): 428.1 [M+H] + .

[0422] Example 12: Synthesis of P012

[0423] The synthesis method was the same as Example 11, except that P12-1 was used instead of P11-1. .

[0424] P012A: LCMS (ESI) m / z: 1015.4 [M+H] + .

[0425] P012B: LCMS (ESI) m / z: 1015.4 [M+H] + .

[0426] Example 13: Synthesis of P013

[0427] The same as the synthesis method of P006A, except that P13-4

[0428] P013A: 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 10.15 (s, 1H), 9.40 (d, J = 18.9 Hz, 1H), 7.97 (dd, J = 9.1, 6.0 Hz, 1H), 7.47 (dd, J = 11.5, 9.1 Hz, 2H), 7.39 (d, J = 2.5 Hz, 1H), 7.27 (s, 0.5H), 7.17 (d, J = 2.2 Hz, 1H), 7.06 (s, 0.5H), 6.90 (d, J = 8.3 Hz, 1H), 6.82 (s, 1H), 4.85 (s, 2H), 4.51 (s, 1H), 4.25 (dd, J = 9.0, 5.1 Hz, 1H), 3.90 (s, 1H), 3.88 (s, 3H), 3.77-3.75 (m, 2H), 3.62-3.60 (m, 1H), 3.43 (d, J = 5.6 Hz, 2H), 3.20 (s, 4H), 3.03 (s, 2H), 2.67–2.59 (m, 4H), 2.39 (s, 4H), 2.28 (s, 2H), 2.21 (s, 2H), 1.90 (s, 3H), 1.51 (s, 4H), 1.41 (s, 2H), 1.31–1.23 (m, 1H), 0.82-0.80 (m, 1H). LCMS (ESI) m / z: 981.5 [M+H] + .

[0429] P013B: 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.40 (d, J = 20.0 Hz, 1H), 7.95 (s, 1H), 7.48 (t, J = 8.6 Hz, 2H), 7.37 (s, 1H), 7.17 (s, 1H), 7.04 (s, 0.5H), 6.91-6.89 (m, 1H), 6.83 (s, 0.5H), 6.82 (s, 1H), 4.96 (s, 2H), 4.52 (s, 1H), 4.24 (d, J = 9.0 Hz, 1H), 3.90 (s, 1H), 3.88 (s, 3H), 3.74 (s, 2H), 3.61 (s, 1H), 3.43 (s, 2H), 3.20 (s, 4H), 2.88 (s, 2H), 2.60 (s, 4H), 2.38 (s, 4H), 2.28 (s, 2H), 2.18 (s, 2H), 1.88 (s, 3H), 1.50 (s, 4H), 1.39 (s, 2H), 1.28 (d, J = 6.5 Hz, 1H), 0.82-0.80 (m, 1H). LCMS (ESI) m / z: 981.4 [M+H] + .

[0430] Synthesis of P13-4:

[0431] Step 1: Synthesis of compound P13-1

[0432] To P1-4 (20 g, 39.968 mmol) in 1,4-dioxane (200 mL) was added piperazine (6.9 g, 79.936 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (3.8 g, 7.994 mmol), cesium carbonate (26 g, 79.936 mmol) and tris(dibenzylideneacetone)dipalladium (3.7 g, 3.997 mmol) sequentially at room temperature. The reaction mixture was stirred at 100 °C for 16 hours. LCMS was used to monitor the reaction. The reaction mixture was diluted with ethyl acetate, filtered through celite, added brine, extracted with ethyl acetate, combined organic phase, dried over anhydrous sodium sulfate, filtered and concentrated to give compound P13-1 (11.1 g, 55%) which was purified by column chromatography (dichloromethane:methanol = 10:1). LCMS (ESI) m / z: 506.2 [M+H] + .

[0433] Step 2: Synthesis of compound P13-2

[0434] To a solution of P13-1 (11.1 g, 21.953 mmol) in dimethyl sulfoxide (110 mL) was added 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (7.9 g, 32.930 mmol), sodium triacetoxyborohydride (14 g, 65.859 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 16 hours. LCMS was used to monitor the reaction completeness. Ethyl acetate (200 mL) and brine were added, the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to give compound P13-2 (11 g, 69%) which was purified by column chromatography (dichloromethane:methanol = 10:1). LCMS (ESI) m / z: 729.9 [M+H] + .

[0435] Step 3: Synthesis of compound P13-3

[0436] To a solution of P13-2 (2 g) in ethyl acetate / ethanol (40 mL / 40 mL) was added Pd / C (4 g) at room temperature. The reaction mixture was stirred at 30 °C for 16 hours under hydrogen atmosphere. Celite was added to the reaction mixture and filtered. The filtrate was concentrated and purified by column chromatography (dichloromethane:methanol = 10:1) to give compound P13-3 (0.8 g, 53%). LCMS (ESI) m / z: 551.4 [M+H] + .

[0437] Step 4: Synthesis of compound P13-4

[0438] To a solution of P13-3 (1.2 g) in dichloromethane (28 mL) was added trifluoroacetic acid (6 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated and triturated with anhydrous diethyl ether to give compound P13-4 (900 mg, 82%). 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.39 (s, 1H), 7.58 (d, J = 9.5 Hz, 1H), 6.99 (s, 1H), 4.28 (dd, J = 9.4, 5.0 Hz, 1H), 3.97 (s, 2H), 3.80 (s, 2H), 3.48 (s, 4H), 3.03-3.00 (m, 8H), 2.65-2.63 (m, 2H), 2.34–2.23 (m, 3H), 2.17–1.99 (m, 3H), 1.72 (d, J = 6.8 Hz, 4H). LCMS (ESI) m / z: 451.3 [M+H] + .

[0439] Example 14: Synthesis of P014

[0440] The synthesis method was the same as P002, except that change into

[0441] P014A: 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.99 (s, 1H), 9.23 (s, 1H), 7.77 (dd, J = 9.0, 6.0 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.43 (s, 1H), 7.36 - 7.34 (m, 2H), 7.27 (s, 0.5H), 7.13 - 7.03 (m, 2H), 7.02 (s, 0.5H), 4.90 (s, 2H), 4.56 - 4.37 (m, 2H), 4.36 - 4.34 (m, 1H), 4.32 - 4.30 (m, 2H), 4.13 (s, 1H), 3.96 (s, 3H), 3.92 (s, 1H), 3.85 - 3.83 (m, 1H), 3.52 (s, 2H), 3.03 (s, 2H), 2.98 (d, J = 10.0 Hz, 2H), 2.79 - 2.59 (m, 4H), 2.41 - 2.31 (m, 4H), 2.29 (s, 1H), 2.20 - 2.14 (m, 2H), 2.12 (s, 1H), 1.91 (s, 4H), 1.89 - 1.79 (m, 4H), 1.75 - 1.73 (m, 3H), 1.53 - 1.51 (m, 4H), 1.39 (s, 2H), 0.75 - 0.73 (m, 3H). LCMS (ESI) m / z: 998.9 [M+H] + .

[0442] P014B: 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.23 (s, 1H), 7.77 (dd, J = 9.1, 6.1 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.35 (dd, J = 11.2, 6.0 Hz, 2H), 7.06 (s, 0.5H), 7.05 - 7.01 (m, 2H), 6.83 (s, 0.5H), 5.01 (s, 2H), 4.47 - 4.43 (m, 2H), 4.37 (d, J = 8.6 Hz, 1H), 4.33 - 4.31 (m, 2H), 4.25 (s, 1H), 4.13 (s, 1H), 3.96 (s, 3H), 3.85 - 3.83 (m, 1H), 3.55 (s, 1H), 3.41 (s, 1H), 2.92 (d, J = 8.1 Hz, 2H), 2.87 (s, 2H), 2.68 - 2.59 (m, 4H), 2.38 - 2.35 (m, 4H), 2.24 (s, 1H), 2.17 (s, 2H), 2.13 - 2.10 (m, 1H), 1.86 - 1.85 (m, 4H), 1.78 - 1.77 (m, 4H), 1.73 - 1.72 (m, 3H), 1.47 - 1.44 (m, 4H), 1.35 (s, 2H), 0.76 - 0.74 (m, 3H). LCMS (ESI) m / z: 998.4 [M+H] + .

[0443] Example 15: Synthesis of P015

[0444] Synthetic procedure was same as P014 except was replaced by

[0445] P015A: 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.96 (s, 1H), 9.24 (d, J = 2.8 Hz, 1H), 8.15 (s, 1H), 7.79 - 7.75 (m, 2H), 7.61 (s, 1H), 7.39 - 7.28 (m, 3.5H), 7.08-7.05 (m, 1.5H), 4.91 (s, 2H), 4.59-4.55 (m, 2H), 4.39-4.36 (m, 3H), 3.97-3.82 (m, 2H), 3.05 (s, 4H), 2.82 - 2.74 (m, 2H), 2.63 (s, 1H), 2.43 - 2.29 (m, 5H), 2.19-2.15 (m, 7H), 1.98 - 1.72 (m, 10H), 1.63 (s, 2H), 1.46-1.43 (m, 4H), 0.77 - 0.72 (m, 3H). LCMS (ESI) m / z: 985.8 [M+H] + .

[0446] P015B: 1 H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 9.96 (s, 1H), 9.23 (s, 1H), 7.76 (m, 2H), 7.61 (s, 1H), 7.34 (m, 3H), 7.05 (d, J = 3.0 Hz, 1H), 7.03 (m, 0.5H), 6.83 (s, 0.5H), 5.01 (s, 2H), 4.56-4.53 (m, 1H), 4.38 (m, 3H), 3.92-3.88 (m, 1H), 2.89-2.87 (m, 4H), 2.75 (d, J = 11.8 Hz, 1H), 2.61 (m, 3H), 2.38 (m, 3H), 2.19-2.17 (m, 5H), 2.00 (d, J = 7.9 Hz, 1H), 1.87 (s, 4H), 1.73-1.71 (m, 6H), 1.45 (m, 4H), 1.34 (s, 2H), 1.23 (s, 4H), 0.77-0.75 (m, 3H). LCMS (ESI) m / z: 985.5 [M+H] + .

[0447] Synthesis of P15-5:

[0448] Step 1: Synthesis of compound P15-2

[0449] To a solution of P15-1 (10 g, 35.198 mmol) and acrylamide (2.5 g, 35.198 mmol) in N,N-dimethylformamide (65 mL) was added potassium tert-butoxide (4 g, 35.198 mmol) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. LCMS was used to monitor the reaction. The reaction mixture was diluted with ethyl acetate, and then brine was added. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 20:1) to give compound P15-2 (5 g, 47%).

[0450] Step 2: Synthesis of compound P15-3

[0451] To a solution of P15-2 (4.5 g, 14.881 mmol) in 1,4-dioxane / water (92 mL / 18 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6- dihydropyridine-1(2H)-carboxylate (6.9 g, 22.326 mmol), sodium acetate (3.7 g, 44.543 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (608 mg, 0.744 mmol) sequentially at room temperature. The reaction mixture was stirred at 90 °C for 16 h. LCMS was used to monitor the reaction. The reaction mixture was diluted with ethyl acetate, and then brine was added. The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (ethyl acetate: petroleum ether = 2:1) to give compound P15-3 (5 g, 85%). 1 H NMR (400 MHz, DMSO-d6) d 11.09 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.76 (s, 1H), 7.53 (t, J = 6.1 Hz, 1H), 6.38 (s, 1H), 4.58 (dd, J = 11.8, 4.8 Hz, 1H), 4.05 (s, 2H), 3.57 (t, J = 5.7 Hz, 2H), 2.82-2.73 (m, 1H), 2.63 (d, J = 4.4 Hz, 1H), 2.56 (s, 2H), 2.25-2.16 (m, 1H), 1.99 (t, J = 7.1 Hz, 1H), 1.43 (s, 9H).

[0452] Step 3: Synthesis of compound P15-4

[0453] To a solution of P15-3 (500 mg) in 1,4-dioxane (25 mL) was added Pd / C (300 mg) at room temperature, and the reaction mixture was stirred at room temperature for 5 hours under hydrogen atmosphere. The reaction was monitored by LCMS. The reaction mixture was filtered through celite, concentrated and purified by column chromatography (ethyl acetate: petroleum ether = 2:1) to give compound P15-4 (400 mg, 80%).

[0454] LCMS (ESI) m / z: 358.0 [M-55] + .

[0455] Step 4: Synthesis of compound P15-5

[0456] To a solution of P15-4 (800 mg) in dichloromethane (15 mL) was added trifluoroacetic acid (4 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The reaction mixture was concentrated and slurry in anhydrous ether to give compound P15-5 (606 mg, crude). LCMS (ESI) m / z: 314.0 [M+H] + .

[0457] Biological test

[0458] Experimental Example 1: Cell proliferation inhibition experiment

[0459] Test 1

[0460] 1. Experimental materials

[0461] GP2D (KRAS G12D mutation) cell line, SW620 (KRAS 12V mutation) cell line, LOVO (KRAS G13D mutation) cell line were purchased from Nanjing CoBioer Biotechnology Co., Ltd.; MIAPaCa-2 (KRAS G12C mutation) cell line was purchased from Shanghai Cell Bank; RMPI1640 medium (Cellmax, CGM112.05), DMER medium (Cellmax, CGM101.05), trypsin (Cellmax, CPT101.02), serum (GEMINI, 900-108), CCK8 (Bimake, B34304).

[0462] 2. Cell activity test method

[0463] 1) Select the logarithmic phase cells (cell passage number P13-P20) to prepare cell suspension and count.

[0464] 2) Inoculate into 96-well plates, 3000 cells / well, 100 μl of medium, set 2 duplicate wells.

[0465] 3) After 18h incubation at 37℃, adhere to the wall, according to the experimental requirements to add the test substance (10mM stock solution).

[0466] 4) When the compound is incubated for 72h, add 10μl CCK8. After adding, mix and shake for 2min. Continue to incubate at 37℃ for 3h.

[0467] 5) 450nM measured absorbance. Curve fitting is performed by Prism software (GraphPad7.0) to obtain IC 50 value.

[0468] Table 1.1

[0469] Test 2

[0470] Test 1 is optimized to perform test 2, the optimization is that the cell passage of logarithmic phase cells is changed to P6-P15, and the serum is replaced with Cellmax (item number SA211.02). The test results are shown in Table 1.2.

[0471] Table 1.2

[0472] Conclusion: The compound of the present application has strong inhibitory activity on KRAS mutant (G12D, G12C, G12V, G13D) cell lines.

[0473] Example 2: Anti-tumor activity pharmacodynamics test

[0474] 100μL of 5×10 6 GP2D tumor cells (CoBioer, Nanjing) suspension, 200μL of 5×10 6 MIA Paca-2 (CoBioer, Nanjing) suspension, 200μL of 1×10 7 LOVO (ATCC) suspension or 100μL of 2×10 6 SW620 tumor cells (CoBioer, Nanjing) suspension were subcutaneously inoculated into the right posterior abdomen of nude mice. The health status of the mice was monitored every day, and the tumor size was measured when the tumor grew to a touchable size.

[0475] The tumor volume was calculated according to the following formula:

[0476] V=0.5a×b 2 ,

[0477] wherein a and b represent the length and width of the tumor, respectively (mm).

[0478] tumor size up to about 200 mm 3 The mice were randomly grouped when the tumor size was up to about 200 mm. According to the administration scheme, the mice were intravenously (i.v.) administered with the corresponding dose of the compound at a dosing frequency of once a week, for a total of three weeks (QW*3). The tumor and body weight of the mice were measured twice a week, and the general state of the mice was monitored during the administration period.

[0479] The tumor growth inhibition rate (TGI (%)) was calculated according to the following formula:

[0480] TGI (%) = [1-(T i / T0) / (C i / C0)] x 100%

[0481] wherein:

[0482] T i is the mean tumor volume of the treatment group on the i-th day of administration,

[0483] T0is the mean tumor volume of the treatment group on the 0-th day of administration,

[0484] C i is the mean tumor volume of the solvent control group on the i-th day of administration, and

[0485] C0is the mean tumor volume of the solvent control group on the 0-th day of administration.

[0486] Table 2.1 Anti-tumor effect on human colon cancer GP2D xenograft model

[0487] Table 2.2 Anti-tumor effect on human pancreatic cancer MIA Paca-2 xenograft model

[0488] Table 2.3 Anti-tumor effect on human colon cancer LOVO xenograft model

[0489] Table 2.4 Anti-tumor effect on human colon cancer SW620 xenograft model

[0490] The results show that the compound of the present application has good anti-tumor effect on multiple KRAS mutant tumor models.

[0491] Numerous modifications to the present application will be apparent to those skilled in the art, in light of the foregoing description. Such modifications are intended to fall within the scope of the appended claims. Each of the references cited in the present application, including all patents, patent applications, journal articles, books, and any other publications, are incorporated herein by reference in their entireties.

Claims

1. A compound of formula (I): [B-L] n - KRAS ligand (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the KRAS ligand is a KRAS inhibitor, further a Pan KRAS inhibitor, B is a degradation tag, such as an E3 ligase ligand, L is a linker between B and the KRAS ligand, n is the number of degradation tags attached on the KRAS ligand, selected from 1, 2 or 3.

2. The compound of claim 1, wherein the KRAS ligand is a compound of Formula (KI): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X1is nitrogen or carbon; R a independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -CN, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2- alkynyl, -CONR 1a R 1b , 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R a cycB, optionally taken together with its adjacent substituents, atoms or structural units, to form a ring, cycB, selected from the group consisting of 5-8 membered cycloalkyl, 5-8 membered heterocyclyl, and 9-14 membered fused heterocyclyl, the heteroatoms of said 5-8 membered heterocyclyl and 9-14 membered fused heterocyclyl being from 1 to 4 optional atoms selected from N, O or S; R1is selected from hydrogen, halogen, amino, oxo, hydroxyl, -C 1-8 alkyl, -S-C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1a , -SO2R 1a , -COR 1a , -CO2R 1a , -CONR 1a R 1b , -CH2C(=O)NR 1a R 1b , -C 2-8 alkynyl (NR 1a )2, -C(=NR 1a )NR 1b R 1c , -NR 1a R 1b , -NR 1a COR 1b , -NR 1a CONR 1b R 1c , -NR 1a CO2R 1b , -NR 1a SONR 1b R 1c , -NR 1a SO2NR 1b R 1c , or -NR 1a SO2R 1b , wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with hydrogen, deuterium, oxo, halogen, cyano, hydroxyl, -C 1-8 alkoxy, -C(O)NR 1d R 1e , -NR 1d R 1e , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl; each R 1a , R 1b , and R 1c is independently hydrogen, deuterium, halogen, cyano, amino, hydroxyl, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl is each optionally substituted with at least one substituent R 1d ; or (R 1a and R 1b ), (R 1b and R 1c ), or (R 1c and R 1a ) together with the atom(s) to which they are attached form cycA, which is a 3- to 10-membered ring comprising 0, 1, 2, or 3 heteroatoms independently selected from N, O, or optionally oxidized S as one or more ring members, which ring is optionally substituted with at least one substituent R 1e ; R 1d and R 1e are each independently hydrogen, oxo, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1f , -SO2R 1f , -COR 1f , -CO2R 1f , -CONR 1f R 1g , -C(=NR 1f )NR 1g R 1h , -NR 1f R 1g , -NR 1f COR 1g , -NR 1f CONR 1g R 1h , -NR 1f CO2R 1g , -NR 1f SONR 1g R 1h , -NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with at least one substituent selected from halogen, -C 1-8 alkyl, -OR 1i , -NR 1i R 1j , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl; R 1f R 1g R 1h R 1i and R 1j Each is independently hydrogen, -C 1-3 Alkyl, -C 1-3 Alkoxy, -C 2-8 alkenyl, -C 2-8 Alkynyl, 3-8 membered cycloalkyl, 5-6 membered heterocyclic, aryl or 5-6 membered heteroaryl; R2is selected from R3and R4are each independently hydrogen, halogen, cyano, -OC 1-8 alkyl, C 1-8 alkyl or cycloalkyl, wherein said -C 1-8 alkyl, -OC 1-8 alkyl and cycloalkyl are each optionally substituted with deuterium, halogen, cyano, hydroxyl, amino, -OC 1-8 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, provided that at least one of R3or R4is F, Cl, -NO2, or -CN; m is selected from 0, 1, 2 or 3.

3. The compound of claim 1, wherein the KRAS ligand is a compound of Formula (KII): or a pharmaceutically acceptable salt or stereoisomer, wherein: X1is N or CH; R1' is -NR 1a R 1b , or the formula the ring CyA; R 1a is -C 1-8 alkyl; R 1b Selected from cycloCyB, wherein the CyB is a 3-7 membered cycloalkyl or a 3-7 membered heterocycloalkyl, and wherein the 3-7 membered cycloalkyl or the 3-7 membered heterocycloalkyl is optionally converted by a halogen, hydroxyl, cyano, amino, oxo, or -C group. 1-8 Alkyl, -C 1-8 Halogenated alkyl groups, -OC 1-8 Alkyl, -OC 1-8 Haloalkyl, -C(O)NR 1d R 1e , or -NR 1d R 1e Substitution, and one available ring atom of the 3-7 membered cycloalkyl or 3-7 membered heterocycloalkyl is attached to one available ring atom of a six-membered aromatic ring having X1, such that the formula moieties have the formula the structure of L 1 is selected from O, S, NH, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -CH2-NH-, -O-CH2-, -S-CH2-, and -NH-CH2-; and the ring CyC is optionally substituted with 1-4 R a2 substituents; R a1 and R a2 independently hydrogen, or -C 1-8 alkyl optionally substituted with halogen, hydroxyl, cyano, or amino; the ring CyA is selected from: (1) a 3-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, wherein said 3-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl has 1, 2, or 3 N, and 0, 1, or 2 O or S in the ring, and is optionally fused to 1 ring CyD, which is 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, and said 3-7 membered cycloalkyl, 3-7 membered heterocycloalkyl, phenyl, or 5-6 membered heteroaryl, when present, are each optionally substituted with 1, 2, or 3 substituents independently selected from halogen, hydroxyl, cyano, oxo, -C(O)R 1- 8alkyl, -C 1-8 haloalkyl, -OC 1-8 alkyl, -OC 1-8 haloalkoxy, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e ; (2) a 6-10 membered spiroazacycloalkyl, wherein said 6-10 membered spiro nitrogen heterocycloalkyl has 1, 2 or 3 N and 0, 1 or 2 O or S in the ring and is optionally substituted with 1, 2 or 3 substituents independently selected from halo, hydroxy, cyano, oxo, -C(=O)R 1-8 alkyl, -C(=O)R 1-8 haloalkyl, -C(=O)R 1d , -C(=O)NR 1d R 1e and -NR 1d R 1e ; and (3) It is optionally composed of 1, 2, or 3 independently selected from halogen, hydroxyl, cyano, -C 1-8 Alkyl, -C 1-8 Halogenated alkyl groups, -OC 1-8 Alkyl, -OC 1-8 Halogenated alkoxy groups, -C(O)R 1d -C(O)NR 1d R 1e and -NR 1d R 1e Substituents of the substituents; When R1' is the ring CyA and the ring CyA is selected from the 3-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, then one available ring atom of the ring CyA is optionally annelated with one available ring atom of the six-membered aromatic ring having X1, such that the formula moieties have the formula the structure of L 2 is selected from O, S, NH, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -CH2-NH-, -O-CH2-, -S-CH2-, and -NH-CH2-; and the ring CyE is optionally substituted with 1-4 R a3 substituents; each R is independently selected from -C(O)NR a3 halo, hydroxyl, cyano, or amino; and each R is independently selected from -C(O)NR 1-8 alkyl; R a independently hydrogen, deuterium, halogen, hydroxyl, cyano, amino, -C 1-8 alkyl, -OC 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, -CONR 1a’ R 1b’ , 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl are each optionally substituted with one or more deuterium, halogen, cyano, hydroxyl, C 1-3 alkoxy, C 1-3 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl; R 1a’ and R 1b’ each independently is hydrogen, deuterium, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, wherein the -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl are each optionally substituted with at least one R 1d substituent; R 1d and R 1e each independently is hydrogen, oxo, halogen, -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, 5-6 membered heteroaryl, -CN, -NO2, -OR 1f , -SO2R 1f , -COR 1f , -CO2R 1f , -CONR 1f R 1g , -C(=NR 1f )NR 1g R 1h , -NR 1f R 1g , -NR 1f COR 1g , -NR 1f CONR 1g R 1h , -NR 1f CO2R 1g , -NR 1f SONR 1g R 1h , -NR 1f SO2NR 1g R 1h , or -NR 1f SO2R 1g , wherein said -C 1-8 alkyl, -C 2-8 alkenyl, -C 2-8 alkynyl, 3-8 membered cycloalkyl, 3-10 membered heterocyclyl, aryl, or 5-6 membered heteroaryl is optionally substituted with at least one substituent chosen from halogen, -C 1-8 alkyl, -OR 1i , -NR 1i R 1j , 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl; R 1f , R 1g , R 1h , R 1i , and R 1j are each independently hydrogen, -C 1-3 (C1-C6)alkyl, -C 1-3 (C1-C6)alkoxy, -C 2-8 (C1-C6)alkenyl, -C 2-8 (C1-C6)alkynyl, 3-8 membered cycloalkyl, 5-6 membered heterocyclyl, aryl, or 5-6 membered heteroaryl; R2is selected from R3and R4are each independently hydrogen, halogen, cyano, -OC 1-8 alkyl, C 1-8 alkyl or 3-8 membered cycloalkyl, said -C 1-8 alkyl, -OC 1-8 alkyl and 3-8 membered cycloalkyl are each optionally substituted with deuterium, halogen, cyano, hydroxyl, amino, -OC 1-8 alkyl, 3-6 membered cycloalkyl, 3-8 membered heterocyclyl, aryl, or 5-6 membered heteroaryl, provided that at least one of R3or R4is F, Cl, -NO2, or -CN; and m is selected from 0, 1, 2 or 3.

4. The compound according to claim 2 or 3, wherein at least one of R3or R4is F, preferably one of R3or R4is F; more preferably one of R3or R4is F, and the other is preferably H.

5. The compound according to any one of claims 2-4, wherein X1is CH, preferably N.

6. The compound of any one of claims 3-5, wherein the compound of Formula (KII) has a structure according to Formula (KII-1): wherein: the CyB is preferably a 5, 6 or 7 membered cycloalkyl, or a 5, 6 or 7 membered heterocycloalkyl, more preferably cyclopentyl, cyclohexyl, cycloheptyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, pyrrolidinyl, piperidinyl or azepanyl; and / or L 1 preferably selected from O, S, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -O-CH2-, and -CH2-S-, preferably O, -CH2-O-, and -O-CH2-; and / or R a1 and R a2 are preferably independently hydrogen, or -C 1-3 alkyl, more preferably hydrogen, methyl or ethyl; More preferably, in said (KII-1) the part of preferably 7. The compound according to any one of claims 3-5, wherein in the compound of formula (KII), R1’ is the ring CyA; wherein: said ring CyA is preferably a 4-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, wherein said 4-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl has 1 or 2 N and 0 or 1 O or S in the ring and is optionally fused with 1 ring CyD, said ring CyD being a 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5 or 6 membered heteroaryl, wherein said 4-7 membered nitrogen-containing monocyclic heterocycloalkyl or heterocycloalkenyl, and said 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, phenyl or 5 or 6 membered heteroaryl, when present, are optionally substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, oxo, -C(O)R 1-3 alkyl, -C 1-3 haloalkyl, -C(O)R 1d , -C(O)NR 1d R 1e and -NR 1d R 1e , more preferably optionally substituted with 1 or 2 substituents independently selected from the group consisting of F, Cl, hydroxyl, cyano, amino, oxo, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)CH3, -C(O)NH2, -C(O)NH(C 1- 3alkyl) and -C(O)N(C 1-3 alkyl)2; More preferably, R1' is selected from 8. The compound of any one of claims 3-5 and 7, wherein the compound of Formula (KII) has a structure according to Formula (KII-2): wherein: said ring CyA is preferably a 6- or 7-membered nitrogen-containing monocyclic heterocycloalkyl, wherein said 6- or 7-membered nitrogen-containing monocyclic heterocycloalkyl has 1 or 2 N and 0 or 1 O or S in the ring, wherein said 6- or 7-membered nitrogen-containing monocyclic heterocycloalkyl is optionally substituted with 1, 2 or 3 substituents independently selected from F, CI, hydroxyl, cyano, amino, oxo, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)CH3, -C(O)NH2, -C(O)NH(C 1-3 alkyl), and -C(O)N(C 1-3 alkyl)2; and / or L 2 preferably selected from O, S, -CH2-, -CH2-CH2-, -CH2-O-, -CH2-S-, -O-CH2-, and -CH2-S-, preferably O, -CH2-O-, and -O-CH2-; More preferably, in said (KII-2) the formula the portion of the user's body is preferably and / or Each R a3 Preferably, it is independently selected from -C groups optionally substituted with F, Cl, hydroxyl, cyano or amino groups. 1-3 Alkyl, more preferably methyl or ethyl.

9. The compound according to any one of claims 3-5, wherein in the compound of formula (KII), R1’ is the 6-10 membered spiroazacycloalkyl, wherein: Preferably, the 6-10 membered spiro nitrogen heterocycloalkyl has 1, 2, or 3 N and 0 or 1 O or S in the ring and is optionally substituted with 1, 2, or 3 substituents independently selected from halo, hydroxyl, cyano, oxo, -C(O)R 1-3 alkyl, -C 1-3 haloalkyl, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e , more preferably optionally substituted with 1, 2, or 3 substituents independently selected from F, Cl, hydroxyl, cyano, amino, oxo, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)CH3, -C(O)NH2, -C(O)NH(C 1-3 alkyl), and -C(O)N(C 1-3 alkyl)2; More preferably, R1' is preferably 10. The compound according to any one of claims 3-5, wherein in the compound of formula (KII), R1’ is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, hydroxyl, cyano, -C 1-3 alkyl, -C 1-3 haloalkyl, -OC 1-3 alkyl, -OC 1-3 haloalkoxy, -C(O)R 1d , -C(O)NR 1d R 1e , and -NR 1d R 1e , more preferably optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of F, Cl, hydroxyl, cyano, amino, methyl, ethyl, -CH2F, -CHF2, -CF3, -NH(C 1-3 alkyl), -N(C 1-3 alkyl)2, -C(O)CH3, -C(O)NH2, -C(O)NH(C 1-3 alkyl), and -C(O)N(C 1-3 alkyl)2; Preferably, R1' is 11. The compound according to any one of claims 2-10, wherein: R a independently selected from hydrogen, halogen, hydroxyl, amino, cyano, -C 1-8 alkyl, -OC 1-8 alkyl or 3-8 membered cycloalkyl, preferably hydrogen, halogen, cyano, -OC 1-3 alkyl or 3-8 membered cycloalkyl, more preferably H, F, CI, methoxy and cyclopropyl; and / or m is selected from 0, 1 or 2, preferably 0 or 1; and / or R2is selected from preferably 12. The compound according to any one of claims 1-11, wherein the B is a group that binds an E3 ligase, wherein the E3 ligase is selected from von Hippel-Lindau (VHL), Cereblon (CRBN), XIAP, E3A, MDM2, anaphase-promoting complex (APC), UBR5 (EDD1), SOCS / BC-box / eloBC / CUL5 / RING, LNX p80, CBX4, CBLL1, HACE1, HECTD1, HECTD2, HECTD3, HECW1, HECW2, HERC1, HERC2, HERC3, HERC4, HUWE1, ITCH, NEDD4, NEDD4L, PPIL2, PRPF19, PIAS1, PIAS2, PIAS3, PIAS4, RANBP2, RNF4, RBX1, SMURF1, SMURF2, STUB1, TOPORS, TRIP12, UBE3A, UBE3B, UBE3C, UBE4A, UBE4B, UBOX5, UBR5, WWP1, WWP2, Parkin, A20 / TNFAIP3, AMFR / gp78, ARA54, β-TrCP1 / BTRC, BRCA1, CBL, CHIP / STUB1, E6, E6AP / UBE3A, F-box protein 15 / FBXO15, FBXW7 / Cdc4, GRAIL / RNF128, HOIP / RNF31, cIAP-1 / HIAP-2, cIAP-2 / HIAP-1, cIAP (pan), ITCH / AIP4, KAP1, MARCH8, MindBomb1 / MIB1, MindBomb2 / MIB2, MuRF1 / TRIM63, NDFIP1, NEDD4, NleL, Parkin, RNF2, RNF4, RNF8, RNF168, RNF43, SART1, Skp2, SMURF2, TRAF-1, TRAF-2, TRAF-3, TRAF-4, TRAF-5, TRAF-6, TRIM5, TRIM21, TRIM32, UBR5, or ZNRF3; Preferably, the B is a group that binds an E3 ligase selected from VHL, CRBN, MDM2, or cIAP. Preferably, the B is a group that binds CRBN.

13. The compound according to any one of claims 1-12, wherein the B is selected from: and V1is selected from a single bond, -O-, -CH2-, -CH=CH-, -C(O)-NH-, or -NH-.

14. The compound according to any one of claims 1-13, wherein the B is selected from: Said B is preferably more preferably 15. The compound of any one of claims 1-14, wherein L is (LNK) u and wherein: u is 1, 2, 3, 4, 5, or 6; each LNK is independently absent, or selected from: (1) C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene, wherein said C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene are optionally substituted with 1 or more substituents independently selected from the group consisting of halogen, OH and -OC 1-4 alkyl; -N(C 1- 8alkyl)-, -CON(C 1-8 alkyl)-, -N(C 1-8 alkyl)CO-; preferably C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene, wherein the C 1-8 alkylene, C 2-8 alkenylene and C 2-8 alkynylene are optionally substituted with 1 or more substituents independently selected from the group consisting of F, CI, OH and -OC 1-3 alkyl; N(C 1-8 alkyl)-, -CON(C 1-8 alkyl)-, -N(C 1-8 alkyl)CO-; more preferably C 1-8 alkylene (preferably C 1-3 alkylene, more preferably C 2-8 alkenyl (preferably C) 2-3 (alkenyl), C 2-8 Alynyl group (preferably C) 2-3 (ethynyl), halogenated C 1-8 Alkylene (preferably halogenated C) 1-3 Alkylene, more preferably C 1-3 alkoxy-substituted C 1-8 Alkylene (preferably C) 1-3 alkoxy-substituted C 1-3 Alkylene, more preferably )、 or (2) optionally substituted by one or more halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylhydroxy, cyano, amino, oxo, C 1-4 alkoxy, 4- to 8-membered heteromonocyclic, 4- to 10-membered heteroannular, 5- to 12-membered heterospirocyclic, 7- to 10-membered heterobridged, 3- to 7-membered monocyclic alkyl, 4- to 10-membered annular alkyl, 5- to 12-membered spiroalkyl, 7- to 10-membered bridged alkyl, 5- to 10-membered heteroaryl, or 6- to 10-membered aryl, wherein the plurality of halogen, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkylhydroxy, cyano, amino, oxo, C 1-4 alkoxy can form a 3- to 5-membered carbocyclic or heterocyclic ring, and the heteroaryl, heteromonocyclic, heteroannular, heterospirocyclic, heterobridged contains 1-4 heteroatoms independently selected from O, S, N; wherein the monocyclic alkyl is preferably The heteromonocyclic group is preferably The heterospirocyclyl group is preferably The spirocycloalkyl is preferably The heteroaromatic group is preferably The heterocyclyl ring group is preferably The heteroaryl group is preferably The aryl group is preferably 16. The compound of any one of claims 1-15, wherein the L is (LNK) u and wherein: u is 1, 2, 3, 4, 5, or 6; and each LNK is independently absent, or selected from C 1-8 alkylene (preferably C 1-3 alkylene, more preferably ), C 2-8 alkylene, C 2-8 alkynylene, haloC 1-8 alkylene (preferably haloC 1-3 alkylene, more preferably C 1-3 alkoxy-substituted C 1-3 Alkylene (preferred) )、 17. The compound of any one of claims 1-16, wherein the L or (LNK) u selected from: preferably 18. The compound according to any one of claims 15-17, wherein: The compound of formula (I) is a compound of formula (VI): Preferably, the compound is of formula (VI): or Preferred are compounds of formula (VI-1): More preferred are compounds of formula (VI-1 '): or The compound of formula (I) is a compound represented by formula (VI-2): Preferred are compounds of formula (VI-2'): or or The compound of formula (I) is a compound represented by formula (VI-3): Preferred are compounds of formula (VI-3'):

19. The compound of any one of claims 1-3, wherein the KRAS ligand, or compound of Formula (KI), or compound of Formula (KII) is selected from:

20. The compound of formula (I) according to any one of claims 1 to 3, selected from: preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably preferably are preferably selected from the group consisting of 21. A pharmaceutical composition comprising a compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

22. Use of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for Pan-KRas inhibition or degradation.

23. Use of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 21, for the manufacture of a medicament for the treatment and / or prevention of a disease or disorder mediated by KRas wild-type and / or mutant, wherein the KRas mutant is selected from KRAS G12A, G12C, G12D, G12V, G12R, G12S, G13C and Q61H; and the disease or disorder is preferably selected from lung cancer, breast cancer, multiple myeloma, bladder cancer, endometrial cancer, colorectal cancer, bone cancer, kidney cancer, stomach cancer, liver cancer, large intestine cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, esophageal cancer, melanoma, lymphoma, blood cancer, brain tumor, myeloma, soft tissue sarcoma, pancreatic cancer, skin cancer, colorectal cancer, hepatocellular carcinoma, head and neck tumor, cholangiocellular carcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, schwannoma, lung squamous cell carcinoma, keratosis lichenoides, synovial sarcoma, testicular cancer or liposarcoma, preferably pancreatic cancer, colorectal cancer, endometrial cancer or lung cancer.

24. A method of treating or preventing a Pan-KRas mutant protein related disease, comprising administering to a patient in need thereof an effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 21.