Pan-ras inhibitor compound

Abstract

The present invention relates to a compound as represented by formula (A), a pharmaceutical composition comprising the compound, and a use of the compound of formula (A) for preventing and / or treating RAS-related cancers, tumors, inflammatory diseases, autoimmune diseases or immune-mediated diseases.

Description

A pan-RAS inhibitor compound TECHNICAL FIELD

[0001] The present application relates to a compound, in particular to a highly active pan-RAS inhibitor and its use. BACKGROUND

[0002] RAS is one of the most frequently mutated genes in human tumors, with mutations occurring in about 30% of tumor patients, of which KRAS accounts for about 85% of RAS mutations. Mutations of KRAS exist in 88% of pancreatic cancer, 50% of colorectal adenocarcinoma, and 32% of lung adenocarcinoma, and the development of KRAS targeting inhibitors has great clinical significance and value.

[0003] KRAS is a membrane-bound protein with GTPase activity, which cycles between the GDP-bound inactive conformation and the GTP-bound active conformation through nucleotide exchange, performing the function of a "molecular switch". KRAS in the GTP-bound state can activate multiple signaling pathways including RAF-MEK-ERK, PI3K-AKT, and regulate cell growth, proliferation, differentiation, and apoptosis, and other life processes.

[0004] KRAS mutations (such as G12C, G12D, G12V, G13D, etc.) affect GTPase activating proteins (GAPs) mediated GTP hydrolysis, increase KRAS in the GTP-bound active state, and overactivate downstream signaling pathways, ultimately leading to tumor occurrence and development. However, due to the lack of a corresponding hydrophobic pocket suitable for drug binding in the KRAS protein, and its affinity to GTP and GDP is at the picomolar level (~ 20 pM), it is very difficult to develop inhibitors that compete for KRAS, and in the past few decades, KRAS has been considered an undruggable target.

[0005] In May 2021, AMG510 was approved by FDA for marketing, used for the treatment of locally advanced or metastatic non-small cell lung cancer carrying KRAS G12C G12C mutations, breaking the history of KRAS "undruggable". However, G12C mutations only account for a small part of KRAS mutations, and for KRAS mutations at other sites, there is currently a lack of satisfactory and effective inhibitor compounds, and a large number of clinical needs have not been met, therefore, developing effective pan-RAS inhibitor compounds is a need in the prior art. SUMMARY

[0006] The present application provides a pan-RAS inhibitor. Such structure is different from the existing KRAS G12CInstead of inhibiting the activity of the GTPase domain of RAS, the inhibitors of the present application function by mediating the formation of a ternary complex between a ubiquitous chaperone protein (such as Cyclophilin A) and the RAS protein. The formation of the ternary complex is able to block the binding of RAS to its downstream effectors (such as RAF) through steric hindrance, inhibit the activation of the MAPK, PI3K-AKT signaling pathways, and thus inhibit the occurrence and development of tumors, play a role in the treatment of tumors and other diseases.

[0007] In one aspect, the present application provides a compound having the structure of Formula (A), an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0008] wherein:

[0009] Cya represents or which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl;

[0010] A represents 4- to 6-membered heterocycloalkylene, phenylene, or 5- to 6-membered heteroarylene, each of which is independently substituted with 0, 1, 2, 3, or 4 R x substituents;

[0011] B represents 5- to 6-membered heteroarylene or phenylene, each of which is independently substituted with 0, 1, 2, 3, or 4 R x substituents, wherein B is not or

[0012] X, Y each independently represents hydrogen, C1-C6aminoalkyl, C1-C6hydroxyalkyl, C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12 C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12 C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C x C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C x C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C

[0013] Z represents -OR a, -SR a or -NR a R a ’;

[0014] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’; any methylene of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is optionally replaced by a carbonyl, -NR a -, -O-, or -S-; and optionally, each of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom, said 3-8 membered ring optionally further containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of said C3-C8cycloalkyl or 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl), or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a , -NR a C(O)R a , -OC(O)R a , -OC(O)NR a R a , -NR a C(O)NR a R a , -S(O)R a , -S(O)2R a , -NR a S(O)2R a ’;

[0015] R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), which optionally can be substituted with 0, 1, or 2 substituents selected from the group consisting of -OR a , -SR a , or -NR a R a ’;

[0016] R3, R3’ each independently represents hydrogen, halogen, C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-CN;

[0017] R4represents hydrogen, C1-C6alkyl, -(C0-C6alkylene)-OR a , -(C0-C6alkylene)-SR a , -(C0-C6alkylene)-NR a R a ’, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-12 membered heterocycloalkyl), -(C0-C6alkylene)-phenyl, or -(C0-C6alkylene)-(5-6 membered heteroaryl), any methylene of said C0-C6alkylene, C1-C6alkyl can be replaced by a carbonyl, -NR a -, -O-, or -S-, and optionally, said C0-C6alkylene, C1-C6alkyl can be substituted with 0, 1, 2, 3, or 4 substituents selected from halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring, which optionally can contain 0, 1, 2, or 3 heteroatoms selected from N, O, or S; said C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl each independently can be substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a ’, cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl), or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a ’, -NR a C(O)R a ’, -OC(O)R a ’, -OC(O)NRa R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0018] L1 and L2 each independently represent a single bond or a -(C1-C6)alkylene group, wherein any methylene group on the -(C1-C6)alkylene group can be replaced by a carbonyl group or -NR. a -, -O- or -S-, and optionally, the methylene groups on the -(C1-C6) alkylene groups can each be independently replaced by 0, 1, 2, 3 or 4 C1-C3 alkyl groups, and the two substituents on the same C atom can form a 3-8 membered ring with the C atom;

[0019] E represents C1-C6 alkyl, C3-C 12 Cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 The ring can be aryl or 5-10 heteroaryl, and the ring can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring;

[0020] R5 represents hydrogen, halogen, oxidative oxidation, and =NR independently. a -OR a -SR a -NR a R a ', cyano, -C(O)OR a -C(O)R a -C(O)NR a R a '、-S(O)2R a -S(O)R a -S(O)(NR) a )R a ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; each of the above-mentioned C1-C6 alkyl, C3-C8 cycloalkyl, and 4-8 membered heterocyclic alkyl can be independently selected from 0, 1, 2, 3, or 4 alkyl groups selected from halogen, oxo, -OR a -SR a -NR a R a Substitution with ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-C3-C8 cycloalkyl or -(C0-C3 alkylene)-4-8 heterocyclic alkyl groups;

[0021] wherein m represents 0, 1, 2 or 3;

[0022] R x each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl;

[0023] R a , R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a and R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, which optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S;

[0024] each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

[0025] In one aspect, the present application provides a compound having the structure of Formula (I), an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0026] wherein:

[0027] Cya represents or which optionally can be substituted with 0, 1, 2 or 3 substituents selected from halogen or C1-C3alkyl;

[0028] A represents 4- to 6-membered heterocycloalkylene, phenylene or 5- to 6-membered heteroarylene, each of which independently can be substituted with 0, 1, 2, 3 or 4 R x ;

[0029] B represents a 5- to 6-membered heteroarylene or phenylene, each independently of the other unsubstituted or substituted by 0, 1, 2, 3 or 4 R x , wherein B is not or

[0030] X, Y each independently represent hydrogen, Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12 C8cycloalkyl, 5- to 6-membered heteroaryl or phenyl, each independently of the other unsubstituted or substituted by 0, 1, 2, 3 or 4 R 12 ; optionally, X and Y can form a 3- or 4- to 8-membered ring, which can be unsubstituted or substituted by 0, 1, 2, 3 or 4 R x , which ring can further comprise 0, 1, 2 or 3 heteroatoms selected from N, O, S; x

[0031] Z represents -OR a , -SR a or -NR a R a ;

[0032] R1represents Ci-C6alkyl, Ci-C6haloalkyl, -(Co-C6alkylene)-(C3-C8cycloalkyl), -(Co-C6alkylene)-(4- to 8-membered heterocycloalkyl), -(Ci-C6alkylene)-OR a , -(Ci-C6alkylene)-SR a or -(Ci-C6alkylene)-NR a R a , said Co-C6alkylene, Ci-C6alkylene, Ci-C6alkyl, Ci-C6haloalkyl any methylene group of which can be replaced by a carbonyl group, -NR a ​-, -O-, or -S-, and optionally, each of the C0-C6 alkylene, C1-C6 alkylene, C1-C6 alkyl, and C1-C6 haloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom can form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of the C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl groups can be independently substituted by 0, 1, 2, 3, or 4 substituents selected from halogens, oxoalkyl, -OR-, -O-, -O-, -S-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0033] R2 represents a C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-(4-8 heterocyclic alkyl), which may optionally be substituted with 0, 1, or 2 substituents selected from the following: -OR a -SR a Or -NR a R a ';

[0034] R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0035] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SRa -(C0-C6alkylene)-NR a R a -(C0-C6alkylene)-(C3-C8cycloalkyl) or -(C0-C6alkylene)-(4-12 membered heterocycloalkyl), -(C0-C6alkylene)-phenyl or -(C0-C6alkylene)-(5-6 membered heteroaryl), any methylene of said C0-C6alkylene, C1-C6alkyl can be replaced with a carbonyl, -NR a -O- or -S-, and optionally, said C0-C6alkylene, C1-C6alkyl can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring, which optionally can further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; said C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl each independently can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a -SR a -NR a R a cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl) or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a -C(O)OR a -C(O)NR a R a -NR a C(O)R a -OC(O)R a -OC(O)NR a R a -NR a C(O)NR a R a -S(O)R a -S(O)2R a -NR a S(O)2R a

[0036] L1, L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene of said -(C1-C6)alkylene- can be replaced with a carbonyl, -NR a ​-0-, -S-, -O- or -S-, and optionally, each methylene of said -(C1-C6)alkylene is independently substituted with 0, 1, 2, 3, or 4 C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom;

[0037] Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be monocyclic, spiro, bridged, fused;

[0038] R5each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the above C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl or -(C0-C3alkylene)-4-8 membered heterocycloalkyl;

[0039] wherein m represents 0, 1, 2 or 3;

[0040] R x each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )Ra C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl;

[0041] R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, said 4-8 membered ring optionally can contain 1, 2, or 3 heteroatoms selected from N, O, or S;

[0042] said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene each independently can be substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0043] In some embodiments, the compound of structure of formula (I) has the structure of formula (II):

[0044] wherein:

[0045] Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl;

[0046] B represents 5- to 6-membered heteroarylene optionally substituted with 0, 1, 2, or 3 R x , wherein B is not or

[0047] X, Y each independently represent hydrogen, C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12 8cycloalkyl, 5- to 6-membered heteroaryl, or phenyl, said C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12 8cycloalkyl, 5- to 6-membered heteroaryl, phenyl each independently can be substituted with 0, 1, 2, 3, or 4 R x , optionally, X and Y can form a 3- to 8-membered ring, said ring can be substituted with 0, 1, 2, 3, or 4 R x , said ring can further include 0, 1, 2, or 3 heteroatoms selected from N, O, S;

[0048] Z represents -OR a or -NR a R a ';

[0049] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’;

[0050] L1, L2each independently represents a single bond or -(C1-C6)alkylene-, any methylene in said -(C1-C6)alkylene- being optionally replaced with a carbonyl, -NR a -, -O-, or -S-;

[0051] Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be monocyclic, spiro, bridged, fused;

[0052] R5each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a ’, cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a ’, -S(O)2R a , -S(O)R a , -S(O)(NR a )R a ’, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the aforementioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a ’, cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl;

[0053] wherein m represents 0, 1, 2, or 3;

[0054] R x each independently represents hydrogen, halogen, oxo, -OR a , -SRa , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl;

[0055] R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, said 4-8 membered ring optionally can contain 1, 2, or 3 heteroatoms selected from N, O, or S;

[0056] said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene each independently can be substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0057] In some embodiments, the compound of formula (I) has the structure shown in formula (II), wherein:

[0058] Cya represents or

[0059] B represents or

[0060] X, Y each independently represent hydrogen, C1-C6alkyl, 4 to 8 membered heterocycloalkyl, C3-C6membered cycloalkyl, each of said C1-C6alkyl, 4 to 8 membered heterocycloalkyl, C3-C6membered cycloalkyl independently can be substituted with 0, 1, 2, or 3 R x ; optionally, X and Y can form a 3-8 membered ring, said ring can be substituted with 0, 1, 2, 3, or 4 R x , said ring can further include 0, 1, 2, or 3 heteroatoms selected from N, O, S;

[0061] Z represents -OH or -NHR a ;

[0062] R1represents ethyl or trifluoroethyl;

[0063] L1, L2each independently represent a single bond or -(C1-C6)alkylene-;

[0064] Cy1represents 4-8 membered heterocycloalkyl, said ring can be monocyclic, spirocyclic, bridged cyclic, annelated;

[0065] R5each independently represents C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, each of which is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl, and when R6is C5-C6cycloalkyl or 5-6 membered heterocycloalkyl, the number of substituents is greater than 0

[0066] wherein m represents 0, 1, or 2;

[0067] R x each independently represents hydrogen, halogen, -OH, -NH2, cyano, C1-C3alkyl;

[0068] R a , R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl;

[0069] each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene is independently unsubstituted or substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0070] In one aspect, the present application also provides a pharmaceutical composition comprising a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the present application, and a pharmaceutically acceptable carrier.

[0071] In one aspect, the present application also provides the use of a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the present application, or a pharmaceutical composition according to the present application, in the manufacture of a medicament for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0072] In one aspect, the present application also provides the use of a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the present application, or a pharmaceutical composition according to the present application, in the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0073] In one aspect, the present application provides a method for the prevention and / or treatment of cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease, comprising administering to a mammal in need thereof a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the present application.

[0074] It is specifically noted that, herein, when referring to a "compound" of a structure, stereoisomers, diastereomers, enantiomers, racemic mixtures, and isotopic derivatives thereof are also generally encompassed.

[0075] As is known to those skilled in the art, salts, solvates, hydrates of a compound are alternative forms of the compound, which can be converted into the compound under certain conditions, and therefore, it is specifically noted that, herein, when referring to a compound of a structure, pharmaceutically acceptable salts thereof are also generally encompassed, and further solvates and hydrates thereof are also generally encompassed.

[0076] Similarly, herein, when referring to a compound, prodrugs, metabolites, and nitroso derivatives thereof are also generally encompassed. DETAILED DESCRIPTION

[0077] Definitions

[0078] The terms used in this application, including the specification and claims, are defined as follows, if not otherwise indicated.

[0079] In this application, the term "a" or "an" means "one or more" unless otherwise expressly specified in the context. The term "another" means at least a second or more.

[0080] Although the disclosure supports the definition of "or" as meaning "and / or", the term "or" is used herein to mean "and / or" unless expressly indicated otherwise or the context clearly dictates otherwise.

[0081] The terms "comprising," "including," and "having," are intended to be inclusive and are to be construed as open-ended terms that do not exclude additional components or steps, unless otherwise indicated.

[0082] As used herein, in providing a range, the endpoints are included.

[0083] As used herein, the term "about" is used to mean that a numerical value includes the standard deviation of the error in determining the numerical value. In certain embodiments, the term "about" is a range of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) the stated numerical value, unless otherwise stated or otherwise evident from context (for example, in the case of percentages, the percentage can exceed 100%).

[0084] In the present invention, when a linking group is listed without specifying the direction of attachment, the direction of attachment is arbitrary, e.g. where L is -C(O)NH-, then -C(O)NH- can be attached to the phenyl and cyclohexyl groups in the order read from left to right to form where L is -C(O)NH-, then -C(O)NH- can be attached to the phenyl and cyclohexyl groups in the order read from left to right to form The combination of linking groups and attached groups is only allowed if it results in a stable compound. In some preferred embodiments of the present invention, the order of attachment is read from left to right.

[0085] Unless otherwise defined, the substituents of the present invention are independent of each other and not interdependent, e.g. (by way of illustration and not limitation), in one aspect, for R a (or R a ) in the definition of a different substituent. Specifically, the selection of one meaning for R a (or R a ) in one substituent does not mean that R a (or R a ) has that same meaning in other substituents. More specifically, for example (by way of illustration and not limitation), for NR a R a , when the meaning of R a (or R a ) is selected from hydrogen, it does not mean that R a (or R a ) in -OR a or -C(O)-NR a R a ' must be hydrogen, they can each independently represent other substituents selected from the definition of R a (or R a ). In another aspect, when there is more than one R a (or R a ) in a substituent, the R a (or R a ) are also independent of each other. For example, in the substituent -(CR a R a’ ) m -O-(CR a R a’ ) n -, where m+n is greater than or equal to 2, the m+n R a (or R a ) are each independent and can represent other substituents selected from the definition of R a (or Ra The same or different substituents in the definition of ').

[0086] Unless otherwise defined, the meaning of "substituted by x A substituents or B substituents" as described in this invention is the same as "substituted by x substituents selected from A and B," and when the number of substituents is greater than 1, the x substituents may be the same or different. For example, "R1 may be substituted by 0, 1, or 2 R..." x "Replace" means that R1 can be optionally selected from R1 by 0, 1, or 2. x Substituents are substituted, and when the number of substituents is greater than one, these substituents can be derived from R. x Refers to the same or different substituents. For example, "R1 may be substituted with 0, 1 or 2 H, C1-C3 alkyl or C3-C6 cycloalkyl" means that R1 may optionally be substituted with 0, 1 or 2 substituents selected from H, C1-C3 alkyl or C3-C6 cycloalkyl, and when the number of substituents is greater than 1, these substituents may be the same or different. For example, when the number of substituents is 2, these 2 substituents may be, for example, 2 H, may be, for example, 2 C1-C3 alkyl, may be, for example, one is H and the other is C1-C3 alkyl, may be, for example, one is C1-C3 alkyl and the other is C3-C6 cycloalkyl.

[0087] Unless otherwise defined, the phrase "and the two substituents form a ring" as described in this invention means that two monovalent or polyvalent residues derived from the removal of one or more H atoms from each of the two substituents or any group form one or more covalent bonds, which can be single, double, or triple bonds, thereby forming a cyclic structure together with the same atom attached to them, or together with different atoms attached to them and the atoms between them. This description is a description of the structure, without regard to whether the two substituents can form a ring through a chemical reaction or what kind of chemical reaction is required to form a ring. All stable or chemically feasible cyclic structures formed by the above description are included within the scope of this invention. If further characteristic descriptions are provided (e.g., "forming a 4-12 membered heterocycle", "the ring comprises a monocyclic, bridged, or spirocyclic ring", "the ring may also contain one or two heteroatoms selected from N, O, or S", or "the ring may also be substituted by one or two substituents selected from Rz"), then the above-described cyclic structure may additionally have the features described therein.

[0088] The term "optionally substituted X" (e.g., "optionally substituted alkyl") is intended to mean "X, wherein X is optionally substituted" (e.g., "alkyl, wherein the alkyl is optionally substituted"). It is not intended to mean that the feature "X" (e.g., alkyl) is itself optional. As described herein, certain compounds can contain one or more "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of one or more hydrogen atoms of a specified moiety, e.g., any of the substituents or groups described herein, with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent may, unless otherwise indicated, be either the same or different at every position. For example, in the term "optionally substituted C1-C6alkyl-C5-C6heteroaryl," either the alkyl moiety, the heteroaryl moiety, or both can be optionally substituted. Combinations of substituents and / or variables envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are not substantially altered when subjected to conditions that can comprise production, detection, and in certain embodiments, recovery, purification, and use for one or more of the purposes described herein. In this context, "stable" is intended to mean that the compound does not substantially alter in chemical stability or biological activity. "Optionally substituted" has the same meaning as "arbitrarily substituted" herein. Unless otherwise defined, "optionally substituted" can be substituted with monovalent and / or divalent substituents.For example, a monovalent substituent is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heterocyclyl, halogen, hydroxy, alkoxy, alkanoyl, aryloxy, alkanoyloxy, amino, alkylamino, arylamino, arylalkylamino, disubstituted amino (wherein the two amino substituents are independently selected from the group consisting of alkyl, aryl, or arylalkyl), alkanoylamino, aroylamino, aralkanoylamino, substituted alkanoylamino, substituted aroylamino, substituted aralkanoylamino, thio, alkylthio, arylthio, arylalkylthio, arylthiocarbonyl, arylalkylthiocarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, such as -SO2NH2, substituted sulfonylamino, nitro, cyano, carboxy, carbamoyl, such as -CONH2, substituted carbamoyl, such as -CONHalkyl, -CONHaryl, -CONHarylalkyl, or where the nitrogen has two substituents selected from the group consisting of alkyl, aryl, or arylalkyl, alkoxycarbonyl, aryl, substituted aryl, guanidino, heterocyclyl, such as indolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyrrolidinyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, and substituted heterocyclyl; for example, a divalent substituent can be selected from the group consisting of =0, =S, =NNRr2, =NNHC(O)Rr, =NNHC(O)ORr, =NNHS(O)2Rr, =NRr, =NORr, Xyl (e.g., -(C(Rr2))n-, wherein n is 1, 2, 3, 4, 5, or 6; and each Rr is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, and the like. 2-3 , -(C(Rr2))n- wherein n is 1, 2, 3, 4, 5, or 6; and each Rr is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, and the like. 2-3 , -(C(Rr2))n- wherein n is 1, 2, 3, 4, 5, or 6; and each Rr is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, and the like. 2-3 , -(C(Rr2))n- wherein n is 1, 2, 3, 4, 5, or 6; and each Rr is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, and the like. 2-3 , -(C(Rr2))n- wherein n is 1, 2, 3, 4, 5, or 6; and each Rr is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, and the like. 2-3 , -(C(Rr2))n- wherein n is 1, 2, 3, 4, 5, or 6; and each Rr is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, and the like.

[0089] Unless otherwise defined, the term "single bond" or "bond" or "direct bond" as used herein means that two atoms are connected by a saturated covalent bond. For example, when L represents a single bond, "A-L-B" means that A and B are connected by a saturated covalent bond, i.e., means "A-B"; for another example, when L represents a single bond, "-CH2-L-NH-" means that -CH2- and -NH- are connected by a saturated covalent bond, i.e., means "-CH2-NH-".

[0090] The term "alkyl" or "alkylene" as used herein is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, "Ci-C6alkyl" denotes alkyl groups with one to six carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). The alkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present context, alkyl is an alkyl group having 1 to 12 carbon atoms, preferably an alkyl group having 1 to 10, 1 to 8, 1 to 6, 1 to 4, more preferably 1 to 4 carbon atoms.

[0091] The term "alkylene" as used herein is intended to include both branched and straight chain, saturated aliphatic hydrocarbon groups, including or not including cyclic alkyl groups, having the specified number of carbon atoms, which is a divalent residue derived from removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. For example, "C0-C6alkylene" denotes alkylene groups with zero (i.e., a bond), one, two, three, four, five, or six carbon atoms. Examples of alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (e.g., -(CH2)3-, -(CHCH3)CH2-, -CH(CH2CH3)-, -C(CH3)2-), butylene (e.g., -(CH2)4-, -CH2CH(CH2CH3)-, -CH2CH2CH(CH3)-, etc.). In the present context, alkylene is preferably an alkylene group having 0-6, 0-4, 0-3, 0-2, 1-12, 1-10, 1-8, 1-6, 1-4, 1-3 carbon atoms. In the present context, alkylene is preferably an alkylene group not including cyclic alkyl groups.

[0092] Similarly, "X-ene" or "X-ylene" in the present context is intended to include a divalent residue derived from removal of two hydrogen atoms from the same atom or two different atoms of a parent X. The definition of parent X is as defined in other paragraphs herein. For example, X can be alkyl, cycloalkyl, heterocycloalkyl, phenyl, corresponding to alkylene, cycloalkylene, heterocycloalkylene, phenylene, respectively.

[0093] The term "cycloalkyl" refers to a monocyclic, polycyclic, or branched cyclic alkyl group. For example, C3-C6cycloalkyl denotes cycloalkyl groups with three to six carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available attachment point with one or more substituents selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present context, cycloalkyl is a cycloalkyl group having 3 to 12 carbon atoms, preferably a cycloalkyl group having 3 to 10, 3 to 8, 3 to 6, 4 to 12, 4 to 10, 4 to 8, 4 to 6, 5 to 12, 5 to 10, 5 to 8, 5 to 6 carbon atoms. 12Cyclic alkyl groups, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornel. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of "cycloalkyl". In this invention, cycloalkyl groups are preferably saturated carbocyclic. Polycyclic cycloalkyl groups, such as bicyclic and tricyclic cycloalkyl groups, include bridged rings, spirocyclic, or fused ring cycloalkyl groups. In this invention, cycloalkyl groups are preferably C3-C6. 12 Cycloalkyl, C3-C8 cycloalkyl, C8-C 12 Cycloalkyl, C3-C7 cycloalkyl, C8-C 12 Cycloalkyl, C4-C8 cycloalkyl, C5-C 10 Cycloalkyl, C3-C6 cycloalkyl. For example, in some embodiments, the cycloalkyl group in monocyclic form is C3-C8, C3-C6, or C5-C6. In some embodiments, the cycloalkyl group in bicyclic form is C7-C6. 12 In some embodiments, the cycloalkyl group in spirocyclic form is C5-C6. 12 Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridging bicyclic cycloalkyl groups include, but are not limited to, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, and spiro[4.5]decane. The cycloalkyl group can be unsubstituted or substituted. When substituted, it can be substituted at any usable connection point. The substituent is preferably one or more of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0094] The term “heteroalkyl” refers to an alkyl group as defined herein, wherein one or more carbon atoms in the chain are replaced by heteroatoms selected from O, S and N.

[0095] Similarly, the term "heterocycloalkyl" refers to a cyclic structure in which at least one carbon atom of the cycloalkyl cyclic structure is replaced with a heteroatom selected from N, O, S, and P. Where N atoms can optionally be quaternized, and N and S atoms can optionally be oxidized (i.e., NO, SO, and SO2). It includes monocyclic, bicyclic, and tricyclic ring systems, including spiro, fused, and bridged ring systems. Heterocycloalkyl groups can be unsubstituted or substituted, when substituted, they can be substituted at any available attachment point with one or more substituents preferably selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, oxo, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In the present invention, heterocycloalkyl is preferably 4-12 membered heterocycloalkyl, more preferably 4-8 membered heterocycloalkyl.

[0096] The term "alkenyl" denotes a straight or branched chain hydrocarbon group containing one or more carbon-carbon double bonds and typically having a length of from 2 to 20 carbon atoms. It includes groups having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. For example, "C2-C6alkenyl" is an alkenyl group containing two to six carbon atoms and having 1, 2, or 3 carbon-carbon double bonds. In some examples, the alkenyl group is a C2-C18alkenyl, C2-C16alkenyl, C2-C14alkenyl, C2-C12alkenyl, C2-C10alkenyl, C2-C8alkenyl, C2-C6alkenyl, C2-C4alkenyl, or C2-C3alkenyl. Examples of alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. In the present invention, alkenyl is preferably C2-C6alkenyl. In the present invention, alkenyl preferably contains 1 or 2 double bonds, more preferably 1 double bond.

[0097] The term "alkynyl" denotes a straight or branched chain hydrocarbon group containing one or more carbon-carbon triple bonds and typically having a length of from 2 to 20 carbon atoms. For example, "C2-C6alkynyl" is an alkynyl group containing two to six carbon atoms and having 1, 2, or 3 carbon-carbon triple bonds. In some examples, the alkenyl group is a C2-C18alkynyl, C2-C16alkynyl, C2-C14alkynyl, C2-C12alkynyl, C2-C10alkynyl, C2-C8alkynyl, C2-C6alkynyl, C2-C4alkynyl, or C2-C3alkynyl. Representative alkynyl groups include, but are not limited to, for example, ethynyl, prop-1-ynyl (-C≡C-CH2), prop-2-ynyl (propargyl, -CH2-C≡CH), but-1-ynyl, but-2-ynyl, and but-3-ynyl, and the like. In the present invention, alkynyl is preferably C2-C6alkynyl.

[0098] The term "cycloalkenyl" refers to a non-aromatic hydrocarbon ring group having at least one carbon-carbon double bond. Cycloalkenyl encompasses monocyclic, bicyclic, tricyclic, fused, spiro, or bridged ring ring systems. For example, C3-C8cycloalkenyl, including but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and norbornenyl. Examples of monocyclic cycloalkenyl include monocyclic cycloalkenyl include 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohexen-3-enyl, and cyclohexadienyl. Exemplary arrangements of bicyclic cycloalkenyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkenyl groups include, but are not limited to, bicyclo[2.2.1]heptene, bicyclo[2.2.2]octene, and bicyclo[3.2.2]nonene. Examples of spirocycloalkenyl groups include spiro[2.2]pentene, spiro[2.3]hexene, spiro[2.4]heptene, spiro[2.5]octene, and spiro[4.5]decene. Branched cycloalkenyl groups such as 1-methylcyclopropenyl and 2-methylcyclopropenyl are also included in the definition of "cycloalkenyl". In some embodiments of the application, cycloalkenyl is C3-C5cycloalkenyl, C3-C6cycloalkenyl, C3-C7cycloalkenyl, C3-C8cycloalkenyl, C3-C9cycloalkenyl, C3-C10cycloalkenyl, C3-C11cycloalkenyl, C3-C12cycloalkenyl.

[0099] Similarly, "cycloalkynyl" refers to a non-aromatic hydrocarbon ring group having at least one carbon-carbon triple bond. Cycloalkynyl encompasses monocyclic, bicyclic, tricyclic, fused, spiro, or bridged ring ring systems. In some embodiments of the application, cycloalkynyl is C3-C5cycloalkynyl, C3-C6cycloalkynyl, C3-C7cycloalkynyl, C3-C8cycloalkynyl, C3-C9cycloalkynyl, C3-C10cycloalkynyl, C3-C11cycloalkynyl, C3-C12cycloalkynyl.

[0100] Similarly, the term "heterocycloalkenyl" refers to a non-aromatic heterocyclic ring group having at least one double bond. Heterocycloalkenyl encompasses monocyclic, bicyclic, tricyclic, fused, spiro, or bridged ring ring systems. Wherein each of the double bonds independently can be a carbon-carbon double bond, a carbon-nitrogen double bond, or a nitrogen-nitrogen double bond.

[0101] Similarly, the term "heterocycloalkynyl" refers to a non-aromatic heterocyclic ring group having at least one carbon-carbon triple bond. Heterocycloalkynyl encompasses monocyclic, bicyclic, tricyclic, fused, spiro, or bridged ring ring systems.

[0102] The term "aryl" or "aromatic ring" refers to a carbocyclic aromatic group having the specified number of carbon atoms. If no number of carbon atoms is specified, then up to 14 carbon atoms are present. The aryl group can be unsubstituted or substituted, and when substituted, it can be substituted at any available point of attachment with one or more substituents preferably selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In certain embodiments of the application, aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, 2-naphthyl, and the like.

[0103] The term "heteroaryl" refers to a monocyclic or a fused polycyclic aromatic heterocycle having at least one ring atom selected from oxygen, nitrogen, and sulfur. Suitable heteroaryl groups do not include ring systems that must be charged to be aromatic, such as pyrylium. The heteroaryl group can be a stable 5-, 6-, or 7-membered aromatic monocyclic or aromatic bicyclic or 7-, 8-, 9-, 10-, 11-, 12-membered aromatic polycyclic heterocycle. Suitable 5-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have one oxygen, sulfur, or nitrogen ring atom, or one nitrogen plus one oxygen or sulfur, or 2, 3, or 4 nitrogen ring atoms. Suitable 6-membered heteroaryl rings (as a monocyclic heteroaryl or as part of a polycyclic heteroaryl) have 1, 2, or 3 nitrogen ring atoms. Nitrogen in the heterocycle can optionally be quaternized. Preferably, when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heterocycle is not more than 1. The heteroaryl group can be unsubstituted or substituted, and the heterocyclyl groups described herein can be substituted at any available point of attachment with one or more of the substituents described herein, preferably selected from hydrogen, deuterium, halogen, hydroxyl, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, if the resulting compound is stable. Examples of heteroaryl groups include, but are not limited to, pyridyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridyl. The term "heteroaryl" can also include biaryl structures formed from "aryl" as defined above with monocyclic "heteroaryl", such as, but not limited to, "-phenylbipyridyl-", "-phenylbipyrimidinyl-", "-pyridylbiphenyl-", "-pyridylbipyrimidinyl-", "-pyrimidylbiphenyl-"; wherein the present application also includes fused and spiro compounds containing, for example, the above rings.

[0104] The term "heterocycle" or "heterocyclyl" means any monocyclic, bicyclic, polycyclic, annelated, spirocyclic, or bridged cyclic, fully saturated, partially unsaturated, or fully unsaturated non-aromatic ring system having, for example, 3 to 20 ring atoms, wherein the ring atoms are carbon, and wherein at least one carbon atom is replaced with a heteroatom selected from nitrogen, sulfur, or oxygen. A ring system is heterocyclic if any ring atom of the ring system is a heteroatom, regardless of the point of attachment of the ring system to the rest of the molecule. In one example, a heterocyclyl group includes 3-11 ring atoms ("members"), and includes monocyclic, bicyclic, tricyclic, spirocyclic, and bridged cyclic ring systems, wherein the ring atoms are carbon, wherein at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclyl group includes 4-10 or 5-10 ring atoms. In one example, a heterocyclyl group includes 1 to 4 heteroatoms. In one example, a heterocyclyl group includes 1 to 3 heteroatoms. In another example, a heterocyclyl group includes a 3- to 7-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl group includes a 4- to 6-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclyl group includes a 3-membered monocyclic ring. In another example, a heterocyclyl group includes a 4-membered monocyclic ring. In another example, a heterocyclyl group includes a 5- to 6-membered monocyclic ring. In some embodiments, a heterocyclylalkyl group includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom can optionally be oxidized (e.g., NO, SO, S02), and any nitrogen heteroatom can optionally be quaternized (e.g., [NR4] + Cl - , [NR4] + OH -oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, triazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxo- isothiazolidinyl, oxazolidinyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiazinyl, oxazinyl, thiazetinyl, oxazetinyl, thiazolidinyl, oxazolidinyl, imidazolidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolinyl, indolinyl, thiopyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithiinyl, dithiolanyl, pyrimidinone, pyrimidinedione, pyrimidine-2,4-dicarboxyl, piperazinonyl, piperazinedionyl, pyrazolidinylimine, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]dec-2-yl, azaspiro[5.5]undecane, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindolyl, 1,1-dioxotetrahydrothiopyranyl.

[0105] Similarly, the terms "carbocyclic" or "carbocyclyl" or "cycloalkyl" mean any monocyclic, bicyclic, polycyclic, annulated, spiro, or bridged, fully saturated, partially unsaturated, or fully unsaturated nonaromatic ring system having, for example, 3 to 20 ring atoms, wherein the ring atoms are carbon.

[0106] In particular embodiments, a heterocyclyl group or a heteroaryl group is attached at a carbon atom of the heterocyclyl group or the heteroaryl group. By way of example, carbon-bonded heterocyclyl groups include the following bonding arrangements: at the 2, 3, 4, 5, or 6 position of a pyridine ring, at the 3, 4, 5, or 6 position of a pyridazine ring, at the 2, 4, 5, or 6 position of a pyrimidine ring, at the 2, 3, 5, or 6 position of a pyrazine ring, at the 2, 3, 4, or 5 position of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, at the 2, 4, or 5 position of an oxazole, imidazole, or thiazole ring, at the 3, 4, or 5 position of an isoxazole, pyrazole, or isothiazole ring, at the 2 or 3 position of an aziridine ring, at the 2, 3, or 4 position of an azetidine ring, at the 2, 3, 4, 5, 6, 7, or 8 position of a quinoline ring, or at the 1, 3, 4, 5, 6, 7, or 8 position of an isoquinoline ring.

[0107] In certain embodiments, the heterocyclyl group or the heteroaryl group is N- bonded. By way of example, nitrogen-bonded heterocyclyl or heteroaryl groups include the following bonding arrangements: at the 1 position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, at the 2 position of isoindole or isoindoline, at the 4 position of morpholine, and at the 9 position of carbazole or β-carboline.

[0108] In the present application, the term "annulated" or "fused" refers to a polycyclic group formed by two or more cyclic structures sharing two adjacent atoms with each other.

[0109] In the present application, the term "bridged" refers to a polycyclic group in which two rings in the system share more than two ring atoms.

[0110] In the present application, the term "spiro" refers to a polycyclic group in which a single ring shares one carbon atom (called a spiro atom) with another ring.

[0111] The term "alkoxy" or "alkyloxy" means -O-alkyl. For example "Ci-C6alkoxy" (or alkyloxy) is intended to include Ci, C2, C3, C4, C5, C6alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propyloxy (e.g., n- propyloxy and isopropyloxy), and t-butyloxy. In the present context, alkoxy is preferably alkoxy having 1 to 6, more preferably having 1 to 4 carbon atoms. Similarly, "alkylthio" or "thioalkoxy" denotes an alkyl group as defined above attached through a sulfur bridge with the indicated number of carbon atoms; for example -S-methyl and -S-ethyl. The alkoxy group can be unsubstituted or substituted, when substituted it can be substituted at any available attachment point with one or more substituents preferably selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, amino, cyano, alkyl, alkoxy, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

[0112] In the present application "halo" or "halogen" includes fluorine, chlorine, bromine and iodine. "Haloalkyl" / "haloalkylene" is intended to include branched and straight-chain saturated alkyl / alkylene groups having the indicated number of carbon atoms and substituted with one or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl and heptachloropropyl. Similarly, "halocycloalkyl" / "haloheterocycloalkyl" is intended to include cycloalkyl / heterocycloalkyl groups having the indicated number of carbon atoms and substituted with one or more halogens. In the present application the halogen atoms are preferably fluorine or chlorine, more preferably fluorine. In the present context, unless specifically indicated that a certain alkyl, cycloalkyl, heterocycloalkyl or alkylene group cannot be substituted with halogen, or it can be deduced from the context that the group cannot be halogenated, or it is not suitable to be halogenated according to the common general knowledge in the art, it is considered that these groups can be halogenated, for example, can be substituted with 1, 2, 3 or 4 halogens; for example, can be substituted with 1, 2 or 3 halogens; for example, can be substituted with 1 or 2 halogens; for example, can be substituted with 1 halogen; in other preferred embodiments of the application these groups are not halogenated.

[0113] "Haloalkoxy" or "haloalkyloxy" denotes an haloalkyl group as defined above attached through an oxygen bridge with the indicated number of carbon atoms. For example, "haloCi-C6alkoxy" is intended to include Ci, C2, C3, C4, C5, C6haloalkoxy. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy and pentafluoroethoxy. Similarly, "haloalkylthio" or "thiohaloalkoxy" denotes an haloalkyl group as defined above attached through a sulfur bridge with the indicated number of carbon atoms; for example trifluoromethyl-S- and pentafluoroethyl-S-.

[0114] In the present text, "oxo" denotes that two hydrogens or bondable electrons on at least one atom of the indicated group are replaced by =0. The oxo can occur on a carbon atom and / or a heteroatom. For example, an oxo on a C atom can oxidize -CH2- to -C(=0)-; an oxo on a S atom can oxidize -S- to -S(=0)- or -S(=0)2-. There can be 0, 1, 2, 3, 4 or even more atoms of the indicated group that are replaced by oxo.

[0115] In the present text, a line drawn from a ring system indicates that a bond can be attached to any suitable ring atom. If the ring is a bicyclic fused ring system, the substituent can be attached to any position on either ring of the bicyclic system.

[0116] In the present text, a wavy line intersecting a bond in a chemical structure indicates the point of attachment of the atom or group connected by the wavy bond in the chemical structure to the remainder of the molecule or the remainder of a molecular fragment. When a chemical structure contains two wavy lines intersecting a bond, the structure can be attached to the remainder of the molecule or the remainder of a molecular fragment in either orientation.

[0117] As used herein, in the context of describing adjacent atoms, the term "adjacent" refers to two atoms that are directly connected by a covalent bond.

[0118] In certain embodiments, generally described divalent groups do not have a particular bonding configuration. It will be understood that, unless otherwise specified, the general description is intended to include both bonding configurations. For example, in the group R1-R2-R3, if group R2 is described as -CH2C(O)-, it will be understood that the group can be bonded as R1-CH2C(O)-R3 and R1-C(O)CH2-R3, unless otherwise specified.

[0119] The term "substituted" as used herein means that at least one hydrogen atom is replaced by a non-hydrogen group, provided that normal valency is maintained and that the substitution results in a stable compound. Ring double bonds as used herein are double bonds formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N).

[0120] In the present disclosure, the term "C x1 -C x2The expression indicates that the number of carbon atoms in the substituent group can be x1 to x2. For example, C0-C8 indicates that the group contains 0, 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C1-C8 indicates that the group contains 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C2-C8 indicates that the group contains 2, 3, 4, 5, 6, 7, or 8 carbon atoms; C3-C8 indicates that the group contains 3, 4, 5, 6, 7, or 8 carbon atoms; C4-C8 indicates that the group contains 4, 5, 6, 7, or 8 carbon atoms; C0-C6 indicates that the group contains 0, 1, 2, 3, 4, 5, or 6 carbon atoms; C1-C6 indicates that the group contains 1, 2, 3, 4, 5, or 6 carbon atoms; C2-C6 indicates that the group contains 2, 3, 4, 5, or 6 carbon atoms; and C3-C6 indicates that the group contains 3, 4, 5, or 6 carbon atoms.

[0121] In this disclosure, when referring to cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, and heterocycloalkyl), the expression "x1-x2 membered ring" is used, indicating that the number of ring atoms in the group can be x1 to x2. For example, the 3-12 membered cyclic group can be a 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; a 3-6 membered ring indicates that the cyclic group can be a 3, 4, 5, or 6 membered ring, and its number of ring atoms can be 3, 4, 5, or 6; a 3-8 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, or 8; a 3-9 membered ring indicates that the cyclic group can be a 3, 4, 5, 6, 7, 8, or 9 membered ring, and its number of ring atoms can be 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; 8 or 9; 4-7 membered ring indicates that the cyclic group can be a 4, 5, 6, or 7 membered ring, and its number of ring atoms can be 4, 5, 6, or 7; 5-8 membered ring indicates that the cyclic group can be a 5, 6, 7, or 8 membered ring, and its number of ring atoms can be 5, 6, 7, or 8; 5-12 membered ring indicates that the cyclic group can be a 5, 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 5, 6, 7, 8, 9, 10, 11, or 12; 6-12 membered ring indicates that the cyclic group can be a 6, 7, 8, 9, 10, 11, or 12 membered ring, and its number of ring atoms can be 6, 7, 8, 9, 10, 11, or 12. The ring atoms can be carbon atoms or heteroatoms, for example, heteroatoms selected from N, O, and S. When the ring is a heterocycle, the heterocycle may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cyclic heteroatoms, for example heteroatoms selected from N, O and S.

[0122] In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present application, these nitrogen atoms can be converted to N-oxides by treatment with an oxidizing agent (e.g., m-chloroperoxybenzoic acid and / or hydrogen peroxide) to obtain other compounds of the present application. Thus, a nitrogen atom shown and claimed is considered to cover both the shown nitrogen and its N-oxide to obtain derivatives of the present application.

[0123] When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R's, said group can optionally be substituted with up to three R groups, and at each occurrence R is independently selected from the definition of R. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0124] The terms "compound(s) of the invention" and "compound(s) of the present invention" and the like include the compounds of the general formulae and the compounds listed in the specific list, including stereoisomers, tautomers, solvates, precursors, metabolites, isotopic derivatives, and salts (e.g., pharmaceutically acceptable salts) thereof, unless otherwise stated.

[0125] The "stereoisomerism" described in this invention is divided into conformational isomerism and configurational isomerism. Configurational isomerism can be further divided into cis-trans isomerism (i.e., geometric isomerism) and optical isomerism (also called enantiomerism). Conformational isomerism refers to the phenomenon where organic molecules with a certain configuration exhibit different spatial arrangements of atoms or atomic groups due to the rotation or twisting of carbon atoms or carbon single bonds. Common examples include the structures of alkanes and cycloalkanes, such as the chair and boat conformations in cyclohexane. Cis-trans isomers are isomers caused by the presence of C=C double bonds, C=N double bonds, or ring systems, which make rotation difficult, and are usually represented by Z and E. Optical isomers, also called enantiomers, refer to two stereoisomers of a compound that are non-overlapping mirror images of each other. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l, or (+) and (-), are used to indicate the rotational sign of a compound with respect to plane-polarized light, where (-) or 1 indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Mixtures of enantiomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomer species. The compounds of the present invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist in the form of diastereomers, enantiomers, or mixtures thereof.

[0126] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that interconvert through low-barrier transformations. For example, proton tautomers (also known as proton-transformed tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions that occur through the recombination of some bonded electrons. The compounds described in this invention can exist in tautomer forms, having different hydrogen bonding sites through one or more double bond shifts.

[0127] The term "chirality" refers to a molecule that does not overlap with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0128] The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical procedures (such as electrophoresis) and chromatographic methods (such as HPLC).

[0129] The stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

[0130] All enantiomers, diastereomers, racemates, meso forms, cis forms, trans forms, atropisomers, tautomers, and mixtures thereof, of all compounds are included within the scope of the application. All methods used in the preparation of the compounds of the application and intermediates made therein are considered to be part of the application. In preparing enantiomeric or diastereomeric products, they can be separated by conventional methods, e.g., by chromatography or fractional crystallization. The free forms and salts of these end products are within the scope of the application. If desired, one form of a compound can be converted into another form. A free base or acid can be converted into a salt; a salt can be converted into the free compound or another salt; a mixture of isomeric compounds of the application can be separated into the individual isomers. The compounds of the application, free forms and salts, can exist in a variety of tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecule and the chemical bonds between the atoms of the molecule are rearranged accordingly. It is understood that all tautomeric forms, which can exist, are included within the application.

[0131] In the structures shown herein, where stereochemistry of any particular chiral atom is not specified, all stereoisomers are considered to be within the scope of the application and are included. When stereochemistry is specified by a solid wedge or dashed line indicating a particular configuration, then that stereoisomer is specified and defined. If a solid wedge or dashed line is used, then the opposite stereochemistry is intended unless otherwise specified.

[0132] In the present application, the term "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt" means, within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. The salts can be prepared in situ during the final isolation and purification of the compounds of the application, or separately by reacting the free base or free acid with a suitable reagent, as outlined below. For example, the free base functionality can be reacted with the appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids, for example, acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods known in the art such as ion exchange. Examples of pharmaceutically acceptable inorganic acid addition salts include salts of hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids, for example, acetic, oxalic, maleic, tartaric, citric, succinic or malonic acids, or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0133] Pharmaceutically acceptable salts of the present application can be prepared by conventional methods, for example by dissolving the compound of the present application in an organic solvent which is miscible with water, such as acetone, methanol, ethanol and acetonitrile, adding thereto an excess of aqueous solution of an organic or inorganic acid, so that the salt precipitates from the resulting mixture, removing the solvent and the remaining free acid, and isolating the precipitated salt.

[0134] The precursors or metabolites of the present application can be precursors or metabolites known in the art, so long as the precursors or metabolites are converted by in vivo metabolism to form the compounds. For example, "prodrugs" refers to those precursors of the compounds of the present application which, upon administration, are metabolized in the body to form the compounds of the above formula, within the scope of sound medical judgment, that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compounds of the above formula, such as by hydrolysis in the body, or N-demethylation of the compounds of the present application.

[0135] The term "solvate" of the present application means a physical association between one or more solvent molecules (whether organic or inorganic) and a compound of the present application. This physical association can include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in solvates can be present in a stoichiometric or non-stoichiometric amount. "Solvate" encompasses both solution-phase and isolatable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are well known in the art.

[0136] An "isotopic derivative" of the present application refers to a molecule in which a compound herein is isotopically labeled. Isotopes that are typically employed as isotopic labels include: 2 H and 3 H; carbon isotopes: 11 C, 13 C and 14 C; chlorine isotopes: 35 Cl and 37 Cl; fluorine isotopes: 18 F; iodine isotopes: 123 I and 125 I; nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotopically labeled compounds are useful in metabolic studies relating to distribution, metabolism, and excretion of the parent compound. The presence of such isotopic moieties allows for 3 H and carbon 13 C are preferred for their ease of preparation and detectability. Certain heavy isotopes, such as heavy hydrogen (deuterium), 2Substitution with heavier isotopes such as deuterium can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements, and / or attainment of or

[0137] The terms "patient," "subject," or "host" as used herein refer to the subject upon whom treatment is performed by the methods of the application. Such subjects preferably include, but are not limited to, mammals (e.g., murines, simians, monkeys, horses, cows, pigs, canines, felines, etc.) and most preferably refer to humans.

[0138] The term "effective amount" as used herein means that amount of a drug or pharmaceutical agent (i.e., a compound of the present application), which will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means that amount which results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, as compared to that which would occur in the absence of the administration of the above. An effective amount can be given in one or more administrations, applications, or dosages and is not intended to be limited to a particular formulation or route of administration. The term also includes within its scope amounts effective to enhance normal physiological function.

[0139] The terms "treatment," "treatment regime," or "therapy" as used herein include alleviating, inhibiting or ameliorating a disease symptom or condition; inhibiting the onset of complications; ameliorating or preventing a latent metabolic syndrome; inhibiting the onset of a disease or symptom, such as controlling the development of a disease or condition; reducing a disease or symptom; causing regression of a disease or symptom; reducing complications resulting from a disease or symptom, or prophylaxis and / or treatment of an indication resulting from a disease or symptom.

[0140] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, and / or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0141] The term "pharmaceutically acceptable," as used herein, means that a prescription component or active ingredient has no excessively deleterious effect on the health of the general treatment target, does not produce adverse, allergic, or other untoward reactions.

[0142] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable carrier" refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending

[0143] The term "pharmaceutical composition" means a composition comprising a compound of the present application in combination with at least one other pharmaceutically acceptable carrier.

[0144] The term "co-administration" or its grammatical equivalents, as used herein, means that two or more selected therapeutic agents are administered to a patient such that both agents and / or their metabolites are present in the animal's body at the same time. Co-administration includes administration in the same composition, administration at different times such that both agents will be present at the same time in the body, or administration in separate compositions at the same time.

[0145] The term "enhance" or "enhancing", as used herein, means that the intended result can be increased or prolonged in either potency or duration. Thus, in the context of enhancing the therapeutic effect of a drug, the term "enhancing" means the ability of a drug to increase or prolong potency or duration in the system. "Enhancing value", as used herein, means the ability to maximize the enhancement of another therapeutic agent in an ideal system.

[0146] The term "inhibit" or "reducing", or any variation of these terms, includes any measurable decrease or complete inhibition to achieve an intended result. For example, there can be a decrease of about, at most about, or at least about, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein, in activity as compared to a normal.

[0147] The term "wild type" refers to an entity having the structure or activity which is found in nature in the "normal" (as opposed to mutated, diseased, altered, etc.) state or condition. It will be understood by those skilled in the art that wild type genes and polypeptides often exist in a variety of different forms (e.g., alleles).

[0148] The terms "antagonist" and "inhibitor" are used interchangeably and refer to a compound that inhibits the biological function of a target protein by inhibiting the activity or expression of the protein (e.g., K-Ras, H-Ras, or N-Ras G12C). Thus, the terms "antagonist" and "inhibitor" are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit the biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition. The preferred biological activity inhibited by the antagonist is associated with the occurrence, growth, or spread of a tumor.

[0149] The term "agonist" as used herein refers to a compound that initiates or enhances the biological function of a target protein by inhibiting the activity or expression of the target protein. Thus, the term "agonist" is defined in the context of the biological role of the target polypeptide. While preferred agonists herein specifically interact with (e.g., bind to) the target, compounds that initiate or enhance the biological activity of the target polypeptide by interacting with other members of the signal transduction pathway of which the target polypeptide is a member are also specifically included within this definition.

[0150] The term "immune disease" refers to a disease or condition resulting from an adverse or deleterious reaction to an endogenous or exogenous antigen. The result is usually a dysfunction of cells, or destruction and dysfunction of organs or tissues from which the immune condition can arise.

[0151] The terms "cancer" and "cancerous," "neoplasm" and "tumor," and related terms, describe the physiological condition in mammals that is typically a proliferation of abnormally growing cells that exhibit uncontrolled growth and, under some conditions, are able to metastasize (spread). A "tumor" comprises one or more cancerous cells, including, for example, solid tumors and blood tumors. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia and myeloid or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer) and lung cancers including small-cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous carcinoma of the lung. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophagus, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreas, cervix, ovary, liver, bladder, hepatocellular carcinoma, breast, colon, rectum, colorectal, genito-urinary tract, biliary tract, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anus, penis, bone, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin's Disease, and related metastases. Examples of neoplastic disorders include myeloproliferative disorders, such as polycythemia vera, essential thrombocytosis, myelofibrosis, such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

[0152] The term "therapeutic effect" as used herein encompasses therapeutic benefits and / or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0153] A "chemotherapeutic agent" is an agent that is useful in the treatment of a given disorder (e.g., a cancer or an inflammatory disorder). Examples of chemotherapeutic agents are well known in the art and include, for example, those disclosed in U.S. Publ. Appl. No. 2010 / 0048557, which is incorporated herein by reference. Additionally, a chemotherapeutic agent includes a pharmaceutically acceptable salt, acid, or derivative of any chemotherapeutic agent, as well as combinations of two or more of them.

[0154] The terms "kit" and "product package" are synonymous.

[0155] It is specifically contemplated that any limitation discussed with respect to one embodiment of the present application can be applicable to any other embodiment of the present application. Furthermore, any compound or composition of the present application can be used in any method of the present application, and any method of the present application can be used to produce or utilize any compound or composition of the present application.

[0156] The titles used in this article are for compilation purposes only.

[0157] compound

[0158] In one aspect, the present invention provides a compound having the structure of formula (A) or (Aa), its isotopic derivatives or stereoisomers, or pharmaceutically acceptable salts thereof:

[0159] in:

[0160] Cya said or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups;

[0161] A represents a 4- to 6-membered heterocyclic alkylene, phenylene, or a 5- to 6-membered heterocyclic aryl group, wherein each of the 4- to 6-membered heterocyclic alkylene, phenylene, or 5- to 6-membered heterocyclic aryl group can be independently represented by 0, 1, 2, 3, or 4 R's. x replace;

[0162] B represents a 5- to 6-membered heteroaryl group or a phenylene group, wherein the 5- to 6-membered heteroaryl group or phenylene group can be independently represented by 0, 1, 2, 3, or 4 R groups. x Replacement, where B is not or

[0163] X and Y independently represent hydrogen, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 Cycloalkyl, 5- to 6-membered heteroaryl or phenyl, wherein the C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12 The cycloalkyl, 5- to 6-membered heteroaryl, and phenyl groups can each be independently represented by 0, 1, 2, 3, or 4 R groups. x Alternatively, X and Y can form a 3-membered ring or a 4-8-membered ring, said ring being 0, 1, 2, 3, or 4 R's. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O, and S;

[0164] Z represents -OR a -SR a Or -NR a R a ';

[0165] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ', any methylene of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is optionally replaced with a carbonyl, -NR a -, -O-, or -S-, and optionally, each of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom, said 3-8 membered ring optionally further containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of said C3-C8cycloalkyl or 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a ', cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl), or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a ', -NR a C(O)R a ', -OC(O)R a ', -OC(O)NR a R a ', -NR a C(O)NR a R a ', -S(O)R a , -S(O)2R a , -NR a S(O)2R a ';

[0166] R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), optionally substituted with 0, 1, or 2 substituents selected from -ORa -SR a Or -NR a R a ';

[0167] R3 and R3' each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-CN;

[0168] R4 represents hydrogen, C1-C6 alkyl, -(C0-C6 alkylene)-OR a -(C0-C6 alkylene)-SR a -(C0-C6 alkylene)-NR a R a ', -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be replaced with a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a-S(O)2R a -S(O)2R a -S(O)2R a -S(O)2R

[0169] L1, L2 each independently represent a single bond or -(C1-C6)alkylene-, any methylene of which can be replaced with a carbonyl, -NR a -O- or -S-, and optionally, each methylene of said -(C1-C6)alkylene- can be independently substituted with 0, 1, 2, 3 or 4 C1-C3 alkyl, and two substituents of the same C atom can form a 3-8 membered ring with said C atom;

[0170] E represents C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, which rings can be monocyclic, spiro, bridged, fused; 12 C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, which rings can be monocyclic, spiro, bridged, fused; 10 C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, which rings can be monocyclic, spiro, bridged, fused;

[0171] R5 each independently represents hydrogen, halogen, oxo, =NR a -OR a -SR a -NR a R a cyano, -C(O)OR a -C(O)R a -C(O)NR a R a -S(O)2R a -S(O)R a -S(O)(NR a )R a C1-C6 alkyl, C3-C8 cycloalkyl or 4-8 membered heterocycloalkyl; each of the above C1-C6 alkyl, C3-C8 cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a -SR a -NR a R a cyano, C1-C6 alkyl, -(C0-C3 alkylene)-C3-C8 cycloalkyl or -(C0-C3 alkylene)-4-8 membered heterocycloalkyl;

[0172] wherein m represents 0, 1, 2 or 3;

[0173] R x each independently represents hydrogen, halogen, oxo, =NR a -OR a, -SR a , -NR a R a , -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl;

[0174] R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; when R a and R a are attached to the same N atom, said R a and R a together with the N atom to which they are both attached can form a 4-8 membered ring, which optionally can contain 1, 2, or 3 heteroatoms selected from N, O, or S;

[0175] each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0176] In some embodiments, E represents C3-C 12 cycloalkyl, or 4-12 membered heterocycloalkyl, which ring can be monocyclic, spirocyclic, bridged cyclic, annulated.

[0177] In one aspect, the present application provides a compound having the structure of Formula (I), an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0178] wherein:

[0179] Cya represents or which optionally can be substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl;

[0180] A represents 4- to 6-membered heterocycloalkylene, phenylene, or 5- to 6-membered heteroarylene, each of which independently can be substituted with 0, 1, 2, 3, or 4 R x ;

[0181] B represents a 5- to 6-membered heteroarylene or phenylene, each independently of the other unsubstituted or substituted by 0, 1, 2, 3 or 4 R x , wherein B is not or

[0182] X, Y each independently represent hydrogen, Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12 C8cycloalkyl, 5- to 6-membered heteroaryl or phenyl, each independently of the other unsubstituted or substituted by 0, 1, 2, 3 or 4 R 12 ; optionally, X and Y can form a 3- to 8-membered ring, which can be unsubstituted or substituted by 0, 1, 2, 3 or 4 R x ; the ring can further comprise 0, 1, 2 or 3 heteroatoms selected from N, O, S; x

[0183] Z represents -OR a , -SR a or -NR a R a ;

[0184] R1represents Ci-C6alkyl, Ci-C6haloalkyl, -(Co-C6alkylene)-(C3-C8cycloalkyl), -(Co-C6alkylene)-(4- to 8-membered heterocycloalkyl), -(Ci-C6alkylene)-OR a , -(Ci-C6alkylene)-SR a or -(Ci-C6alkylene)-NR a R a , the C0-C6alkylene, Ci-C6alkylene, Ci-C6alkyl, Ci-C6haloalkyl being optionally substituted by replacement of any methylene group with a carbonyl, -NR a R-0-, -S-, -O- or -S-, and optionally, each of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3alkyl, and two substituents of the same C atom can form a 3-8 membered ring with said C atom, said 3-8 membered ring optionally can further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; each of said C3-C8cycloalkyl or 4-8 membered heterocycloalkyl can independently be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl) or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a , -NR a C(O)R a , -OC(O)R a , -OC(O)NR a R a , -NR a C(O)NR a R a , -S(O)R a , -S(O)2R a , -NR a S(O)2R a ;

[0185] R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), optionally substituted with 0, 1 or 2 substituents selected from -OR a , -SR a or -NR a R a ;

[0186] R3, R3’ each independently represent hydrogen, halogen, C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl) or -(C0-C6alkylene)-CN;

[0187] R4represents hydrogen, C1-C6alkyl, -(C0-C6alkylene)-OR a , -(C0-C6alkylene)-SRa -(C0-C6 alkylene)-NR a R a ', -(C0-C6 alkylene)-(C3-C8 cycloalkyl) or -(C0-C6 alkylene)-(4-12 heterocyclic alkyl), -(C0-C6 alkylene)-phenyl or -(C0-C6 alkylene)-(5-6 heteroaryl), wherein any methylene group on the C0-C6 alkylene or C1-C6 alkyl group can be replaced with a carbonyl group, -NR a -, -O-, or -S-, and optionally, the C0-C6 alkylene or C1-C6 alkyl group may be substituted with 0, 1, 2, 3, or 4 substituents selected from halogens or C1-C3 alkyl groups, and the two substituents of the same C atom may form a 3-8 membered ring with the C atom, the 3-8 membered ring optionally also containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; the C1-C6 alkyl, C3-C8 cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl groups may each be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogens, oxo-, -OR-, -O ... a -SR a -NR a R a ', cyano, C1-C6 alkyl, -(C0-C3 alkylene)-(C3-C8 cycloalkyl) or -(C0-C3 alkylene)-(4-8 heterocyclic alkyl), -C(O)R a -C(O)OR a -C(O)NR a R a '、-NR a C(O)R a '、-OC(O)R a '、-OC(O)NR a R a '、-NR a C(O)NR a R a '、-S(O)R a -S(O)2R a -NR a S(O)2R a Substituents of ';

[0188] L1 and L2 each independently represent a single bond or a -(C1-C6)alkylene group, wherein any methylene group on the -(C1-C6)alkylene group can be replaced by a carbonyl group or -NR. a-0-, -S-, -O- or -S-, and optionally, each methylene of said -(C1-C6)alkylene is independently substituted with 0, 1, 2, 3, or 4 C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom;

[0189] Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be monocyclic, spiro, bridged, fused;

[0190] R5each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the above C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl or -(C0-C3alkylene)-4-8 membered heterocycloalkyl;

[0191] wherein m represents 0, 1, 2 or 3;

[0192] R x each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )Ra ', C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl;

[0193] R a R a Each can independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocyclic alkyl; when R a R a When connected to the same N atom, the R a and R a 'The N atom and the N atom bonded together can form a 4-8 membered ring, which may optionally contain one, two or three heteroatoms selected from N, O or S;

[0194] The alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, and heteroalkylene can each be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0195] In some implementations, the structure of formula (I) has the structure shown in formula (Ia):

[0196] The definitions of each group are shown in formula (I).

[0197] In some implementations, Cya indicates or It may optionally be substituted with 0, 1, 2, or 3 substituents selected from halogens or C1-C3 alkyl groups; preferably, Cya represents or It may optionally be substituted with 0, 1, 2 or 3 substituents selected from halogens or C1-C3 alkyl groups; more preferably, Cya is preferred. or

[0198] In some embodiments, A represents a 5-6 member heteroaryl group, which can be 0, 1, 2, 3, or 4 R groups. x Substitution; preferably, A represents an imidazolyl group, which can be replaced by 0, 1, 2, 3 or 4 R groups. x Substitution; more preferably, A represents an imidazolyl group.

[0199] In some implementations, B is not or

[0200] In some implementations, B represents or The structure can be substituted with 0, 1, 2, 3, or 4 R x Preferably, B represents or

[0201] In some embodiments, X, Y each independently represents hydrogen, Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C x C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C x C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C

[0202] X, Y each independently represents hydrogen, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C x C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C x C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C x C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C

[0203] In some embodiments, X, Y each independently represents hydrogen, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C xAlternatively, X and Y can form a 4-8 element ring, which can be 0, 1, 2, 3, or 4 R elements. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0204] In some embodiments, X and Y independently represent hydrogen, C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 Each cycloalkyl group can be independently represented by 0, 1, 2, 3, or 4 R groups. x Alternatively, X and Y can form a 3-8 element ring, which can be 0, 1, 2, 3, or 4 R elements. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0205] In some embodiments, X and Y independently represent hydrogen, C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 Each cycloalkyl group can be independently represented by 0, 1, 2, 3, or 4 R groups. x Alternatively, X and Y can form a 3-membered ring or a 4-8-membered ring, said ring being composed of 0, 1, 2, 3, or 4 R elements. x Instead, the ring may further include 0, 1, 2, or 3 heteroatoms selected from N, O, and S; preferably, X and Y may optionally form a 4-8 membered ring, which may be composed of 0, 1, 2, 3, or 4 R atoms. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0206] In some embodiments, X and Y independently represent hydrogen, C1-C6 alkyl, 4- to 8-membered heterocyclic alkyl, and C3- to C6-membered cycloalkyl, respectively, wherein the C1-C6 alkyl, 4- to 8-membered heterocyclic alkyl, and C3- to C6-membered cycloalkyl can each be independently represented by 0, 1, 2, or 3 R's. x Alternatively, X and Y can form a 3-membered ring or a 4-8-membered ring, said ring being composed of 0, 1, 2, 3, or 4 R elements. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0207] In some embodiments, when X and Y form a 3-8 membered ring or a 4-8 membered ring, the ring can further include 0 or 1 heteroatom; preferably, the ring includes 0 heteroatom.

[0208] In some embodiments, X, Y each independently represents hydrogen, C1-C6 alkyl, 4- to 8-membered heterocycloalkyl, C3-C6 membered cycloalkyl, each independently of which can be substituted with 0, 1, 2, or 3 R x substituents.

[0209] In some embodiments, Z represents -OR a or -NR a R a , preferably Z represents -OH or -NHR a , more preferably Z represents -OH.

[0210] In some embodiments, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6 alkylene)-ORa, -(C1-C6 alkylene)-SRa, or -(C1-C6 alkylene)-NRaRa'; preferably, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl); more preferably, R1 represents C1-C6 alkyl or C1-C6 haloalkyl; still more preferably, R1 represents ethyl or -CH2CF3.

[0211] In some embodiments, R2 represents C1-C6 alkyl, which can be substituted with 0 or 1 -ORa; preferably, R2 represents 1-methoxyethyl. Wherein, preferably, R a , R a each independently represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4-8 membered heterocycloalkyl; preferably, R a , R a each independently represents hydrogen or C1-C6 alkyl; more preferably, R a , R a each independently represents hydrogen or C1-C3 alkyl; more preferably, R2 represents wherein * indicates the site at which R2 is attached to the site to which it is attached in formula (I).

[0212] In some embodiments, R3, R3' each independently represents hydrogen, halogen, C1-C6 alkyl; preferably, R3, R3' are H.

[0213] In some embodiments, R4represents hydrogen, -OR a , -SR a , or -NR a R a ; preferably, R4represents H.

[0214] In some embodiments, L1, L2each independently represents a single bond or -(C1-C6)alkylene-, any methylene in said -(C1-C6)alkylene- being optionally replaced with a carbonyl, -NR a -, -O-, or -S-; preferably, L1, L2each independently represents a single bond or -(C1-C6)alkylene-.

[0215] In some embodiments, Cy1represents a 4-12 membered heterocycloalkyl, which ring can be monocyclic, spiro, bridged, or fused; preferably, Cy1represents a 4-8 membered heterocycloalkyl, which ring can be monocyclic, spiro, bridged, or fused.

[0216] In some embodiments, R5each independently represents hydrogen, oxo, =NR a , -S(O)2R a , -C(O)R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the aforementioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; preferably, R5each independently represents C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, each of the aforementioned C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl, and when R5is C5-C6cycloalkyl or 5-6 membered heterocycloalkyl, the number of substituents is greater than 0. Preferably, R a , R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; preferably, R a , R aeach independently represents hydrogen or C1-C6alkyl; more preferably, R a , R a each independently represents hydrogen or C1-C3alkyl.

[0217] In some embodiments, m represents 0, 1 or 2.

[0218] In some embodiments, R x each independently represents hydrogen, halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R x each independently represents hydrogen, halogen, oxo, -OH, -SH, -NH2, cyano, C1-C6alkyl; more preferably, R x each independently represents hydrogen, halogen, -OH, -NH2, cyano, C1-C3alkyl.

[0219] In some embodiments, R a , R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R a , R a each independently represents hydrogen or C1-C6alkyl; more preferably, R a , R a each independently represents hydrogen or C1-C3alkyl.

[0220] In one aspect, the present application provides a compound having the structure of Formula (II), an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0221] wherein:

[0222] Cya represents or more preferably or which is optionally substituted with 0, 1, 2 or 3 substituents selected from halogen or C1-C3alkyl;

[0223] B represents 5- to 6-membered heteroarylene, which can be substituted with 0, 1, 2 or 3 R x ;

[0224] X, Y each independently represents hydrogen, C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C 12C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C8cycloalkyl, 5- to 6-membered heteroaryl, or phenyl, each independently optionally substituted with 0, 1, 2, 3, or 4 R 12 C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C8cycloalkyl, 5- to 6-membered heteroaryl, or phenyl, each independently optionally substituted with 0, 1, 2, 3, or 4 R x C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C8cycloalkyl, 5- to 6-membered heteroaryl, or phenyl, each independently optionally substituted with 0, 1, 2, 3, or 4 R x C1-C6alkyl, 4- to 12-membered heterocycloalkyl, C3-C8cycloalkyl, 5- to 6-membered heteroaryl, or phenyl, each independently optionally substituted with 0, 1, 2, 3, or 4 R

[0225] Z represents -OR a or -NR a R a ’;

[0226] R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’;

[0227] L1, L2each independently represents a single bond or -(C1-C6)alkylene-, any methylene of said -(C1-C6)alkylene- can be optionally replaced with a carbonyl, -NR a -, -O-, or -S-;

[0228] Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which cycloalkyl or heterocycloalkyl can be monocyclic, spiro, bridged, fused;

[0229] R5each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a ’, cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R aC1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above-mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl;

[0230] wherein m represents 0, 1, 2, or 3;

[0231] R x each independently represents hydrogen, halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl;

[0232] R a , R a each independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, said 4-8 membered ring optionally can contain 1, 2, or 3 heteroatoms selected from N, O, or S;

[0233] each of the alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0234] In some embodiments, the structure of formula (II) has a structure of formula (IIa):

[0235] wherein each of the groups is defined as in formula (II).

[0236] In some embodiments, Cya represents or which optionally can be substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3alkyl; preferably, preferred Cya represents or

[0237] In some implementations, B is not or

[0238] In some implementations, B represents or The structure can be 0, 1, 2, 3, or 4 Rs. x Replacement; preferably, B indicates or

[0239] In some embodiments, X and Y independently represent hydrogen, C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 C1-C6 alkyl, 4-12 heterocyclic alkyl, C3-C6 alkyl, 5-6 heterocyclic alkyl, or phenyl, wherein the C1-C6 alkyl, 4-12 heterocyclic alkyl, or C3-C6 alkyl is a cyclic alkyl group. 12 The cycloalkyl, 5- to 6-membered heteroaryl, and phenyl groups can each be independently represented by 0, 1, 2, 3, or 4 R groups. x Alternatively, X and Y can form a 4-8 element ring, which can be 0, 1, 2, 3, or 4 R elements. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0240] In some embodiments, X and Y independently represent hydrogen, C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 Each cycloalkyl group can be independently represented by 0, 1, 2, 3, or 4 R groups. x Alternatively, X and Y can form a 3-8 element ring, which can be 0, 1, 2, 3, or 4 R elements. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O or S.

[0241] In some embodiments, X and Y independently represent hydrogen, C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, C3-C 12 Each cycloalkyl group can be independently represented by 0, 1, 2, 3, or 4 R groups. x Alternatively, X and Y can form a 4-8 element ring, which can be 0, 1, 2, 3, or 4 R elements. xThe ring can further include 0, 1, 2, or 3 heteroatoms selected from N, O, S.

[0242] In some embodiments, X, Y each independently represents hydrogen, C1-C6 alkyl, 4-8 membered heterocycloalkyl, C3-C6 cycloalkyl, each independently of the other(s) optionally substituted with 0, 1, 2, or 3 R x In some embodiments, X and Y can form a 3-8 membered ring, said ring optionally substituted with 0, 1, 2, 3, or 4 R x The ring can further include 0, 1, 2, or 3 heteroatoms selected from N, O, S.

[0243] In some embodiments, when X and Y form a 3-8 membered ring or a 4-8 membered ring, said ring can further include 0 or 1 heteroatom; preferably, said ring includes 0 heteroatom.

[0244] In some embodiments, X, Y each independently represents hydrogen, C1-C6 alkyl, 4-8 membered heterocycloalkyl, C3-C6 cycloalkyl, each independently of the other(s) optionally substituted with 0, 1, 2, or 3 R x substituted.

[0245] In some embodiments, Z represents -OH or -NHR a ; more preferably, Z represents -OH.

[0246] In some embodiments, R1 represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8 membered heterocycloalkyl); preferably, R1 represents C1-C6 alkyl or C1-C6 haloalkyl; more preferably, R1 represents ethyl or -CH2CF3.

[0247] In some embodiments, L1, L2 each independently represents a single bond or -(C1-C6) alkylene-.

[0248] In some embodiments, Cy1 represents 4-12 membered heterocycloalkyl, said ring can be monocyclic, spiro, bridged, fused; preferably, Cy1 represents 4-8 membered heterocycloalkyl, said ring can be monocyclic, spiro, bridged, fused.

[0249] In some embodiments, R5 each independently represents hydrogen, oxo, =NR a , -S(O)2R a , -C(O)R aC1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above-mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; preferably, each R5independently represents C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, each of the above-mentioned C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently unsubstituted or substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl, and when R5is C5-C6cycloalkyl or 5-6 membered heterocycloalkyl, the number of substituents is greater than 0.

[0250] In some embodiments, m represents 0, 1, or 2.

[0251] In some embodiments, each R x independently represents hydrogen, halogen, oxo, -OH, -SH, -NH2, cyano, C1-C6alkyl; more preferably, each R x independently represents hydrogen, halogen, -OH, -NH2, cyano, C1-C3alkyl.

[0252] In some embodiments, each R a , R a independently represents hydrogen, C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; preferably, each R a , R a independently represents hydrogen or C1-C6alkyl; more preferably, each R a , R a independently represents hydrogen or C1-C3alkyl.

[0253] In some embodiments, in the compound of structure (II):

[0254] Cya represents or

[0255] B represents or

[0256] X, Y each independently represent hydrogen, C1-C6 alkyl, 4- to 8-membered heterocycloalkyl, C3-C6 cycloalkyl, each of which C1-C6 alkyl, 4- to 8-membered heterocycloalkyl, C3-C6 cycloalkyl can be independently substituted with 0, 1, 2, or 3 R x X and Y can form a 3- to 8-membered ring, which ring can be substituted with 0, 1, 2, 3, or 4 R x , the ring can further include 0, 1, 2, or 3 heteroatoms selected from N, O, S;

[0257] Z represents -OH or -NHR a ;

[0258] R1 represents ethyl or trifluoroethyl;

[0259] L1, L2 each independently represent a single bond or -(C1-C6)alkylene-;

[0260] Cy1 represents 4- to 8-membered heterocycloalkyl, which ring can be monocyclic, spirocyclic, bridged, annelated;

[0261] R5 each independently represents C3-C8 cycloalkyl or 4- to 8-membered heterocycloalkyl, each of which C3-C8 cycloalkyl, 4- to 8-membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl, and when R6 is C5-C6 cycloalkyl or 5- to 6-membered heterocycloalkyl, the number of substituents is greater than 0

[0262] wherein m represents 0, 1, or 2;

[0263] R x each independently represent hydrogen, halogen, -OH, -NH2, cyano, C1-C3 alkyl;

[0264] R a , R a each independently represent hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or 4- to 8-membered heterocycloalkyl;

[0265] each of which alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

[0266] In some embodiments, when X and Y form a 3- to 8-membered ring, the ring can further include 0 or 1 heteroatom; preferably, the ring includes 0 heteroatom.

[0267] In some embodiments, X, Y each independently represent hydrogen, C1-C6 alkyl, 4- to 8-membered heterocycloalkyl, C3-C6 membered cycloalkyl, each independently of the other(s) optionally substituted with 0, 1, 2, or 3 R x substituted.

[0268] In some embodiments, Z represents -OH.

[0269] In some embodiments, R a , R a each independently represent hydrogen or C1-C6 alkyl; preferably, R a , R a each independently represent hydrogen or C1-C3 alkyl.

[0270] In some embodiments, the compound has the following structure:

[0271] In another aspect, the present application provides use of the aforementioned compound, or an isotopic derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing and / or treating cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0272] In yet another aspect, the present application provides use of the aforementioned compound, or an isotopic derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, in preventing and / or treating cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease.

[0273] In yet another aspect, the present application provides a method for preventing and / or treating cancer, a tumor, an inflammatory disease, an autoimmune disease, or an immune-mediated disease, comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned compound, or an isotopic derivative, a stereoisomer thereof, or a pharmaceutically acceptable salt and / or a pharmaceutical composition thereof.

[0274] In some embodiments, the aforementioned use or method is for preventing and / or treating a disease associated with RAS protein; in some preferred embodiments, the RAS protein is one or more of KRAS protein, NRAS protein, or HRAS protein.

[0275] In some embodiments, the condition, neoplasm, inflammatory disease, autoimmune disease or immune-mediated disease in the above uses or methods comprises a RAS mutation; in some preferred embodiments, the RAS mutation comprises one or more of a KRAS mutation, a NRAS mutation or a HRAS mutation; in particular, the RAS mutation is at position 12, 13 and / or 61; more particularly, the RAS mutation comprises one or more of KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G13D or NRAS Q61L.

[0276] Synthesis

[0277] The compounds described herein can be prepared from commercially available starting materials or using known organic, inorganic, or enzymatic processes.

[0278] The compounds of the present application can be prepared in a variety of ways known to one skilled in the art of organic synthesis. For example, the compounds of the present application can be synthesized using the methods described in the following Schemes, as well as by the techniques of synthetic organic chemistry, known to one skilled in the art, or modifications thereof, as appreciated by those skilled in the art. The methods include, but are not limited to, the methods described in the following Schemes.

[0279] For illustrative purposes, the following reaction schemes provide routes for synthesizing the compounds of the present application, as well as key intermediates. For a detailed description of each reaction step, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes can be used. Although certain specific starting materials and reagents are described in the schemes, and discussed below, other starting materials and reagents can be substituted therefor- to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry methods.

[0280] If desired, the starting materials and intermediates of the synthetic reaction schemes can be isolated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0281] Unless otherwise indicated, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure, in a temperature range of from about -78 °C to about 150 °C, more preferably in a temperature range of from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature or at about 20 °C, unless otherwise indicated.

[0282] Certain compounds in the schemes below bear generalized substituents; however, one skilled in the art will readily recognize that the nature of the substituents can vary to provide the various compounds contemplated in the application. In addition, the reaction conditions are exemplary and alternative conditions are well-known. The reaction sequences in the following examples are not intended to be limiting to the scope of the application as described in the claims.

[0283] Pharmaceutical Descriptions

[0284] Pharmaceutical Compositions and Dosing

[0285] The compounds contemplated by the present application are pan-Kras inhibitors and are useful in the treatment of cancer. Accordingly, one embodiment of the present application provides pharmaceutical compositions comprising a compound of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, as well as methods of using the compounds of the present application to prepare such compositions.

[0286] For use as a therapy in a subject, the compounds of the present application, or pharmaceutically acceptable salts thereof, can be formulated into a pharmaceutical composition. Depending on the subject to be treated, the mode of administration and the type of treatment, e.g., prophylactic, preventative or therapeutic, the compounds, or pharmaceutically acceptable salts thereof, are formulated to suit the parameters. An overview of such techniques can be found in Remington: The Science and Practice of Pharmacy, 21stEd., Lippincott Williams & Wilkins, (2005); and Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J. C. Boylan, eds., 1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference.

[0287] The compositions can be prepared according to conventional mixing, granulation or coating methods, respectively, and the pharmaceutical compositions of the present application can contain about 0.1% to about 99%, about 5% to about 90%, or about 1% to about 20% by weight or volume of the compounds of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt thereof, can be present in an amount totaling 1-95% by weight of the total amount of the composition, e.g., pharmaceutical composition.

[0288] The compositions can be provided in a dosage form suitable for intra-articular, oral, parenteral (e.g., intravenous, intramuscular), rectal, dermal, subcutaneous, topical, transdermal, sublingual, transnasal, vaginal, intracapsular, intraurethral, intrathecal, epidural, otic or ocular administration, or by injection, inhalation, or direct contact with nasal, urogenital, genital, or oral mucosa. Thus, pharmaceutical compositions can be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels (including hydrogels), pastes, ointments, creams, plasters, drops, osmotic delivery devices, suppositories, enemas, injections, implants, sprays, formulations suitable for iontophoretic delivery, or aerosols. The compositions can be formulated in accordance with conventional pharmaceutical practice.

[0289] As used herein, the term "administering" refers to the delivery of a composition (e.g., a compound or a formulation including a compound as described herein) to a subject or system. Administration to an animal subject (e.g., to a human) can be by any appropriate route. For example, in some embodiments, administration can be bronchial (including by bronchial instillation), buccal, enteral, intradermal, intraarterial, intradermal, intragastrical, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intracapsular, transmucosal, transnasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including by tracheal instillation), transdermal, vaginal, or vitreous administration.

[0290] Formulations can be prepared in a manner suitable for systemic administration or for topical or local administration. Systemic formulations include formulations designed for injection (e.g., intramuscular, intravenous, or subcutaneous injection) or can be prepared for transdermal, transmucosal, or oral administration. Formulations will generally include a diluent and, in some cases, an adjuvant, a buffer, a preservative, and the like. The compounds or pharmaceutically acceptable salts thereof can also be administered in a liposome composition or in a microemulsion.

[0291] For injection, the formulations can be prepared in conventional forms, either as liquid solutions or suspensions, or as solid forms suitable for reconstitution into a liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, or the like. These compositions also can contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, and the like, such as, for example, sodium acetate, sorbitan monolaurate, and the like.

[0292] Systemic administration can also include relatively non-invasive methods, such as the use of suppositories, transdermal patches, transmucosal delivery, and intranasal administration. Oral administration is also suitable for the compounds or pharmaceutically acceptable salts thereof of the present application. As will be appreciated by those in the art, suitable forms include syrups, capsules, and tablets.

[0293] Each compound described herein, or a pharmaceutically acceptable salt thereof, can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in a combination therapy can be formulated together or separately. Other modes of combination therapy are also described herein.

[0294] The agents, either individually or separately formulated, can be packaged together in kit form. Non-limiting examples include, but are not limited to, kits containing, for example, two pills, one pill and a powder, a suppository, or a liquid in a vial, two topical creams, etc. The kits can include optional components that facilitate administration of the unit dose to a subject, such as a vial for reconstituting a powder form, a syringe for injection, a custom IV delivery system, an inhaler, etc. In addition, the unit dose kit can contain instructions regarding the preparation and administration of the compositions. The kits can be manufactured as a one-time unit dose for one subject, for multiple uses by a particular subject (constant dose, or where the potency of the individual compounds or pharmaceutically acceptable salts thereof can vary as therapy progresses); or the kit can contain multiple doses suitable for administration to multiple subjects ("bulk packaging"). The kit components can be assembled in a carton, blister pack, bottle, tube, etc.

[0295] Formulations for oral use include tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients. The excipients can be, for example, inert diluents or fillers (such as sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (such as cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginic acid, or alginates); binding agents (such as sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethyl cellulose sodium, methylcellulose, optionally substituted hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, and antiadhesions (such as magnesium stearate, zinc stearate, stearic acid, silicon dioxide, hydrogenated vegetable oil, or talc). Other pharmaceutically acceptable excipients can be colorants, flavorants, plasticizers, humectants, buffering agents, and the like.

[0296] Two or more compounds can be mixed together in a tablet, capsule, or other vehicle, or can be separated. In one example, a first compound is contained on the inside of a tablet, while a second compound is on the outside, thereby causing a substantial portion of the second compound to be released before the first compound is released.

[0297] Formulations for oral use can also be presented as chewable tablets, or as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin); or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, e.g., peanut oil, liquid paraffin or olive oil. Powders, granules and capsules can be prepared using the ingredients mentioned above for tablets and capsules, in the conventional manner, using, e.g., mixers, fluid bed apparatus or spray drying equipment.

[0298] Dissolution or diffusion controlled release can be achieved by suitably coating tablet, capsule, pellet or granular formulations of the compound, or by incorporating the compound or a pharmaceutically acceptable salt thereof into a suitable matrix. The controlled release coating can include one or more of the above-mentioned coating substances, e.g., shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl alcohol, glycerol monostearate, glycerol distearate, glycerol palmitostearate, ethyl cellulose, acrylic resins, dl-poly lactic acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl acetate, vinyl pyrrolidone, polyethylene, polymethacrylate, methyl methacrylate, 2-optionally substituted hydroxymethacrylate, methacrylate hydrogel, 1,3 butylene glycol, ethylene glycol methacrylate or polyethylene glycol. In controlled release matrix formulations, the matrix material can also include, e.g., hydrated methyl cellulose, carnauba wax and stearyl alcohol, carbopol 934, silicone, glyceryl tri-stearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene or halogenated fluorocarbon compounds.

[0299] Liquid forms in which the compounds of the present application or a pharmaceutically acceptable salt thereof and compositions can be incorporated for administration orally include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0300] In general, the oral dosage of any compound of the present application or a pharmaceutically acceptable salt thereof when administered to humans will depend on the nature of the compound and can readily be determined by one of skill in the art. The dosage can be, for example, from about 0.001 mg to about 2000 mg per day, from about 1 mg to about 1000 mg per day, from about 5 mg to about 500 mg per day, from about 100 mg to about 1500 mg per day, from about 500 mg to about 1500 mg per day, from about 500 mg to about 2000 mg per day, or any range derived therein. In some embodiments, the daily dosage for oral administration may, for example, range from about 0.001 mg to about 2000 mg per kilogram of human body weight, administered in a single dose or in divided doses. On the other hand, in some cases it can be necessary to use dosages outside the ranges stated above.

[0301] In some embodiments, the pharmaceutical composition can additionally comprise an additional compound having anti-proliferative activity. Depending on the mode of administration, the compound or a pharmaceutically acceptable salt thereof will be formulated into a suitable composition to facilitate delivery. Each compound or a pharmaceutically acceptable salt thereof in a combination therapy can be formulated in a variety of ways known in the art. For example, the first agent and the second agent in a combination therapy can be formulated together or separately. Desirably, the first agent and the second agent are formulated together so that the agents are administered simultaneously or nearly simultaneously.

[0302] It is understood that the compounds and pharmaceutical compositions of the present application can be formulated and used in combination with other therapeutic agents or procedures as needed, that is, the compounds and pharmaceutical compositions can be formulated with, or administered simultaneously with, prior to, or after administration of one or more other therapeutic agents or procedures. The particular combination of therapies (therapeutic agents or procedures) used in a combination regimen will depend primarily on the particular effects desired and the nature of the disease or condition treated.

[0303] As described herein, administration of each drug in a combination therapy can independently be one to four times daily for one day to one year, and can even last the life of the subject. Chronic / long-term administration can also apply.

[0304] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which this application belongs. Also, any methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The preferred methods and materials are described herein.

[0305] Methods of use

[0306] In some embodiments, the present disclosure provides a method of treating a disease or disorder characterized by aberrant RAS activity caused by a RAS mutant.

[0307] In some embodiments, the disease or disorder is an inflammatory disease, an autoimmune disease, and an immune-mediated disease. Representative examples of which can include, but are not limited to, arthritis, rheumatoid arthritis, spondyloarthritides, gouty arthritis, osteoarthritis, juvenile arthritis, other arthritic conditions, lupus, systemic lupus erythematosus (SLE), skin-related diseases, psoriasis, eczema, dermatitis, allergic dermatitis, pain, lung diseases, lung inflammation, adult respiratory distress syndrome (ARDS), pulmonary sarcoidosis, chronic lung inflammatory disease, chronic obstructive pulmonary disease (COPD), cardiovascular diseases, atherosclerosis, myocardial infarction, congestive heart failure, myocardial ischemia reperfusion injury, inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, asthma, Sjogren's syndrome, autoimmune thyroid disease, urticaria (hives), multiple sclerosis, scleroderma, organ transplant rejection, xenotransplantation, idiopathic thrombocytopenic purpura (ITP), Parkinson's disease, Alzheimer's disease, diabetes-related diseases, inflammation, pelvic inflammatory disease, allergic rhinitis, allergic bronchitis, allergic rhinosinusitis, leukemia, lymphoma, B-cell lymphoma, T-cell lymphoma, myeloma, acute lymphoblastic leukemia (ALL), chronic lymphoblastic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), diffuse large B-cell lymphoma, and follicular lymphoma.

[0308] In some embodiments, the disease or disorder is a cancer or a tumor. Representative examples of cancers or tumors can include, but are not limited to, skin cancer, bladder cancer, ovarian cancer, breast cancer, gastric cancer, pancreatic cancer, prostate cancer, colon cancer, lung cancer, bone cancer, brain cancer, neuroblastoma, rectal cancer, colon cancer, familial adenomatous polyposis cancer, hereditary nonpolyposis colorectal cancer, esophageal cancer, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, stomach cancer, adenocarcinoma, medullary thyroid cancer, papillary thyroid cancer, kidney cancer, renal parenchymal cancer, ovarian cancer, cervical cancer, uterine corpus cancer, endometrial cancer, choriocarcinoma, pancreatic cancer, prostate cancer, testicular cancer, urinary cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma, and peripheral neuroectodermal tumor, Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), adult T-cell leukemia lymphoma, diffuse large B-cell lymphoma (DLBCL), hepatocellular carcinoma, gallbladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basal cell carcinoma, teratocarcinoma, retinoblastoma, choroid melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, or plasmacytoma.

[0309] When a compound of the application or a pharmaceutically acceptable salt thereof is administered in combination with another therapeutic agent for the treatment of an inflammatory disease, autoimmune disease, and immune-mediated disease, the compound of the application or a pharmaceutically acceptable salt thereof can provide an enhanced therapeutic effect.

[0310] The present application also provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such a compound or salt. Also provided is a method of treating a RAS protein-related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising such a compound or salt.

[0311] In some embodiments, the compounds of the present application or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising such compounds or salts, and the methods provided herein can be used to treat a variety of cancers, including tumors, such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, and the like. More particularly, cancers that can be treated by the compounds of the present application or salts thereof, pharmaceutical compositions comprising such compounds or salts, and methods include, but are not limited to, for example, the following tumor types: astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate, and thyroid carcinomas and sarcomas.

[0312] Also provided is a method of inhibiting a RAS protein in a cell, the method comprising contacting the cell with an effective amount of a compound of the application, or a pharmaceutically acceptable salt thereof. The compound, or the pharmaceutically acceptable salt thereof, can inhibit a RAS protein in a cell.

[0313] Combination therapy

[0314] The methods of the application can include a compound of the application used alone or in combination with one or more additional therapies, e.g., non-drug treatments or therapeutic agents. When administered alone, the dosage of one or more of the additional therapies, e.g., non-drug treatments or therapeutic agents, can be reduced relative to the standard dosage. For example, the dosage can be determined empirically or can be inferred by isobolographic analysis (e.g., Black et al., Neurology 65:S3-S6 (2005)), depending on the drug combination and arrangement.

[0315] The compounds of the application can be administered prior to, after or simultaneously with the administration of one or more of the additional therapies. When combined, the dosage of the compound of the application and the dosage of the one or more additional therapies, e.g., non-drug treatments or therapeutic agents, provide a therapeutic effect, e.g., a synergistic or additive therapeutic effect. The compound of the application and the additional therapy, e.g., anticancer agent, can be administered together, e.g., in a single pharmaceutical composition, or separately, and when administered separately, the administration can occur simultaneously or sequentially. Such sequential administration can be close or remote in time.

[0316] In some embodiments, the additional therapy is the administration of a side effect limiting agent, e.g., an agent intended to reduce the occurrence or severity of a side effect of treatment. For example, in some embodiments, the compounds of the application can also be used in combination with a therapeutic agent that treats nausea. Examples of agents that can be used to treat nausea include dronabinol, granisetron, metoclopramide, ondansetron, and prochlorperazine, or a pharmaceutically acceptable salt thereof.

[0317] In some embodiments, the one or more additional therapies comprise a non-drug therapy (e.g., surgery or radiation therapy). In some embodiments, the one or more additional therapies comprise a therapeutic agent (e.g., a compound or biological agent that acts as an anti-angiogenic agent, signal transduction inhibitor, anti-proliferative agent, glycolysis inhibitor, or autophagy inhibitor). In some embodiments, the one or more additional therapies comprise a non-drug therapy (e.g., surgery or radiation therapy) and a therapeutic agent (e.g., a compound or biological agent that acts as an anti-angiogenic agent, signal transduction inhibitor, anti-proliferative agent, glycolysis inhibitor, or autophagy inhibitor). In other embodiments, the one or more additional therapies comprise two therapeutic agents. In yet other embodiments, the one or more additional therapies comprise three therapeutic agents. In some embodiments, the one or more additional therapies comprise four or more therapeutic agents.

[0318] In this combination therapy section, all references to the agents described, or a pharmaceutically acceptable salt, solvate, isomer (e.g., stereoisomer), prodrug, or tautomer thereof, are incorporated by reference, whether or not so expressly stated.

[0319] Examples of non-drug therapies include, but are not limited to, radiation therapy, cryotherapy, hyperthermia treatment, surgery (e.g., surgical removal of tumor tissue), and adoptive transfer (ACT) of T cells therapy.

[0320] In some embodiments, the compounds of the application can be used as post-operative adjuvant therapy. In some embodiments, the compounds of the application can be used as pre-operative neoadjuvant therapy.

[0321] In some embodiments, the compounds of the application can sensitize abnormal cells to radiation treatment for the purpose of killing or inhibiting the growth of such cells. Accordingly, the application is additionally directed to a method for sensitizing abnormal cells in a mammal to radiation treatment, comprising administering to the mammal an amount of a compound of the application effective to sensitize abnormal cells to radiation treatment. The amount of the compound in this method can be determined according to the manner described herein for determining effective amounts of such compounds. In some embodiments, the compounds of the application can be used as adjuvant therapy following radiation therapy or as neoadjuvant therapy prior to radiation therapy.

[0322] In some embodiments, the non-pharmaceutical therapy is adoptive transfer (ACT) of T cells. In some embodiments, the T cells are activated T cells. The T cells can be modified to express a chimeric antigen receptor (CAR). CAR-modified T (CAR-T) cells can be generated by any method known in the art. For example, CAR-T cells can be generated by introducing a suitable expression vector encoding a CAR into a T cell. The source of T cells is obtained from a subject prior to expansion and genetic modification of the T cells. T cells can be obtained from a variety of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, umbilical cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In certain embodiments of the application, a variety of T cell lines available in the art can be used.

[0323] The therapeutic agent can be a compound for treating cancer or a symptom associated therewith.

[0324] For example, the therapeutic agent can be a steroid. Thus, in some embodiments, the one or more additional therapies include a steroid. Suitable steroids can include, but are not limited to, 21-acetoxypregnenolone, alclometasone, algestone, amcinonide, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, clocortolone, cloprednol, corticosterone, cortisone, cortivazol, deflazacort, desonide, desoximetasone, dexamethasone, diflorasone, diflucortolone, difuprednate, enoxolone, fluazacort, fiucloronide, flumethasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluocortolone, fluorometholone, fluperolone acetate, fluprednidene acetate, fluprednisolone, flurandrenolide, fluticasone propionate, formocortal, halcinonide, halobetasol propionate, halometasone, halopredone acetate, hecogenone, hydrocortisone, hydrocortisone 17-butyrate, hydrocortisone 17- valerate, hydrocortisone probutate, medrysone, meprednisone, methylprednisolone, momethamone, mometasone, naflocort, nicocortonide, oxazocort, paramethasone, prednicarbate, prednisolone 25-diethylaminoacetate, prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone tebutate, prednisolone 21 -tert-butyldimethylacetate, prednisone, prednival, prenaflam, resocortol, rofleponide, rimiterol, tixocortol, triamcinolone, triamcinolone benetonide, triamcinolone hexacetonide, and 21- trimethylacetoxypregnenolone.halometasone, hydrocortisone, loteprednoletabonate, mazipredone, medrysone, meprednisone, methylprednisolone, mometasone furoate, paramethasone, prednicarbate, prednisolone, prednisolone 25- diethylaminoacetate, prednisolone sodium phosphate, prednisone, prednival, prednylidene, rimexolone, tixocortol, triamcinolone, triamcinolone acetonide, triamcinolone benetonide, triamcinolone hexacetonide, and salts or derivatives thereof.

[0325] The therapeutic agent can be a biological agent (e.g., a cytokine (e.g., an interferon or a leukin, such as IL-2)) for treating cancer or its associated symptoms. In some embodiments, the biological agent is an immunoglobulin-based biological agent, such as a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonizes an antigen important for cancer. Antibody-drug conjugates are also included.

[0326] The therapeutic agent can be a T cell checkpoint inhibitor. In one embodiment, the checkpoint inhibitor is an inhibitory antibody (e.g., a monospecific antibody, e.g., a monoclonal antibody). The antibody can be, e.g., a humanized or fully human antibody. In some embodiments, the checkpoint inhibitor is a fusion protein, e.g., an Fc-receptor fusion protein. In some embodiments, the checkpoint inhibitor is an agent, e.g., an antibody, that interacts with a checkpoint protein. In some embodiments, the checkpoint inhibitor is an agent, e.g., an antibody, that interacts with a ligand of a checkpoint protein. In some embodiments, the checkpoint inhibitor is an inhibitor (e.g., an inhibitory antibody or a small molecule inhibitor) of CTLA-4 (e.g., an anti-CTLA-4 antibody or fusion protein). In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L1 inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor). In some embodiments, the checkpoint inhibitor is a PD-L2 inhibitor or antagonist (e.g., an inhibitory antibody or Fc fusion or a small molecule inhibitor) (e.g., a PD-L2 / Ig fusion protein). In some embodiments, the checkpoint inhibitor is an inhibitor or antagonist (e.g., an inhibitory antibody or a small molecule inhibitor) of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or combinations thereof. In some embodiments, the checkpoint inhibitor is pembrolizumab, nivolumab, PDR001 (NVS), REGN2810 (Sanofi / Regeneron), a PD-L1 antibody such as avelumab, durvalumab, atezolizumab, pidilizumab, JNJ-63723283 (JNJ), BGB-A317 (BeiGene & Celgene), or a checkpoint inhibitor disclosed in Preusser, M. et al. (2015) Nat. Rev. Neurol., including but not limited to ipilimumab, tremelimumab, nivolumab, pembrolizumab, AMP224, AMP514 / MEDI0680, BMS936559, MEDI4736, MPDL3280A, MSB0010718C, BMS986016, IMP321, lirilumab, IPH2101, 1-7F9, and KW-6002.

[0327] The therapeutic agent can be an anti-TIGIT antibody, such as MBSA43, BMS- 986207, MK-7684, COM902, AB154, MTIG7192A, or OMP-313M32 (etigilimab).

[0328] The therapeutic agent can be an agent that treats cancer or a symptom related thereto (e.g., a cytotoxic agent, a non-peptide small molecule, or other compound useful in treating cancer or a symptom related thereto, collectively referred to as an “anti-cancer agent”). The anti-cancer agent can be, for example, a chemotherapeutic agent or a targeted therapeutic agent.

[0329] Anti-cancer agents include mitotic inhibitors, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, alkylating agents, antimetabolites, folate analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L- asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted urea, methyl hydrazine derivatives, adrenocortical suppressors, adrenocortical steroids, luteinizing hormone-releasing hormone analogs, and the like. Other anti-cancer agents include leucovorin (LV), irenotecan, oxaliplatin, capecitabine, paclitaxel, and doxetaxel. In some embodiments, the one or more additional therapies include two or more anti-cancer agents. The two or more anti-cancer agents can be used in a cocktail for combined administration or administered separately.

[0330] Other non-limiting representative examples of anti-cancer agents can include cell signal transduction inhibitors, chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozocin, cisplatin, carboplatin, oxaliplatin, dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, topotecan, irinotecan, etoposide, trabectedin, dactinomycin, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mytomycin C, ixabepilone, tamoxifen, flutamide, goserelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferon alpha, leucovorin, sirolimus, sirolimus lipidate, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crotetuzumab, dabrafenib, dacotuzumab, danusertib, dasatinib, devimistat, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, seribantumab, sorafenib, sunitinib, talabantumab, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, velpatasarin, vemurafenib, vismodegib, volasertib, alemtuzumab, bevacizumab, brentuximab vedotin, catumaxomab, cetuximab, denosumab, gemtuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, tositumab, trastuzumab, PI3K inhibitors, CSF1R inhibitors, A2A and / or A2B receptor antagonists, IDO inhibitors, anti-PD-1 antibodies, anti-PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, and anti-CTLA-4 antibodies, or any combination thereof.

[0331] The above-mentioned features of the present application, or features mentioned in the embodiments, can be combined in any combination. All features disclosed in the specification can be used in any combination, and each individual feature disclosed in the specification can be replaced by alternative features which serve the same, equivalent or similar purpose. Thus, unless specifically noted, the features disclosed are only general examples of equivalent or similar features.

[0332] The compounds of the present application can be prepared in a number of ways known to one skilled in the art of organic synthesis, either by using the methods described below, or by using synthetic methods known in the art of organic synthesis or by using modifications of these methods as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. The synthesis of the compounds of the present application will be readily apparent to those skilled in the art.

[0333] The present application is further illustrated by the following examples. It is to be understood that these examples are merely illustrative of the present application and do not in any way limit the scope of the application. Unless otherwise indicated, the experimental procedures in the following examples were carried out under conventional conditions or under conditions recommended by the manufacturer. Unless otherwise indicated, all percentages, ratios, proportions, or parts are by weight.

[0334] Examples

[0335] General procedure

[0336] When a preparation route is not included, the starting materials and reagents used in the present application are known products, which can be synthesized according to the methods known in the art, or can be obtained by purchasing commercially available products. The commercially available reagents used are not required to be further purified.

[0337] Room temperature refers to 20-30°C.

[0338] Unless otherwise specified in the reaction examples, the reactions were carried out under a nitrogen atmosphere. The nitrogen atmosphere refers to that the reaction flask is connected to a nitrogen balloon of about 1 L.

[0339] The hydrogenation reaction is usually carried out by vacuum and hydrogen filling, and the operation is repeated 3 times. The hydrogen atmosphere refers to that the reaction flask is connected to a hydrogen balloon of about 1 L.

[0340] Microwave reaction uses Initiator + microwave reactor.

[0341] The structure of the compounds of the present application is determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is expressed in 10 -6ppm) units. NMR measurements were made on a (Bruker Ascend TM 500) NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCI3), deuterated methanol (CD3OD) as the solvent and tetramethylsilane (TMS) as the internal standard. The following abbreviations are used for NMR signal multiplicities: s = singlet, br s = broad singlet, d = doublet, t = triplet, m = multiplet. Coupling constants are given in Hz.

[0342] Preparative reverse phase chromatography was performed using a Thermo (UltiMate 3000) preparative reverse phase chromatograph. Flash column chromatography was performed using an Eiger (FS-9200T) automated column chromatography machine, and silica gel pre-packed columns were purchased from Tristar Pre-packed columns. Thin layer chromatography silica gel plates were purchased from Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, and the specifications used for thin layer chromatography separation and purification of products were 0.4 mm to 0.5 mm.

[0343] LC-MS analysis method was as follows:

[0344] 1) Mass spectrometry method: Thermo Fisher MSQ PLUS mass spectrometer, ESI source, positive ion mode. Ion source parameters: drying gas temperature 350 °C; drying gas flow rate 10 L / min; MS Range: 120-1000. 2) Liquid chromatography conditions: column: Waters XBridge (3.5 pm, 50 mm x 4.6 mm); mobile phase A: 0.1% ammonium bicarbonate aqueous solution, mobile phase B: acetonitrile solution, linear gradient elution according to the following Table 1; flow rate: 2 mL / min; column temperature: 30 °C; ultraviolet detection wavelength: 214 nm, 254 nm, 280 nm; injection volume 2 pL.

[0345] Table 1. Gradient elution conditions

[0346] The synthesis method of some intermediates in the invention is as follows:

[0347] Intermediate 1

[0348] Intermediate 1 was prepared by the following steps:

[0349] Step 1: 2.2-dimethyl-3-hydroxypropionic acid methyl ester INT-1a (100 g, 756.67 mmol) was dissolved in N,N-dimethylformamide (1 L), and imidazole (128.79 g, 1.89 mol) was added. The solution was stirred and dissolved, and tert-butyldiphenylsilyl chloride (228.78 g, 832.34 mmol) was added dropwise at 20 °C. After the dropwise addition was completed, stirring was continued for 4 hours. After the reaction was completed, the reaction solution was poured into 3 L of ice water, and the suspension was extracted with ethyl acetate (1 L*2). The organic phase was washed with water (1 L*2) three times, and then concentrated under reduced pressure to obtain colorless oil INT-1b, which was used directly in the next step without purification. ESI-MS (m / z): 371.2 [M+H] + ;

[0350] Step 2: The residue INT-1b obtained in the previous step was added to methanol (2 L), and 360 g of 33% aqueous sodium hydroxide solution was added. The mixture was stirred at 20 °C for 17 hours. After the reaction was completed, 1 L of water was added, and the methanol was removed under reduced pressure. The residue was extracted with petroleum ether (1 L*5), and the aqueous phase was adjusted to pH 4-5 with hydrochloric acid. A large amount of white solid was precipitated, and stirring was continued for 30 minutes. The mixture was filtered and dried to obtain white solid INT-1c (269 g, yield 90%). ESI-MS (m / z): 357.8 [M+H] + ;

[0351] Step 3: INT-1c (130 g, 364.63 mmol) was dissolved in dichloromethane (500 mL), and dichlorosulfoxide (130.14 g, 1.09 mol, 79.35 mL) was added at room temperature. N,N-dimethylformamide (0.05 mL) was added dropwise, and the mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the dichloromethane and the remaining dichlorosulfoxide were removed under reduced pressure. The residue was added to petroleum ether (300 mL) and distilled until no distillate was obtained, to obtain yellowish oil INT-1d, which was used directly in the next step without purification.

[0352] Fourth step: 5-bromoindole INT-1e (64.8 g, 331 mmol) was dissolved in dichloromethane (400 mL), diethylaluminum chloride solution (198 mL, 2 mol / L in hexanes) was added at 0 °C, and INT-1d in dichloromethane solution obtained in the previous step was added dropwise to the reaction bottle. After the dropwise addition was completed, stirring was continued for 30 minutes. After the reaction was completed, the reaction solution was slowly poured into an ice potassium sodium tartrate aqueous solution (1 L) and stirred for 16 hours. After the system was stable, the dichloromethane was removed under reduced pressure, and the residue was extracted with ethyl acetate (1 L*2) and washed with water (1 L*2). The organic phase was rotary evaporated to obtain a brown oil. The oil was added to a mixture of petroleum ether / ethyl acetate = 10 / 1 (2 L), and a solid was precipitated by stirring at 20 °C. Filtration under suction gave yellow solid INT-1f (139 g, yield 78%). ESI-MS (m / z): 534.8 [M+H] + ;

[0353] Fifth step: INT-1f (100 g, 187.07 mmol) was dissolved in tetrahydrofuran (500 mL), and lithium borohydride (12.23 g, 561.21 mmol) was added under ice bath conditions. After the addition was completed, stirring was continued for 20 minutes. After the system was stable, the temperature was increased to 60 °C, and stirring was continued overnight. After the starting material was consumed, the reaction solution was slowly added to ice water (200 mL) to quench, and extracted with ethyl acetate (500 mL*3). The organic phase was washed with water, dried, and concentrated under reduced pressure. The residue was dissolved in dichloromethane (500 mL), and 2,6-dimethyl-1,4-dihydro-3,5-pyridine dicarboxylic acid diethyl ester (28.43 g, 112.24 mmol) and p-toluenesulfonic acid (21.35 g, 112.24 mmol) were added. After stirring at room temperature for 3 hours, the reaction was completed, and the dichloromethane was removed under reduced pressure. The residue was dissolved in methanol (500 mL), and a previously prepared 14% aqueous lithium hydroxide solution (100 mL) was added. After stirring at room temperature for 3 hours, the reaction was filtered under suction, and dried at room temperature to obtain yellow solid INT-1g (84 g, yield 86.26%). ESI-MS (m / z): 520.2 [M+H] + ;

[0354] Step 6: Dissolve INT-1g (50 g, 96 mmol) in tetrahydrofuran (250 mL), add tetrabutylammonium fluoride (197 mL, 1 mol / L in THF), stir at 60 °C overnight, after the reaction is completed, the reaction solution is added to water (300 mL), extracted with ethyl acetate (200 mL*3), washed with water, concentrated under reduced pressure to obtain brown oil. The obtained residue is dissolved in methanol (40 mL), water (20 mL) is added, the mixed solution is washed with petroleum ether (40 mL*5), then concentrated under reduced pressure to remove methanol, the residue is extracted with ethyl acetate (50 mL*2), the organic phase is washed with water (50 mL), dried to obtain yellowish oil INT-1h (25 g, yield 90.40%). ESI-MS (m / z): 282.8 [M+H] + ;

[0355] Step 7: Dissolve compound INT-1h (25 g, 88.7 mmol) in dioxane (250 mL), add potassium acetate (21.7 g, 221.8 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.24 g, 4.4 mmol), boronic acid neopentyl glycol ester (24.1 g, 106.4 mmol), protect with nitrogen, react at 90 °C for 4 hours, monitor the complete reaction of the raw material by LCMS, filter with diatomite, concentrate the filtrate, add dichloromethane (200 mL) to the concentrated solution, continue to concentrate under reduced pressure until the aqueous phase is clear, filter, extract the aqueous phase with dichloromethane (300 mL) once, adjust the pH of the aqueous phase to 3-4 with hydrochloric acid under ice bath conditions, a large amount of yellow solid precipitates, continue to stir for 30 minutes, filter to obtain yellow solid compound INT-1i (17.96 g, yield 82.1%). ESI-MS (m / z): 248.4 [M+H] + ;

[0356] Step 8: Dissolve compound INT-1i (35 g, 142 mmol) and compound INT-1k (51.8 g, 142 mmol) in dioxane (350 mL) and water (17.5 mL), add potassium carbonate (39.2 g, 284 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.2 g, 7.1 mmol), protect with nitrogen, react at 90 °C for 17 hours, monitor the complete reaction of the raw material by LCMS, filter the reaction solution with diatomite, concentrate under reduced pressure, dissolve the residue in ethyl acetate (300 mL), wash with water (100 mL), dry to obtain brown oil compound INT-1j, which is directly used in the next step reaction. ESI-MS (m / z): 488.4 [M+H] + ;

[0357] Step 9: Compound INT-1j crude was dissolved in dichloromethane (700 mL). 4- dimethylaminopyridine (866 mg, 7.1 mmol), triethylamine (43.0 g, 426 mmol) were added, acetic anhydride (14.5 g, 142 mmol) was added dropwise at 0 °C, after the addition was completed, the ice bath was removed and the temperature was allowed to rise naturally, and stirred for 1-2 hours. After the reaction was completed, the reaction liquid was washed with water (300 mL*2), dried and concentrated to obtain a brown oil. Purification by silica gel column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain a yellowish oil INT-1l (62.3 g, yield 83.2%). ESI-MS (m / z): 530.5 [M+H] + ;

[0358] Step 10: Compound INT-1l (62.3 g, 117.9 mmol) was dissolved in N,N- dimethylformamide (620 mL), N-iodosuccinimide (26.5 g, 117.9 mmol) was added, and the reaction was carried out at 10 °C overnight. LCMS was used to monitor the completion of the reaction. The reaction liquid was slowly poured into ice water (3000 mL), and a solid was precipitated after stirring. Filtration, washing with water (100 mL), and air drying yielded a yellow solid compound INT-1m (64.2 g, yield 87%). ESI-MS (m / z): 656.3 [M+H] + ;

[0359] Step 11: Compound INT-1m (64 g, 99.1 mmol) was dissolved in tetrahydrofuran (640 mL) and water (128 mL), lithium hydroxide monohydrate (11.86 g, 282.4 mmol) was added, and the reaction was carried out at 70 °C for 1 hour. LCMS was used to monitor the completion of the reaction. Water (300 mL) was added to the reaction liquid, and then concentrated under reduced pressure. Methyltetrahydrofuran (200 mL) was added, and the pH was adjusted to 4-5 with 4M hydrochloric acid. The organic phase was extracted with methyltetrahydrofuran (200 mL*3), washed with brine (100 mL), and dried thoroughly to obtain a yellow solid compound INT-1n (56.5 g, yield 95%). ESI-MS (m / z): 600.5 [M+H] + ;

[0360] Twelfth step: Compound INT-1n (57 g, 95.0 mmol), 1-methylimidazole (38.9 g, 475 mmol) and (S)-methyl hexahydro pyridazine-3-carboxylate trifluoroacetate salt (52.7 g, 142.5 mmol) were dissolved in acetonitrile (800 mL), N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (40.0 g, 142.5 mmol) acetonitrile solution (400 mL) was added at 0 °C, and the reaction was stirred for 1 h after dropwise addition was completed. LCMS monitoring showed that the reaction of the raw material was complete. Water (1000 mL) was added to the reaction solution, and dichloromethane (1000 mL*3) was extracted. Yellow solid compound INT-1o (56.5 g, yield 95%) was obtained after rotary evaporation. ESI-MS (m / z): 726.3 [M+H] + ;

[0361] Thirteenth step: Compound INT-1o (56.5 g, 77.8 mmol) was dissolved in tetrahydrofuran (560 mL) and water (112 mL), and lithium hydroxide (4.66 g, 194.7 mmol) was added. The reaction was carried out at 10 °C for 2 h. LCMS monitoring showed that the reaction of the raw material was complete. Water (300 mL) was added, and 4 mol / L hydrochloric acid was used to adjust the pH to 5-6. After concentration, methyl tetrahydrofuran (200 mL*3) was extracted, and salt water (100 mL) was washed. After complete layering, the solvent was removed by rotary evaporation to obtain yellow solid compound INT-1p (55.4 g, yield 88.16%). ESI-MS (m / z): 712.6 [M+H] + ;

[0362] Fourteenth step: N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (59.1 g, 210.8 mmol) and 1-methylimidazole (26.5 g, 323.2 mmol) were added to acetonitrile (2000 mL) and stirred to dissolve. A THF solution of compound INT-1p (100 g / 1000 mL, 140.5 mmol) was added dropwise at 10-20 °C. After dropwise addition was completed, the reaction was stirred for 1-2 h. LCMS monitoring showed that the reaction of the raw material was complete. Rotary evaporation was performed to remove the solvent, water (1000 mL) was added to the residue, dichloromethane (1000 mL*3) was extracted, and hydrochloric acid was used to adjust the pH to 3-4. The organic phase was rotary evaporated to obtain a yellow solid. Recrystallization with isopropyl alcohol obtained compound INT-1q (59 g, yield 60%). ESI-MS (m / z): 694.6 [M+H] + ;

[0363] Fifteenth step: Compound INT-1q (37 g, 53.35 mmol), 2-dicyclohexylphosphino-2',6'-dimethyl-biphenyl (6.6 g, 16.0 mmol), tris(dibenzylideneacetone)dipalladium (5.86 g, 6.40 mmol), potassium acetate (18.3 g, 186.7 mmol) were dissolved in toluene (370 mL), pinacolborane (34.1 g, 266.7 mmol, 38.7 mL) was added under nitrogen protection, the reaction was stirred at 50 °C for 3 hours under nitrogen protection, LCMS monitoring showed that the raw material was completely reacted, the reaction solution was filtered, and the yellow solid compound INT-1 (31 g, yield 82%) was obtained by silica gel column chromatography. ESI-MS (m / z): 694.8 [M+H] + .

[0364] Intermediate 2

[0365] Intermediate 2 was prepared by the following steps:

[0366] First step: Compound INT-2a (43 g, 199 mmol), pinacol diborane (55.6 g, 219 mmol), methoxy (cyclooctadiene) iridium dimer (1.30 g, 1.99 mmol) and 4,4-di-tert-butylbipyridine (2.67 g, 9.95 mmol) were added to tetrahydrofuran (500 mL), and the reaction was stirred at 75 °C under nitrogen protection for 16 hours. LCMS monitoring showed that the raw material was completely converted. The excess tetrahydrofuran was removed by rotary evaporation to obtain a brown residue INT-2b, which was used directly in the next step without purification. ESI-MS (m / z): 342.4 [M+H] + .

[0367] Second step: The residue INT-2b obtained in the previous step was added to methanol (200 mL), and concentrated hydrochloric acid (100 mL) was added. The reaction solution was refluxed for 3 hours, and LCMS monitoring showed that the raw material disappeared. The methanol was removed by rotary evaporation, and the residue was added to water (200 mL). The pH was adjusted to 13 with 30% sodium hydroxide solution, and dichloromethane (400 mL*2) was added for extraction to remove impurities. The aqueous phase was cooled to 0-5 °C, and hydrochloric acid was added to adjust the pH to 6-7. The solid was washed out by continuous stirring, and then filtered and air-dried to obtain white solid compound INT-2c (41.3 g, yield 80%). ESI-MS (m / z): 260.2 [M+H] + .

[0368] Step 3: Compound INT-2c (41.3 g, 159 mmol) was dissolved in acetonitrile (400 mL), N-iodosuccinimide (35.8 g, 239 mmol) was added, and the reaction was stirred at 80 °C overnight. LCMS showed that the starting material was consumed. The reaction was concentrated by rotary evaporation, and the residue was added to ethyl acetate (300 mL), washed with water (100 mL), dried, and purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound INT-2d (45.6 g, 85% yield) as a white solid. ESI-MS (m / z): 342.5 [M+H] + .

[0369] Step 4: Compound INT-2d (5 g, 14.6 mmol) was dissolved in N,N-dimethylformamide (50 mL), and zinc cyanide (1.03 g, 8.8 mmol) and tetrakis(triphenylphosphine)palladium (1.69 g, 1.46 mmol) were added sequentially. The reaction was stirred at 100 °C under nitrogen overnight. LCMS showed that the starting material was consumed. Ammonia water (5 mL) was added to quench the reaction, and the reaction was extracted with ethyl acetate (200 mL*2). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give compound INT-2e (2.1 g, 59.6% yield) as a colorless oil. ESI-MS (m / z): 241.2 [M+H] + .

[0370] Step 5: Compound INT-2e (2.1 g, 8.7 mmol) was dissolved in a mixture of ethanol (20 mL) and water (4 mL), and potassium hydroxide (0.54 g, 9.6 mmol) was added. The reaction was refluxed for 16 hours. LCMS showed that the starting material was consumed. The reaction was concentrated to give compound INT-2f (2.26 g, 100% yield) as a white solid. ESI-MS (m / z): 258.0 [M-H] - .

[0371] Step 6: Compound INT-2f (770 mg, 2.96 mmol) was dissolved in methanol (10 mL), and sulfurous dichloride (1.06 g, 8.9 mmol) was added. The reaction was stirred at 70 °C for 3 hours. LCMS showed that the starting material was consumed. The reaction was concentrated to give compound INT-2g (800 mg, 98.6% yield) as a yellowish solid. ESI-MS (m / z): 274.1 [M+H] + .

[0372] Step 7: Dissolve compound INT-2 g (600 mg, 2.19 mmol) in ethanol (6 mL), and add hydrazine hydrate (329 mg, 6.57 mmol). Stir the reaction mixture at 90 °C for 16 hours. Monitor the reaction progress using LC-MS until complete. Concentrate the reaction mixture. Purify the residue by column chromatography (dichloromethane / methanol = 20:1) to obtain a colorless oily compound INT-2h (550 mg, yield 91.7%). ESI-MS (m / z): 274.2 [M+H] + .

[0373] Step 8: Compound INT-2h (300 mg, 1.09 mmol) was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of INT-2i (376 mg, 1.64 mmol), 1-hydroxybenzotriazole (222 mg, 1.64 mmol), N,N-diisopropylethylamine (424 mg, 3.28 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.64 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was monitored by LCMS until the starting material was completely reacted. Water (40 mL) was added to the system, and the mixture was extracted with dichloromethane (60 mL * 3). The organic phase was dried, dried over anhydrous sodium sulfate, and concentrated by filtration. The residue was purified by column chromatography (dichloromethane / methanol = 10:1) to give a pale yellow oily compound INT-2j (480 mg, yield 90.4%). ESI-MS (m / z): 485.3 [M+H] + .

[0374] Step 9: Compound INT-2j (480 mg, 0.99 mmol) was dissolved in tetrahydrofuran (5 mL), and Burgess reagent (354 mg, 1.48 mmol) was added. The reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was monitored by LCMS until the starting material was completely reacted, and the reaction mixture was concentrated. The residue was purified by column chromatography (dichloromethane / methanol = 20:1) to give a colorless oily compound INT-2k (320 mg, yield 69.2%). ESI-MS (m / z): 467.2 [M+H] + .

[0375] Step 10: Trifluoroacetic acid (2 mL) was added dropwise to a solution of compound INT-2k (390 mg, 0.83 mmol) in dichloromethane (6 mL). The reaction mixture was stirred at room temperature for 1 hour, and the reaction was monitored by LCMS until completion. The reaction mixture was concentrated by vacuum distillation to obtain the crude product INT-2l. ESI-MS (m / z): 366.8 [M+H] + .

[0376] Tenth step: The above crude product INT-21 was dissolved in tetrahydrofuran (4 mL), N, N-diisopropylethylamine (539 mg, 4.17 mmol) was added, followed by dropwise addition of benzyl chloroformate (214 mg, 1.25 mmol) into the reaction solution, which was stirred at room temperature for 16 hours. After the reaction was monitored to completion by LCMS, the reaction solution was concentrated by distillation under reduced pressure and purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain compound INT-2 (350 mg, yield 83.7%) as colorless oil. ESI-MS (m / z): 501.0 [M+H] + .

[0377] Intermediate 3

[0378] Intermediate 3 was prepared by the following steps:

[0379] First step: INT-3a (663 mg, 2.92 mmol) was dissolved in ethanol (8 mL), sodium ethoxide (199 mg, 2.92 mmol) was added at room temperature, and stirred at room temperature for 30 minutes. The solid was removed by filtration, and then INT-2h (400 mg, 1.46 mmol) in ethanol was added to the filtrate, and the reaction solution was stirred at 85°C for 16 hours. After the reaction was completed, it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20:1) to obtain compound INT-3b (516 mg, yield 75.8%) as a light yellow solid. ESI-MS (m / z): 466.3 [M+H] + .

[0380] Second step: Sodium hydride (48 mg, 1.2 mmol, 60% dispersion in oil) was added to a tetrahydrofuran solution of compound INT-3b (160 mg, 0.343 mmol) under nitrogen atmosphere and ice bath conditions. After the reaction solution was stirred at room temperature for 2 hours, it was cooled to 0°C, 2-(trimethylsilyl)ethoxymethyl chloride (114 mg, 0.686 mmol) was added dropwise, and after the addition was completed, it was warmed to room temperature and stirred for 16 hours. After the raw material was completely reacted by LCMS monitoring, water (40 mL) was added, and ethyl acetate (40 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase silica gel column chromatography (acetonitrile = 100%) to obtain compound INT-3 (134 mg, yield 65.6%). ESI-MS (m / z): 596.4 [M+H] + .

[0381] Intermediate 4

[0382] Intermediate 4 was prepared by the following steps:

[0383] Step 1: Compound INT-4a (5.0 g, 39.0 mmol) was dissolved in dichloromethane (50 mL) and methanol (10 mL), trimethylsilyldiazomethane (2 mol / L, 29.3 mL) was added dropwise at 0 °C, after the addition was completed, continue to stir for 1 hour, TLC monitoring of the reaction was complete. Concentration to get colorless oil compound INT-4b (5.6 g, yield 100%). ESI-MS (m / z): 143.4 [M+H] + . 1 H NMR (500 MHz, Chloroform-d) δ 3.70 (s, 3H), 3.32 - 3.20 (m, 2H), 2.87 - 2.77 (m, 3H), 2.68 - 2.60 (m, 2H).

[0384] Step 2: Compound INT-4b (5.6 g, 39.4 mmol) was dissolved in n-heptane (60 mL), tert-butyl carbazate (5.5 g, 41.4 mmol) was added, the reaction was raised to 70 °C and stirred for 16 hours, LCMS monitoring of the reaction was complete. The reaction was concentrated, the residue obtained was recrystallized with (n-heptane / isopropyl alcohol = 30 / 1) to obtain white solid compound INT-4c (9.0 g, yield 89.1%). ESI-MS (m / z): 257.3 [M+H] + .

[0385] Step 3: Compound INT-4c (3.0 g, 11.7 mmol) was dissolved in methanol (30 mL), platinum dioxide (300 mg, 10% wt) was added, the reaction was stirred under hydrogen atmosphere for 16 hours, LC-MS monitoring of the reaction was complete. The reaction was filtered with diatomite, the filtrate was concentrated to obtain colorless oil compound INT-4d (3.0 g, yield 99.2%). ESI-MS (m / z): 259.3 [M+H] + .

[0386] Fourth step: Compound INT-4d (3.0 g, 11.6 mmol) was dissolved in tetrahydrofuran (30 mL), and di-tert-butyl dicarbonate (3.0 g, 14.0 mmol), triethylamine (3.5 g, 34.8 mmol) and 4-dimethylaminopyridine (0.14 g, 1.2 mmol) were added successively at 0 °C. The reaction was stirred at room temperature for 2 hours, and LCMS was used to monitor the reaction. Water (60 mL) was added to quench the reaction, and the product was extracted with ethyl acetate (70 mL*3). The organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound INT-4e (3.2 g, yield 75.7%) as a colorless oil. ESI-MS (m / z): 359.2 [M+H] + .

[0387] Fifth step: Compound INT-4e (2.0 g, 5.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), and lithium bis(trimethylsilyl)amide (1 mol / L, 16.7 mL) was added dropwise at -70 °C under nitrogen atmosphere. After the addition was completed, the reaction was stirred at the temperature for 30 minutes. Then, trimethylchlorosilane (1.8 g, 16.7 mmol) was added, and the reaction was stirred for 1 hour. N-bromosuccinimide (3.0 g, 16.7 mmol) was added, and the reaction was stirred at room temperature for 16 hours. LC-MS was used to monitor the reaction. Water (60 mL) was added to quench the reaction, and the product was extracted with ethyl acetate (70 mL*3). The organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude INT-4f was directly used in the next step. ESI-MS (m / z): 509.3 [M+H] + .

[0388] Sixth step: The crude compound INT-4f was dissolved in methanol (20 mL), and potassium carbonate (1.5 g, 11.2 mmol) was added at 0 °C. The reaction was stirred at room temperature for 2 hours, and LCMS was used to monitor the reaction. Water (60 mL) was added to quench the reaction, and the product was extracted with ethyl acetate (70 mL*3). The organic phase was combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain compound INT-4g (1.4 g, two-step yield 57.4%) as a colorless oil. ESI-MS (m / z): 437.2 [M+H] + .

[0389] Seventh step: Compound INT-4g (1.4 g, 3.2 mmol) was dissolved in acetonitrile (140 mL), and cesium carbonate (3.1 g, 9.6 mmol) was added thereto. The reaction was stirred at 60 °C for 16 hours, and LCMS was used to monitor the reaction until the raw material was completely consumed. Water (100 mL) was added to quench the reaction, and extraction was performed with ethyl acetate (100 mL*3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by preparative liquid chromatography and SFC to obtain compound INT-4h (0.21 g, yield 18.4%) as a white solid. ESI-MS (m / z): 357.2 [M+H] + . 1 H NMR (500 MHz, Chloroform-d) δ 5.24-4.93 (m, 1H), 4.52-4.42 (m, 1H), 3.78-3.71 (m, 3H), 2.93-2.84 (m, 1H), 2.42-2.35 (m, 1H), 2.17-2.09 (m, 1H), 1.61-1.55 (m, 2H), 1.55-1.46 (m, 18H).

[0390] Eighth step: Compound INT-4h (100 mg, 0.24 mmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added thereto under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain compound INT-4 (91 mg, yield 100%) as a colorless oil. ESI-MS (m / z): 157.3 [M+H] + .

[0391] Intermediate 5

[0392] Intermediate 5 was prepared by the following steps:

[0393] First step: Compound INT-1k (1.0 g, 2.7 mmol) was dissolved in tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide monohydrate (230 mg, 5.5 mmol) was added thereto at 0 °C. Stirring was continued for 2 hours, and LCMS was used to monitor the reaction until the raw material was completely consumed. Dilution was performed with water (60 mL), and the pH was adjusted to 5 with dilute hydrochloric acid. Extraction was performed with ethyl acetate (100 mL*3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound INT-5a (900 mg, yield 93.6%) as a yellow solid. ESI-MS (m / z): 350.8 [M+H] + .

[0394] Second Step: Compound INT-4 (91 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL), diisopropylethylamine (118 mg, 0.91 mmol), compound INT-5a (80 mg, 0.23 mmol) and 2-(7-azobenzo-triazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (104 mg, 0.27 mmol) were added successively at room temperature. The reaction was stirred at room temperature for 2 hours. LCMS was used to monitor the reaction. When the reaction was completed, water (40 mL) was added to quench the reaction. The reaction was extracted with ethyl acetate (40 mL*3). The organic phase was combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound INT-5 (100 mg, yield 89.7%) as colorless oil. ESI-MS (m / z): 489.2 [M+H] + .

[0395] Intermediate 6

[0396] Intermediate 6 was prepared by the following steps:

[0397] Compound INT-6 was synthesized by replacing compound INT-4 in the synthesis procedure of compound INT-5 with compound INT-6a, using similar methods and reaction procedures. ESI-MS (m / z): 477.3 [M+H] + .

[0398] Intermediate 7

[0399] Intermediate 7 was prepared by the following steps:

[0400] First Step: Compound INT-2k (10 g, 21.4 mmol) was dissolved in 1,4-dioxane (300 mL). Potassium acetate (4.2 g, 42.8 mmol), bis(pinacolato)diboron (7.3 g, 32.1 mmol) and [1,1'-bis(ditert-butylphosphino)ferrocene]dichloropalladium (1.4 g, 2.14 mmol) were added successively. The reaction was stirred at 85 °C for 16 hours under nitrogen atmosphere. LCMS was used to monitor the reaction. When the reaction was completed, water (100 mL) was added to quench the reaction. The reaction was extracted with ethyl acetate (200 mL*3). The organic phase was combined and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product INT-7a as brown oil. The crude product was used directly in the next step without further purification. ESI-MS (m / z): 501.2 [M+H] + .

[0401] Second step: dissolve the crude compound INT-7a obtained above in 1,4-dioxane (150 mL) and water (15 mL), add INT-7b (8.5 g, 13.2 mmol), potassium carbonate (5.5 g, 39.4 mmol), and [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (0.96 g, 1.3 mmol) in sequence, and stir the reaction solution at 85°C under a nitrogen atmosphere for 16 hours. Monitor the reaction completion by LCMS. Add water (100 mL) to the system, extract with ethyl acetate (200 mL*3), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, and concentrate. Purify the obtained residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain compound INT-7c (4.1 g, 20.5% yield for two steps) in colorless oil. ESI-MS (m / z): 906.7 [M+H] + .

[0402] Third step: dissolve compound INT-7c (1.4 g, 1.5 mmol) in N,N-dimethylformamide (15 mL), and add cesium carbonate (1.5 g, 4.5 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.0 g, 4.5 mmol) thereto. Stir the reaction solution at room temperature for 16 hours. After the reaction is completed, add water (150 mL) to the reaction system, extract with ethyl acetate (100 mL*2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound INT-7d (770 mg, 51.3% yield) in light yellow solid. ESI-MS (m / z): 988.7 [M+H] + .

[0403] Fourth step: dissolve compound INT-7d (770 mg, 0.78 mmol) in tetrahydrofuran (3 mL), and add tetrabutylammonium fluoride (1M, 3.9 mL) thereto. Stir the reaction mixture at room temperature for 16 hours. After the reaction is completed, add water (40 mL) to the reaction system, extract with ethyl acetate (40 mL*3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 3) to obtain compound INT-7e (526 mg, 90.0% yield) in light yellow solid. ESI-MS (m / z): 750.6 [M+H] + .

[0404] Step 5: Compound INT-7e (400 mg, 0.54 mmol) was dissolved in acetonitrile (4 mL), and trimethylsilyl iodide (190 mg, 0.8 mmol) was added to the mixture under ice bath. The reaction mixture was stirred for 1 h under ice bath. After the reaction was completed, sodium bicarbonate aqueous solution (40 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (40 mL*2), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-7f (325 mg, yield 93.8%) as a light yellow solid. ESI-MS (m / z): 650.6 [M+H] + .

[0405] Step 6: Compound INT-7f (325 mg, 0.5 mmol) was dissolved in dichloromethane (5 mL), and 3-oxetanone (72 mg, 1.0 mmol) was added to the mixture at room temperature. The reaction mixture was stirred for 10 min at room temperature, and sodium triacetoxyborohydride (318 mg, 1.5 mmol) was added, and the stirring was continued for 2 h. After the reaction was completed, sodium bicarbonate aqueous solution (20 mL) was added to the reaction system, and the mixture was extracted with dichloromethane (40 mL*3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-7 (225 mg, yield 77.9%) as a light yellow solid. ESI-MS (m / z): 706.6 [M+H] + .

[0406] Intermediate 8

[0407] Intermediate 8 was prepared by the following steps:

[0408] First Step: Compound INT-7 (220 mg, 0.31 mmol) was dissolved in 1,4-dioxane (5 mL), potassium acetate (92 mg, 0.94 mmol), bis(pinacolato)diboron (118 mg, 0.47 mmol) and [1,1'-bis (di-tert-butylphosphino) ferrocene] palladium dichloride (20 mg, 0.031 mmol) were added successively, and the reaction was stirred at 70 °C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LCMS. Water (40 mL) was added to the system, and extraction was performed with ethyl acetate (40 mL*3). The organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-8a (173 mg, yield 73.9%) as a light yellow solid. ESI-MS (m / z): 754.6 [M+H] + .

[0409] Second Step: Compound INT-8a (101 mg, 0.13 mmol) was dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and INT-5 (66 mg, 0.13 mmol), potassium carbonate (46 mg, 0.34 mmol), and [1,1'-bis (di-tert-butylphosphino) ferrocene] palladium dichloride (8.7 mg, 0.013 mmol) were added successively. The reaction was stirred at 70 °C under a nitrogen atmosphere for 16 hours. The reaction was monitored by LCMS. Water (40 mL) was added to the system, and extraction was performed with ethyl acetate (40 mL*3). The organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-8b (118 mg, yield 85.0%) as a light yellow solid. ESI-MS (m / z): 1036.7 [M+H] + .

[0410] Third Step: Compound INT-8b (118 mg, 0.11 mmol) was dissolved in tetrahydrofuran (2 mL) and water (1 mL), and lithium hydroxide monohydrate (14 mg, 0.33 mmol) was added at 0 °C. The reaction was stirred for 1 hour, and the reaction was monitored by LCMS. Water (40 mL) was added to dilute the reaction, and the pH was adjusted to 5 with dilute hydrochloric acid. Extraction was performed with ethyl acetate (40 mL*3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound INT-8c (101 mg, yield 90.0%) as a light yellow solid. ESI-MS (m / z): 1022.7 [M+H] + .

[0411] Fourth step: N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (56 mg, 0.2 mmol), 1-methylimidazole (41 mg, 0.5 mmol) were added to acetonitrile (3 mL) and stirred to dissolve. A solution of compound INT-8c (101 mg, 0.1 mmol) in THF (1 mL) was added dropwise at room temperature. After the addition was completed, the reaction was stirred for 1 hour. LCMS was used to monitor the reaction. When the reaction was completed, water (40 mL) was added to the system. The organic phase was extracted with ethyl acetate (40 mL*3), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-8d (72 mg, yield 65.0%) as a light yellow solid. ESI-MS (m / z): 1004.7 [M+H] + .

[0412] Fifth step: Compound INT-8d (30 mg, 0.03 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added to the solution under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8. The organic phase was extracted with dichloromethane (40 mL*2), combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-8 (25 mg, yield 92.6%) as a light yellow solid. ESI-MS (m / z): 904.7 [M+H] + .

[0413] Intermediate 9

[0414] Compound INT-9 can be obtained by replacing compound INT-5 with compound INT-6 in the synthesis steps of compound INT-8, using similar methods and reaction steps. ESI-MS (m / z): 892.6 [M+H] + .

[0415] Intermediate 10

[0416] Intermediate 10 was prepared by the following steps:

[0417] Step 1: Compound INT-2 (200 mg, 0.40 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), and INT-1 (332 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (29 mg, 0.040 mmol) and potassium phosphate (251 mg, 1.20 mmol) were added successively. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, water (40 mL) was added to the reaction system, and the product was extracted with ethyl acetate (40 mL*3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin-layer chromatography (ethyl acetate) to obtain compound INT-10a (300 mg, yield 76.1%) as a light yellow solid. ESI-MS (m / z): 988.0 [M+H] + .

[0418] Step 2: Compound INT-10a (300 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (198 mg, 0.61 mmol) and iodoethane (71 mg, 0.46 mmol) were added thereto. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction system, and the product was extracted with ethyl acetate (60 mL*3), the organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin-layer chromatography (petroleum ether / ethyl acetate = 1:2) to obtain compound INT-10b (110 mg, yield 35.7%) as a light yellow solid. ESI-MS (m / z): 1016.9 [M+H] + .

[0419] Step 3: Compound INT-10b (110 mg, 0.108 mmol), 10% palladium hydroxide (22 mg), 10% palladium on carbon (22 mg) and isopropanol (5 mL) were added to a reaction bottle. The reaction mixture was stirred at 60 °C for 16 hours under hydrogen atmosphere. The reaction solution was filtered through diatomite, and the filtrate was concentrated to obtain compound INT-10 (85 mg, yield 89.0%). ESI-MS (m / z): 882.2 [M+H] + .

[0420] Intermediate 11

[0421] Intermediate 11 was prepared by the following steps:

[0422] First step: Compound INT-10 (140 mg, 0.16 mmol) was dissolved in 1,2-dichloroethane (2 mL) / methanol (2 mL), to which 1-methylazetidin-3-one hydrochloride (41 mg, 0.48 mmol) was added at room temperature. After 20 minutes, sodium cyanoborohydride (50 mg, 0.79 mmol) was slowly added to the reaction, which continued to stir at 40 °C for 16 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL) to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin layer chromatography (dichloromethane / methanol = 15:1) to obtain compound INT-11a (60 mg, yield 39%) as a gray-white solid. ESI-MS (m / z): 951.1 [M+H] + .

[0423] Second step: Compound INT-11a (44 mg, 0.081 mmol) was dissolved in dichloromethane (3 mL), to which trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with ethyl acetate (40 mL*2), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-11 (29 mg, yield 81.0%) as a gray-white solid. ESI-MS (m / z): 850.2 [M+H] + .

[0424] Intermediate 12

[0425] Compound INT-12 can be obtained by replacing 1-methylazetidin-3-one hydrochloride in the synthesis step of compound INT-11 with 3-oxetanone, using similar methods and reaction steps. ESI-MS (m / z): 837.8 [M+H] + ; LC-MS retention time RT = 1.55 min.

[0426] Intermediate 13

[0427] Compound INT-13 can be obtained by replacing 1-methylazetidin-3-one hydrochloride in the synthesis step of compound INT-11 with formaldehyde aqueous solution, using similar methods and reaction steps. ESI-MS (m / z): 796.0 [M+H] + ; LC-MS retention time RT = 1.58 min.

[0428] Intermediate 14

[0429] Intermediate 14 was prepared from the following steps:

[0430] Step 1: Compound INT-7d (2.0 g, 2.02 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (5 mL) was added to the solution under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (40 mL*2), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a light yellow solid compound INT-14a (1.3 g, yield 72.3%). ESI-MS (m / z): 890.4 [M+H] + .

[0431] Step 2: Compound INT-14a (1.0 g, 1.12 mmol) was dissolved in tetrahydrofuran (10 mL), N,N-diisopropyl ethylamine (436 mg, 3.37 mmol) and benzyl chloroformate (288 mg, 1.69 mmol) were added to the solution under ice bath. The reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate solution (20 mL) was added to the system, extracted with ethyl acetate (30 mL*3), the organic phase was combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a light yellow solid compound INT-14b (1.15 g, yield 100%). ESI-MS (m / z): 1022.6 [M+H] + .

[0432] Step 3: Compound INT-14b (1.15 g, 1.12 mmol) was dissolved in tetrahydrofuran (6 mL), tetrabutylammonium fluoride (1 M, 3.4 mL) was added to the solution. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (40 mL) was added to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain a light yellow solid compound INT-14c (551 mg, yield 62.5%). ESI-MS (m / z): 785.2 [M+H] + .

[0433] Fourth step: Compound INT-14c (551 mg, 0.70 mmol) was dissolved in 1,4-dioxane (10 mL), potassium acetate (207 mg, 2.11 mmol), bis(pinacolato)diboron (267 mg, 1.05 mmol) and [1,1'-bis(ditert-butylphosphine)ferrocene] palladium dichloride (51 mg, 0.070 mmol) were added successively, and the reaction was stirred at 80 °C for 16 hours under a nitrogen atmosphere. Water (40 mL) was added to the system, and extraction was performed with ethyl acetate (40 mL*3). The organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound INT-14d (467 mg, yield 80%) as a light yellow solid. ESI-MS (m / z): 832.2 [M+H] + .

[0434] Fifth step: Compound INT-14d (467 mg, 0.56 mmol) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), and INT-5 (261 mg, 0.53 mmol), potassium carbonate (233 mg, 1.68 mmol) and [1,1'-bis(ditert-butylphosphine)ferrocene] palladium dichloride (36 mg, 0.056 mmol) were added successively. The reaction was stirred at 50 °C for 20 hours under a nitrogen atmosphere. Water (40 mL) was added to the system, and extraction was performed with ethyl acetate (40 mL*3). The organic phase was combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:9) to obtain compound INT-14e (529 mg, yield 84.5%) as a light yellow solid. ESI-MS (m / z): 1114.0 [M+H] + .

[0435] Sixth step: Compound INT-14e (519 mg, 0.46 mmol) was dissolved in tetrahydrofuran (5 mL) and water (2.5 mL), and lithium hydroxide monohydrate (14 mg, 0.33 mmol) was added at 0 °C. Stirring was continued for 1 hour, water (40 mL) was added for dilution, and adjustment was made to pH = 5 with dilute hydrochloric acid. Extraction was performed with ethyl acetate (40 mL*3), and the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound INT-14f (512 mg, yield 100%) as a light yellow solid. ESI-MS (m / z): 1100.7 [M+H] + .

[0436] Step 7: N,N,N',N'-tetramethylchloromethaniminium hexafluorophosphate (261 mg, 0.93 mmol) and 1-methylimidazole (191 mg, 2.33 mmol) were added to acetonitrile (10 mL) and stirred to dissolve. A solution of compound INT-14f (512 mg, 0.46 mmol) in THF (5 mL) was added dropwise at room temperature. After the addition was completed, the reaction was stirred for 1 h. Water (40 mL) was added to the system, and the organic phase was extracted with ethyl acetate (40 mL*3), combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:9) to obtain compound INT-14g (348 mg, yield 69.1%) as a light yellow solid. ESI-MS (m / z): 1081.6 [M+H] + .

[0437] Step 8: Compound INT-14g (230 mg, 0.212 mmol), 10% palladium hydroxide (23 mg), 10% palladium on carbon (23 mg), and isopropanol (5 mL) were added to a reaction bottle. The reaction mixture was stirred at 70 °C for 16 h under a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated to obtain compound INT-14 (180 mg, yield 89.0%). ESI-MS (m / z): 948.8 [M+H] + .

[0438] Intermediate 15

[0439] Intermediate 15 was prepared by the following steps:

[0440] Step 1: Compound INT-5 (137 mg, 0.28 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (2 mL) was added to the solution under ice bath. The reaction mixture was stirred at room temperature for 2 h. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, and the organic phase was extracted with dichloromethane (20 mL*2), combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound INT-15a (108 mg, yield 94.1%) as a light yellow solid. ESI-MS (m / z): 389.5 [M+H] + .

[0441] Second Step: To a solution of compound INT-15a (135 mg, 0.277 mmol) in N,N- dimethylformamide (2 mL), (R)-2-hydroxy-3-methylbutanoic acid (65 mg, 0.554 mmol), N,N- diisopropylethylamine (107 mg, 0.832 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (200 mg, 0.527 mmol) were added successively under ice-bath condition. The reaction was continued to stir for 2 hours under the same condition. After the reaction was completed, water (20 mL) was added to the system, and the organic phase was extracted with ethyl acetate (30 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 95:5) to obtain compound INT-15 (130 mg, yield 95.7%) as a light yellow oil. ESI-MS (m / z): 489.5 [M+H] + .

[0442] Intermediate 16

[0443] Intermediate 16 was prepared by the following steps:

[0444] First Step: Compound INT-16a (50.0 g, 499.4 mmol) was dissolved in toluene (250 mL), and ethylene glycol (31.0 g, 499.4 mmol) and p-toluenesulfonic acid (8.6 g, 49.94 mmol) were added at room temperature. The reaction mixture was stirred at 105 °C for 16 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (200 mL) was added to the reaction system, and the organic phase was extracted with ethyl acetate (200 mL*2), combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-16b (38.6 g, yield 53.6%) as a brown oil. 1 H NMR (500 MHz, Chloroform-d) d 3.91 (s, 4H), 3.76 - 3.66 (m, 4H), 1.70 - 1.63 (m, 4H).

[0445] Second Step: Compound INT-16b (10.0 g, 69.36 mmol) was dissolved in tetrahydrofuran (100 mL) under nitrogen atmosphere, borane dimethyl sulfide (41.62 mL, 83.42 mmol, 2 mol / L tetrahydrofuran solution) was added at -78 °C, then trimethylsilyl trifluoromethanesulfonate (770.8 mg, 3.47 mmol) was added dropwise into the system. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, methanol (100 mL) was added into the reaction system under ice bath to quench the reaction, and concentrated to obtain brown oil compound INT-16c (10.1 g, yield 100.0%). 1 H NMR (500 MHz, Chloroform-d) δ 3.99-3.90 (m, 2H), 3.78-3.69 (m, 2H), 3.63-3.49 (m, 3H), 3.49-3.39 (m, 3H), 1.97-1.88 (m, 2H), 1.67-1.52 (m, 2H).

[0446] Third Step: Compound INT-16c (10.0 g, 68.41 mmol) was dissolved in dichloromethane (100 mL), p-toluenesulfonyl chloride (19.56 g, 102.61 mmol), triethylamine (20.77 g, 205.22 mmol) and 4-dimethylaminopyridine (835.8 mg, 6.84 mmol) were added under ice bath. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (100 mL) was added into the reaction system under ice bath, the pH was adjusted to ~7 with dilute hydrochloric acid, extracted with dichloromethane (100 mL x 2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was purified by silica gel column chromatography to obtain yellow oil compound INT-16 (16.0 g, yield 77.9%). ESI-MS (m / z): 301.1 [M+H] + .

[0447] 1 H NMR (500 MHz, Chloroform-d) δ 7.85-7.78 (m, 2H), 7.39-7.31 (m, 2H), 4.19-4.15 (m, 2H), 3.93-3.84 (m, 2H), 3.71-3.62 (m, 2H), 3.50-3.44 (m, 1H), 3.44-3.35 (m, 2H), 2.46 (s, 3H), 1.87-1.76 (m, 2H), 1.57-1.46 (m, 2H).

[0448] Intermediate 17

[0449] Intermediate 17 was prepared by the following steps:

[0450] Step 1: Compound INT-7c (6 g, 6.62 mmol) was dissolved in N,N-dimethylformamide (60 mL), cesium carbonate (4.31 g, 13.23 mmol) and INT-16 (2.58 g, 8.6 mmol) were added. The reaction mixture was stirred at 60 °C for 16 hours. After the reaction was completed, ice water (200 mL) was added to the reaction system, stirred for half an hour, and then filtered to obtain white solid compound INT-17a (6.2 g, yield 90%). ESI-MS (m / z): 1035.1 [M+H] + .

[0451] Step 2: Compound INT-17a (6.2 g, 5.99 mmol) was dissolved in tetrabutylammonium fluoride (1 M, 59.89 mL). The reaction mixture was stirred at room temperature for 48 hours. After the reaction was completed, water (60 mL) was added to the reaction system, extracted with ethyl acetate (60 mL x 2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound INT-17b (1 g, yield 20%). ESI-MS (m / z): 797.9 [M+H] + .

[0452] Step 3: Compound INT-17b (1 g, 1.26 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL) was added at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (50 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-17c (850 mg, yield 97%). ESI-MS (m / z): 696.8 [M+H] + .

[0453] Fourth step: Compound INT-17c (850 mg, 1.22 mmol) was dissolved in dichloromethane (10 mL), 3-oxetanone (263.77 mg, 3.66 mmol) was added at room temperature. After the reaction mixture was stirred at room temperature for 10 minutes, sodium triacetoxyborohydride (1.03 g, 4.88 mmol) was added, and stirring was continued for 16 hours. After the reaction was completed, an aqueous sodium bicarbonate solution (30 mL) was added to the reaction system, extracted with dichloromethane (30 mL x 2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain compound INT-17d (850 mg, yield 92%) as a yellow solid. ESI-MS (m / z): 752.8 [M+H] + .

[0454] Fifth step: Compound INT-17d (850 mg, 1.13 mmol) was dissolved in 1,4-dioxane (10 mL), and potassium acetate (221.64 mg, 2.26 mmol), pinacol diboronic acid (430.13 mg, 1.69 mmol) and [1,1'-bis (di-tert-butylphosphine) ferrocene] dichloropalladium (82.62 mg, 0.11 mmol) were added in sequence. The reaction was stirred at 80°C under nitrogen atmosphere for 16 hours, and LCMS was used to monitor the completion of the reaction. Water was added to the system, and extracted with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-17 (800 mg, yield 88%) as a yellow solid. ESI-MS (m / z): 800.9 [M+H] + .

[0455] Intermediate 18

[0456] Intermediate 18 was prepared by the following steps:

[0457] Step 1 : Compound INT-18a (1 g, 9.60 mmol) was dissolved in dichloromethane (10 mL), p-toluenesulfonyl chloride (2.20 g, 11.52 mmol), triethylamine (2.91 g, 28.81 mmol) and 4-dimethylaminopyridine (117 mg, 0.96 mmol) were added under ice-bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, water (100 mL) was added to the reaction system under ice-bath, the pH was adjusted to about 7 with dilute hydrochloric acid, extracted with dichloromethane (100 mL x 2), the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain compound INT-18 (1.6 g, yield 64.5%) as a yellow oil. ESI-MS (m / z): 259.2 [M+H] + .

[0458] Intermediate 19

[0459] Intermediate 19 was prepared by the following steps:

[0460] Step 1 : Compound INT-7c (11.80 g, 13.01 mmol) was dissolved in dichloromethane (45 mL), trifluoroacetic acid (15 mL) was added to the above reaction solution at 0 °C. After the reaction was completed, saturated aqueous sodium bicarbonate solution (200 mL) was added to quench the reaction, extracted with dichloromethane (150 mL x 3), the organic phase was dried and concentrated to obtain crude INT-19a. The crude product was directly used in the next step reaction (8.65 g, yield 82.4%). ESI-MS (m / z): 806.8 [M+H] + .

[0461] Step 2: INT-19a (3.3 g, 4.09 mmol) was dissolved in dichloromethane (40 mL), 3-oxetanone (1.47 g, 20.45 mmol) was added to the above reaction solution. The reaction solution was stirred at room temperature for 1 hour. Then sodium triacetoxyborohydride (4.33 g, 20.45 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (150 mL) was added to quench the reaction, extracted with dichloromethane (150 mL x 3), the organic phase was dried and concentrated to obtain crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain INT-19b (2.3 g, yield 65.2%). ESI-MS (m / z): 862.3 [M+H] + .

[0462] Step 3: Compound INT-19b (700 mg, 0.81 mmol), INT-18 (419 mg, 1.62 mmol), cesium carbonate (792 mg, 2.43 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was stirred at 60 °C for 12 h. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (20 mL x 3), and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by column chromatography (dichloromethane / methanol = 20 / 1) to obtain INT-19c (564 mg, yield 73.3%). ESI-MS (m / z): 947.8 [M+H] + .

[0463] Step 4: Compound INT-19c (515 mg, 0.54 mmol) was dissolved in a solution of tetrabutylammonium fluoride (5.43 mL, 5.43 mmol, 1 mol / L) in tetrahydrofuran, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was extracted with ethyl acetate (30 mL x 3), and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by high performance liquid chromatography to obtain the target product INT-19d (122 mg, yield 31.6%). ESI-MS (m / z): 710.9 [M+H] + .

[0464] Step 5: Compound INT-19d (122 mg, 0.17 mmol) was dissolved in 1,4-dioxane (3 mL), and potassium acetate (50 mg, 0.51 mmol), bis(pinacolato)diboron (65 mg, 0.25 mmol) and [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (12 mg, 0.02 mmol) were added in sequence. The reaction was stirred at 85 °C under a nitrogen atmosphere for 16 h, and LCMS was used to monitor the completion of the reaction. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain yellow solid compound INT-19 (93 mg, yield 71.7%). ESI-MS (m / z): 758.7 [M+H] + .

[0465] Intermediate 20

[0466] Using 3-hydroxycyclobutanenitrile to replace INT-18a in the synthesis step of intermediate INT-18, compound INT-20 can be obtained by using similar methods and reaction steps. ESI-MS (m / z): 269.3 [M+NH4] + .

[0467] Intermediate 21

[0468] INT-21 was obtained by replacing INT-16 in the synthesis step of intermediate INT-17 with INT-20, using similar methods and reaction steps. ESI-MS (m / z): 752.1 [M+H] + .

[0469] Intermediate 22

[0470] Intermediate 22 was prepared by the following steps:

[0471] Step 1: Compound INT-19a (8.55 g, 10.60 mmol) was dissolved in tetrahydrofuran (45 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (8.88 g, 31.79 mmol, 1 M) was added to the above reaction solution at 0 °C. The reaction solution was stirred at 60 °C overnight. After the reaction was completed, ethyl acetate (150 mL x 3) was extracted, and the organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target product INT-22a (3.55 g, yield 58.93%). ESI-MS (m / z): 568.8 [M+H] + .

[0472] Step 3: INT-22a (3.60 g, 6.33 mmol) was dissolved in dichloromethane (40 mL), and 3-oxetanone (1.37 g, 19.00 mmol) was added to the above reaction solution. The reaction solution was stirred at room temperature for 1 hour. Then, sodium triacetoxyborohydride (4.03 g, 19.00 mmol) was added, and the reaction solution was stirred at room temperature for 12 hours. After the reaction was completed, saturated aqueous sodium bicarbonate solution (150 mL) was added to quench the reaction, and dichloromethane (150 mL x 3) was extracted. The organic phase was dried and concentrated to obtain a crude product. The crude product was subjected to column chromatography to obtain INT-22b (3.80 g, yield 96.08%). ESI-MS (m / z): 623.5 [M+H] + .

[0473] Step 4: Compound INT-22b (3.30 g, 5.28 mmol), INT-22c (7.48 g, 26.42 mmol), cesium carbonate (8.61 g, 26.42 mmol) were dissolved in N,N-dimethylformamide (30 mL), and the reaction was stirred at 80 °C under nitrogen protection for 12 hours. After the reaction was completed, ethyl acetate (150 mL x 3) was extracted, and the organic phase was dried and concentrated to obtain a crude product. The crude product was purified by reversed-phase column chromatography (chromatography column: welch Ultimate XB-C18 (10 um, 250 mm x 21.2 mm); mobile phase A was 10Mm ammonium bicarbonate solution, mobile phase B was acetonitrile, linear gradient elution was performed according to the following table; flow rate: 20 mL / min; ultraviolet detection wavelength: 214 nm, 254 nm, 280 nm, 320 nm; sample injection volume 0.5 mL, to obtain the target product INT-22 (1.5 g, INT-22 retention time: 1.94 min (by-product retention time: 1.89 min), yield 36.41%). ESI-MS (m / z): 779.4 [M+H] + .

[0474] Gradient elution conditions

[0475] Intermediate 23

[0476] Intermediate 23 was prepared by the following steps:

[0477] Step 1: Compound INT-23a (1.5 g, 3.28 mmol) and INT-23b (497.64 mg, 4.92 mmol) were dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (847.83 mg, 6.56 mmol) was added at room temperature. The reaction was stirred at room temperature for 16 hours, and LCMS was used to monitor the completion of the reaction. After direct concentration, ethyl acetate (10 mL) and saturated sodium dihydrogen phosphate aqueous solution (20 mL) were added to the system, and the system was further reacted at 50 °C for 16 hours. LCMS was used to monitor the completion of the reaction. Ethyl acetate (30 mL x 2) was used for extraction, and the combined organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-23c (1.2 g, yield 76%). ESI-MS (m / z): 478.4 [M+H] + .

[0478] Second Step: Compound INT-23c (1.2 g, 2.51 mmol) was dissolved in a mixed solvent of methanol (5 mL), tetrahydrofuran (5 mL) and water (5 mL), potassium hydroxide (422.23 mg, 7.53 mmol) was added at 0 °C, and the stirring was continued at room temperature for 2 hours. The reaction was monitored by LCMS. After direct concentration, saturated sodium phosphate aqueous solution (20 mL) was added to the system, and extraction was performed with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound INT-23d (0.52 g, yield 47%). ESI-MS (m / z): 436.5 [M+H] + .

[0479] Third Step: Compound INT-23d (0.52 g, 1.19 mmol) was dissolved in acetone (10 mL), and Jones reagent (1.19 mL, 2.38 mmol, 2 mol / L) was added at 0 °C. The stirring was continued at room temperature for 4 hours. The reaction was monitored by LCMS. The reaction liquid was purified by reversed-phase column chromatography to obtain compound INT-23e (0.28 g, yield 52%). ESI-MS (m / z): 450.0 [M+H] + .

[0480] Fourth Step: Compound INT-23e (280 mg, 0.62 mmol), INT-4 (201.6 mg, 0.75 mmol) and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (261.67 mg, 0.93 mmol) were dissolved in acetonitrile (5 mL), and N-methylimidazole (153.14 mg, 1.87 mmol) was added at 0 °C. The stirring was continued at 0 °C for 2 hours. The reaction was monitored by LCMS. Water (10 mL) was added to the system to quench the reaction, and extraction was performed with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain white solid compound INT-23 (280 mg, yield 76%). ESI-MS (m / z): 588.5 [M+H] + .

[0481] Intermediate 24

[0482] Compound INT-24 can be obtained by replacing INT-23b in the synthesis step of intermediate INT-23 with ethanol, using similar methods and reaction steps. ESI-MS (m / z): 533.5 [M+H] + .

[0483] Intermediate 25

[0484] Compound INT-25 was obtained by replacing INT-16 in the synthesis step of intermediate INT-17 with iodocyclobutane, in a similar manner and reaction procedure. ESI-MS (m / z): 726.9 [M+H] + .

[0485] Intermediate 26

[0486] Intermediate 26 was prepared by the following steps:

[0487] Step 1: Compound INT-5 (10.0 g, 20.43 mmol) was dissolved in 1,4-dioxane (100 mL), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (974.1 mg, 2.04 mmol), tris(dibenzylideneacetone)dipalladium (935.6 mg, 1.02 mmol) and potassium acetate (6.02 g, 61.30 mmol) were added successively. The reaction mixture was stirred at 110 °C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was filtered and concentrated. The residue was dissolved in methyl tert-butyl ether (100 mL), water (100 mL) was added, and the pH was adjusted to 9 with sodium carbonate solution. It was extracted with methyl tert-butyl ether (50 mL x 2), and the organic phase was discarded. The aqueous phase was adjusted to pH 7 with dilute hydrochloric acid, extracted with ethyl acetate (50 mL x 2), the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain white solid compound INT-26 (6.5 g, yield 70.0%). ESI-MS (m / z): 455.2 [M+H] + .

[0488] Intermediate 27

[0489] Intermediate 27 was prepared by the following steps:

[0490] Step 1: Dissolve INT-17d (1.6 g, 2.13 mmol), INT-26 (1.35 g, 2.98 mmol), [1,1'- bis(ditertbutylphosphino)ferrocene]dichloropalladium (137.25 mg, 0.21 mmol), potassium carbonate (881.33 mg, 6.38 mmol) in a mixed solvent of 1,4-dioxane (20 mL) and water (2 mL), and stir the reaction solution at 80 °C under a nitrogen atmosphere for 5 hours. After the reaction is completed, filter the reaction solution, concentrate the filtrate, and purify the residue by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to obtain compound INT-27a (2 g, yield 86%). ESI-MS (m / z): 1083.5 [M+H] + .

[0491] Step 2: Dissolve INT-27a (2.8 g, 2.59 mmol) in a mixed solvent of tetrahydrofuran (30 mL) and water (3 mL), and add lithium hydroxide monohydrate (325.66 mg, 7.76 mmol) to the above reaction solution at 0 °C. Stir the reaction solution at 0 °C for 3 hours. After the reaction is completed, directly purify by reverse-phase preparative liquid chromatography to obtain compound INT-27b (2.5 g, yield 90%). ESI-MS (m / z): 1069.5 [M+H] + .

[0492] Step 3: Dissolve N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (1.31 g, 4.68 mmol) and N-methylimidazole (960.66 mg, 11.7 mmol) in acetonitrile (100 mL), and add INT-27b (2.5 g, 2.34 mmol) dissolved in tetrahydrofuran (50 mL) dropwise to the above reaction solution at 0 °C. After the dropwise addition is completed, stir the reaction solution at 0 °C for one hour. After the reaction is completed, quench the reaction by adding water (50 mL), extract with ethyl acetate (50 mL x 3), dry and concentrate the organic phase to obtain a crude product. Purify the crude product by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain the target product INT-27c (2.4 g, yield 97%). ESI-MS (m / z): 1051.1 [M+H] + .

[0493] Step 4: Compound INT-27c (1.2 g, 01.14 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (5 mL) was added at 0 degree. The reaction mixture was stirred at 0 degree for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (50 mL x 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound INT-27 (1 g, yield 92%). ESI-MS (m / z): 951.3 [M+H] + .

[0494] Example 1

[0495] (2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-hydroxy-3-methylbutanamide

[0496] Example 1 was prepared by the following steps:

[0497] Step 1: Compound INT-2 (200 mg, 0.40 mmol) was dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL), and INT-1 (332 mg, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (29 mg, 0.040 mmol) and potassium phosphate (251 mg, 1.20 mmol) were added successively. The reaction mixture was stirred at 70 °C for 16 hours under nitrogen protection. After the reaction was completed, water (40 mL) was added to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative thin layer chromatography (ethyl acetate) to obtain compound 1a (300 mg, yield 76.1%) as a light yellow solid. ESI-MS (m / z): 988.0 [M+H] + .

[0498] Step 2: Compound 1a (300 mg, 0.30 mmol) was dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (198 mg, 0.61 mmol) and iodoethane (71 mg, 0.46 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction system, extracted with ethyl acetate (60 mL*3), the organic phase was combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative thin layer chromatography (petroleum ether / ethyl acetate = 1:2) to obtain compound 1b (110 mg, yield 35.7%) as a light yellow solid. ESI-MS (m / z): 1016.9 [M+H] + .

[0499] Step 3: Compound 1b (110 mg, 0.108 mmol), 10% palladium hydroxide (22 mg), 10% palladium on carbon (22 mg) and isopropanol (5 mL) were added to the reaction bottle. The reaction mixture was stirred at 60 °C for 16 hours under hydrogen atmosphere. The reaction liquid was filtered through diatomite, and the filtrate was concentrated to obtain compound 1c (85 mg, yield 89.0%). ESI-MS (m / z): 882.2 [M+H] + .

[0500] Fourth step: Compound 1c (250 mg, 0.283 mmol) was dissolved in 1,2-dichloroethane (6 mL), and an aqueous formaldehyde solution (69 mg, 37%) was added at room temperature. The reaction solution was stirred at room temperature for 10 minutes. Then sodium borohydride acetate (300 mg, 1.42 mmol) was slowly added to the reaction solution, and the reaction solution was continuously stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL) to the reaction system, extracted with ethyl acetate (40 mL*3), and the organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (dichloromethane / methanol = 10:1) to obtain compound 1d (208 mg, yield 81.9%) as a light yellow solid. ESI-MS (m / z): 896.5 [M+H] + .

[0501] Fifth step: Compound 1d (70 mg, 0.078 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the pH of the reaction system was adjusted to 8 by adding saturated sodium bicarbonate solution under ice bath, extracted with dichloromethane (40 mL*3), and the organic phases were combined and washed with saturated brine (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1e (60 mg, yield 96.5%) as a light yellow solid. ESI-MS (m / z): 796.8 [M+H] + .

[0502] Sixth step: To a solution of compound 1e (30 mg, 0.038 mmol) in N,N-dimethylformamide (3 mL), (S)-2-hydroxy-3-methylbutanoic acid (4.5 mg, 0.038 mmol), N,N-diisopropylethylamine (14.6 mg, 0.113 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14 mg, 0.038 mmol) were added in sequence under ice bath condition. The reaction solution was continuously stirred at this condition for 2 hours. After the reaction was completed, water (20 mL) was added to the system, extracted with ethyl acetate (30 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to obtain compound 1 (13 mg, yield 38.5%) as a white solid. ESI-MS (m / z): 896.4 [M+H] + ; LC-MS retention time RT = 1.70 min.

[0503] 1H NMR (500 MHz, DMSO-d6) δ 9.32 (d, J = 2.0 Hz, 1H), 8.54 - 8.50 (m, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.86 (s, 1H), 7.78 (dd, J = 8.5, 1.6 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.62 - 5.55 (m, 2H), 5.18 - 5.13 (m, 1H), 4.42 - 4.35 (m, 2H), 4.27 - 4.20 (m, 2H), 4.15 - 4.07 (m, 1H), 3.73 - 3.70 (m, 1H), 3.61 - 3.57 (m, 2H), 3.30 (s, 3H), 3.03 - 2.98 (m, 2H), 2.81 - 2.75 (m, 3H), 2.45 - 2.42 (m, 1H), 2.18 (s, 3H), 2.13 - 2.00 (m, 7H), 1.86 - 1.77 (m, 4H), 1.55 - 1.48 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 1.25 - 1.23 (m, 1H), 0.96 (d, J = 7.0 Hz, 3H), 0.92 (s, 3H), 0.91 - 0.86 (m, 6H), 0.36 (s, 3H).

[0504] Example 2

[0505] (2R)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-hydroxy-3-methylbutanamide

[0506] Compound 2 was synthesized by replacing (S)-2-hydroxy-3-methylbutanoic acid with (R)-2-hydroxy-3-methylbutanoic acid in the synthesis of Compound 1 using similar methods and reaction sequences. ESI-MS (m / z): 896.7 [M+H] + ; LC-MS retention time RT = 1.66 min.

[0507] 1 H NMR (500 MHz, DMSO-d6) δ 9.32 (d, J = 2.0 Hz, 1H), 8.53 (d, J = 1.5 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.62 - 5.55 (m, 1H), 5.37 - 5.31 (m, 1H), 5.17 - 5.13 (m, 1H), 4.41 - 4.35 (m, 2H), 4.27 - 4.20 (m, 2H), 4.15 - 4.08 (m, 1H), 3.82 - 3.78 (m, 1H), 3.61 - 3.56 (m, 2H), 3.30 (s, 3H), 3.04 - 2.98 (m, 2H), 2.82 - 2.75 (m, 3H), 2.46 - 2.42 (m, 1H), 2.18 (s, 3H), 2.13 - 1.98 (m, 7H), 1.87 - 1.76 (m, 4H), 1.58 - 1.46 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 1.23 (s, 1H), 0.94 (d, J = 7.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.78 (d, J = 6.5 Hz, 3H), 0.37 (s, 3H).

[0508] Example 3

[0509] (2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-(1-methylazetidin-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,66 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-hydroxy-3-methylbutanamide

[0510] Example 3 was prepared from the following steps:

[0511] First step: Compound 1c (165 mg, 0.19 mmol) was dissolved in 1,2-dichloroethane (5 mL), to which 1-benzyloxycarbonylazetidin-3-one (115 mg, 0.56 mmol) was added at room temperature. After 20 minutes, sodium borohydride (198 mg, 0.94 mmol) was slowly added to the reaction, which continued to stir at room temperature for 16 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL) to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin layer chromatography (dichloromethane / methanol = 20:1) to obtain compound 3a (163 mg, yield 81.3%) as a light yellow solid. ESI-MS (m / z): 1071.9 [M+H] + .

[0512] Second step: Compound 3a (163 mg, 0.108 mmol), 10% palladium hydroxide (33 mg), 10% palladium on carbon (33 mg) and methanol (5 mL) were added to the reaction bottle. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction was filtered through diatomite, and the filtrate was concentrated to obtain the crude product 3b. ESI-MS (m / z): 937.2 [M+H] + .

[0513] Third step: The above crude product 3b was dissolved in 1,2-dichloroethane (5 mL), to which aqueous formaldehyde solution (37 mg, 37%) was added at room temperature. After 10 minutes, sodium borohydride (161 mg, 0.76 mmol) was slowly added to the reaction, which continued to stir at room temperature for 3 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL) to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin layer chromatography (dichloromethane / methanol = 10:1) to obtain compound 3c (77 mg, two-step yield 53.2%) as a light yellow solid. ESI-MS (m / z): 951.1 [M+H]+ .

[0514] Fourth step: Compound 3c (77 mg, 0.081 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (40 mL*2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 3d (62 mg, yield 90.0%) as a light yellow solid. ESI-MS (m / z): 851.2 [M+H] + .

[0515] Fifth step: To the solution of compound 3d (31 mg, 0.036 mmol) in N,N- dimethylformamide (3 mL), (S)-2-hydroxy-3-methylbutanoic acid (4.3 mg, 0.036 mmol), N,N- diisopropylethylamine (14 mg, 0.109 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (13.9 mg, 0.036 mmol) were added in turn under ice bath condition, and the reaction was continued to stir for 2 hours. After the reaction was completed, water (20 mL) was added to the system, extracted with ethyl acetate (40 mL*3), the organic phase was dried, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to obtain compound 3 (12 mg, yield 34.6%) as a white solid. ESI-MS (m / z): 851.9 [M+H] + LC-MS retention time RT = 1.65 min.

[0516] 1H NMR (500 MHz, DMSO-d6) δ 9.32 (d, J = 2.0 Hz, 1H), 8.54 - 8.49 (m, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.86 (s, 1H), 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.62 - 5.56 (m, 2H), 5.19 - 5.13 (m, 1H), 4.42 - 4.35 (m, 2H), 4.27 - 4.20 (m, 2H), 4.15 - 4.08 (m, 1H), 3.73 - 3.70 (m, 1H), 3.60 - 3.57 (m, 2H), 3.30 (s, 3H), 3.06 - 3.00 (m, 2H), 2.83 - 2.68 (m, 7H), 2.45 - 2.41 (m, 1H), 2.22 (s, 3H), 2.13 - 2.09 (m, 1H), 2.08 - 1.89 (m, 7H), 1.83 - 1.74 (m, 4H), 1.55 - 1.49 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 1.32 - 1.26 (m, 1H), 0.98 - 0.95 (m, 3H), 0.92 (s, 3H), 0.90 - 0.86 (m, 6H), 0.36 (s, 3H).

[0517] Example 4

[0518] (2R)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-(1-methylazetidin-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-hydroxy-3-methylbutanamide

[0519] Compound 4 was synthesized by replacing (S)-2-hydroxy-3-methylbutanoic acid with (R)-2-hydroxy-3-methylbutanoic acid in the synthesis of compound 3 using similar methods and reaction procedures. ESI-MS (m / z): 851.2 [M+H] + ; LC-MS retention time RT = 1.61 min.

[0520] 1 H NMR (500 MHz, DMSO-d6) δ 9.32 (d, J = 2.0 Hz, 1H), 8.55 - 8.51 (m, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.78 (dd, J = 8.5, 1.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.61 - 5.55 (m, 1H), 5.38 - 5.31 (m, 1H), 5.17 - 5.12 (m, 1H), 4.41 - 4.35 (m, 2H), 4.26 - 4.20 (m, 2H), 4.15 - 4.08 (m, 1H), 3.82 - 3.79 (m, 1H), 3.60 - 3.57 (m, 2H), 3.30 (s, 3H), 3.07 - 2.99 (m, 2H), 2.85 - 2.80 (m, 1H), 2.79 - 2.66 (m, 6H), 2.47 - 2.42 (m, 1H), 2.22 (s, 3H), 2.13 - 1.97 (m, 5H), 1.96 - 1.89 (m, 2H), 1.85 - 1.75 (m, 4H), 1.55 - 1.48 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 1.32 - 1.25 (m, 1H), 0.94 (d, J = 7.0 Hz, 3H), 0.92 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H), 0.78 (d, J = 7.0 Hz, 3H), 0.37 (s, 3H).

[0521] Example 5

[0522] (2R)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,64 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-hydroxy-3-methylbutanamide

[0523] Compound 5 can be obtained by replacing the aqueous formaldehyde solution in the synthesis of Compound 1 with 3-oxetanone, (R)-2-hydroxy-3-methylbutanoic acid for (S)-2-hydroxy-3-methylbutanoic acid, using similar methods and reaction procedures. ESI-MS (m / z): 938.9 [M+H] + ; LC-MS retention time RT = 1.63 min.

[0524] 1 H NMR (500 MHz, DMSO-d6) δ 9.33 (d, J = 2.0 Hz, 1H), 8.53 (s, 1H), 8.34 - 8.27 (m, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.61 - 5.55 (m, 1H), 5.40 - 5.29 (m, 1H), 5.19 - 5.11 (m, 1H), 4.53 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 4.41 - 4.35 (m, 2H), 4.27 - 4.19 (m, 2H), 4.15 - 4.07 (m, 1H), 3.82 - 3.78 (m, 1H), 3.61 - 3.56 (m, 2H), 3.43 - 3.41 (m, 2H), 3.30 (s, 3H), 3.11 - 3.06 (m, 1H), 3.03 - 2.98 (m, 1H), 2.80 - 2.70 (m, 3H), 2.46 - 2.42 (m, 1H), 2.13 - 2.06 (m, 3H), 2.05 - 1.91 (m, 4H), 1.88 - 1.76 (m, 4H), 1.56 - 1.48 (m, 1H), 1.41 (d, J = 6.0 Hz, 3H), 0.97 - 0.90 (m, 6H), 0.88 (t, J = 7.0 Hz, 3H), 0.78 (d, J = 6.5 Hz, 3H), 0.37 (s, 3H).

[0525] Example 6

[0526] (2R)-2-hydroxy-N-((6 3 S,4S,Z)-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-1 1 -(2,2,2-trifluoroethyl)-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-3-methylbutanamide

[0527] Replacing compound 1e in the synthesis of compound 1 with compound INT-9, (R)-2-hydroxy-3-methylbutanoic acid in place of (S)-2-hydroxy-3-methylbutanoic acid, compound 6 can be obtained in a similar manner and reaction sequence. ESI-MS (m / z): 992.9 [M+H]; LC-MS retention time RT = 1.68 min. + ; LC-MS retention time RT = 1.68 min.

[0528] 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J = 2.0 Hz, 1H), 8.56 - 8.51 (m, 1H), 8.29 - 8.26 (m, 1H), 8.06 (d, J = 9.5 Hz, 1H), 7.91 (s, 1H), 7.87 (dd, J = 9.0, 1.5 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 5.71 - 5.61 (m, 1H), 5.59 - 5.53 (m, 1H), 5.37 - 5.31 (m, 1H), 5.15 - 5.11 (m, 1H), 4.91 - 4.81 (m, 1H), 4.54 (t, J = 6.5 Hz, 2H), 4.43 (t, J = 6.0 Hz, 2H), 4.37 - 4.32 (m, 1H), 4.29 - 4.21 (m, 2H), 3.83 - 3.79 (m, 1H), 3.61 - 3.56 (m, 2H), 3.43 - 3.41 (m, 2H), 3.33 (s, 3H), 3.10 - 3.03 (m, 2H), 2.79 - 2.70 (m, 3H), 2.46 - 2.42 (m, 1H), 2.13 - 2.06 (m, 3H), 2.04 - 1.93 (m, 4H), 1.87 - 1.78 (m, 4H), 1.55 - 1.49 (m, 1H), 1.42 (d, J = 6.0 Hz, 3H), 0.96 - 0.91 (m, 6H), 0.78 (d, J = 7.0 Hz, 3H), 0.33 (s, 3H).

[0529] Example 7

[0530] (2S)-N-((6 3 S,4S,Z)-1 1 -ethyl-1 2 -(2-((S)-1-methoxyethyl)-5-(5-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-6 1 ,6 2 ,6 3 ,6 4 ,6 5 ,6 6 -hexahydro-1 1 H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-hydroxy-3-methylbutanamide

[0531] Example 7 was prepared by the following steps:

[0532] First Step: Compound INT-1 (18.5 g, 26.67 mmol) was dissolved in dichloromethane (80 mL), trifluoroacetic acid (40 mL) was added, and the reaction was stirred at room temperature for 4 hours. LCMS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL), washed twice with saturated aqueous sodium bicarbonate solution, washed with water (80 mL), dried over sodium sulfate, filtered, and concentrated to obtain yellow solid compound 7a (15.5 g, yield 97.9%). ESI-MS (m / z): 594.3 [M+H] + .

[0533] Second Step: To a solution of compound 7a (1.0 g, 1.68 mmol) in N,N-dimethylformamide (10 mL), (S)-2-hydroxy-3-methylbutanoic acid (199 mg, 1.68 mmol), N,N-diisopropylethylamine (653 mg, 5.05 mmol), and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (641 mg, 1.68 mmol) were added successively under ice bath conditions. The reaction was stirred at this condition for 2 hours. After the reaction was completed, water (50 mL) was added to the system, and the reaction was extracted with ethyl acetate (60 mL*3). The organic phase was washed with water (50 mL*3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:8) to obtain yellow solid compound 7b (853 mg, yield 73.0%). ESI-MS (m / z): 694.7 [M+H] + .

[0534] Third Step: Compound 7b (108 mg, 0.155 mmol) was dissolved in a mixture of 1,4-dioxane (4 mL) and water (0.4 mL), and INT-3 (84 mg, 0.141 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), and potassium phosphate (90 mg, 0.423 mmol) were added successively. The reaction mixture was stirred at 70°C under nitrogen protection for 16 hours. After the reaction was completed, water (40 mL) was added to the reaction system, and the reaction was extracted with ethyl acetate (40 mL*3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude compound 7c. ESI-MS (m / z): 1083.5 [M+H] + .

[0535] Fourth step: The above crude compound 7c was dissolved in N,N-dimethylformamide (4 mL), and cesium carbonate (138 mg, 0.423 mmol) and iodoethane (66 mg, 0.423 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (40 mL) was added to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phase was combined and washed with water (30 mL*2) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative thin layer chromatography (dichloromethane / methanol = 20:1) to obtain compound 7d (83 mg, yield 53.0%). ESI-MS (m / z): 1111.3 [M+H] + .

[0536] Fifth step: Compound 7d (83 mg, 0.075 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (40 mL*3), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain crude compound 7e. ESI-MS (m / z): 881.3 [M+H] + .

[0537] Sixth step: The above crude product 7e was dissolved in 1,2-dichloroethane (3 mL), and aqueous formaldehyde solution (19 mg, 37%) was added at room temperature. After 10 minutes, sodium borohydride acetate (79 mg, 0.373 mmol) was slowly added to the reaction solution, and the reaction solution was continued to be stirred at room temperature for 3 hours. Saturated ammonium chloride aqueous solution (5 mL) was added to the reaction system to quench the reaction, extracted with ethyl acetate (40 mL*3), the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin layer chromatography (dichloromethane / methanol = 12:1) and preparative liquid chromatography to obtain white solid compound 7 (13 mg, two-step yield 19.5%). ESI-MS (m / z): 895.1 [M+H] + ; LC-MS retention time RT = 1.58 min.

[0538] 1H NMR (500 MHz, DMSO-d6) δ 9.29 (d, J = 2.0 Hz, 1H), 8.53 - 8.50 (m, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 9.5 Hz, 1H), 7.84 (s, 1H), 7.78 - 7.74 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 5.62 - 5.52 (m, 2H), 5.17 - 5.12 (m, 1H), 4.39 - 4.31 (m, 2H), 4.27 - 4.22 (m, 2H), 4.17 - 4.11 (m, 1H), 3.73 - 3.71 (m, 1H), 3.60 - 3.57 (m, 2H), 3.29 (s, 3H), 3.03 - 2.99 (m, 1H), 2.84 - 2.74 (m, 5H), 2.43 - 2.41 (m, 1H), 2.18 (s, 3H), 2.13 - 2.08 (m, 1H), 2.05 - 1.91 (m, 7H), 1.83 - 1.76 (m, 4H), 1.54 - 1.49 (m, 1H), 1.40 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H), 0.92 - 0.85 (m, 9H), 0.37 (s, 3H).

[0539] Example 8

[0540] Compound 8 was obtained by replacing compound le in the synthesis of compound 1 with compound INT-8, (R)-2-hydroxy-3-methylbutyric acid instead of (S)-2-hydroxy-3-methylbutyric acid, using similar methods and reaction procedures. ESI-MS (m / z): 1004.5 [M+H] + ; LC-MS retention time RT = 1.76 min.

[0541] 1H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 8.9 Hz, 1H), 7.92 (s, 1H), 7.87 (dd, J = 8.8, 1.6 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 6.01 (d, J = 11.1 Hz, 1H), 5.73 - 5.59 (m, 1H), 5.41 (d, J = 5.9 Hz, 1H), 5.37 - 5.29 (m, 1H), 4.86 (dd, J = 16.8, 9.0 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.52 (dt, J = 11.0, 5.9 Hz, 3H), 4.43 (t, J = 6.1 Hz, 2H), 4.35 (q, J = 6.0 Hz, 1H), 3.83 (dd, J = 5.9, 3.6 Hz, 1H), 3.62 - 3.49 (m, 5H), 3.41 (t, J = 6.4 Hz, 1H), 3.35 (s, 1H), 3.31 (s, 1H), 3.11 - 3.02 (m, 2H), 2.73 (s, 2H), 2.68 - 2.63 (m, 1H), 2.44 (s, 2H), 2.34 (dd, J = 11.7, 6.3 Hz, 1H), 2.15 (t, J = 9.8 Hz, 1H), 2.08 (d, J = 8.1 Hz, 2H), 2.02 (td, J = 6.9, 3.6 Hz, 1H), 1.97 (t, J = 11.8 Hz, 2H), 1.83 (d, J = 12.6 Hz, 2H), 1.64 (t, J = 9.3 Hz, 1H), 1.42 (d, J = 6.0 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 0.92 (s, 3H), 0.80 (d, J = 6.8 Hz, 3H), 0.30 (s, 3H).

[0542] Example 9

[0543] (2S)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide

[0544] Example 9 was prepared by the following steps:

[0545] First step: Compound INT-12 (15 mg, 0.018 mmol), BOC-N-methyl-L-valine (6 mg, 0.027 mmol) and N,N-diisopropyl ethylamine (7 mg, 0.054 mmol) were dissolved in N,N-dimethylformamide (2 mL), HATU (13 mg, 0.033 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to obtain compound 9a (13 mg, yield 69%) in yellow oil. ESI-MS (m / z): 1050.7 [M+H] + .

[0546] Second step: Compound 9a (13 mg, 0.012 mmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (40 mL*3), and the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the residue was purified by preparative liquid chromatography to obtain compound 9 (6 mg, yield 35%) in white solid. ESI-MS (m / z): 950.5 [M+H] + ; LC-MS retention time RT = 1.58 min.

[0547] Example 10

[0548] (2R)-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-3-methyl-2-(methylamino)butanamide

[0549] Compound 10 can be obtained by replacing compound BOC-N-methyl-L-valine in the synthesis of compound 9 with compound Boc-N-methyl-D-valine, using similar methods and reaction procedures. ESI-MS (m / z): 950.5 [M+H] + ; LC-MS retention time RT = 1.57 min.

[0550] Example 11

[0551] N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-1-hydroxycyclopropane-1-carboxamide

[0552] Compound 11 can be obtained by replacing INT-13 in the synthesis of compound 1 with INT-12, 1-hydroxycyclopropane carboxylic acid in place of (S)-2-hydroxy-3-methylbutanoic acid, using similar methods and reaction procedures. ESI-MS (m / z): 922.2 [M+H] + ; LC-MS retention time RT = 1.54 min.

[0553] Example 12

[0554] (2R)-2-cyclopentyl-N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-2-hydroxyacetamide

[0555] Replacing INT-13 in the synthesis of Compound 1 with INT-12, (R)-2-cyclopentyl-2- hydroxyacetic acid in place of (S)-2-hydroxy-3-methylbutanoic acid, Compound 12 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 964.8 [M+H] + ; LC-MS retention time RT = 1.66 min.

[0556] Example 13

[0557] N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-1-hydroxycyclobutane-1-carboxamide

[0558] Replacing INT-13 in the synthesis of Compound 1 with INT-12, 1-hydroxycyclobutane carboxylic acid in place of (S)-2-hydroxy-3-methylbutanoic acid, Compound 13 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 936.1 [M+H] +LC-MS retention time RT = 1.59 min.

[0559] Example 14

[0560] N-((63S,4S,Z)-11-ethyl-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-61,62,63,64,65,66-hexahydro-11H-8-oxa-2(4,2)-thiazola-1(5,3)-indola-6(1,3)-pyridazinacycloundecaphane-4-yl)-1-hydroxycyclopentane-1-carboxamide

[0561] Replacing INT-13 with INT-12 and (S)-2-hydroxy-3-methylbutanoic acid with 1- hydroxy-cyclopentanecarboxylic acid in the synthesis of Compound 1, Compound 14 can be obtained using similar methods and reaction procedures. ESI-MS (m / z): 950.2 [M+H] + LC-MS retention time RT = 1.63 min.

[0562] Example 15

[0563] (2R)-2-hydroxy-N-((64S,4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(5-(piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methylbutanamide

[0564] Example 15 is prepared from the following steps:

[0565] Step 1: Compound INT-7e (217 mg, 0.318 mmol) was dissolved in 1,4-dioxane (5 mL) and water (0.5 mL). INT-15 (130 mg, 0.265 mmol), potassium carbonate (110 mg, 0.796 mmol), and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (17 mg, 0.026 mmol) were added sequentially. The reaction mixture was stirred at 50 °C under a nitrogen atmosphere for 16 hours. Water (40 mL) was added to the system, and the mixture was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95:5) to give a pale yellow solid compound 15a (153 mg, yield 53.3%). ESI-MS (m / z): 1081.3 [M+H] + .

[0566] Step 2: Compound 15a (64 mg, 0.059 mmol) was dissolved in tetrahydrofuran (5 mL) and water (2.5 mL). Lithium hydroxide monohydrate (4.26 mg, 0.177 mmol) was added at 0 °C, and stirring was continued for 1 hour. The mixture was diluted with water (20 mL), adjusted to pH 5 with dilute hydrochloric acid, and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated to give a pale yellow solid, compound 15b (51 mg, yield 80.7%). ESI-MS (m / z): 1067.1 [M+H] + .

[0567] Step 3: N,N,N',N'-Tetramethylchloromethanesulfonamide hexafluorophosphate (26.8 mg, 0.096 mmol) and 1-methylimidazole (19.6 mg, 0.026 mmol) were added to acetonitrile (10 mL), stirred until dissolved, and a THF solution of compound 15b (51 mg, 0.047 mmol) in 5 mL was added dropwise at room temperature. After the addition was complete, the mixture was stirred for 1 hour. Water (40 mL) was added to the system, and the mixture was extracted with ethyl acetate (40 mL * 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 95:5) to give a pale yellow solid compound 15c (28 mg, yield 55.8%). ESI-MS (m / z): 1049.1 [M+H] + .

[0568] Step 4: Compound 15c (28 mg, 0.026 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (20 mL*2), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative liquid chromatography to obtain white solid compound 15 (10 mg, yield 39.5%). ESI-MS (m / z): 948.4 [M+H] + ; LC-MS retention time RT = 1.53 min.

[0569] 1 H NMR (500 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.27 (d, J = 26.9 Hz, 1H), 8.15 - 8.00 (m, 1H), 7.97 - 7.66 (m, 4H), 6.00 (d, J = 11.2 Hz, 1H), 5.71 - 5.56 (m, 1H), 5.35 (d, J = 27.0 Hz, 2H), 4.94 - 4.80 (m, 1H), 4.74 (d, J = 11.0 Hz, 1H), 4.57 - 4.31 (m, 3H), 4.05 - 3.99 (m, 1H), 3.97 - 3.90 (m, 1H), 3.82 (s, 1H), 3.31 (s, 3H), 3.05 - 3.00 (m, 1H), 2.89 (s, 2H), 2.68 - 2.61 (m, 1H), 2.45 - 2.41 (m, 2H), 2.38 - 2.29 (m, 3H), 2.17 - 2.09 (m, 1H), 2.04 - 1.98 (m, 1H), 1.91 - 1.80 (m, 1H), 1.68 - 1.58 (m, 1H), 1.45 - 1.32 (m, 4H), 1.31 - 1.20 (m, 1H), 1.17 - 1.08 (m, 1H), 0.98 - 0.87 (m, 6H), 0.80 (s, 3H), 0.29 (s, 3H).

[0570] Example 16

[0571] (2R)-2-hydroxy-N-((64S,4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(5-(1'-methyl-[1,4'-bipiperidin]-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methylbutanamide

[0572] Example 16 was prepared by the following steps:

[0573] First step: Compound INT14 (35 mg, 0.037 mmol) was dissolved in 1,2-dichloroethane (6 mL), N-methyl-4-piperidone (12.5 mg, 0.11 mmol) was added to it at room temperature. After 20 minutes, sodium borohydride (39 mg, 0.184 mmol) was slowly added to the reaction, and the reaction was continued to stir at room temperature for 2 hours. The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL) to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by preparative thin layer chromatography (dichloromethane / methanol = 8:1) to obtain compound 16a (22 mg, yield 57%) as a colorless oil. ESI-MS (m / z): 1043.8 [M+H] + .

[0574] Second step: Compound 16a (22 mg, 0.021 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (2 mL) was added to it under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (20 mL*2), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 16b (19 mg, yield 96%) as a light yellow solid. ESI-MS (m / z): 944.8 [M+H] + .

[0575] Step 3: To a solution of compound 16b (19 mg, 0.20 mmol) in N,N- dimethylformamide (2 mL) was added (R)-2-hydroxy-3-methylbutanoic acid (3.7 mg, 0.031 mmol), N,N-diisopropyl ethylamine (8.2 mg, 0.063 mmol) and 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (14.4 mg, 0.038 mmol) successively under ice-bath condition. The reaction was continued to stir for 2 hours under the same condition. The reaction was purified by preparative liquid chromatography to give compound 16 (4 mg, yield 18.1%) as a white solid. ESI-MS (m / z): 1044.5 [M+H] + ; LC-MS retention time RT = 1.56 min.

[0576] 1 H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J = 2.1 Hz, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 8.9 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H), 6.02 (d, J = 11.0 Hz, 1H), 5.70 - 5.61 (m, 1H), 5.46 - 5.39 (m, 1H), 5.37 - 5.30 (m, 1H), 4.94 - 4.81 (m, 1H), 4.76 (d, J = 11.1 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.39 - 4.32 (m, 1H), 3.83 (d, J = 3.6 Hz, 1H), 3.58 - 3.51 (m, 5H), 3.33 (s, 3H), 3.09 - 3.02 (m, 3H), 2.94 - 2.88 (m, 2H), 2.83 - 2.79 (m, 2H), 2.69 - 2.63 (m, 2H), 2.35 - 2.27 (m, 3H), 2.15 (s, 3H), 2.10 - 2.00 (m, 4H), 1.92 - 1.84 (m, 2H), 1.81 - 1.76 (m, 2H), 1.71 - 1.63 (m, 3H), 1.51 - 1.46 (m, 1H), 1.43 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.92 (s, 3H), 0.81 (d, J = 6.8 Hz, 3H), 0.31 (s, 3H).

[0577] Example 17

[0578] (2R)-2-hydroxy-N-((64S,4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(1-methylazetidin-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methylbutanamide

[0579] Example 17 was prepared from the following steps:

[0580] First Step: Compound INT14 (171 mg, 0.18 mmol) was dissolved in 1,2-dichloroethane (6 mL), to which 1-benzyloxycarbonyl-3-ketazetidine (111 mg, 0.54 mmol) was added at room temperature. After 20 minutes, sodium borohydride (191 mg, 0.901 mmol) was slowly added to the reaction, which was continued to stir at room temperature for 16 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL) to the reaction system, extracted with ethyl acetate (40 mL*3), the organic phases were combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and the organic phase was concentrated and purified by silica gel column chromatography (dichloromethane / methanol = 93:7) to obtain compound 17a (180 mg, yield 87%) as a colorless oil. ESI-MS (m / z): 1137.4 [M+H] + .

[0581] Second Step: Compound 17a (180 mg, 0.158 mmol), 10% palladium hydroxide (18 mg), 10% palladium on carbon (18 mg) and methanol (5 mL) were added to the reaction bottle. The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction was filtered through celite, and the filtrate was concentrated to obtain compound 17b (150 mg, yield 94.5%). ESI-MS (m / z): 1003.3 [M+H] + .

[0582] Step 3: Compound 17b (150 mg, 0.119 mmol) was dissolved in methanol (5 mL), and aqueous formaldehyde (0.5 mL) was added to it at room temperature. After 20 minutes, sodium borohydride (127 mg, 0.598 mmol) was slowly added to the reaction solution, and the reaction solution was continuously stirred at room temperature for 16 hours. The reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL) to the reaction system, extracted with ethyl acetate (40 mL*3), and the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane / methanol = 8:1) to obtain compound 17c (60 mg, yield 49.3%) as a colorless oil. ESI-MS (m / z): 1016.8 [M+H] + .

[0583] Step 4: Compound 17c (10 mg, 0.009 mmol) was dissolved in dichloromethane (6 mL), and trifluoroacetic acid (1 mL) was added to it under ice bath. The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, saturated sodium bicarbonate solution was added to the reaction system under ice bath to adjust pH = 8, extracted with dichloromethane (20 mL*2), and the organic phase was combined and washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 17d (ESI-MS (m / z): 917.3 [M+H] + .

[0584] Step 5: To a solution of compound 17d (9 mg, 0.009 mmol) in N,N-dimethylformamide (2 mL), (R)-2-hydroxy-3-methylbutanoic acid (1.74 mg, 0.015 mmol), N,N-diisopropylethylamine (3.81 mg, 0.029 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (6.73 mg, 0.017 mmol) were added successively under ice bath, and the reaction solution was continuously stirred at this condition for 2 hours. The reaction solution was purified by preparative liquid chromatography to obtain compound 17 (5 mg, yield 50%) as a white solid. ESI-MS (m / z): 1016.8 [M+H] + ; LC-MS retention time RT = 1.53 min.

[0585] 1H NMR (500 MHz, DMSO-d6) δ 9.35 (d, J = 2.1 Hz, 1H), 8.46 (s, 1H), 8.28 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.92 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 6.02 (d, J = 11.1 Hz, 1H), 5.71 - 5.61 (m, 1H), 5.46 - 5.39 (m, 1H), 5.37 - 5.29 (m, 1H), 4.93 - 4.82 (m, 1H), 4.76 (d, J = 11.0 Hz, 1H), 4.54 - 4.49 (m, 1H), 4.40 - 4.33 (m, 1H), 3.83 (d, J = 3.6 Hz, 1H), 3.57 - 3.55 (m, 4H), 3.33 (s, 3H), 3.09 - 3.01 (m, 2H), 2.87 - 2.82 (m, 2H), 2.79 - 2.76 (m, 2H), 2.74 - 2.69 (m, 2H), 2.68 - 2.64 (m, 2H), 2.36 - 2.34 (m, 1H), 2.23 (s, 3H), 2.18 - 2.12 (m, 1H), 2.09 - 2.02 (m, 3H), 1.97 - 1.91 (m, 2H), 1.84 - 1.76 (m, 2H), 1.67 - 1.63 (m, 1H), 1.43 (d, J = 6.0 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H), 0.92 (s, 3H), 0.89 - 0.86 (m, 1H), 0.81 (d, J = 6.8 Hz, 3H), 0.31 (s, 3H).

[0586] Example 18

[0587] (2S)-2-hydroxy-N-((64S,4S,Z)-12-(2-((S)-1-methoxyethyl)-5-(5-(1-(oxetan-3-yl)piperidin-4-yl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-11-(2,2,2-trifluoroethyl)-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-1(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-3-methylbutanamide

[0588] Compound 18 was obtained using a similar method and reaction procedure as in the synthesis of compound 1e by replacing compound 1 with compound INT-8. ESI-MS (m / z): 1004.5 [M+H] + ; LC-MS retention time RT = 1.64 min.

[0589] 1 H NMR (500 MHz, DMSO-d6) δ 9.34 (d, J = 2.2 Hz, 1H), 8.44 (s, 1H), 8.28 (s, 1H), 8.10 (d, J = 9.0 Hz, 1H), 7.93 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 6.03 (d, J = 11.0 Hz, 1H), 5.71 - 5.65 (m, 1H), 5.62 (d, J = 6.0 Hz, 1H), 5.39 - 5.31 (m, 1H), 4.92 - 4.81 (m, 1H), 4.76 (d, J = 11.0 Hz, 1H), 4.56 - 4.47 (m, 3H), 4.43 (t, J = 6.1 Hz, 2H), 4.35 (d, J = 6.1 Hz, 1H), 3.78 - 3.74 (m, 1H), 3.55 (s, 2H), 3.43 - 3.38 (m, 3H), 3.33 (s, 3H), 3.12 - 3.03 (m, 2H), 2.75 - 2.70 (m, 2H), 2.68 - 2.64 (m, 1H), 2.48 - 2.44 (m, 2H), 2.37 - 2.32 (m, 1H), 2.14 (t, J = 9.8 Hz, 1H), 2.10 - 2.06 (m, 3H), 2.00 - 1.93 (m, 2H), 1.87 - 1.79 (m, 2H), 1.64 (t, J = 9.3 Hz, 1H), 1.42 (d, J = 6.0 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.96 - 0.90 (m, 6H), 0.30 (s, 3H).

[0590] RAS inhibitor biological screening and results

[0591] Test Example 1: In vitro cell proliferation inhibition test

[0592] Due to the diversity of RAS mutations, and in order to evaluate the activity of the compounds in different RAS mutant cell lines, we selected KRAS G12C , KRAS G12D , KRAS G12V and KRAS G13D mutant cell lines (see table below) for in vitro activity evaluation and screening of the compounds.

[0593] Experimental protocol: Cell Luminescent Viability Assay (Promega)

[0594] According to the doubling time of different cell lines, different amounts of cells (1000-5000 cells / well) were inoculated in 96-well plates containing 180 μL of corresponding medium, and cultured in a 37°C cell incubator containing 5% CO2 overnight. The next day, the test compound was pre-diluted by 3-fold gradient, with the highest concentration of 100 μM, a total of 10 concentration gradients; then 20 μL of medium containing different concentrations of compound was added to the cells in the 96-well plate, ensuring that the final concentration of the compound was the highest 10 μM, 3-fold dilution of 10 concentration gradients. After 72 h of incubation of cells and compounds, the 96-well plate was taken out of the incubator and equilibrated at room temperature for 30 min, then 25 μL Reagent was mixed well, incubated at room temperature for 10 min, then 100 μL of sample was transferred to a white 96-well plate (OptiPlate TM -96, PerkinElmer), and the fluorescence signal value was read using a multifunctional enzyme marker (Victor i3x, Molecular devices). The signal value was subsequently standardized, and a four-parameter fitting regression equation was used for curve fitting to calculate the half inhibitory concentration (half maximal inhibitory concentration, IC 50 ) of the compound on the cell line.

[0595] Table 2: Anti-proliferative activity of the compounds of the present application on KRAS cell mutant strains

[0596] The above test results show that the compounds of the present application have high cell proliferation inhibition activity on various KRAS mutant cell lines.

Claims

1. A compound having the structure of Formula (A), an isotopic derivative or stereoisomer thereof, or a pharmaceutically acceptable salt thereof: ###00001### (A). wherein: Cya denotes or which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; A represents 4- to 6-membered heterocycloalkylene, phenylene, or 5- to 6-membered heteroarylene, each independently of the other, unsubstituted or substituted by 0, 1, 2, 3, or 4 R x substituents; B represents a 5- to 6-membered heteroarylene or phenylene, each independently of the other being unsubstituted or substituted by 0, 1, 2, 3 or 4 R x substituted, wherein B is not or X, Y each independently represent hydrogen, Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C6cycloalkyl, 5 to 6 membered heteroaryl, or phenyl, each of said Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C6cycloalkyl, 5 to 6 membered heteroaryl, or phenyl being independently unsubstituted or substituted with 0, 1, 2, 3, or 4 R 12 substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R 12 substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R x substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R x substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R Z represents -OR a , -SR a or -NR a R a ’; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ', any methylene of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is optionally replaced with a carbonyl, -NR a -, -O-, or -S-, and optionally, each of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom, said 3-8 membered ring optionally further containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of said C3-C8cycloalkyl or 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a ', cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl), or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a ', -NR a C(O)R a ', -OC(O)R a ', -OC(O)NR a R a ', -NR a C(O)NR a R a ', -S(O)R a , -S(O)2R a , -NR a S(O)2R a '; R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), which optionally can be substituted with 0, 1, or 2 substituents selected from: -OR a , -SR a , or -NR a R a ’; R3, R3’ each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-CN; R4represents hydrogen, C1-C6alkyl, -(C0-C6alkylene)-OR a , -(C0-C6alkylene)-SR a , -(C0-C6alkylene)-NR a R a ', -(C0-C6alkylene)-(C3-C8cycloalkyl) or -(C0-C6alkylene)-(4-12 membered heterocycloalkyl), -(C0-C6alkylene)-phenyl or -(C0-C6alkylene)-(5-6 membered heteroaryl), any methylene of said C0-C6alkylene, C1-C6alkyl can be replaced with a carbonyl, -NR a -, -O- or -S-, and optionally, said C0-C6alkylene, C1-C6alkyl can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom, said 3-8 membered ring optionally can further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; said C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl each independently can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a ', cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl) or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a ', -NR a C(O)R a ', -OC(O)R a ', -OC(O)NR a R a ', -NR a C(O)NR a R a ', -S(O)R a , -S(O)2R a , -NR a S(O)2R a '; L1, L2each independently represents a single bond or -(C1-C6)alkylene-, any methylene of which is optionally replaced with a carbonyl, -NR a -, -O- or -S-, and optionally, each methylene of said -(C1-C6)alkylene is independently substituted with 0, 1, 2, 3 or 4 C1-C3alkyl, and two substituents of the same C atom can form a 3-8 membered ring with said C atom; E represents C1-C6 alkyl, C3-C 12 Cycloalkyl, 4-12 membered heterocycloalkyl, C6-C 10 The ring can be aryl or 5-10 heteroaryl, and the ring can be a monocyclic ring, a spirocyclic ring, a bridged ring, or a fused ring; each R5independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; wherein m represents 0, 1, 2, or 3; R x each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a ', cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a ', -S(O)2R a , -S(O)R a , -S(O)(NR a )R a ', C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are both attached can form a 4-8 membered ring, which optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

2. The compound, isotopic derivative, or stereoisomer of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Said E represents C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl, the ring can be monocyclic, spiro, bridged, annelated.

3. The compound, isotopic derivative, or stereoisomer of either of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, The compounds have the structure of formula (I): wherein: Cya denotes or which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; A represents 4- to 6-membered heterocycloalkylene, phenylene, or 5- to 6-membered heteroarylene, each independently of the other, unsubstituted or substituted by 0, 1, 2, 3, or 4 R x substituents; B represents a 5- to 6-membered heteroarylene or phenylene, each independently of the other being unsubstituted or substituted by 0, 1, 2, 3 or 4 R x substituted, wherein B is not or X, Y each independently represent hydrogen, Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C6cycloalkyl, 5 to 6 membered heteroaryl, or phenyl, each of said Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C6cycloalkyl, 5 to 6 membered heteroaryl, or phenyl being independently unsubstituted or substituted with 0, 1, 2, 3, or 4 R 12 substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R 12 substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R x substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R x substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R Z represents -OR a , -SR a or -NR a R a ’; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ', any methylene of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is optionally replaced with a carbonyl, -NR a -, -O-, or -S-, and optionally, each of said C0-C6alkylene, C1-C6alkylene, C1-C6alkyl, C1-C6haloalkyl is independently substituted with 0, 1, 2, 3, or 4 substituents selected from halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom, said 3-8 membered ring optionally further containing 0, 1, 2, or 3 heteroatoms selected from N, O, or S; each of said C3-C8cycloalkyl or 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a ', cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl), or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a ', -NR a C(O)R a ', -OC(O)R a ', -OC(O)NR a R a ', -NR a C(O)NR a R a ', -S(O)R a , -S(O)2R a , -NR a S(O)2R a '; R2represents C1-C6alkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), or -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), which optionally can be substituted with 0, 1, or 2 substituents selected from: -OR a , -SR a , or -NR a R a ’; R3, R3’ each independently represent hydrogen, halogen, C1-C6 alkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), or -(C0-C6 alkylene)-CN; R4represents hydrogen, C1-C6alkyl, -(C0-C6alkylene)-OR a , -(C0-C6alkylene)-SR a , -(C0-C6alkylene)-NR a R a ', -(C0-C6alkylene)-(C3-C8cycloalkyl) or -(C0-C6alkylene)-(4-12 membered heterocycloalkyl), -(C0-C6alkylene)-phenyl or -(C0-C6alkylene)-(5-6 membered heteroaryl), any methylene of said C0-C6alkylene, C1-C6alkyl can be replaced with a carbonyl, -NR a -, -O- or -S-, and optionally, said C0-C6alkylene, C1-C6alkyl can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen or C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom, said 3-8 membered ring optionally can further contain 0, 1, 2 or 3 heteroatoms selected from N, O or S; said C1-C6alkyl, C3-C8cycloalkyl, 4-12 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl each independently can be substituted with 0, 1, 2, 3 or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a ', cyano, C1-C6alkyl, -(C0-C3alkylene)-(C3-C8cycloalkyl) or -(C0-C3alkylene)-(4-8 membered heterocycloalkyl), -C(O)R a , -C(O)OR a , -C(O)NR a R a ', -NR a C(O)R a ', -OC(O)R a ', -OC(O)NR a R a ', -NR a C(O)NR a R a ', -S(O)R a , -S(O)2R a , -NR a S(O)2R a '; L1, L2each independently represents a single bond or -(C1-C6)alkylene-, each methylene in said -(C1-C6)alkylene- being optionally replaced with a carbonyl, -NR a -O- or -S-, and optionally, each methylene in said -(C1-C6)alkylene- is independently substituted with 0, 1, 2, 3 or 4 C1-C3alkyl, and two substituents on the same C atom can form a 3-8 membered ring with said C atom; Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be monocyclic, spiro, bridged, fused; each R5independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; wherein m represents 0, 1, 2, or 3; R x each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a ', cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a ', -S(O)2R a , -S(O)R a , -S(O)(NR a )R a ', C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are attached can form a 4-8 membered ring, which optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

4. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; preferably, Cya represents or optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; more preferably, preferably Cya represents or 5. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, A represents a 5-6 membered heteroarylene group, which can be substituted by 0, 1, 2, 3 or 4 R x substituents; preferably, A represents thiazolylene, which can be substituted by 0, 1, 2, 3 or 4 R x substituents; more preferably, A represents thiazolylene.

6. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, B represents or The structure can be substituted with 0, 1, 2, 3 or 4 R x ; preferably, B represents or 7. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, X, Y each independently represent hydrogen, Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C6cycloalkyl, 5 to 6 membered heteroaryl, or phenyl, each of said Ci-C6aminoalkyl, Ci-C6hydroxyalkyl, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C6cycloalkyl, 5 to 6 membered heteroaryl, or phenyl being independently unsubstituted or substituted with 0, 1, 2, 3, or 4 R 12 substituents; optionally, X and Y can form a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R 12 substituents; optionally, X and Y can form a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R x substituents; optionally, X and Y can form a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R x substituents; optionally, X and Y can form a 4-8 membered ring, said ring being unsubstituted or substituted with 0, 1, 2, 3, or 4 R 8. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, X and Y independently represent hydrogen, C1-C6 alkyl, 4- to 12-membered heterocyclic alkyl, and C3-C6 alkyl. 12 C1-C6 alkyl, 4-12 heterocyclic alkyl, C3-C6 alkyl, 5-6 heterocyclic alkyl, or phenyl, wherein the C1-C6 alkyl, 4-12 heterocyclic alkyl, or C3-C6 alkyl is a cyclic alkyl group. 12 The cycloalkyl, 5- to 6-membered heteroaryl, and phenyl groups can each be independently represented by 0, 1, 2, 3, or 4 R groups. x Alternatively, X and Y can form a 3-membered ring or a 4-8-membered ring, said ring being composed of 0, 1, 2, 3, or 4 R elements. x Instead, the ring may further include 0, 1, 2, or 3 heteroatoms selected from N, O, and S; preferably, X and Y may optionally form a 4-8 membered ring, which may be composed of 0, 1, 2, 3, or 4 R atoms. x The ring may further include 0, 1, 2 or 3 heteroatoms selected from N, O or S.

9. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, X, Y each independently represent hydrogen, Ci-C6alkyl, 4 to 12 membered 12 heterocycloalkyl, C3-C6cycloalkyl, each of said Ci-C6alkyl, 4 to 12 membered 12 heterocycloalkyl, C3-C6cycloalkyl, each of said Ci-C6alkyl, 4 to 12 membered x heterocycloalkyl, C3-C6cycloalkyl, each of said Ci-C6alkyl, 4 to 12 membered x heterocycloalkyl, C3-C6cycloalkyl, each of said Ci-C6alkyl, 4 to 12 membered x heterocycloalkyl, C3-C6cycloalkyl, each of said Ci-C6alkyl, 4 to 12 membered 10. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, X, Y each independently represent hydrogen, Ci-C6alkyl, 4 to 8 membered heterocycloalkyl, C3-C6cycloalkyl, each of which independently can be substituted with 0, 1, 2, or 3 R x substituents, optionally, X and Y can form a 3 membered ring or a 4-8 membered ring, which ring can be substituted with 0, 1, 2, 3, or 4 R x substituents, the ring can further comprise 0, 1, 2, or 3 heteroatoms selected from N, O, S.

11. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, When X and Y form a 3-membered ring or a 4-8-membered ring, the ring can further comprise 0 or 1 heteroatoms; preferably, the ring comprises 0 heteroatoms.

12. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, X, Y each independently represent hydrogen, Ci-C6alkyl, 4- to 8-membered heterocycloalkyl, C3-C6cycloalkyl, each of which independently can be substituted with 0, 1, 2, or 3 R x substituted.

13. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, Z represents -OR a or -NR a R a , preferably Z represents -OH or -NHR a , more preferably Z represents -OH.

14. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R1represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8-membered heterocycloalkyl), -(C1-C6 alkylene)-ORa, -(C1-C6 alkylene)-SRa, or -(C1-C6 alkylene)-NRaRa’.

15. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R1represents C1-C6 alkyl, C1-C6 haloalkyl, -(C0-C6 alkylene)-(C3-C8 cycloalkyl), -(C0-C6 alkylene)-(4-8-membered heterocycloalkyl); preferably, R1represents C1-C6 alkyl or C1-C6 haloalkyl; more preferably, R1represents ethyl or -CH2CF3.

16. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R2represents C1-C6 alkyl, which can be substituted with 0 or 1 -ORa; preferably, R2represents 1-methoxyethyl.

17. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R3, R3’ each independently represent hydrogen, halogen, C1-C6 alkyl; preferably, R3, R3’ are H.

18. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R4represents hydrogen, -OR a , -SR a or -NR a R a ’ 19. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R4represents H.

20. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, L1, L2each independently represent a single bond or -(C1-C6)alkylene-, it being possible for any methylene group in said -(C1-C6)alkylene- to be replaced by a carbonyl group, -NR a -O- or -S-; preferably, L1, L2each independently represent a single bond or -(C1-C6)alkylene-.

21. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, Cy1represents 4-12-membered heterocycloalkyl, which can be monocyclic, spiro, bridged, annelated; preferably, Cy1represents 4-8-membered heterocycloalkyl, which can be monocyclic, spiro, bridged, annelated.

22. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R5each independently represents hydrogen, oxo, =NR a , -S(O)2R a , -C(O)R a , C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably R5each independently represents C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, each of the above mentioned C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, and when R5is C5-C6cycloalkyl or 5-6 membered heterocycloalkyl, the number of substituents is greater than 0.

23. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, m represents 0, 1, or 2.

24. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R x each independently represents hydrogen, halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R x each independently represents hydrogen, halogen, oxo, -OH, -SH, -NH2, cyano, C1-C6alkyl; more preferably, R x each independently represents hydrogen, halogen, -OH, -NH2, cyano, C1-C3alkyl.

25. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; preferably, R a , R a each independently represent hydrogen or C1-C6alkyl; more preferably, R a , R a each independently represent hydrogen or C1-C3alkyl.

26. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, The compounds of the structure of formula (I) have the structure of formula (II): wherein: Cya denotes or which is optionally substituted with 0, 1, 2, or 3 substituents selected from halogen or C1-C3 alkyl; B represents a 5- to 6-membered heteroarylene group, which can be substituted with 0, 1, 2 or 3 R x substituted, wherein B is not or X, Y each independently represent hydrogen, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 cycloalkyl, 5 to 6 membered heteroaryl or phenyl, each of said Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 cycloalkyl, 5 to 6 membered heteroaryl, phenyl can be independently substituted with 0, 1, 2, 3 or 4 R x optionally, X and Y can form a 3 membered ring or a 4-8 membered ring, said ring can be substituted with 0, 1, 2, 3 or 4 R x said ring can further comprise 0, 1, 2 or 3 heteroatoms selected from N, O, S; Z represents -OR a or -NR a R a ’; R1represents C1-C6alkyl, C1-C6haloalkyl, -(C0-C6alkylene)-(C3-C8cycloalkyl), -(C0-C6alkylene)-(4-8 membered heterocycloalkyl), -(C1-C6alkylene)-OR a , -(C1-C6alkylene)-SR a , or -(C1-C6alkylene)-NR a R a ’; L1, L2each independently represent a single bond or -(C1-C6)alkylene-, it being possible for any methylene group in said -(C1-C6)alkylene- to be replaced by a carbonyl group, -NR a -, -O- or -S-; Cy1represents C3-C 12 cycloalkyl or 4-12 membered heterocycloalkyl, which ring can be monocyclic, spiro, bridged, fused; R5each independently represents hydrogen, halogen, oxo, =NR a , -OR a , -SR a , -NR a R a , cyano, -C(O)OR a , -C(O)R a , -C(O)NR a R a , -S(O)2R a , -S(O)R a , -S(O)(NR a )R a , C1-C6alkyl, C3-C8cycloalkyl, or 4-8 membered heterocycloalkyl; each of the above mentioned C1-C6alkyl, C3-C8cycloalkyl, 4-8 membered heterocycloalkyl is independently optionally substituted with 0, 1, 2, 3, or 4 substituents selected from halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, -(C0-C3alkylene)-C3-C8cycloalkyl, or -(C0-C3alkylene)-4-8 membered heterocycloalkyl; wherein m represents 0, 1, 2, or 3; R x each independently represents hydrogen, halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; R a , R a each independently represent hydrogen, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; when R a , R a are attached to the same N atom, said R a and R a together with the N atom to which they are both attached can form a 4-8 membered ring, which optionally can contain 1, 2 or 3 heteroatoms selected from N, O or S; each of said alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5, or 6 halogen atoms.

27. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, X, Y each independently represent hydrogen, Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 cycloalkyl, 5 to 6 membered heteroaryl or phenyl, each of said Ci-C6alkyl, 4 to 12 membered heterocycloalkyl, C3-C 12 cycloalkyl, 5 to 6 membered heteroaryl, phenyl can be independently substituted with 0, 1, 2, 3 or 4 R x optionally, X and Y can form a 4-8 membered ring, said ring can be substituted with 0, 1, 2, 3 or 4 R x said ring can further comprise 0, 1, 2 or 3 heteroatoms selected from N, O, S.

28. The compound, isotopic derivative, or stereoisomer of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II): wherein: Cya denotes or B represents or X, Y each independently represent hydrogen, Ci-C6alkyl, 4 to 8 membered heterocycloalkyl, C3-C6cycloalkyl, each of which independently can be substituted with 0, 1, 2, or 3 R x substituents; optionally, X and Y can form a 3-membered ring or a 4-8 membered ring, which ring can be substituted with 0, 1, 2, 3, or 4 R x substituents, which ring can further comprise 0, 1, 2, or 3 heteroatoms selected from N, O, S; Z represents -OH or -NHR a ; R1represents ethyl or trifluoroethyl group; L1, L2each independently represents a single bond; Cy1represents a 4-8 membered heterocycloalkyl group, which ring can be monocyclic, spirocyclic, bridged, annelated; R5each independently represents C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, each of which above-mentioned C3-C8cycloalkyl, 4-8 membered heterocycloalkyl can be independently substituted with 0, 1, 2, 3 or 4 substituents selected from the group consisting of halogen, oxo, -OR a , -SR a , -NR a R a , cyano, C1-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, and when R5is C5-C6cycloalkyl or 5-6 membered heterocycloalkyl, the number of substituents is more than 0; wherein m represents 0, 1 or 2; R x each independently represents hydrogen, halogen, -OH, -NH2, cyano, C1-C3 alkyl; R a , R a each independently represent hydrogen, Ci-C6alkyl, C3-C8cycloalkyl or 4-8 membered heterocycloalkyl; each of the alkyl, alkylene, cycloalkyl, cycloalkylene, heterocycloalkyl, heterocycloalkylene can be independently substituted with 0, 1, 2, 3, 4, 5 or 6 halogen atoms.

29. The compound, isotopic derivative, or stereoisomer of any of the preceding claims, or a pharmaceutically acceptable salt thereof, having the structure:

30. A pharmaceutical composition comprising a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any preceding claim, and a pharmaceutically acceptable carrier.

31. Use of a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 29, or a pharmaceutical composition as claimed in claim 30, for the manufacture of a medicament for the prevention and / or treatment of a RAS-associated cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease.

32. Use of a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 29, or a pharmaceutical composition as claimed in claim 30, for the prevention and / or treatment of a RAS-associated cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease.

33. A method for the prevention and / or treatment of a RAS-associated cancer, a tumor, an inflammatory disease, an autoimmune disease or an immune-mediated disease, comprising administering to a patient in need thereof an effective amount of a compound, an isotopic derivative or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 29, or a pharmaceutical composition as claimed in claim 30.

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