Macrocyclic heterocycles as anticancer agents

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using them. The compounds and methods have a range of uses as therapeutic, diagnostic, and research tools. In particular, the subject compositions and methods are used to reduce signaling output of oncogenic proteins.

Description

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 63 / 640,406, filed April 30, 2024, and U.S. Provisional Application No. 63 / 715,311, filed November 1, 2024, each of which is incorporated herein by reference in its entirety. Background Technology

[0002] Cancer (e.g., tumors, growths, metastases) is the second leading cause of death worldwide, estimated to kill approximately 10 million people each year. Many types of cancer are marked by mutations in one or more proteins involved in various signaling pathways, which lead to the uncontrolled growth of cancer cells. In some cases, approximately 25% to 30% of tumors are known to contain rat sarcoma (RAS) mutations. In particular, mutations in the Kirsten Ras oncogene (KRAS) are among the most common RAS mutations detected in human cancers, including lung adenocarcinoma (LUAD) and pancreatic ductal adenocarcinoma (PDAC). These mutations typically lead to constitutive activation of KRAS and downstream signaling pathways that regulate tumor cell growth, differentiation, proliferation, and apoptosis, including the phosphoinositol 3-kinase (PI3K) and the rapidly accelerating fibrosarcoma (RAF) pathway.

[0003] RAS proteins have long been considered "undruggable," partly due to their high affinity for their substrate guanosine-5'-triphosphate (GTP) and / or their smooth surface lacking any apparent target region. Specific G12C KRAS mutations have been identified as druggable targets, and numerous G12C-specific inhibitors have been developed. However, the application of such therapies remains limited because the G12C mutation in RAS exhibits a much lower prevalence compared to other known RAS mutations, such as G12D and G12V. Drug resistance and lack of persistence further restrict the use of such therapies.

[0004] Aberrant activation of the PI3K pathway is frequently detected in human cancers, and the interaction of RAS proteins with the RAS-binding domain (RBD) of PI3K promotes PI3K activation. Therefore, PI3K inhibition is another attractive therapeutic approach for treating human cancers. Numerous PI3K inhibitors have been reported, most of which are reversible ATP-competitive kinase inhibitors. However, these therapies are generally ineffective against RAS-driven cancers, primarily due to drug resistance and toxicity. Summary of the Invention

[0005] Given the foregoing, there remains a significant need for novel therapeutic and diagnostic designs that can inhibit the activity of oncogenic RAS (including wild-type RAS, mutants, and / or RAS-related proteins) to reduce RAS signaling output. Of particular interest for inhibiting oncogenic RAS activity are inhibitors of the interaction between RAS and PI3K for the treatment of RAS and / or PI3K-mediated diseases (e.g., cancer). Such compositions and methods can be used against any oncogenic RAS mutant (e.g., G12C, G12D, G12S, G13D, and / or G12V), thereby increasing the therapeutic potential of the method relative to mutation-selective RAS inhibitors (e.g., KRAS G12C inhibitors) and can be particularly used to treat a variety of diseases, including but not limited to cancer and tumorigenetic conditions. Furthermore, such compositions and methods can have little or no effect on the kinase activity of PI3K proteins (e.g., PI3Kα), which can lead to reduced side effects and / or improved efficacy compared to ATP-competitive PI3K inhibitors. This disclosure addresses these needs and provides additional advantages for the diagnosis, prognosis, and / or treatment of a wide range of diseases.

[0006] In some respects, this disclosure provides compounds of formula (I): (I), Or a pharmaceutically acceptable salt or solvate thereof, wherein: G is selected from C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R G replace; X 1 Selected from N and C(R) 1 ); X 2 Selected from N and C(R) 2 ); X 3 Selected from N, C(R) 3 ) and C(O); X is selected from N and C; J is selected from C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R J replace; L 1 Selected from C 5-15 Alkylene, C 5-15 imidene group, C 5-15 Alynyl, 5- to 15-membered heteroalkyl, and 5- to 15-membered heteroenyl, each optionally bound by one or more R L1 replace; A 1 Selected from key, C 3-12Carbon rings and 3- to 12-membered heterocycles, of which C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. A1 replace; L is selected from key, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -O-, -N(R) 12 -, -C(O)-, -C(R) 12 )=, -S-, -S(O)-, -S(O)2-, -P(O)R 12 -、-P(O)R 12 O-、-N(R 12 )C(O)-、-N(R 12 )S(O)-、-N(R 12 )S(O)2-、-N(R 12 )P(O)R 12 -、-OP(O)R 12 -、-C(O)N(R 12 )-、-S(O)N(R 12 )-、-S(O)2N(R 12 )- and -P(O)R 12 N(R 12 )-, where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl and 3- to 6-membered heteroynyl groups are each optionally surrounded by one, two or three R groups. L replace; A 2 Selected from C 3-12 Carbon rings and 3- to 12-membered heterocycles, each optionally bound by one, two, or three R... A2 replace; R A Selected from hydrogen, R 20 and E, where E is optionally connected to A. 2 The combination is the part that can covalently bind to the C242 residue of the PI3Kα protein; R 1 R 2 and R 3 Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)N(R 12 (R) 13 ), -N(R 12 )C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -S(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 -S(O)(NR) 12 )R 12 -S(O)2N(R) 12 (R) 13 ) and -S(O)(NR 12 )N(R 12 (R) 13 ), or R 1 and R 2 Together with the atoms they are attached to, they form C 5-8 Monocyclic carbon rings or 5- to 8-membered monocyclic heterocycles, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 5-8Monocyclic carbon rings and 5- to 8-membered monocyclic heterocycles are each optionally divided by one, two, or three Rs. 20 replace; R G R L1 R J R A1 R L and R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SF5, -SR 12 -N(R) 12 (R) 13 =NR 12 =C(R) 14 )2、-C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)N(R 12 (R) 13 ), -N(R 12 )C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -S(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 -OS(O)2R 12 -S(O)(NR) 12 )R 12 -S(O)2N(R) 12 (R) 13 ), -S(O)(NR 12)N(R 12 (R) 13 ), -N(R 12 )P(O)R 12 R 13 and -P(O)R 12 R 13 Two of them R L1 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; in which two Rs A1 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; in which two Rs A2 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic), wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles) are each optionally surrounded by one, two, or three R groups. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; or R groups attached to the same nitrogen atom 12 and R 13 Formed by one, two or three R 20 Replacement of 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl group (3- to 12-membered heterocyclic rings), or two R groups 14 Together with the carbon atoms they are attached to, they form C 3-12 Carbon rings or 3- to 12-membered heterocycles, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocycles), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace; R 20 Each occurrence is independently selected from halogen, oxo, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 22 -SF5, -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 Two of them R 20 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbide ring and the 3- to 12-membered heterocycles are each optionally and independently selected from halogens, oxocycles, -CN, -NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 22 -SF5, -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 One or more substituents are substituted; R 21 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl group (3- to 12-membered heterocycle), or two R groups 21 Together with the carbon atoms they are attached to, they form C 3-12 Carbon rings or 3- to 12-membered heterocycles, each optionally and independently selected from halogens, C 1-3 Alkyl, C 1-3 The alkyl halogroup and -OH are substituted with one, two or three substituents; R 22 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles); R 23 Each time it appears, it is independently selected from hydrogen and C. 1-6Alkyl group; or R group attached to the same nitrogen atom 22 and R 23 Formation of 3- to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0007] In some embodiments, for compounds of formula (I), G is selected from phenyl and 5- to 10-membered heteroaryl groups, each heteroaryl group optionally being surrounded by one or more R groups. G Replacement, for example, one, two, or three Rs G In some embodiments, G is selected from phenyl and benzofuran, and each heteroaryl group is optionally surrounded by one or more R groups. G Replacement, for example, one, two, or three Rs G .

[0008] In some embodiments, the compound of formula (I) is the compound of formula (I-1): (I-1), Or a pharmaceutically acceptable salt or solvate thereof, wherein g1 is 0, 1, 2 or 3.

[0009] In some embodiments, for compounds of formula (I) or (I-1), X 1 It is C(R) 1 And X 2 It is C(R) 2 In some implementations, R 1 and R 2 Each is hydrogen; or R 1 and R 2 Together with the atoms they are attached to, they form C6 aryl or 5-membered heteroaryl groups, each optionally bonded by one, two, or three R atoms. 20 Replacement. In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form thiophene, benzene, cyclopentene, or pyrazole. In some embodiments, X is C.

[0010] In some embodiments, the compound of formula (I) is a compound of formula (I-2a), (I-2b), (I-2c), or (I-2d): (I-2a) (I-2b) (I-2c) or (I-2d), Or a pharmaceutically acceptable salt or solvate thereof, wherein g1 is 0, 1, 2 or 3.

[0011] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), or (I-2d), J is selected from phenyl, 5- to 6-membered monocyclic heterocycles, and 7- to 11-membered bicyclic heterocycles, each optionally being surrounded by one or more R J (such as one, two or three R) J ) is replaced. In some implementations, J is optionally replaced by one or more R. J (such as one, two or three R) J ) substituted phenyl. In some embodiments, R J Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 and -S(O)2N(R 12 (R) 13 )-; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 Replacement. In some implementations, R J Selected from halogens and C 1-3 alkyl.

[0012] In some embodiments, the compound of formula (I) is a compound of formula (I-3): (I-3), Or a pharmaceutically acceptable salt thereof, wherein g1 is 0, 1, 2 or 3; and j1 is 0, 1, 2, 3 or 4.

[0013] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), X 3 It is N.

[0014] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R G Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic) and -OR 12 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 Replacement. In some implementations, R G Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, 2- to 6-membered heteroalkyl and -OR 12 ; where C 1-6 Alkyl groups and 2- to 6-membered heteroalkyl groups are each optionally and independently selected from halogens, oxo groups, -CN groups, C groups. 1-6 Alkyl, C 1-6Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted. In some embodiments, R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3.

[0015] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), L 1 Selected from C 8-12 Alkylene, C 8-12 alkenyl, 8- to 12-membered heteroalkyl, and 8- to 12-membered heteroalkyl, each optionally bound by one or more R L1 Substitution. In some embodiments, the alkenyl and heteroalkyl groups contain a carbon-carbon double bond. In some embodiments, the heteroalkyl and heteroalkyl groups contain at least one oxygen or nitrogen atom. In some embodiments, R L1 Each time it appears, it is independently selected from halogen, oxidative, and C. 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH.

[0016] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), A 1 Selected from bonds, 4- to 10-membered saturated heterocycles, and 5- to 8-membered partially unsaturated heterocycles, wherein the 4- to 10-membered saturated heterocycles and the 5- to 8-membered partially unsaturated heterocycles are each optionally bounded by one, two, or three R... A1 Replacement. In some implementations, A 1 Selected from aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroaziridine, and 1,4-diazacycloheptane, each optionally separated by one, two, or three R... A1 Replacement. In some implementations, A 1 It is a key. In some implementations, R A1 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 Two of them R A1 Optionally joined to form bridges of 1 to 4 atoms; wherein C 1-6 Alkyl, C 2-6 The alkenyl group and the bridge of 1 to 4 atoms are each optionally and independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted.

[0017] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), L is selected from the bond, C 1-3 Alkyl and -C(O)-, where C 1-3 Alkyl groups are optionally surrounded by one, two, or three R groups. L Replacement. In some implementations, R L Each time it appears, it is independently selected from halogen, oxo, -CN, and C. 1-6 Alkyl group. In some embodiments, L is a bond.

[0018] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replacement of 4- to 12-membered heterocyclic rings. In some implementations, A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 Replacement. In some implementations, A 2 Selected from tetrahydronaphthyl, tetrahydropyrazolopyrazine, pyridone, pyrazole, aziridine, pyrrolidine, piperidine, piperazine, aziridine, 1,4-diazacycloheptane, and 2-azispiro[3.3]heptane, each optionally separated by one, two, or three R A2 Replacement. In some implementations, A 2 Selected from tetrahydronaphthyl and tetrahydropyrazolopyrazine, each optionally constituting one, two, or three R... A2 Replacement. In some implementations, R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 Two of them R A2 Optionally joined to form bridges of 1 to 4 atoms; wherein C 1-6 Alkyl, C 2-6 The alkenyl group and the bridge of 1 to 4 atoms are each optionally and independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR22 One or more substituents are substituted.

[0019] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R A It is E. In some implementations, R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one or two R 20 Replacement. In some implementations, R A yes .

[0020] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3; A 1 Selected from aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroazine, and 1,4-diazacycloheptane, wherein aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroazine, and 1,4-diazacycloheptane are each optionally separated by one, two, or three R... A1 Substitution; L is a bond; A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 Replace; and R A yes .

[0021] In some aspects, this disclosure provides a pharmaceutical composition comprising the compound described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0022] In some aspects, this disclosure provides a method for modifying a PI3Kα protein, comprising contacting the PI3Kα protein with an effective amount of a compound described herein or a salt or solvation thereof. In some embodiments, the kinase activity of the modified PI3Kα protein is not significantly inhibited. In some aspects, this disclosure provides a method for inhibiting the interaction between a RAS protein and a PI3Kα protein, comprising contacting the PI3Kα protein with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvation thereof.

[0023] In some aspects, this disclosure provides a method of treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt or solvate thereof. The cancer may exhibit one or more of aberrant activation of PI3Kα or PI3Kα mutations, optionally wherein the PI3Kα mutation is selected from E81K, E110del, K111E, K111N, G118D, N345K, C420R, E453K, E542K, E545A, E545G, E545K, Q546K, Q546P, Q546R, E726K, M1043I, N1044K, H1047L, H1047R, and G1049R. In some embodiments, the cancer comprises a RAS mutant protein. In some aspects, this disclosure provides a method for treating cancer in a subject containing a RAS mutant protein, the method comprising: inhibiting the interaction between the RAS mutant protein of the subject and the PI3Kα protein by administering a compound described herein to the subject. The RAS mutant protein may be a KRAS mutant protein containing mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, or Q61H. The cancer in the method described herein may be a solid tumor or a hematologic cancer. In some aspects, this disclosure provides a method for inhibiting cell growth, comprising administering an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof to cells expressing the PI3Kα protein, thereby inhibiting the growth of the cells. The method described herein may also include the administration of additional agents.

[0024] Incorporation by Reference All publications, patents and patent applications mentioned in this specification are incorporated herein by reference, just as each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference. Detailed Implementation

[0025] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. If multiple definitions exist for terms herein, those defined in this section shall prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated herein by reference. Chemical structures herein are based on, as stated in ChemDraw... ®Naming follows the IUPAC conventions implemented in the software (Perkin Elmer, Inc., Cambridge, MA). The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. As used in the specification and claims, the singular forms “a,” “an,” and “the,” include plural referents unless the context clearly specifies otherwise. Furthermore, the use of the term “comprising,” as well as other forms such as “including,” is not limited. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0026] Term "C" x-y "or "C x -C y When used in conjunction with chemical moieties such as alkyl, alkenyl, or alkynyl, it means to include groups containing x to y carbons in the chain. For example, the term "C x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched alkyl groups containing x to y carbons in the chain.

[0027] "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain and branched alkyl groups. Alkyl groups can contain 1 to 12 carbon atoms (e.g., C12). 1-12 Alkyl groups, such as those with 1 to 8 carbon atoms (C 1-8 Alkyl groups or 1 to 6 carbon atoms (C 1-6 Alkyl groups. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group may optionally be substituted with one or more substituents (such as those described herein).

[0028] "Halogenated alkyl" refers to an alkyl group that is substituted with one or more halogens. Exemplary halogenated alkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0029] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one double bond, including straight-chain and branched alkenyl groups. Alkenyl groups can contain 2 to 12 carbon atoms (e.g., C12). 2-12 Alkenyl groups, such as those with 2 to 8 carbon atoms (C 2-8 alkenyl) or 2 to 6 carbon atoms (C 2-6Alkenyl groups. Exemplary alkenyl groups include ethenyl (i.e., vinyl), propenyl, butenyl, pentenyl, pent-1,4-dienyl, etc. Unless otherwise specifically stated in the specification, alkenyl groups may optionally be substituted with one or more substituents (such as those described herein).

[0030] "Alynyl" refers to a substituted or unsubstituted hydrocarbon group containing at least one triple bond, including straight-chain and branched alkynyl groups. Alynyl groups can contain 2 to 12 carbon atoms (e.g., C12, C23, C12, C23, C24 ...23, C24, C23, C24, C25, C26, C27, C28, C29, C29 2-12 Alkyne group), such as 2 to 8 carbon atoms (C 2-8 (alkynyl group) or 2 to 6 carbon atoms (C 2-6 Alynyl group. Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentylyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkynyl group may optionally be substituted by one or more substituents (such as those described herein).

[0031] "alkylene" or "alkylene chain" refers to a substituted or unsubstituted divalent saturated hydrocarbon group, including straight-chain alkylene and branched-chain alkylene, which contains 1 to 12 carbon atoms (e.g., C12). 1-12 Alkylenes, such as those with 1 to 8 carbon atoms (C 1-8 Alkylene or 1 to 6 carbon atoms (C 1-6 Alkylenes. Exemplary alkylenes include methylene, ethylene, propylene, and n-butylene. Similarly, "alkenylene" and "ynyneene" refer to alkylenes as defined above, each containing one or more carbon-carbon double or triple bonds. The connection point between the alkylene, alkenyl, or ynyneene chain and the rest of the molecule can be through one or any two carbons in the chain. Unless otherwise specifically stated in the specification, alkylene, alkenyl, or ynyneenes may optionally be substituted with one or more substituents (such as those described herein).

[0032] “Heteroalkyl,” “heteroalkenyl,” and “heteroyneyl” refer to substituted or unsubstituted alkyl, alkenyl, and ynyl groups, respectively, in which one or more (e.g., one, two, or three) carbon atoms are substituted with heteroatoms (e.g., O, N, P, Si, S, or combinations thereof). Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatomium may optionally be quaternized. If given, numerical ranges refer to the total chain length. For example, 3- to 8-membered heteroalkyl groups have chain lengths of 3 to 8 atoms. Connection to the remainder of the molecule can be made via heteroatoms or carbons in the heteroalkyl, heteroalkenyl, or heteroyneyl chain. Unless otherwise specifically stated in the specification, heteroalkyl, heteroalkenyl, or heteroyne groups are optionally substituted with one or more substituents (as described herein).

[0033] “Hypoalkylene,” “heteroenylene,” and “heteroynylene” refer to substituted or unsubstituted alkylene, alkenylene, and ynylene groups, respectively, in which one or more (e.g., one, two, or three) carbon atoms are substituted with heteroatoms (e.g., O, N, P, Si, S, or combinations thereof). Any nitrogen, phosphorus, and sulfur heteroatoms present in the chain may optionally be oxidized, and any nitrogen heteroatom may optionally be quaternized. If given, numerical ranges refer to the total chain length. For example, 3- to 8-membered heteroalkylene groups have chain lengths of 3 to 8 atoms. The connection point between the heteroalkylene, alkenylene, or ynylene group and the rest of the molecule may be through one heteroatom or one carbon atom in the heteroalkylene, alkenylene, or ynylene group, or any two heteroatoms, any two carbons, or any one heteroatom and any one carbon. Unless otherwise specifically stated in the specification, the heteroalkylene, alkenylene, or ynylene group may optionally be substituted with one or more substituents (as described herein).

[0034] A "carbon ring" refers to a saturated ring, unsaturated ring, or aromatic ring, where each atom of the ring is a carbon atom. Carbon rings can include C atoms. 3-10 Single ring, C 5-12 Double ring, C 5-12 Multi-ring, C 5-12 Spiral rings and C 5-12 Bridged rings. Each ring of a bicyclic or polycyclic carbon ring can be selected from saturated rings, unsaturated rings, and aromatic rings. A polycyclic carbon ring contains one or more rings, the number of which equals the minimum shear number required to convert the carbon ring into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). In some embodiments, the carbon ring is C 6-12 Aryl, such as C 6-10 Aryl. In some embodiments, the carbide ring is C. 3-12 Cycloalkyl. In some embodiments, the carbide ring is C10. 5-12 Cycloalkenyl. In an exemplary embodiment, an aromatic ring (e.g., phenyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic rings is included in the definition of a carbocyclic ring, provided the valence allows. A carbocyclic ring may include fused rings, bridged rings, spirocyclic rings, saturated rings, unsaturated rings, aromatic rings, or any combination thereof. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless otherwise specifically stated in the specification, the carbocyclic ring may optionally be substituted with one or more substituents (such as those described herein).

[0035] A "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms, such as 1, 2, 3, or 4 heteroatoms selected from O, S, P, and N. Heterocycles include 3- to 10-membered monocyclic rings, 5- to 12-membered bicyclic rings, 5- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 5- to 12-membered bridged rings. Each ring in a bicyclic or polycyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. A polycyclic heterocycle contains one or more rings, the number of which equals the minimum shear number required to convert the heterocycle into an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). If valence permits, the heterocycle can be attached to the rest of the molecule by any atom of the heterocycle (such as a carbon or nitrogen atom). In some embodiments, the heterocycle is a 5- to 10-membered heteroaryl, such as a 5- or 6-membered heteroaryl. In some embodiments, the heterocycle is a 3- to 12-membered heterocyclic alkyl. Heterocyclic rings can include fused rings, bridged rings, spirocyclic rings, saturated rings, unsaturated rings, aromatic rings, or any combination thereof. In an exemplary embodiment, the heterocyclic ring (e.g., pyridinyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Exemplary heterocyclic rings include pyrrolidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazole, indolyl, benzothiophenyl, benzoxazolyl, and quinolinyl. Unless otherwise specifically stated in the specification, the heterocyclic ring may optionally be substituted with one or more substituents (such as those described herein).

[0036] "Heteroaryl" refers to an aromatic ring containing at least one heteroatom, such as 1, 2, 3, or 4 heteroatoms selected from O, S, and N. Heteroaryls can include 5- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, 6- to 18-membered polycyclic rings, 5- to 12-membered spirocyclic rings, and 6- to 12-membered bridged rings. As used herein, the heteroaryl ring can be selected from monocyclic, bicyclic, or polycyclic systems—including fused ring systems, spirocyclic systems, and bridged ring systems—where at least one ring in the ring system is aromatic and includes at least one heteroatom. Polycyclic heteroaryls contain one or more rings, the number of which equals the minimum cleavage number required to convert the heteroaryl to an acyclic skeleton (e.g., bicyclic, tricyclic, tetracyclic, etc.). The heteroatoms in the heteroaryl may optionally be oxidized. One or more nitrogen atoms (if present) may optionally be quaternized. If valence permits, the heteroaryl can be attached to the rest of the molecule by any atom of the heteroaryl (such as a carbon or nitrogen atom of the heteroaryl). Examples of heteroaryl groups include, but are not limited to, aziridine, benzimidazolyl, benzisisothiazolyl, benzisisooxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzooxazolyl, furanyl, imidazolyl, indazole, indolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrazinyl, pyrazolylalkyl, pyrazolyl, pyridazolyl, pyridinyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, quinoxalolinyl, tetrahydroquinolinyl, thiadiazolyl, thiazolyl, and thiophenyl. Unless otherwise specifically stated in the specification, heteroaryl groups may optionally be substituted with one or more substituents (such as those described herein).

[0037] As used herein, when used to modify ring moieties, the term "unsaturated" refers to a ring moieties containing at least one double or triple bond between ring atoms. The term "unsaturated" is intended to cover rings with multiple unsaturated sites, including maximally unsaturated non-aromatic rings, but not aromatic rings. When used to modify ring moieties, the term "partially unsaturated" refers to a ring moieties containing at least one double or triple bond between ring atoms. The term "partially unsaturated" is intended to cover rings with multiple unsaturated sites, but not maximally unsaturated non-aromatic or aromatic rings. A partially unsaturated ring may contain exactly one double bond. Exemplary partially unsaturated rings include dihydropyrrole (e.g., 2,5-dihydro-1-dihydropyrrole). H -pyrrole), tetrahydropyridine (e.g., 1,2,3,6-tetrahydropyridine), 8-azabicyclo[3.2.1]oct-2-ene and tetrahydroazabicyclo[3.2.1]oct-2-ene and tetrahydroazabicyclo[3.2.1]oct-2-ene (e.g., 2,3,4,7-tetrahydro-1-2-ene). H -Nitrogen oxides and 2,3,6,7-tetrahydro-1 H -Nitrogen hybridization).

[0038] Unless otherwise stated, hydrogen atoms are implicitly included in the structure described herein as necessary to satisfy the valence requirements.

[0039] A wavy line drawn across a key or at the end of a key. "and dashed key" "These terms can be used interchangeably in this document to indicate where a key break or connection occurs. For example, in a structure..." In the middle, if G is like this In the 4-fluorophenyl group, G can be described as " " "or" ".

[0040] The term "substituted" refers to a portion of a structure having a substituent that replaces hydrogen atom on one or more carbon or heteroatoms. It should be understood that "substituted" or "replaced by" includes the implicit limiting condition that such substitution meets the permissible valence of the substituted atom and the substituent, and that the substitution results in a stable compound, for example, which does not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For a suitable organic compound, permissible substituents may be one or more, and may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have any permissible substituent in organic compounds that meet the valence of heteroatoms as described herein.

[0041] The compounds disclosed herein, such as those of formula (I), are optionally substituted by one or more (e.g., one, two, or three) substituents selected from the following: Halogen, oxo, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 22 -SF5, -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 Two substituents attached to the same or adjacent atoms may optionally combine to form C. 3-12 Carbon rings or 3- to 12-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbide ring and 3- to 12-membered heterocycles are optionally and independently selected from halogens, oxometalates, -CN, -NO2, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 22 -SF5-SR 22 -N(R) 22 (R) 23 =NR22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 One or more substituents are substituted; R 21 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl group (3- to 12-membered heterocycle), or two R groups 21 Together with the carbon atoms they are attached to, they form C 3-12 Carbon rings or 3- to 12-membered heterocycles, each optionally and independently selected from halogens, C 1-3 Alkyl, C 1-3 The alkyl halogroup and -OH are substituted with one, two or three substituents; R 22 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic), wherein -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles) are optionally and independently selected from halogens and C. 1-6 One, two, or three alkyl groups are substituted; and R 23 Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups; or R groups attached to the same nitrogen atom 22 and R 23 Formation of 3- to 10-membered heterocycles.

[0042] In some embodiments, the compounds disclosed herein, such as those of formula (I), are optionally substituted with one or more (e.g., one, two, or three) substituents selected from the following: Halogen, Oxide, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 22 -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R)23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -S(O)(NR) 22 )R 22 and -S(O)2N(R 22 (R) 23 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbide ring and 3- to 12-membered heterocycles are optionally and independently selected from halogens, oxocycles, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 22 -SR 22 -N(R) 22 (R) 23 =NR 22 and = C(R) 21 One or more substituents of )2 are substituted; R 21 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R 22 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic), wherein -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles) are optionally and independently selected from halogens and C. 1-6 One, two, or three alkyl groups are substituted; R 23 Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl groups; or R groups attached to the same nitrogen atom 22 and R 23 Formation of 3- to 10-membered heterocycles.

[0043] In some embodiments, the compounds disclosed herein, such as those of formula (I), are optionally substituted with one or more (e.g., one, two, or three) substituents selected from the following: halogen, oxo, =NH, -CN, -NO2, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3, where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbon ring, 3- to 10-membered heterocycles and -CH2- (3- to 10-membered heterocycles) are optionally substituted by one, two or three groups independently selected from halogens, oxo-, =NH, -CN, -NO2, -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)3, -OH, -OCH3, -OCH2CH3, -NH2, -NHCH3 and -NHCH2CH3.

[0044] Those skilled in the art will understand that the substituted element itself can be substituted if appropriate. Unless specifically stated as “unsubstituted,” references to the chemical part herein should be understood to include substituted variants. For example, references to a “heteroaryl” group or partly implicitly include both substituted and unsubstituted variants.

[0045] In cases where divalent substituents are specified in this text by their conventional chemical formulas written from left to right, they are intended to cover isomers produced by structures written from right to left, for example, -CH2O- is also intended to cover -OCH2-.

[0046] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes both scenarios in which the event or situation occurs and scenarios in which the event or situation does not occur. For example, "optionally substituted" groups may be unsubstituted or substituted.

[0047] The compounds of the present disclosure also include crystalline and amorphous forms, pharmaceutically acceptable salts and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, amorphous forms of the compounds, and mixtures thereof.

[0048] The compounds described herein may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a specific isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted as 1 H (protium), 2 H (deuterium) and 3 H (tritium). Protium is the most abundant hydrogen isotope in nature. Enrichment with deuterium may provide certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide compounds that can be used to study in vivo drug elimination and metabolic pathways. Examples of isotopes that can be incorporated into the compounds of the present disclosure include, but are not limited to 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 36 Cl and 18 F. Of particular interest are compounds of Formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d) or (I-3) enriched with tritium or carbon-14, which can be used, for example, in tissue distribution studies; compounds of the present disclosure enriched with deuterium (especially at metabolic sites) result in, for example, compounds with higher metabolic stability; and compounds of Formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d) or (I-3) enriched with positron-emitting isotopes such as 11 C, 18 F, 15 O and 13 N), which can be used, for example, in positron emission tomography (PET) studies. Isotopically enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0049] As used herein, the phrases "of the formula", "having the formula" or "having the structure" are not intended to be limiting and are used in the same manner as the term "comprising" is commonly used. For example, if a structure is described, it should be understood to encompass all stereoisomeric and tautomeric forms unless otherwise specified.

[0050] Some of the compounds described herein contain one or more asymmetric centers and are therefore capable of producing enantiomers, diastereomers, and other stereoisomers, the asymmetric centers of which may be defined as (R)- or (S)- according to absolute stereochemistry. In some embodiments, to optimize the therapeutic activity of the compounds of this disclosure, for example, to treat cancer, it may be necessary for the carbon atoms to have a specific configuration (e.g., (R,R), (S,S), (S,R), or (R,S)) or be rich in stereoisomers having such configurations. The compounds of this disclosure may be provided as racemic mixtures. Therefore, unless otherwise stated, this disclosure relates to racemic mixtures, pure stereoisomers (e.g., enantiomers and diastereomers), mixtures rich in stereoisomers, etc. When a chemical structure without any stereochemistry is described herein, it should be understood that all possible stereoisomers are covered by such structures. Similarly, when specific stereoisomers are shown or named herein, those skilled in the art will understand that, unless otherwise stated, small amounts of other stereoisomers may be present in the compositions disclosed herein, provided that the presence of such other isomers does not negate the utility of the composition as a whole. Individual stereoisomers can be obtained by many methods known in the art, including preparation using chiral synthons or chiral reagents, resolution using chiral chromatography utilizing a suitable chiral stationary phase or support, or by chemically converting them to diastereomers, separating diastereomers by conventional means such as chromatography or recrystallization, and then regenerating the original stereoisomers.

[0051] Furthermore, where applicable, unless otherwise stated, all cis-trans or cis-trans compounds described herein are not part of the above description. E / Z Isomers (geometric isomers), tautomers, and topological isomers are all included within the scope of this disclosure.

[0052] The term "pharmaceutically acceptable" refers to materials that, when used in the subject composition and methods, will not be biologically or otherwise unacceptable. For example, the term "pharmaceutically acceptable carrier" refers to materials such as excipients, glidants, glidants, sweeteners, diluents, preservatives, dyes, colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that can be incorporated into a composition and administered to a patient without causing unacceptable biological effects or interacting with other components in the composition in an unacceptable manner. Such pharmaceutically acceptable materials generally meet the requirements of toxicological and manufacturing testing standards, including those materials that have been determined by the U.S. Food and Drug Administration to be suitable inactive ingredients.

[0053] The terms "salt" and "pharmaceutically acceptable salt" refer to salts prepared from bases or acids. Pharmaceutically acceptable salts are suitable for administration to patients, such as mammals (e.g., salts with acceptable mammalian safety for a given dosage regimen). Salts can be formed from inorganic bases, organic bases, inorganic acids, and organic acids. Furthermore, when a compound comprises both a basic moiety (such as an amine, pyridine, or imidazole) and an acidic moiety (such as a carboxylic acid or tetraazole), zwitterions can be formed and included in the term "salt" as used herein. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0054] "Pharmaceutically acceptable acid addition salts" refer to salts that retain the biological effectiveness and properties of the free base, are not biologically or otherwise undesirable, and are formed from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid. This also includes salts formed with organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., including, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, caprylates, sebacic acid salts, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids such as arginine salts, gluconates, and galacturons are also considered (see, for example, Berge SM et al., “Pharmaceutical Salts”). Journal of Pharmaceutical Science , 66:1-19 (1997). In some embodiments, the acid addition salt of a basic compound is prepared by contacting a sufficient amount of the desired acid with a method and technique familiar to a skilled craftsman to produce a salt.

[0055] "Pharmaceutically acceptable base addition salts" refer to salts that retain the bioavailability and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to a free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed using metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following substances: primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, and procaine. N,N -Dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine N methyl-reduced glucosamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N -Ethylpiperidine, polyamine resins, etc. See Berge et al. (ibid.).

[0056] The term "effective amount" or "therapeutic effective amount" refers to the amount of a pharmaceutical agent sufficient to achieve a beneficial or desired result. Therapeutic effective amounts can vary based on one or more of the following: the subject and disease condition being treated, the subject's weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by those skilled in the art. An effective amount of an active pharmaceutical agent can be administered in a single dose or in multiple doses. A component can be described herein as having at least an effective amount, such as an amount associated with a specific target or purpose as described herein. The term "effective amount" also applies to the dose that will provide a detection image via a suitable imaging method. A specific dose can vary based on one or more of the following: the specific pharmaceutical agent selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to be imaged, and the physical delivery system in which it is carried.

[0057] As used herein, “treatment” refers to methods used to achieve beneficial or desired outcomes for a subject’s disease, symptom, or medical condition (such as cancer), including but not limited to: (a) improving the disease or medical condition, such as eliminating or resolving the subject’s disease or medical condition; (b) inhibiting the disease or medical condition, such as slowing or halting the progression of the subject’s disease or medical condition; or (c) alleviating the symptoms of the subject’s disease or medical condition. For example, “treating cancer” includes preventing cancer recurrence, improving cancer, inhibiting cancer, and alleviating cancer symptoms. Furthermore, therapeutic benefits are achieved by eradicating or improving one or more of the physiological symptoms associated with an underlying condition, resulting in an observed improvement in the subject, even if the subject may still have the underlying condition.

[0058] As used herein, the term "therapeutic effect" encompasses the therapeutic benefits and / or preventive benefits described above. Preventive effects include delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0059] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to compounds that have the ability to inhibit the biological function (e.g., activity, expression, binding, protein-protein interactions) of a target protein (e.g., PI3Kα). Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. While the preferred antagonists herein specifically interact with the target (e.g., bind to the target), compounds that inhibit the biological activity of a target protein by interacting with other members of a signal transduction pathway, wherein the target protein is a member of that signal transduction pathway, are also specifically included within this definition.

[0060] The term "selective inhibition" or "selective inhibition" refers to the ability of a bioactive drug to preferentially reduce the activity of target signal transduction compared to off-target signaling activity through direct or indirect interaction with the target.

[0061] The terms "object" and "patient" refer to animals, such as mammals, like humans. The methods described herein can be used for both human treatment and veterinary applications. In some implementations, the object is a mammal, such as a human. "Mammalian" includes humans and livestock, such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits), as well as non-livestock animals, such as wild animals, etc.

[0062] The terms “therapeutic agent,” “therapeutic agent,” or “medicinal agent” are used interchangeably and refer to a molecule or compound that, when applied to a subject, imparts a beneficial effect. Beneficial effects include enabling a diagnosis to be confirmed; improving a disease, symptom, condition, or pathological condition; reducing or preventing the onset of a disease, symptom, condition, or pathological condition; and generally combating a disease, symptom, condition, or pathological condition.

[0063] The terms “polypeptide,” “peptide,” and “protein” are used interchangeably herein and refer to a polymer of amino acids of any length. This polymer may be linear or branched, may contain modified amino acids, and may be interrupted by non-amino acid components. The term also encompasses amino acid polymers that have been modified (e.g., by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeled component). As used herein, the term “amino acid” refers to natural and / or non-natural or synthetic amino acids, including glycine and its D or L optical isomers, as well as amino acid analogs and peptide mimics.

[0064] The terms “polynucleotide,” “nucleotide sequence,” “nucleic acid,” and “oligonucleotide” are used interchangeably. They refer to polymeric forms of nucleotides or their analogues of deoxyribonucleotides or ribonucleotides of any length. Polynucleotides can have any three-dimensional structure and can perform any known or unknown function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of genes or gene segments, loci (loci / locus) defined by linkage analysis, exons, introns, messenger RNA (mRNA), transfer RNA, ribosomal RNA, short interfering RNA (siRNA), short hairpin RNA (shRNA), microRNA (miRNA), ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA with any sequence, isolated RNA with any sequence, nucleic acid probes, and primers. Polynucleotides can contain one or more modified nucleotides, such as methylated nucleotides and nucleotide analogs, such as peptide nucleic acids (PNAs), morpholino oligonucleotides and locked nucleic acids (LNAs), glycerol nucleic acids (GNAs), threonine nucleic acids (TNAs), 2'-fluoronucleotides, 2'-OMe nucleic acids, and phosphorylated DNA. If present, modifications to the nucleotide structure can be conferred before or after polymer assembly. The sequence of the nucleotides can be interrupted by non-nucleotide components. Polynucleotides can be further modified after polymerization, such as by conjugation with labeled components or other conjugation targets.

[0065] As used herein, “expression” refers to the process by which polynucleotides are transcribed from a DNA template (e.g., into mRNA or other RNA transcripts) and / or the transcribed mRNA is subsequently translated into peptides, polypeptides, or proteins. Transcripts and encoded polypeptides can be collectively referred to as “gene products.” If the polynucleotides are derived from genomic DNA, expression can include the splicing of mRNA in eukaryotic cells.

[0066] An "antigen" is a part or molecule of an antibody that contains an epitope and therefore specifically binds to it. An "antigen-binding unit" can be the whole or a fragment (or multiple fragments) of a full-length antibody, a structural variant of it, a functional variant of it, or a combination thereof. Full-length antibodies can be, for example, monoclonal antibodies, recombinant antibodies, chimeric antibodies, deimmunized antibodies, humanized antibodies, and human antibodies. Examples of fragments of full-length antibodies can include, but are not limited to, variable heavy chains (VH), variable light chains (VL), and heavy chains (VHH or VL) found in camelidae animals such as camels, llamas, and alpacas. H H), heavy chains (V-NAR domains) found in sharks, single-domain antibodies (sdAbs, i.e. "nanobodies") containing a single antigen-binding domain, Fv, Fd, Fab, Fab', F(ab')2 and "rIgG" (or haptens). Examples of modified fragments of antibodies may include, but are not limited to, scFv, di-scFv or bi(s)-scFv, scFv-Fc, scFv-zipper, scFab, Fab2, Fab3, diabody, single-chain bifunctional antibody, tandem bifunctional antibody (Tandab), tandem di-scFv, tandem tri-scFv, minibody (e.g., (VH-VL-CH3)2, (scFv-CH3)2, ((scFv)2-CH3+CH3), ((scFv)2-CH3) or (scFv-CH3-scFv)2), and multibody (e.g., triabody or tetraabody).

[0067] The term "antibody" encompasses any antigen-binding unit, including but not limited to: monoclonal antibodies, human antibodies, humanized antibodies, camel-derived antibodies, chimeric antibodies, and any other epitope-binding fragments.

[0068] "Prodrug" means a compound that can be converted into the bioactive compound described herein (e.g., a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3)) under physiological conditions or by solvent degradation. Therefore, the term "prodrug" refers to a precursor of a pharmaceutically acceptable bioactive compound. In some respects, a prodrug is inactive when administered to a subject but is converted into an active compound in vivo, for example, through hydrolysis. Prodrug compounds often offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7–9, 21–24 (Elsevier, Amsterdam); Higuchi, T. et al., “Pro-drugs as Novel Delivery Systems,” (1987) ACS Symposium Series, Vol. 14; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, each incorporated herein by reference in its entirety). The term “prodrug” also means any covalently bonded carrier that, when administered to a mammalian subject, releases the active compound in vivo. As described herein, prodrugs of active compounds are typically prepared by modifying functional groups present in the active compound in such a manner that the modification is cleaved into the parent active compound under conventional procedures or in vivo. Prodrugs include compounds in which a hydroxyl, amino, or thiol group is bonded to any group that, when a prodrug of an active compound is administered to a mammalian subject, cleaves these groups to form a free hydroxyl, free amino, or free thiol group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives with hydroxyl functional groups, or acetamide, formamide, and benzamide derivatives with amine functional groups in the active compound.

[0069] The term "in vivo" refers to an event that occurs within the body of an object. The term "ex vivo" refers to an event that first occurs outside the body of an object, intended for subsequent application inside the body. For example, ex vivo preparation may involve preparing cells outside the body of an object for the purpose of introducing the prepared cells into the body of the same or different objects. The term "in vitro" refers to an event that occurs outside the body of an object. For example, in vitro assays cover any assay performed outside the body of an object. In vitro assays cover cell-based assays in which live or dead cells are used. In vitro assays also cover cell-free assays in which intact cells are not used.

[0070] This disclosure also refers to the in vivo metabolites of the disclosed compounds. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the applied compound, primarily due to enzymatic processes. Therefore, this disclosure includes compounds produced by a process comprising administering the disclosed compound to a mammal for a duration sufficient to produce its metabolites. Such products are typically identified by administering the radiolabeled compound of this disclosure at a detectable dose to an animal (e.g., rat, mouse, guinea pig, monkey, or human), allowing sufficient time for metabolism, and isolating its metabolites from urine, blood, or other biological samples.

[0071] The term "PI3K" refers to the phosphoinositol 3-kinase family of enzymes, also known as phosphatidylinositol 3-kinases, which includes class 1 catalytic proteins (e.g., p110α, p110β, p110γ, and p110δ), class 1 regulatory proteins (e.g., p85α, p55α, p50α, p85β, p55γ, p101, p150, p84, and p87), class 2 catalytic proteins (e.g., PI3KC2α, PI3KC2β, and PI3KC2γ), and class 3 proteins (e.g., Vps34). In some embodiments, the PI3K protein is PI3Kα. PI3Kα is composed of... PIK3CA The gene encodes, and may also be referred to as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α; phosphatidylinositol-3-kinase, catalytic, α polypeptide; PI3K, catalytic, α polypeptide; PI3K-alpha; PI3K-α; PI3-kinase α; PIK3CA; or p110α.

[0072] The term "Ras" or "RAS" refers to proteins in the rat sarcoma (RAS) superfamily of small GTPases, such as proteins in the RAS subfamily. The RAS superfamily includes, but is not limited to, the Ras subfamily, Rho subfamily, Rab subfamily, Rap subfamily, Arf subfamily, Ran subfamily, Rheb subfamily, RGK subfamily, Rit subfamily, Miro subfamily, and unclassified subfamilies. In some embodiments, the Ras protein is selected from KRAS (which may also be used interchangeably herein as K-Ras, K-ras, or Kras), HRAS (or H-Ras), NRAS (or N-Ras), MRAS (or M-Ras), ERAS (or E-Ras), RRAS2 (or R-Ras2), RALA (or RalA), RALB (or RalB), RIT1, and any combination thereof, such as those selected from KRAS, HRAS, NRAS, RALA, RALB, and any combination thereof.

[0073] As may be used interchangeably herein, the terms "mutant RAS" and "RAS mutant" refer to a RAS protein having one or more amino acid mutations relative to a common reference sequence such as a wild-type (WT) sequence. In some embodiments, the mutant RAS is selected from mutant KRAS, mutant HRAS, mutant NRAS, mutant MRAS, mutant ERAS, mutant RRAS2, mutant RALA, mutant RALB, mutant RIT1, and any combination thereof, such as mutant KRAS, mutant HRAS, mutant NRAS, mutant RALA, mutant RALB, and any combination thereof. In some embodiments, the mutation can be an introduced mutation, a naturally occurring mutation, or a non-naturally occurring mutation. In some embodiments, the mutation can be a substitution (e.g., a substituted amino acid), an insertion (e.g., the addition of one or more amino acids), or a deletion (e.g., the removal of one or more amino acids). In some embodiments, two or more mutations can be sequential, discontinuous, or a combination thereof. In some embodiments, the mutation can be present at any position in Ras. In some embodiments, the mutation may be present at positions 12, 13, 62, 92, 95, 96 (e.g., Y96D) of Ras, or any combination thereof. In some embodiments, the mutant Ras may contain about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, or more than 50 mutations. In some embodiments, the mutant Ras may contain up to about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, or 50 mutations. In some embodiments, the mutant Ras has a length of about or at most about 500, 400, 300, 250, 240, 233, 230, 220, 219, 210, 208, 206, 204, 200, 195, 190, 189, 188, 187, 186, 185, 180, 175, 174, 173, 172, 171, 170, 169, 168, 167, 166, 165, 160, 155, 150, 125, 100, 90, 80, 70, 60, 50 or less amino acids. In some embodiments, the mutated amino acids are protein amino acids, natural amino acids, standard amino acids, non-standard amino acids, atypical amino acids, essential amino acids, non-essential amino acids or non-natural amino acids. In some embodiments, the mutated amino acid has a positively charged side chain, a negatively charged side chain, a polar uncharged side chain, a nonpolar side chain, a hydrophobic side chain, a hydrophilic side chain, an aliphatic side chain, an aromatic side chain, a cyclic side chain, an acyclic side chain, a basic side chain, or an acidic side chain.In some embodiments, the mutation includes a reactive moiety. In some embodiments, the substituted amino acid includes a reactive moiety. In some embodiments, the mutant Ras may be further modified, such as by conjugation to a detectable tag. In some embodiments, the mutant Ras is a full-length or truncated polypeptide. For example, the mutant Ras may be a truncated polypeptide containing residues 1-169 or residues 11-183 (e.g., residues 11-183 of mutant RALA or mutant RALB).

[0074] As used herein, the term "corresponds to" when applied to amino acid residues in a polypeptide sequence refers to the correspondence of such amino acids to a reference sequence when optimal alignment is performed (e.g., taking into account gaps, insertions, and mismatches; where the alignment can be a primary sequence alignment of a folded protein or a three-dimensional structure alignment). When an amino acid of a mutant Ras protein corresponds to an amino acid position in a wild-type Ras protein, it should be understood that although the amino acid of the mutant Ras protein may be a different amino acid (e.g., G12D, where the wild-type G at position 12 is replaced by an aspartic acid at position 12), the mutant amino acid is located at the position corresponding to the wild-type amino acid. In embodiments, the modified Ras mutant proteins disclosed herein may include a truncation at the C-terminus or an N-terminus preceding a serine residue.

[0075] The term “leaving group” as used in this article is consistent with its well-known meaning in chemistry, referring to an atom or group of atoms that detaches from the rest of the molecule, taking away the electron pair that once formed the bond between the leaving group and the rest of the molecule.

[0076] RAS signaling via PI3K is crucial for normal lymphatic system development and RAS-induced transformation, particularly in lung cancer. The interaction between mutant RAS and the RAS-binding domain (RBD) of PI3Kα contributes to tumorigenesis and maintenance. The RAS:PI3Kα interaction has been shown to play a role in epidermal growth factor (EGF) signaling to PI3K. Interference with RAS:PI3Kα has been shown to inhibit AKT and RaC1 activation in EGFR-mutant lung cancer cells, leading to reduced growth and survival. In EGFR-driven lung adenocarcinomas, RAS binding to PI3Kα promotes tumor progression driven by upstream activators of the RAS pathway, and not only in those where RAS is mutated and activated.

[0077] Besides RAS, other small GTPases (such as Rac1 and CDC42) are also expected to bind to the RBD of PI3Kα, thereby activating signal transduction. Therefore, compounds that bind to the RBD of PI3Kα in this disclosure could be used to treat cancers and other diseases mediated by the binding of small GTPases to PI3Kα. Such small GTPases may be selected from CDC42, Rac1, and RAS (e.g., HRAS, KRAS, and NRAS).

[0078] Numerous PI3K inhibitors have entered clinical development, most of which are reversible ATP-competitive kinase inhibitors. Despite significant efforts, clinical results for PI3K inhibitors remain disappointing, primarily due to drug resistance and intolerable toxicities. Alpelisib, a PI3Kα-specific inhibitor, has been approved in combination with fulvestrant for the treatment of patients diagnosed with HR+, HER2-, PIK3CA mutations in advanced or metastatic breast cancer. Hyperglycemia and hyperinsulinemia are considered targeted effects of PI3Kα inhibition because inhibiting the PI3K / AKT pathway reduces glucose uptake, leading to increased insulin secretion, which subsequently activates insulin / insulin-like growth factor I receptors in tumor cells, providing a survival mechanism for tumor cells and limiting the therapeutic efficacy of PI3Kα inhibitors. Furthermore, hyperglycemia and hyperinsulinemia are major dose-limiting toxicities, preventing the use of sufficiently high doses to completely inhibit PI3Kα signaling in tumors. In a phase III trial of appelisib, hyperglycemia was observed in 65% of patients, leading to significant dose interruptions.

[0079] To overcome the limitations of current ATP-competitive PI3Kα inhibitors, this disclosure provides inhibitors of the RAS:PI3Kα interaction. This interaction occurs at the RAS-binding domain (RBD) of PI3Kα and is expected to have little or no effect on the kinase activity of PI3Kα, which may reduce side effects and / or improve efficacy compared to ATP-competitive PI3K inhibitors. Such inhibitors are expected to produce minimal toxicity in adult subjects while effectively leading to tumor regression, particularly in RAS-mediated, mutant RAS-mediated, HER2 / 3-mediated, and RTK mutation- or amplified cancers. Because the compounds of this disclosure target RAS activation of PI3Kα, which is predominantly present in transformed cells, the hyperglycemia and insulin-driven resistance common with other PI3Kα inhibitors is expected to be very small or unobservable.

[0080] compound In some respects, this disclosure provides compounds of formula (I): (I), Or a pharmaceutically acceptable salt or solvate thereof, wherein: G is selected from C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R G replace; X 1 Selected from N and C(R) 1 ); X 2 Selected from N and C(R) 2 ); X 3 Selected from N, C(R) 3 ) and C(O); X is selected from N and C; J is selected from C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R J replace; L 1 Selected from C 5-15 Alkylene, C 5-15 imidene group, C 5-15 Alynyl, 5- to 15-membered heteroalkyl, and 5- to 15-membered heteroenyl, each optionally bound by one or more R L1 replace; A 1 Selected from key, C 3-12 Carbon rings and 3- to 12-membered heterocycles, of which C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. A1 replace; L is selected from key, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -O-, -N(R) 12 -, -C(O)-, -C(R) 12 )=, -S-, -S(O)-, -S(O)2-, -P(O)R 12 -、-P(O)R 12 O-、-N(R 12 )C(O)-、-N(R 12 )S(O)-、-N(R 12 )S(O)2-、-N(R 12 )P(O)R 12 -、-OP(O)R 12 -、-C(O)N(R 12 )-、-S(O)N(R 12 )-、-S(O)2N(R 12 )- and -P(O)R 12 N(R12 )-, where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl and 3- to 6-membered heteroynyl groups are each optionally surrounded by one, two or three R groups. L replace; A 2 Selected from C 3-12 Carbon rings and 3- to 12-membered heterocycles, each optionally bound by one, two, or three R... A2 replace; R A Selected from hydrogen, R 20 and E, where E is optionally connected to A. 2 The combination is the part that can covalently bind to the C242 residue of the PI3Kα protein; R 1 R 2 and R 3 Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)N(R 12 (R) 13 ), -N(R 12 )C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -S(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R12 )C(O)R 12 -S(O)2R 12 -S(O)(NR) 12 )R 12 -S(O)2N(R) 12 (R) 13 ) and -S(O)(NR 12 )N(R 12 (R) 13 ), or R 1 and R 2 Together with the atoms they are attached to, they form C 5-8 Monocyclic carbon rings or 5- to 8-membered monocyclic heterocycles, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 5-8 Monocyclic carbon rings and 5- to 8-membered monocyclic heterocycles are each optionally divided by one, two, or three Rs. 20 replace; R G R L1 R J R A1 R L and R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SF5, -SR 12 -N(R) 12 (R) 13 =NR 12 =C(R) 14 )2、-C(O)OR 12 -OC(O)N(R) 12 (R)13 ), -N(R 12 )C(O)N(R 12 (R) 13 ), -N(R 12 )C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -S(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 -OS(O)2R 12 -S(O)(NR) 12 )R 12 -S(O)2N(R) 12 (R) 13 ), -S(O)(NR 12 )N(R 12 (R) 13 ), -N(R 12 )P(O)R 12 R 13 and -P(O)R 12 R 13 Two of them R L1 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; in which two Rs A1 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; in which two Rs A2 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic), wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles) are each optionally surrounded by one, two, or three R groups. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; or R groups attached to the same nitrogen atom 12 and R 13 Formed by one, two or three R 20 Replacement of 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl group (3- to 12-membered heterocyclic rings), or two R groups 14 Together with the carbon atoms they are attached to, they form C 3-12 Carbon rings or 3- to 12-membered heterocycles, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocycles), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace; R 20 Each occurrence is independently selected from halogen, oxo, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 22 -SF5, -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 Two of them R 20 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbide ring and the 3- to 12-membered heterocycles are each optionally and independently selected from halogens, oxocycles, -CN, -NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 22 -SF5, -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 One or more substituents are substituted; R 21 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl group (3- to 12-membered heterocycle), or two R groups 21 Together with the carbon atoms they are attached to, they form C 3-12 Carbon rings or 3- to 12-membered heterocycles, each optionally and independently selected from halogens, C 1-3 Alkyl, C 1-3 The alkyl halogroup and -OH are substituted with one, two or three substituents; R 22 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles); R 23 Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl group; or R group attached to the same nitrogen atom 22 and R 23 Formation of 3- to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

[0081] In some embodiments, for compounds of formula (I), G is an optionally substituted C. 3-12 Carbon rings, such as those composed of one or more R G (such as one, two or three R) G ) replaced by C 3-12 Carbon ring. In some embodiments, G is optionally replaced by one, two, or three R. G Replaced monocyclic C 3-8 Carbon rings, such as those optionally composed of one, two, or three R... G Substituted phenyl groups. In some embodiments, G is optionally replaced by one, two, or three R groups. G Replaced bicyclic C 8-12 Carbocyclic rings, such as tetrahydronaphthalene, dihydronaphthalene, or naphthalene, each optionally bounded by one, two, or three R... G Substitution. In some embodiments, G is an optionally substituted 3- to 12-membered heterocyclic ring, such as one, two, or three R... G Replacement of 3- to 12-membered heterocycles. In some embodiments, G is optionally replaced by one, two, or three R... GSubstituted monocyclic 3- to 8-membered heterocycles, such as pyrrolidine, pyrazole, pyridine, or pyrimidine, each optionally replaced by one, two, or three R... G Replacement. In some implementations, G is optionally replaced by one, two, or three R. G The substituted bicyclic 8- to 12-membered heterocycles, such as benzofuran, indole, benzothiophene, quinazoline, or pyridopyrimidine, are each optionally surrounded by one, two, or three R... G Substitution. In some embodiments, G is selected from phenyl and 5- to 10-membered heteroaryl groups, each optionally replaced by one, two, or three R groups. G Substitution. In some embodiments, G is selected from phenyl and benzofuran, each optionally replaced by one, two, or three R. G Replacement. In some implementations, G is optionally replaced by one, two, or three R. G Substituted phenyl groups. In some embodiments, G is optionally replaced by one, two, or three R groups. G The substituted 5- to 10-membered heteroaryl groups, such as those optionally replaced by one, two, or three R groups. G Substituted benzofurans. In some embodiments, G is replaced by one or more R... G (such as one, two or three R) G ) is replaced. In some implementations, G is replaced by at least one R. G Replacement. In some implementations, G is replaced by an R. G Replacement. In some implementations, G is replaced by two Rs. G Replacement. In some implementations, G is replaced by three Rs. G replace.

[0082] In some implementations, for compounds of formula (I), G is Where g1 is 0, 1, 2, or 3. In some implementations, g1 is 0 or 1. In some implementations, G is selected from... , and In some implementations, G is selected from... , and In some implementations, G is selected from... and .

[0083] In some embodiments, the compound of formula (I) is the compound of formula (I-1): (I-1), Or a pharmaceutically acceptable salt or solvate thereof, wherein g1 is 0, 1, 2 or 3.

[0084] In some embodiments, for compounds of formula (I) or (I-1), X 1 It is C(R) 1 And X 2 It is C(R) 2 In some implementations, X 1 It is N and X 2 It is C(R) 2 In some implementations, X 1 It is C(R) 1 And X 2 It is N. In some implementations, X 1 It is C(R) 1 ), X 2 It is C(R) 2 ), and X 3 It is N. In some implementations, X 1 It is C(R) 1 ), X 2 It is C(R) 2 ), and X 3 It is C(R) 3 In some implementations, X 1 It is C(R) 1 ), X 2 It is C(R) 2 ), and X 3 It is C(O). In some implementations, X 1 It is N, X 2 It is C(R) 2 ), and X 3 It is N. In some implementations, X 1 It is N, X 2 It is C(R) 2 ), and X 3 It is C(R) 3 In some implementations, X 1 It is N, X 2 It is C(R) 2 ), and X 3 It is C(O). In some implementations, X 1 It is C(R) 1 ), X 2 It is N, and X 3 It is N. In some implementations, X 1 It is C(R) 1 ), X 2 It is N, and X 3 It is C(R) 3 In some implementations, X 1 It is C(R) 1 ), X 2 It is C(R)2 X is C, and X 3 It is N. In some implementations, X 1 It is C(R) 1 ), X 2 It is C(R) 2 X is C, and X 3 It is C(R) 3 In some implementations, X 1 It is C(R) 1 ), X 2 It is C(R) 2 ), X is N, and X 3 It is C(O). In some implementations, X 1 It is N, X 2 It is C(R) 2 X is C, and X 3 It is N. In some implementations, X 1 It is N, X 2 It is C(R) 2 X is C, and X 3 It is C(R) 3 In some implementations, X 1 It is N, X 2 It is C(R) 2 ), X is N, and X 3 It is C(O). In some implementations, X 1 It is C(R) 1 ), X 2 N is C, X is C, and X 3 It is N. In some implementations, X 1 It is C(R) 1 ), X 2 N is C, X is C, and X 3 It is C(R) 3 In some implementations, X 3 It is N. In some implementations, X 3 It is C(R) 3 In some implementations, X 3 X is C(O). In some implementations, X is N. In some implementations, X is C.

[0085] In some implementations, for compounds of formula (I) or (I-1), R 1 and R 2 Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, -OR 12-N(R) 12 (R) 13 ), -N(R 12 )S(O)2R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 and -S(O)2N(R 12 (R) 13 ), or R 1 and R 2 Together with the atoms they are attached to, they form C 5-8 Monocyclic carbon rings or 5- to 8-membered monocyclic heterocycles, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, C 5-8 Monocyclic carbon rings and 5- to 8-membered monocyclic heterocycles are each optionally divided by one, two, or three Rs. 20 Replacement. In some implementations, R 1 and R 2 Each is hydrogen; or R 1 and R 2 Together with the atoms they are attached to, they form C6 aryl or 5-membered heteroaryl groups, each optionally bonded by one, two, or three R atoms. 20 Replacement. In some implementations, R 1 and R 2 Each is hydrogen. In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form C6 aryl or 5-membered heteroaryl groups, each optionally bonded by one, two, or three R atoms. 20 Replacement. In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form C 5-8 Monocyclic carbon rings or 5- to 8-membered monocyclic heterocycles, each optionally bound by one, two, or three R... 20 Replacement. In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form thiophene, benzene, cyclopentene, or pyrazole, each optionally bonded by one, two, or three R atoms. 20 Replacement. In some implementations, R 1 and R 2 Together with the atoms they are attached to, they form thiophene, benzene, cyclopentene, or pyrazole. In some embodiments, R 1 and R 2 Together with the atoms they are attached to, they form thiophene, which is optionally separated by one or two R atoms.20 replace.

[0086] In some implementations, for compounds of formula (I) or (I-1), Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one or more R 20 Replacement. In some implementations, Selected from , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one or more R 20 Replacement. In some implementations, Selected from , , , , , , , , , , , , , , , and Each of them is optionally controlled by one or more R 20 replace.

[0087] In some embodiments, the compound of formula (I) is a compound of formula (I-2a), (I-2b), (I-2c), or (I-2d): (I-2a) (I-2b) (I-2c) or (I-2d), Or a pharmaceutically acceptable salt or solvate thereof, wherein g1 is 0, 1, 2 or 3.

[0088] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), or (I-2d), J is optionally composed of one or more R J (e.g., 1, 2, 3 or 4 Rs) J The 3- to 12-membered heterocycle is replaced by a 3- to 12-membered heterocycle. In some embodiments, J is a 7- to 11-membered bicyclic heterocycle containing one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the 7- to 11-membered bicyclic heterocycle is optionally replaced by one, two, or three R atoms. J Replacement. In some embodiments, J is a 7- to 11-membered bicyclic heterocycle containing at least one nitrogen atom, wherein the 7- to 11-membered bicyclic heterocycle is optionally replaced by one, two, or three R atoms. J Substitution. In some embodiments, J is selected from phenyl, 5- to 6-membered monocyclic heterocycles, and 7- to 10-membered bicyclic heterocycles, each optionally replaced by one, two, or three R. J Replacement. In some implementations, J is optionally replaced by one, two, or three R. J Substituted phenyl groups. In some embodiments, J is optionally replaced by one, two, or three R groups. J Substituted indazole. In some embodiments, J is optionally replaced by one, two, or three R. J Replacement C 3-12 Carbon ring. In some embodiments, J is selected from phenyl, naphthalene, dihydroindene, and indene, each optionally surrounded by one, two, or three R.J Replacement. In some implementations, J is replaced by one or more R. J (such as one, two, three or four R) J ) is replaced. In some implementations, J is replaced by at least one R. J Replacement. In some implementations, J is replaced by an R. J Replacement. In some implementations, J is replaced by two Rs. J Replacement. In some implementations, J is replaced by three Rs. J replace.

[0089] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), or (I-2d), J is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and In some implementations, each J described in this paragraph is optionally defined by one or more R. J (such as one, two or three R) J ) is replaced. In some implementations, J is optionally replaced by one, two, or three R. J Replacement In some implementations, J is optionally represented by one, two, or three R. J Replacement ,like In some implementations, J is... In some implementations, J is... In some implementations, J is selected from... , , , , , , , , , and In some implementations, J is selected from... , , , , , and .

[0090] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), or (I-2d), R J Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12-N(R) 12 )S(O)2R 12 -C(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 and -S(O)2N(R 12 (R) 13 )-; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 Replacement. In some implementations, R J Each time it appears, it is independently selected from halogens, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -OR 12 -N(R) 12 (R) 13 ), -N(R 12 )S(O)2R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 and -S(O)2N(R 12 (R) 13 )-; where C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Each alkynyl group is optionally and independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 22 -N(R) 22 (R) 23 ), -N(R 22 )S(O)2R 22-C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 and -S(O)2N(R 22 (R) 23 One or more substituents of ) are substituted. In some embodiments, R J Each time it appears, it is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups. In some embodiments, R J Selected from halogens and C 1-3 Alkyl group. In some embodiments, R J Each time it appears, it is independently selected from C. 1-6 Alkyl groups, such as methyl groups. In some embodiments, R J Each time it appears, it is independently selected from oxidative and C-phases. 1-6 Alkyl, -C 0-6 Alkyl-(3- to 12-membered heterocycles) and -C(O)OR 12 C 1-6 Alkyl and -C 0-6 Alkyl groups (3- to 12-membered heterocycles) are each optionally and independently selected from halogens, oxo- and C-shaped groups. 1-6 One or more substituents of the alkyl group are substituted; and wherein R 12 It is -C 1-3 Alkyl-(C 6-10 (Carbon ring).

[0091] In some embodiments, the compound of formula (I) is a compound of formula (I-3): (I-3), Or a pharmaceutically acceptable salt thereof, wherein g1 is 0, 1, 2 or 3; and j1 is 0, 1, 2, 3 or 4.

[0092] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), X 3 It is N. In some implementations, X 3 It is C(R) 3 In some implementations, R 3 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, -OR 12 -N(R) 12 (R)13 ), -N(R 12 )S(O)2R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 and -S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 2- to 6-membered heteroalkyl, and 3- to 6-membered heteroalkenyl groups are each optionally surrounded by one, two, or three R groups. 20 Replacement. In some implementations, R 3 Selected from hydrogen, halogens, -CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OH, -OCH3, -OCF3, -NH2, -NHCH3, and -N(CH3)2. In some embodiments, R 3 It is hydrogen. In some implementations, X 3 It is CH. In some implementations, X 3 It is C(O).

[0093] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), X is N. In some embodiments, X is N and X 3 It is C(O). In some implementations, X is C. In some implementations, X is C and X 3 It is N.

[0094] In some implementations, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R G Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic) and -OR 12 ; where C 1-6 Alkyl, C 2-6 alkenyl, C2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 Replacement. In some implementations, R G Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, 2- to 6-membered heteroalkyl and -OR 12 ; where C 1-6 Alkyl groups and 2- to 6-membered heteroalkyl groups are each optionally and independently selected from halogens, oxo groups, -CN groups, C groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted. In some embodiments, R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3. In some embodiments, at least one R G It is fluorine. In some implementations, R G It's fluorine.

[0095] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), L 1 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. L1 The replacement of the 13- to 28-yuan large rings, such as those optionally replaced by one or more R... L1 Replaces the 13- to 23-yuan large rings. In some implementations, L 1 Together with the atoms they are attached to, they form a group optionally bounded by one or more R atoms. L1 Replaces the 15-20 yuan large ring. In some implementation schemes, L 1 It is optionally controlled by one or more R L1 Replacement C 5-15 Alkylene. In some embodiments, L 1 It is optionally controlled by one or more R L1 Replacement C 5-15 Alkenyl group. In some embodiments, L 1 It is optionally controlled by one or more R L1Replacement C 5-15 Alynyl group. In some embodiments, L 1 It is optionally controlled by one or more R L1 Substituted 5- to 15-membered heteroalkylene groups. In some embodiments, L 1 It is optionally controlled by one or more R L1 The substituted 5- to 15-membered hemienyl group. In some embodiments, L 1 Selected from C 8-12 Alkylene, C 8-12 alkenyl, 8- to 12-membered heteroalkyl, and 8- to 12-membered heteroalkyl, each optionally bound by one or more R L1 Replacement. In some implementations, L 1 Selected from 8- to 12-membered heteroalkyl and 8- to 12-membered heteroalkylene groups, each optionally bound by one or more R L1 Substitution. In some embodiments, the alkenyl and heteroalkyl groups contain one carbon-carbon double bond. In some embodiments, the alkenyl and heteroalkyl groups contain at least one carbon-carbon double bond, such as two carbon-carbon double bonds. In some embodiments, the heteroalkyl and heteroalkyl groups contain at least one oxygen or nitrogen atom. In some embodiments, L... 1 It is optionally controlled by one or more R L1 The substituted 5- to 15-membered heteroene group, wherein the heteroene group contains a carbon-carbon double bond and at least one oxygen atom.

[0096] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), L 1 Selected from , , , , , , , , , , , , , , , and In some implementations, L 1 Selected from , , , , , , and In some implementations, L 1 Selected from , , , , , , and In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes In some implementations, L 1 yes The above L 1 The symbol depicted in the specific instance "and" "Represents the connection points with ring J and ring G respectively.

[0097] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), L 1 Yes -L 2 -DL 3 -, where L 2 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2- to 10-membered heteroalkyl, and 3- to 10-membered heteroalkylene, each optionally bound by one or more R L1 Replacement; D does not exist or is selected from C. 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R 20 Replace; and L 3 Selected from C 1-10 Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2- to 10-membered heteroalkyl, and 3- to 10-membered heteroalkylene, each optionally bound by one or more R L1 Replacement. In some implementations, L 1 Yes -L 2 -DL 3 -, where L 2 Selected from C 1-10Alkylene, C 2-10 imidene group, C 2-10 Alynyl, 2- to 10-membered heteroalkyl, and 3- to 10-membered heteroalkylene, each optionally bound by one or more R L1 Replace; D is selected from C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R 20 Replace; and L 3 It does not exist. In some implementations, L 1 Yes -L 2 -DL 3 -, where L 2 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each optionally bound by one or more R L1 Replacement; D does not exist or is selected from C. 3-10 Carbocyclic rings and 3- to 10-membered heterocycles, each optionally bounded by one or more R... 20 Replace; and L 3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each optionally bound by one or more R L1 Replacement. In some implementations, L 1 Yes -L 2 -DL 3 -, where L 2 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each optionally bound by one or more R L1 Replace; D is selected from C 3-10 Carbocyclic rings and 3- to 10-membered heterocycles, each optionally bounded by one or more R... 20 Replace; and L 3 Selected from C 1-8 Alkylene, C 2-8 alkenyl, 2- to 8-membered heteroalkyl, and 3- to 8-membered heteroalkyl, each optionally bound by one or more R L1 Substitution. In some embodiments, D is selected from phenyl and 3- to 8-membered heterocycles, such as imidazoles, triazoles, azacyclobutanes, pyrrolidines, piperidines, piperazines, and piperidin-2-ones. In some embodiments, D is not substituted. In some embodiments, D is substituted with one or more R... 20 (such as one, two or three R) 20 )replace.

[0098] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R L1 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -N(R) 12 (R) 13 =NR 12 =C(R) 14 )2、-N(R 12 )S(O)2R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 and -S(O)2N(R 12 (R) 13 ); two of the R's L1 Optional joining to form C 3-9 Carbon rings or 3- to 9-membered heterocycles; of which C 1-6 Alkyl, C 2-6 alkenyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-9 The carbon ring and the 3- to 9-membered heterocycles are each optionally bound by one, two, or three Rs. 20 Replacement. In some implementations, R L1 Each time it appears, it is independently selected from halogen, oxidative, and C. 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH.

[0099] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), A1 It can be arbitrarily determined by one, two, or three Rs. A1 Replacement of 3- to 12-membered saturated heterocycles. In some embodiments, A 1 It can be arbitrarily determined by one, two, or three Rs. A1 The substituted 4- to 10-membered saturated heterocycles, such as aziridine, pyrrolidine, piperidine, aziridine, aziridine, or 1,4-diazacycloheptane, are each optionally replaced by one, two, or three R... A1 Replacement. In some implementations, A 1 It can be arbitrarily determined by one, two, or three Rs. A1 The 4- to 12-membered partially unsaturated heterocycles are replaced. In some embodiments, A 1 It can be arbitrarily determined by one, two, or three Rs. A1 The substituted 5- to 8-membered partially unsaturated heterocycles, wherein the 5- to 8-membered partially unsaturated heterocycle contains a double bond, such as dihydropyrrole, tetrahydropyridine, or tetrahydroaza, each optionally separated by one, two, or three R atoms. A1 Replacement. In some implementations, A 1 It is a key. In some implementations, A 1 Selected from bonds, 4- to 10-membered saturated heterocycles, and 5- to 8-membered partially unsaturated heterocycles, wherein the 4- to 10-membered saturated heterocycles and the 5- to 8-membered partially unsaturated heterocycles are each optionally bounded by one, two, or three R... A1 Replacement. In some implementations, A 1 Selected from 4- to 10-membered saturated heterocycles and 5- to 8-membered partially unsaturated heterocycles, each optionally bounded by one, two, or three R... A1 The substitution occurs when the 5- to 8-membered partially unsaturated heterocycle contains a double bond. In some embodiments, A 1 Selected from aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroaziridine, and 1,4-diazacycloheptane, each optionally separated by one, two, or three R... A1 Replacement. In some implementations, A 1 It has not been replaced. In some implementations, A 1 By at least one R A1 Replacement. In some implementations, A 1 By an R A1 Replacement. In some implementations, A 1 By two R A1 Replacement. In some implementations, A 1 by three R A1 replace.

[0100] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), A 1 Selected from , , , , and Each of them is optionally controlled by one, two, or three Rs. A1 Replacement. In some implementations, A 1 Selected from , , and Each of them is optionally controlled by one, two, or three Rs. A1 Replacement. In some implementations, A 1 Selected from and Each of them is optionally controlled by one, two, or three Rs. A1 replace.

[0101] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R A1 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, -OR 12 -N(R) 12 (R) 13 =NR 12 =C(R) 14 )2、-N(R 12 )S(O)2R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 and -S(O)2N(R 12 (R) 13 )-; where two R A1 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20Replacement. In some implementations, R A1 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 Two of them R A1 Optionally joined to form bridges of 1 to 4 atoms; wherein C 1-6 Alkyl, C 2-6 The alkenyl group and the bridge of 1 to 4 atoms are each optionally and independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted. In some embodiments, R A1 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 In some implementations, two Rs A1 The atoms are joined to form a bridge with optional substitutions of 1 to 4 atoms. In some embodiments, the two R atoms... A1 They are joined to form bridges of 1 to 4 atoms. In some embodiments, two R atoms are connected to two different and non-adjacent carbon atoms. A1 The atoms are joined to form a bridge of 1 to 4 atoms, optionally substituted. In some embodiments, the 1 to 4-atom bridge is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH2OCH2-.

[0102] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), L is selected from the bond, C 1-3 Alkyl, C 2-3 alkenyl, 2- to 3-membered heteroalkyl, -O-, -N(R) 12 -, -C(O)-, -C(R) 12 =, -N(R) 12 )C(O)-、-N(R 12 S(O)2-、-C(O)N(R) 12 )- and -S(O)2N(R 12 )-, where C 1-3 Alkyl, C 2-3 The alkenyl group and the 2- to 3-membered heteroalkyl group are each optionally surrounded by one, two, or three R groups. L Replacement. In some implementations, L is selected from key, C 1-3 Alkyl and -C(O)-, where C1-3 Alkyl groups are optionally surrounded by one, two, or three R groups. L Replacement. In some implementations, L is the key. In some implementations, L is optionally replaced by one, two, or three R. L Replacement C 1-3 Alkyl group. In some embodiments, L is -C(O)-. In some embodiments, L is selected from -CH2-, -CHF-, -CF2-, -CH2CH2-, and -C(O)-. In some embodiments, L is unsubstituted. In some embodiments, L is substituted with at least one R-. L Replacement. In some implementations, R L Each time it appears, it is independently selected from halogen, oxo, -CN, and C. 1-6 alkyl.

[0103] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replacement of 3- to 12-membered saturated heterocycles. In some embodiments, A 2 It can be arbitrarily determined by one, two, or three Rs. A2 The substituted 4- to 10-membered saturated heterocycles, such as aziridine, pyrrolidine, piperidine, piperazine, aziridine-heptane, 1,4-diazacycloheptane, or 2-azispiro[3.3]heptane, are each optionally replaced by one, two, or three R... A2 Replacement. In some implementations, A 2 It can be arbitrarily determined by one, two, or three Rs. A2 The 4- to 12-membered partially unsaturated heterocycles are replaced. In some embodiments, A 2 It can be arbitrarily determined by one, two, or three Rs. A2 The substituted 5- to 8-membered partially unsaturated heterocycles, wherein the 5- to 8-membered partially unsaturated heterocycle contains a double bond, such as dihydropyrrole, tetrahydropyridine, or tetrahydroaza, each optionally separated by one, two, or three R atoms. A2 Replacement. In some implementations, A 2 Selected from 4- to 10-membered saturated heterocycles and 5- to 8-membered partially unsaturated heterocycles, each optionally bounded by one, two, or three R... A2 Replacement. In some implementations, A 2 Selected from 4- to 10-membered saturated heterocycles and 5- to 8-membered partially unsaturated heterocycles, each optionally bounded by one, two, or three R... A2 The substitution occurs where the 5- to 8-membered partially unsaturated heterocycle contains a double bond. In some embodiments, A 2Selected from aziridine, pyrrolidine, piperidine, piperazine, aziridine, 1,4-diazacycloheptane, and 2-azispiro[3.3]heptane, each optionally separated by one, two, or three R A2 replace.

[0104] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replacement C 3-12 Carbon ring. In some implementations, A 2 Selected from monocyclic C 3-8 Carbon rings and bicyclic C 7-11 Carbon rings, each optionally bounded by one, two, or three R... A2 Replacement. In some implementations, A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replacement of 4- to 12-membered heterocyclic rings. In some implementations, A 2 These are 4- to 8-membered monocyclic heterocycles and 7- to 11-membered bicyclic heterocycles, each optionally bounded by one, two, or three R... A2 Replacement. In some implementations, A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replaces the 7- to 11-membered bicyclic heterocyclic rings. In some implementations, A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 Replacement. In some implementations, A 2 Selected from tetrahydronaphthyl, tetrahydropyrazolopyrazine, pyridone, pyrazole, aziridine, pyrrolidine, piperidine, piperazine, aziridine, 1,4-diazacycloheptane, and 2-azispiro[3.3]heptane, each optionally separated by one, two, or three R A2 Replacement. In some implementations, A 2 Selected from tetrahydronaphthyl and tetrahydropyrazolopyrazine, each optionally constituting one, two, or three R... A2 Replacement. In some implementations, A 2 Selected from 5,6,7,8-tetrahydro-1,6-naphthidine and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine, each optionally separated by one, two or three R... A2 Replacement. In some implementations, A 2 It has not been replaced. In some implementations, A 2 By at least one R A2 Replacement. In some implementations, A 2 By an RA2 Replacement. In some implementations, A 2 By two R A2 Replacement. In some implementations, A 2 by three R A2 replace.

[0105] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), A 2 Selected from , , , , , , and Each of them is optionally controlled by one, two, or three Rs. A2 Replacement. In some implementations, A 2 Selected from and Each of them is optionally controlled by one, two, or three Rs. A2 Replacement. In some implementations, A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replacement In some implementations, A 2 Selected from and Each of them is optionally controlled by one, two, or three Rs. A2 Replacement. In some implementations, A 2 Selected from and Each of them is optionally controlled by one, two, or three Rs. A2 Replacement. In some implementations, A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replacement In some implementations, A 2 Selected from and Each of them is optionally controlled by one, two, or three Rs. A2 Replacement. In some implementations, A 2 Selected from and In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 Selected from , , , , , and In some implementations, A 2 Selected from , , , , , , , , , , , , and In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes In some implementations, A 2 yes .

[0106] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, -OR 12 -N(R) 12 (R) 13 =NR 12=C(R) 14 )2、-N(R 12 )S(O)2R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 and -S(O)2N(R 12 (R) 13 )-; where two R A2 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 Replacement. In some implementations, R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 Two of them R A2 Optionally joined to form bridges of 1 to 4 atoms; wherein C 1-6 Alkyl, C 2-6 The alkenyl group and the bridge of 1 to 4 atoms are each optionally and independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted. In some embodiments, R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 In some implementations, two Rs A2 The atoms are joined to form a bridge with optional substitutions of 1 to 4 atoms. In some embodiments, the two R atoms... A2 They are joined to form bridges of 1 to 4 atoms. In some embodiments, two R atoms are connected to two different and non-adjacent carbon atoms. A2 The atoms are joined to form a bridge of 1 to 4 atoms, optionally substituted. In some embodiments, the 1 to 4-atom bridge is selected from -CH2-, -CH2CH2-, -CH2CH2CH2-, and -CH2OCH2-.

[0107] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), -A 1 -LA 2 -Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one, two, or three Rs. A1 One, two, or three R A2 Replacement. In some implementations, -A 1 -LA 2 -Selected from , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one, two, or three Rs. A1 One, two, or three R A2 Replacement. In some implementations, -A 1 -LA 2 -Selected from , , , , , , , , , , , , , and Each of them is optionally controlled by one, two, or three Rs. A1 One, two, or three R A2 Replacement. In some implementations, -A 1 -LA 2 -Selected from , , , and Each of them is optionally controlled by one, two, or three Rs. A1 One, two, or three R A2 Replacement. In some implementations, -A 1 -LA 2 -Selected from , , , , , , , , , , , , , and Each of them is optionally controlled by one, two, or three Rs. A1 One, two, or three R A2 Replacement. In some implementations, -A 1 -LA 2 -Selected from , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one, two, or three Rs. A2 Replacement. In some implementations, -A 1 -LA 2 -Selected from , and Each of them is optionally controlled by one, two, or three Rs. A2 Replacement. In some implementations, -A 1 -LA 2 -Selected from , and In some implementations, A 1 -LA 2-Selected from and In some implementations, -A 1 -LA 2 -Selected from , , , , , and In some implementations, -A 1 -LA 2 - is selected from , , , , , , , , , , , , and In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A 1 -LA 2 -yes In some implementations, -A1 -LA 2 -yes .

[0108] In some embodiments, for compounds of formula (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), R A Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -OR 22 -N(R) 22 (R) 23 -C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ) and E; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, and 3- to 6-membered heteroalkynyl groups are each optionally and independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 22 -SR 22 -N(R) 22 (R)23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 ))C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 One or more substituents are substituted. In some embodiments, R A E, wherein E, optionally combined with the nitrogen atom to which it is attached, is a portion capable of covalently binding to the C242 residue of the PI3Kα protein. In some embodiments, E comprises a leaving group. In some embodiments, E comprises a Michael receptor. In some embodiments, E comprises a strain-release motif. In some embodiments, E is selected from... , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one or two R 20 Replacement. In some implementations, E is selected from... , , , and In some implementations, E is selected from... , , , and Each of them is optionally controlled by one or two R 20 Replacement. In some implementations, E is... .

[0109] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), E is selected from... , , , , , , , and , where R 20 and R 22 As described herein, in some implementations, E is selected from... , , , , , , and In some implementations, E is... In some implementations, E is... In some implementations, E is... In some implementations, E is... In some implementations, E is... In some implementations, E is... In some implementations, E is... In some implementations, E is... In some implementations, E is selected from... , , , , , , and , where R 20 and R 22 As described herein, in some implementations, E is selected from... , , and In some implementations, E is... In some implementations, E is... .

[0110] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3): R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3; A 1Selected from aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroazine, and 1,4-diazacycloheptane, wherein aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroazine, and 1,4-diazacycloheptane are each optionally separated by one, two, or three R... A1 replace.

[0111] L is a bond; A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 Replace; and R A yes .

[0112] In some embodiments, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3): A 1 It is a key; L is a bond; A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 Replace; and R A It is E.

[0113] In some implementations, for compounds of formula (I): G is selected from phenyl and 5- to 10-membered heteroaryl groups, each optionally surrounded by one, two, or three R groups. G replace; R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3; X 3 It is N; R 1 and R 2 Together with the atoms they are attached to, they form C 5-8 Monocyclic carbon rings or 5- to 8-membered monocyclic heterocycles, each optionally bound by one, two, or three R... 20 replace; J is selected from phenyl, 5- to 6-membered monocyclic heterocycles, and 7- to 11-membered bicyclic heterocycles, each optionally surrounded by one, two, or three R. J replace; R J Each time it appears, it is independently selected from halogens, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; A 1 It is a key; L is a bond; A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 replace; R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 ;and R A yes .

[0114] In some embodiments, the compound of formula (I) is selected from the following compounds: , , , , , , , , , , , , , , , , , , , , and or its pharmaceutically acceptable salts or solvates, wherein G, X 1 X 2 X 3 X, J, A 1 L, L 1 A 2 R A R G R Jg1 and j1 are defined above, for example, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). Embodiments of one or more of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3) disclosed herein are also intended to apply to compounds of any formula described in this paragraph. If any provision of embodiments of one or more of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3) enumerates substituents or variables not depicted in the compound (e.g., X...), this is intended to apply. 1 If the remaining part of the implementation scheme is considered divisible and unaffected by missing substituents or variables, then the rest of the implementation scheme should be considered divisible and unaffected by missing substituents or variables.

[0115] In some embodiments, the compound of formula (I) is selected from the following compounds: , , and Or its pharmaceutically acceptable salts or solvates, wherein X 3 X, J, A 1 L, L 1 A 2 R A R G and R J As defined above, this refers, for example, to compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). In some embodiments, the compound of formula (I) is selected from the following: , , and Or its pharmaceutically acceptable salts or solvates, wherein X 3 X, J, A 1 L, L 1 A 2 R A R G and R J As defined above, this refers, for example, to compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). In some embodiments, the compound of formula (I) is selected from the following: , , and Or its pharmaceutically acceptable salts or solvates, wherein X 3 X, J, A 1 L, L 1 A 2 R A R G and R J As defined above, this refers, for example, to compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). In some embodiments, the compound of formula (I) is selected from the following: , , and Or its pharmaceutically acceptable salts or solvates, wherein X 3 X, J, A 1 L, L 1 A 2 R A R G and R J As defined above, this refers, for example, to compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). In some embodiments, the compound of formula (I) is selected from the following: , , and Or its pharmaceutically acceptable salts or solvates, wherein X 3 X, J, A 1 L, L 1 A 2 R A R G and R J As defined above, this refers, for example, to compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). In some embodiments, the compound of formula (I) is selected from the following: , , and Or its pharmaceutically acceptable salts or solvates, wherein X 3 X, J, A 1 L, L 1 A 2 R A R G and R JAs defined above, this refers, for example, to compounds of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). In some embodiments, the compound of formula (I) is selected from the following: , , , and or its pharmaceutically acceptable salts or solvates, wherein G, X 1 X 2 X 3 X, J, A 1 L, L 1 A 2 R A R G R J g1 and j1 are defined above, for example, for compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), and / or (I-3). Embodiments of one or more of the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3) disclosed herein are also intended to apply to compounds of any formula depicted in this paragraph. If any provision of embodiments of one or more of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3) enumerates substituents or variables not depicted in the compound (e.g., X...), this is intended to apply. 1 If the remaining part of the implementation scheme is considered divisible and unaffected by missing substituents or variables, then the rest of the implementation scheme should be considered divisible and unaffected by missing substituents or variables.

[0116] In some respects, this disclosure provides compounds selected from the following: , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , and Or pharmaceutically acceptable salts or solvates thereof. In some respects, this disclosure provides compounds selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Or, or a pharmaceutically acceptable salt or solvate thereof.

[0117] In some embodiments, the compounds disclosed herein, such as those of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), exhibit selective and potent binding to PI3Kα (i.e., p110α) relative to other PI3K isoforms (e.g., p110β, p110γ, or p110δ). In some embodiments, the subject compounds exhibit at least 1-fold, and in some cases greater than 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, or 20-fold, or even higher, selective binding to PI3Kα relative to p110β, p110γ, or p110δ. In some embodiments, the subject compound exhibits selective and rapid binding to PI3Kα, producing at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% or even higher PI3Kα binding rates within 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 20 hours, or 24 hours. In some embodiments, the selective and rapid binding to PI3Kα is demonstrated by at least 50% binding within 24 hours. In some embodiments, the subject compound specifically covalently binds to PI3Kα, with substantially no detectable markers of p110β, p110γ, or p110δ when measured under comparable conditions.

[0118] The addition of the warhead disclosed herein can enhance the efficacy or effectiveness in suppressing RAS:PI3Kα. In some embodiments, the subject compound containing the subject warhead suppresses RAS:PI3Kα with higher potency, such as by comparing the IC50 of the corresponding control compound without the warhead. 50 IC values ​​that are at least 10%, 20%, 50%, 100%, 200%, 300%, 400%, or at least 500% lower 50 As demonstrated by the value. In some embodiments, the subject compound containing the subject warhead inhibits RAS:PI3Kα with higher potency, as demonstrated by the IC50 compared to the corresponding control compound not containing the warhead. 50 The value is reduced to at least 1 / 1.1, 1 / 1.2, 1 / 1.5, 1 / 2, 1 / 3, 1 / 4, 1 / 5, 1 / 6, 1 / 7, 1 / 8, 1 / 9, 1 / 10, 1 / 15 or at least 1 / 20 of the IC. 50 The values ​​are as demonstrated by the biochemical assays exemplified in Example 2.

[0119] In some embodiments, the compounds described herein, such as those of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), are provided as substantially pure stereoisomers. In some embodiments, the stereoisomers are provided in an enantiomer excess of at least 80%, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9%.

[0120] In some embodiments, this disclosure provides transisomers of the compounds described herein (such as compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3). In some embodiments, the transisomer is provided in enantiomeric excess. In some embodiments, the transisomer is provided in enantiomeric excess of at least 80%, such as at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 99.9%. In some embodiments, the compounds of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3) are preferably used as non-racemic mixtures, wherein the presence of one transisomer exceeds that of its corresponding enantiomeric or epimeric form. Typically, such mixtures contain two isomers in a ratio of at least 9:1, preferably at least 19:1. In some embodiments, the transisomer is provided in an enantiomer excess of at least 96%, meaning the compound has less than 2% of the corresponding enantiomer. In some embodiments, the transisomer is provided in an enantiomer excess of at least 96%, meaning the compound has less than 2% of the corresponding diastereomer.

[0121] The term "transisomer" refers to conformational stereoisomerism that occurs when rotation around a single bond in a molecule is blocked, restricted, or significantly slowed down due to steric interactions with other parts of the molecule, and in which the substituents at both ends of the single bond are asymmetric (i.e., optically active without the need for an asymmetric carbon center or stereocenter). Separation and isolation of isomeric species can be allowed when the rotational barrier around the single bond is sufficiently high and the interconversion between conformations is slow enough. Transisomers are enantiomers (or epimers) without a single asymmetric atom. Transisomers are generally considered stable if the interconversion barrier is high enough to allow the transisomer to undergo little or no interconversion at room temperature for at least one week (preferably at least one year). In some embodiments, when the transisomer compound is in substantially pure form (which is typically solid), the transisomer compounds of this disclosure do not undergo more than about 5% interconversion with their opposite transisomers within one week at room temperature. In some embodiments, the transisomer compounds of this disclosure do not undergo more than about 5% interconversion with their opposite transisomers within one year at room temperature (about 25°C). This chemical entity, pharmaceutical composition, and method are intended to include all such possible transisomers, including racemic mixtures, diastereomer mixtures, epimeric mixtures, optically pure single transisomers, and intermediate mixtures.

[0122] In some embodiments, the compounds described herein are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0123] In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a number of inorganic or organic bases or inorganic or organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final isolation and purification of the compounds described herein, or by reacting the purified compound in its free form with a suitable acid or base and isolating the resulting salt.

[0124] In some embodiments, the compounds described herein are present in the form of solvates. In some embodiments, methods of treating a disease are performed by applying such solvates. Methods of treating a disease by applying such solvates as pharmaceutical compositions are also described herein.

[0125] The solvate contains a stoichiometric or non-stoichiometric amount of solvent and, in some embodiments, is formed during a crystallization process using a pharmaceutically acceptable solvent (such as water, ethanol, etc.). When the solvent is water, a hydrate is formed; or when the solvent is an alcohol, a purified product is formed. The solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, the hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous solvent / organic solvent mixture using an organic solvent, including but not limited to dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in both unsolvated and solvated forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the unsolvated form.

[0126] The chemical entities described herein can be synthesized according to one or more illustrative schemes described herein and / or techniques known in the art. The materials used herein are commercially available or prepared by synthetic methods known in the art. These schemes are not limited to the compounds listed in the examples or any particular substituents, which are for illustrative purposes. Although the individual steps are described and depicted in Scheme 1, in some cases, the order in which these steps are performed may differ from the order shown in Scheme 1. Various modifications can be made to these synthetic reaction schemes, and such modifications will occur to those skilled in the art upon reference to this disclosure. Unless otherwise stated, the numbering or R group in each scheme generally has the same meaning as defined elsewhere herein.

[0127] Unless otherwise stated, all reactions described herein are carried out at atmospheric pressure and typically at temperatures ranging from -10°C to 200°C. Furthermore, unless otherwise stated, reaction times and conditions are intended to be approximate, for example, at approximately atmospheric pressure and at a temperature range of approximately -10°C to approximately 110°C, over a period of approximately 1 to approximately 24 hours; reactions left to run overnight typically last approximately 16 hours.

[0128] Typically, the compounds disclosed herein can be prepared via the following reaction scheme: Option 1 In some embodiments, compounds of formula 1e can be prepared according to scheme 1. For example, ring J can be installed via a nucleophilic aromatic substitution reaction or cross-coupling reaction with trifluoromethanesulfonate 1a (e.g., a Suzuki reaction with a suitable boric acid or ester) to provide 1b. Ring J can be substituted with an alkyl or heteroalkyl chain containing a vinyl group as described above to give diene 1c, which can undergo a cross-metathesis reaction (such as a Grubbs cross-metathesis reaction) to form macrocycle 1d. The resulting double bond can optionally be hydrogenated, and then R can be installed. A (For example, via A in the presence of a suitable base)2 (The amine undergoes a substitution reaction) to provide a compound of formula 1e.

[0129] In some embodiments, the disclosed compounds, such as those of the formulas given in Table 1, are synthesized according to one of the general routes outlined in Example 1 or by methods known in the art. In some embodiments, exemplary compounds may include, but are not limited to, compounds selected from Table 1 or their salts or solvates.

[0130] Table 1 1 Mixtures of blocked isomers; 2Single, unspecified trans-isomer. The compounds in Table 1 are depicted with flat, wedge, and / or cleaved wedge bonds. It should be understood that the compounds depicted in Table 1 cover all possible stereoisomers of the compounds in Table 1, including E / Z isomers and trans-isomers. In some cases, the relative stereochemistry of one or more stereocenters of the compound has been determined; in some cases, the absolute stereochemistry has been determined. In some cases, a single compound number represents a mixture of stereoisomers, including E / Z isomers and / or trans-isomers. In some cases, a single compound number represents a single stereoisomer, such as a single E or Z isomer and a single trans-isomer. Therefore, it should be understood that if two or more compound numbers in Table 1 are provided with the same depicted structure, each compound number represents a different stereoisomer or mixture of stereoisomers having that depicted structure.

[0131] In some embodiments, the compounds of this disclosure exhibit one or more functional properties disclosed herein. For example, the subject compound binds to the PI3K protein, the PI3Kα protein, or a mutant form thereof. In some embodiments, the subject compound specifically binds to and also inhibits the PI3K protein, the PI3Kα protein, or a mutant form thereof. In some embodiments, the subject compound selectively inhibits the binding of RAS to PI3Kα relative to other PI3K isoforms (e.g., p110γ or p110δ). In some embodiments, the IC50 of the subject compound against PI3Kα:RAS is less than about 5 μM, less than about 1 μM, less than about 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, or even lower, as measured in in vitro assays known in the art or exemplified herein. In some embodiments, the subject compound is covalently bound to PI3Kα.

[0132] In some embodiments, the compounds of this disclosure are capable of reducing RAS-driven PI3Kα activation. Such reduction can be demonstrated by one or more of the following: (i) a decrease in phosphorylated AKTs473; (ii) a decrease (e.g., inhibition) in RAS-driven tumor cell growth; (iii) a decrease (e.g., inhibition) in HER2 / 3-driven tumor cell growth; (iv) a decrease in the interaction between RAS and PI3Kα; (v) no significant change in phosphorylated PIP2; (vi) no significant change in phosphorylated ERK; (vii) no significant inhibition of intrinsic PI3Kα kinase activity; (viii) no significant change in blood glucose levels; and (ix) no hyperglycemia. In some cases, the reduction in RAS-driven PI3Kα activation can be demonstrated by two, three, four, five, six, seven, eight, or all of the above (i)-(ix).

[0133] It should be understood that the different aspects of this disclosure can be understood individually, jointly, or in combination. Each aspect described herein can be applied to any particular application of this disclosure. The material compositions of this disclosure (including compounds of any chemical formula disclosed in the Compounds section) can be used in the Methods section (including the methods of use and production disclosed herein), and vice versa.

[0134] method The compounds described herein, including pharmaceutically acceptable salts or solvates thereof, are capable of disrupting (e.g., modulating, blocking, and / or inhibiting) the interaction between PI3Kα and small GTPases (e.g., CDC42, Rac1, or RAS proteins such as HRAS, KRAS, MRAS, NRAS, RRAS, RRAS2, or RIT1), and have broad applications in therapeutic, diagnostic, and other biomedical research. In some embodiments, the small GTPase is capable of binding to the RAS-binding domain (RBD) of the PI3Kα protein. In some embodiments, the small GTPase is selected from CDC42, Rac1, and RAS proteins. In some embodiments, this disclosure provides a method for inhibiting the interaction between the RAS protein and the PI3Kα protein, the method comprising contacting the PI3Kα protein with an effective amount of the compounds described herein or their pharmaceutically acceptable salts or solvates. In some embodiments, this disclosure provides a method for inhibiting the interaction between PI3Kα and RAS proteins (such as wild-type RAS or RAS mutant proteins (e.g., G12S, G12C, G12D, G12V, G13C and / or G13D)). In some embodiments, the RAS protein is selected from HRAS, KRAS, MRAS, NRAS, RRAS, RRAS2, or RIT1. In some embodiments, the RAS protein is a wild-type RAS protein. In some embodiments, the RAS protein is a RAS mutant protein selected from KRAS, HRAS, and NRAS (e.g., G12S, G12C, G12D, G12V, G13C and / or G13D). In some embodiments, the RAS protein is a KRAS mutant protein selected from G12S, G12C, G12D, and G12V. In some embodiments, the PI3Kα protein is a wild-type PI3Kα protein. In some embodiments, the PI3Kα protein is a PI3Kα mutant protein (e.g., E81K, E110del, K111E, K111N, G118D, N345K, C420R, E453K, E542K, E545A, E545G, E545K, Q546K, Q546P, Q546R, E726K, M1043I, N1044K, H1047L, H1047R and / or G1049R).

[0135] In some aspects, this disclosure provides a method for treating cancer in a subject in need, comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt or solvate thereof. In some aspects, this disclosure provides a method for treating cancer in a subject comprising amplified wild-type RAS or RAS mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) protein, comprising inhibiting the interaction between the subject's PI3Kα and the RAS protein by administering the compound to the subject, wherein the compound is characterized by a reduction in RAS-driven PI3Kα activation upon contact with the PI3Kα protein. In some implementations, the cancer exhibits one or more of the following abnormal activations of PI3Kα or PI3Kα mutations (e.g., E81K, E110del, K111E, K111N, G118D, N345K, C420R, E453K, E542K, E545A, E545G, E545K, Q546K, Q546P, Q546R, E726K, M1043I, N1044K, H1047L, H1047R, and G1049R). In some implementations, the cancer contains a RAS mutant protein, such as a KRAS mutant protein containing mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, or Q61H. In some aspects, this disclosure provides a method for treating cancers comprising amplified wild-type PI3Kα or PI3Kα mutant (e.g., E81K, E110del, K111E, K111N, G118D, N345K, C420R, E453K, E542K, E545A, E545G, E545K, Q546K, Q546P, Q546R, E726K, M1043I, N1044K, H1047L, H1047R and / or G1049R) proteins in a subject, comprising inhibiting the interaction between the PI3Kα of the subject and a RAS protein by administering a compound to the subject, wherein the compound is characterized by a reduction in RAS-driven PI3Kα activation upon contact with the PI3Kα protein. In some aspects, this disclosure provides a method for treating HER2 / 3-driven cancer in a subject, comprising inhibiting the interaction between the subject's PI3Kα and RAS protein by administering a compound to the subject, wherein the compound is characterized in that, upon contact with the PI3Kα protein, RAS-driven PI3Kα activation is reduced.

[0136] In some aspects, this disclosure provides a method for modulating the activity of RAS proteins (e.g., KRAS, mutant KRAS, KRASG12S, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G13C, and / or KRAS G13D), comprising contacting a PI3Kα protein with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvation thereof, thereby modulating the activity of the RAS protein. In some aspects, this disclosure provides a method for modulating the activity of a PI3Kα protein, comprising contacting a PI3Kα protein with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvation thereof, thereby modulating the activity of the PI3Kα protein.

[0137] In some aspects, this disclosure provides a method for inhibiting cell growth, comprising administering an effective amount of the compound described herein or a pharmaceutically acceptable salt or solvate thereof to cells expressing RAS (e.g., KRAS) protein, thereby inhibiting the growth of the cells. In some aspects, this disclosure provides a method for inhibiting cell growth, comprising administering an effective amount of the compound described herein or a pharmaceutically acceptable salt or solvate thereof to cells expressing PI3Kα protein, thereby inhibiting the growth of the cells. In some embodiments, the subject method includes administering additional agents to the cells.

[0138] In some aspects, this disclosure provides a method for treating a disease mediated at least partially by a RAS protein (such as KRAS or a mutant thereof) in a subject of need, comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt or solvation thereof. In some aspects, this disclosure provides a method for treating a disease mediated at least partially by a PI3Kα protein in a subject of need, comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt or solvation thereof. In some aspects, this disclosure provides a method for treating a disease mediated at least partially by HER2 and / or HER3 proteins in a subject of need, comprising administering to the subject an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, the disease is cancer, such as a solid tumor or hematologic malignancy. In some embodiments, the method further includes administering to the subject additional agents, such as KRAS inhibitors, SHP2 inhibitors, SOS inhibitors, EGFR inhibitors, MEK inhibitors, ERK inhibitors, CDK4 / 6 inhibitors, BRAF inhibitors, or combinations thereof.

[0139] In some aspects, this disclosure provides a method for inhibiting the interaction between a PI3Kα protein and a RAS protein (such as KRAS or a mutant thereof), comprising contacting the PI3Kα protein with a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound exhibits an IC50 of less than 10 μM, such as less than 5 μM, 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or lower, against the RAS:PI3Kα interaction.

[0140] In some aspects, this disclosure provides a method for treating RAS-mediated cancer in a subject of need, comprising administering to the subject a KRAS inhibitor, SHP2 inhibitor, SOS inhibitor, EGFR inhibitor, MEK inhibitor, ERK inhibitor, CDK4 / 6 inhibitor, or BRAF inhibitor and an effective amount of a compound disclosed herein, such as a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), or a pharmaceutically acceptable salt or solvate thereof. In some aspects, this disclosure provides a method for treating HER2 and / or HER3-mediated cancers in a subject of need, comprising administering to the subject a KRAS inhibitor, SHP2 inhibitor, SOS inhibitor, EGFR inhibitor, MEK inhibitor, ERK inhibitor, CDK4 / 6 inhibitor, or BRAF inhibitor and an effective amount of a compound disclosed herein, such as a compound of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer.

[0141] In any of the methods disclosed herein, the PI3Kα protein to which the subject compound covalently or reversibly binds may be a PI3Kα mutant (e.g., E81K, E110del, K111E, K111N, G118D, N345K, C420R, E453K, E542K, E545A, E545G, E545K, Q546K, Q546P, Q546R, E726K, M1043I, N1044K, H1047L, H1047R, and / or G1049R). In any of the methods disclosed herein, the RAS protein to which the subject compound inhibits its binding to PI3Kα may be a RAS mutant (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D), including mutants of KRAS, HRAS, or NRAS. In some implementations, the methods for treating cancer can be applied to treat solid tumors or hematologic cancers. In some implementation schemes, the cancers treated may include, but are not limited to, prostate cancer, brain cancer, colon cancer, rectal cancer, renal cell carcinoma, liver cancer, various lung cancers (including non-small cell lung cancer), small bowel cancer, esophageal cancer, melanoma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, endocrine system cancers, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, pediatric solid tumors, bladder cancer, kidney or ureteral cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brainstem glioma, pituitary adenoma, and Kaposi's sarcoma. Sarcoma), epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, combinations of said cancers, and metastatic lesions of said cancers. In some embodiments, it is a method of treating cancer in a subject of need, comprising administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematologic cancer.In some embodiments, a method of treating cancer in a subject of need includes administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is a hematologic cancer selected from one or more of the following: chronic lymphocytic leukemia (CLL), acute leukemia, acute lymphoblastic leukemia (ALL), B-cell acute lymphoblastic leukemia (B-ALL), T-cell acute lymphoblastic leukemia (T-ALL), chronic myeloid leukemia (CML), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell tumor, Burkitt's lymphoma. Lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell follicular lymphoma, malignant lymphoproliferative disorders, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic syndromes, non-Hodgkin lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell tumor, Waldenstrom macroglobulinemia, and pre-leukemia. In some embodiments, a method of treating cancer in a subject of need includes administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt or solvation thereof, wherein the cancer is selected from one or more of the following: chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), B-cell acute lymphoblastic leukemia (B-ALL), and / or acute lymphoblastic leukemia (ALL). In some embodiments, a method of treating cancer in a subject of need includes administering to the subject a therapeutically effective amount of the compound described herein or a pharmaceutically acceptable salt or solvation thereof, wherein the cancer is selected from breast cancer, colon cancer, colorectal cancer, endometrial cancer, brain cancer, liver cancer, stomach cancer, lung cancer (e.g., NSCLC), ovarian cancer, and esophageal cancer. In some embodiments, the cancer is selected from lung cancer (e.g., NSCLC), colorectal cancer, and esophageal cancer.

[0142] Any treatment method disclosed herein may be administered alone or in combination with another therapy or another agent. “Combination” means (a) formulating a subject composition containing the subject compound and another agent, or (b) using the subject composition separately from another agent as an overall treatment regimen. “Combination” means administering another therapy or agent simultaneously, concurrently, or sequentially (without a specific time limit) with a subject composition containing a compound disclosed herein, wherein such combined administration provides a therapeutic effect.

[0143] In some embodiments, the subject treatment method is combined with surgery, cell therapy, chemotherapy, radiation, and / or immunosuppressive agents. Additionally, the compositions of this disclosure can be combined with other therapeutic agents such as other anticancer agents, anti-allergy agents, anti-nausea agents (or antiemetics), analgesics, cytoprotective agents, immunostimulants, and combinations thereof. In one embodiment, the subject treatment method is combined with a chemotherapy agent.

[0144] Exemplary chemotherapy agents include anthracyclines (e.g., doxorubicin, liposomal doxorubicin), vinblastine alkaloids (e.g., vincristine, vinorelbine, vinorelbine), alkylating agents (e.g., cyclophosphamide, decarbazine, melphalan, ifosfamide, temozolomide), and immune cell antibodies (e.g., aleemtuzumab, gemtuzumab). (e.g., zumab), rituximab, ofatumumab, tositumomab, brentuximab), antimetabolites (including, for example, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors (e.g., fludarabine)), TNFR glucocorticoid-induced TNFR-associated protein (GITR) agonists, proteasome inhibitors (e.g., aclacinomycin A, gliotoxin or bortezomib), and immunomodulators such as thalidomide or thalidomide derivatives (e.g., lenalidomide). Other chemotherapy agents considered for combination use include Myleran®, Busulfex®, Leustatin®, Cytoxan® or Neosar®, Cytarabine, Cytosine arabinoside (Cytosar-U®), DepoCyt®, Cerubidine®, Daunorubicin hydrochloride, Daunorubicin Xome®, Dexamethasone, Adriamycin® or Rubex®, Vepesid®, Fludarabine®, Hydroxyurea®, and Idarubicin. (Idamycin®), mitoxantrone (Novantrone®), gemtuzumab (Mylotarg®), anastrozoleArimidex®, Bicalutamide (Casodex®), Bleomycin Sulfate (Blenoxane®), Busulex®, Capecitabine (Xeloda®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, Paraplatin®, Carmustine (BiCNU®), Leukeran®, Cisplatin®, Dacarbazine (DTIC-Dome®), Dactinomycin (Actinomycin D, Cosmegan), Dexamethasone, Docetaxel (Taxotere®), 5-Fluorouracil (Adrucil®, Efudex®), Flutamide (Eulexin®), Tezacitibine, Gemcitabine (Difluorodeoxycytidine), Ifosfamide (IFEX®), Irinotecan (Camptosar®), L-asparaginase (ELSPAR®), Leucovorin calcium, Alkeran®, Purinethol®, Methotrexate (Folex®), Novantrone®, Mylotarg, Taxol®, Phoenix (Yttrium 90 / MX-DTPA), Pentostatin, Gliadel® (polyphenylprotein 20 and carmustine implant), Nolvadex® (tamoxifencitrate), Teniposide Vumon®, 6-thioguanine, thiotepa, tirapazamine (Tirazone®), topotecan hydrochloride for injection (Hycamptin®), vinblastine (Velban®), vincristine (Oncovin®), and vinorelbine (Navelbine®).

[0145] Particularly interesting anticancer agents for use in combination with the compounds disclosed herein include: anthracyclines; alkylating agents; antimetabolites; inhibitors of calcium-dependent phosphatase calcineurin or p70S6 kinase FK506 or drugs that inhibit p70S6 kinase; mTOR inhibitors; immunomodulators; anthracyclines; vinca alkaloids; proteasome inhibitors; GITR agonists; protein tyrosine phosphatase inhibitors; CDK4 kinase inhibitors; BTK inhibitors; MKN kinase inhibitors; DGK kinase inhibitors; or oncolytic viruses.

[0146] Exemplary antimetabolites include, but are not limited to, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors: methotrexate (Rheumatrex®, Trexall®), 5-fluorouracil (Adrucil®, Efudex®, Fluoroplex®), fluorouridine (FUDF®), cytarabine (Cytosar-U®, Tarabine PFS), 6-mercaptopurine (Puri-Nethol®), 6-thioguanine (thioguanine Tabloid®), fludarabine phosphate (Fludara®), pentostatin (Nipent®), pemetrexed (Alimta®), raltitrexed (Tomudex®), cladribine (Leustatin®), clofarabine (Clofarex®, Clolar®), azacitidine (Vidaza®), decitabine, and gemcitabine (Gemzar®). Preferred antimetabolites include cytarabine, clofarabine, and fludarabine.

[0147] Exemplary alkylating agents include, but are not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazines: uracil nitrogen mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), chlorambucil (Leukeran®), and pipebroman. Amedel®, Vercyte®, triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphate, temozolomide (Temodar®), thioplex®, busilvex®, Myleran®, carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®).Other exemplary alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); temozolomide (Temodar® and Temodal®); styromycin (also known as actinomycin-D, Cosmegen®); melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); tretamine (also known as hexamethylmelamine (HMM), Hexalen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); paraplatin®; lomustine (also known as CCNU, CeeNU®); and cisplatin. (Also known as CDDP, Platinol®, and Platinol®-AQ); chlorambucil (Leukeran®); cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC, and imidazocarbamide, DTIC-Dome®); hexamethylmelamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosfamide (Ifex®); prednumustine; procarbazine (Matulane®); dichloromethyldiethylamine (also known as nitrogen mustard) Mustard, nitrogen mustard, and dichloromethyldiethylamine hydrochloride (Mustargen®); streptozotocin (Zanosar®); thiophosphoamide (also known as thiophosphoamide, TESPA, and TSPA, Thioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and bendamustine hydrochloride (Treanda®).

[0148] In some respects, the compositions provided herein can be administered in combination with radiotherapy, such as radiation. Whole-body radiation can be administered at a dose of 12 Gy. The radiation dose can include a cumulative dose of 12 Gy to the whole body, including healthy tissue. The radiation dose can range from 5 Gy to 20 Gy. The radiation dose can be 5 Gy, 6 Gy, 7 Gy, 8 Gy, 9 Gy, 10 Gy, 11 Gy, 12 Gy, 13 Gy, 14 Gy, 15 Gy, 16 Gy, 17 Gy, 18 Gy, 19 Gy, or up to 20 Gy. Radiation can be whole-body or partial-body radiation. In the case of whole-body radiation, it may be homogeneous or non-homogeneous. For example, when radiation may not be homogeneous, narrower areas of the body, such as the neck, may receive a higher dose than wider areas, such as the hips.

[0149] When appropriate, immunosuppressants may be used in combination with the subject treatment. Exemplary immunosuppressants include, but are not limited to, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil and FK506, antibodies or other immunoablative agents such as CAMPATH, anti-CD3 antibodies (e.g., muromonab, otelixizumab) or other antibody therapies, cytotoxins, fludarabine, cyclosporine, FK506, rapamycin, mycophenolate mofetil, steroids, FR901228, cytokines and irradiation, peptide vaccines, and any combination thereof. According to the subject matter of this disclosure, the various methods described above may include the administration of at least one immunomodulator. In some embodiments, at least one immunomodulatory agent is selected from immunostimulants, checkpoint immunoblockers (e.g., blockers or inhibitors of immune checkpoint genes such as PD-1, PD-L1, CTLA-4, IDO, TIM3, LAG3, TIGIT, BTLA, VISTA, ICOS, KIR, and CD39), radiotherapy agents, chemotherapeutic agents, and combinations thereof. In some embodiments, the immunostimulant is selected from IL-12, agonist-co-stimulatory monoclonal antibodies, and combinations thereof. In one embodiment, the immunostimulant is IL-12. In some embodiments, the agonist co-stimulatory monoclonal antibody is selected from anti-4-1BB antibodies (e.g., urelumab, PF-05082566), anti-OX40 antibodies (pogalizumab, tavolixizumab, PF-04518600), anti-ICOS antibodies (BMS986226, MEDI-570, GSK3359609, JTX-2011), and combinations thereof. In one embodiment, the agonist co-stimulatory monoclonal antibody is an anti-4-1BB antibody. In some implementations, the checkpoint immune blocker is selected from anti-PD-L1 antibodies (atezolizumab, avelumab, durvalumab, BMS-936559), anti-CTLA-4 antibodies (e.g., tremelimumab, ipilimumab), anti-PD-1 antibodies (e.g., pembrolizumab, nivolumab, cemiplimab), anti-LAG3 antibodies (e.g., C9B7W, 410C9), anti-B7-H3 antibodies (e.g., DS-5573a), anti-TIM3 antibodies (e.g., F38-2E2), and combinations thereof.In one embodiment, the checkpoint immune blocker is an anti-PD-L1 antibody. In some cases, the compounds disclosed herein may be administered to the subject in combination with bone marrow transplantation, T-cell purification therapy using chemotherapeutic agents such as fludarabine, external beam radiotherapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH (e.g., before, during, or after). In some cases, expanded cells may be administered before or after surgery. Alternatively, compositions comprising the compounds described herein may be administered with an immunostimulant. The immunostimulant may be a vaccine, colony stimulant, interferon, interleukin, virus, antigen, co-stimulant, immunogenic agent, immunomodulatory agent, or immunotherapeutic agent. The immunostimulant may be a cytokine such as interleukin. One or more cytokines may be introduced together with the modified cells provided herein. Cytokines may be used to enhance the function of modified T lymphocytes (including adoptively metastatic tumor-specific cytotoxic T lymphocytes) to expand within the tumor microenvironment. In some cases, IL-2 may be used to promote the expansion of the modified cells described herein. Cytokines such as IL-15 can also be used. Other relevant cytokines in the field of immunotherapy, such as IL-2, IL-7, IL-12, IL-15, IL-21, or any combination thereof, can also be utilized. Interleukin can be IL-2 or aldeskeukin. Aldeskeukin can be administered in low or high doses. A high-dose aldeskeukin regimen may involve intravenous administration of approximately 0.037 mg / kg (600,000 IU / kg) every 8 hours for up to approximately 14 doses, if tolerated. Immunostimulants (e.g., aldeskeukin) can be administered within 24 hours after cell infusion. Immunostimulants (e.g., aldeskeukin) can be administered via infusion approximately every 8 hours over approximately 15 minutes for up to approximately 4 days. Immunostimulants (e.g., adeleukin) can be administered at doses of about 100,000 IU / kg, 200,000 IU / kg, 300,000 IU / kg, 400,000 IU / kg, 500,000 IU / kg, 600,000 IU / kg, 700,000 IU / kg, 800,000 IU / kg, 900,000 IU / kg, or up to about 1,000,000 IU / kg. In some cases, adeleukin can be administered at doses of approximately 100,000 IU / kg to 300,000 IU / kg, 300,000 IU / kg to 500,000 IU / kg, 500,000 IU / kg to 700,000 IU / kg, 700,000 IU / kg to approximately 1,000,000 IU / kg.

[0150] In some embodiments, the compounds described herein, such as compounds, salts, or solvates of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), are administered in combination with or in combination with one or more pharmacologically active agents selected from: (1) inhibitors of MEK (e.g., MEK1, MEK2) or mutants thereof (e.g., trametinib, cobimetinib, binimetinib, selumetinib, remetinib, AZD6244); (2) inhibitors of epidermal growth factor receptor (EGFR) and / or mutants thereof (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab). (2) Panitumumab, osimertinib, olmutinib, EGF-816; (3) Immunotherapy agents (e.g., checkpoint immune blockers, as disclosed herein); (4) Taxanes (e.g., paclitaxel, docetaxel); (5) Antimetabolites (e.g., antifolate agents such as methotrexate, raltitrexed, pyrimidine analogs such as 5-fluorouracil (5-FU), ribonucleoside and deoxyribonucleoside analogs, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine). (c) Fludarabine; (6) Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 and / or FGFR4 and / or their mutants (e.g., nintedanib); (7) Mitotic kinase inhibitors (e.g., CDK4 / 6 inhibitors, such as palbociclib, ribociclib, abemaciclib); (8) Anti-angiogenic drugs (e.g., anti-VEGF antibodies, such as bevacizumab); (9) Topoisomerase inhibitors (e.g., epipodophyllotoxin, such as etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantrone); (10) Platinum-containing compounds (e.g., cisplatin, oxaliplatin, carboplatin); (11) Inhibitors of ALK and / or its mutants (e.g., crizotinib, alectinib, entrectinib, brigatinib);(12) Inhibitors of c-MET and / or its mutants (e.g., K252a, SU11274, PHA665752, PF2341066); (13) Inhibitors of BCR-ABL and / or its mutants (e.g., imatinib, dasatinib, nilotinib); (14) Inhibitors of ErbB2 (Her2) and / or its mutants (e.g., afatinib, lapatinib, trastuzumab, pertuzumab); (15) Inhibitors of AXL and / or its mutants (e.g., R428, amuvatinib, XL-880); (16) Inhibitors of NTRK1 and / or its mutants (e.g., mesatinib); (17) Inhibitors of RET and / or its mutants (e.g., BLU-667, Lenvatinib); (18) Inhibitors of A-Raf and / or B-Raf and / or C-Raf and / or its mutants (RAF-709, LY-3009120, sorafenib, vemurafenib, dabrafenib, encorafenib, regorafenib, GDC-879); (19) Inhibitors of ERK and / or its mutants (e.g., ulixertinib, MK-8353, LTT462, AZD0364, SCH772984, BIX02189, LY3214996, ravoxertinib); (20) MDM2 inhibitors (e.g., HDM-201, NVP-CGM097, RG-7112, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-115); (21) mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, ridaforolimus); (22) BET inhibitors (e.g., I-BET 151, I-BET762, OTX-015, TEN-010, CPI-203, CPI-0610, olionon, RVX-208, ABBC-744, LY294002, AZD5153, MT-1, MS645); (23) Inhibitors of IGF1 / 2 and / or IGF1-R (e.g., xentuzumab, MEDI-573);(24) CDK9 inhibitors (e.g., DRB, flavopiridol, CR8, AZD 5438, purvalanol B, AT7519, dinaciclib, SNS-032); (25) Farnesyltransferase inhibitors (e.g., tipifarnib); (26) SHIP pathway inhibitors, including SHIP2 inhibitors and SHIP1 inhibitors; (27) SRC inhibitors (e.g., dasatinib); (28) JAK inhibitors (e.g., tofacitinib); (29) PARP inhibitors (e.g., olaparib, rucaparib, niraparib, talazoparib); (30) BTK inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib); (31) ROS1 inhibitors (e.g., entrectinib); (32) inhibitors of Src, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl or AKT;(33) Inhibitors of KRAS G12C mutants (e.g., including but not limited to AMG510, MRTX849, and any covalent inhibitors that bind to cysteine ​​residue 12 of KRAS, the structures of which are known) (e.g., as in US20180334454, US20190144444, US20150239900, US10246424, US20180086753, WO2018143315, WO2018206539, WO20191107519, WO2019141250, WO2019150305, US9862701, US20170197) 945, US20180086753, US10144724, US20190055211, US20190092767, US20180127396, US201802 73523, US10280172, US20180319775, US20180273515, US20180282307, US20180282308, WO20190 51291, WO2019213526, WO2019213516, WO2019217691, WO2019241157, WO2019217307, WO202004 7192, WO2017087528, WO2018218070, WO2018218069, WO2018218071, WO2020027083, WO20200270 84. Ras as described in WO2019215203, WO2019155399, WO2020035031, WO2014160200, WO2018195349, WO2018112240, WO2019204442, WO2019204449, WO2019104505, WO2016179558, WO2016176338 or related patents and applications. (34) G12C inhibitors, each incorporated herein by reference in its entirety; (35) SHC inhibitors (e.g., PP2, AID371185); (36) GAB inhibitors (e.g., GAB-0001); (37) GRB inhibitors; (38) PI-3 kinase inhibitors (e.g., idelalisib, copanlisib, duvelisib, apelelisib, taselisib, perifosine, buparlisib, umbralisib, NVP-BEZ235-AN); (39) MARPK inhibitors;(39) CDK4 / 6 inhibitors (e.g., palbociclib, ribociclib, abeciclib); (40) MAPK inhibitors (e.g., VX-745, VX-702, RO-4402257, SCIO-469, BIRB-796, SD-0006, PH-797804, AMG-548, LY2228820, SB-681323, GW-856553, RWJ67657, BCT-197); or (41) SHP pathway inhibitors, such as SHP2 inhibitors (e.g., RMC-4630, ERAS-601, ...); , , , and Or SHP1 inhibitors. In some embodiments, the RAS:PI3Kα inhibitors described herein, such as compounds, salts, or solvates of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), are administered in combination with or in combination with one or more checkpoint immune blockers (e.g., anti-PD-1 and / or anti-PD-L1 antibodies, anti-CLTA-4 antibodies). In some embodiments, the RAS:PI3Kα inhibitors described herein, such as compounds, salts, or solvates of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), are administered in combination with or in combination with one or more pharmacologically active agents comprising inhibitors against one or more targets selected from: MEK, epidermal growth factor receptor (EGFR), FGFR1, FGFR2, FGFR3, mitotic kinases. Topoisomerase, ALK, ALK5, c-MET, ErbB2, AXL, NTRK1, RET, A-Raf, B-Raf, C-Raf, ERK, MDM2, mTOR, BET, IGF1 / 2, IGF1-R, CDK9, SHIP1, SHIP2, SHP2, SRC, JAK, PARP, BTK, FLT3, HDAC, VEGFR, PDGFR, LCK, Bcr-Abl, AKT, KRAS, KRAS G12C mutant and ROS1. In some embodiments, the RAS:PI3Kα inhibitors described herein, such as compounds, salts, or solvates of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), are administered in combination or in conjunction with one or more other pharmacologically active agents, including inhibitors of SOS (e.g., SOS1, SOS2) or mutants thereof, such as... , , RMC-5845 or BI-1701963. In some embodiments, the RAS:PI3Kα inhibitors described herein, such as compounds, salts, or solvates of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), are used in combination or in conjunction with the SOS inhibitors described in WO2021092115, WO2018172250, WO2019201848, WO2019122129, WO2018115380, WO2021127429, WO2020180768, or WO2020180770, each of which is incorporated herein by reference in its entirety for all purposes.

[0151] In some embodiments, the compounds described herein, such as compounds, salts or solvates of formula (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d) or (I-3), and one or more pharmacologically active agents are administered simultaneously, in parallel or sequentially without a specific time limit, wherein such administration provides therapeutically effective levels of two or more compounds in the patient's body.

[0152] In some embodiments, the compounds described herein, such as compounds, salts, or solvates of formulas (I), (I-1), (I-2a), (I-2b), (I-2c), (I-2d), or (I-3), and one or more pharmacologically active agents, are administered sequentially via a suitable route (e.g., infusion or oral administration) in any order. The dosing regimen can vary based on the stage of the disease, the patient's level of health, the safety profile and tolerability of each drug, and other guidelines known to the attending physician and medical practitioner for administering the combination. Depending on the specific period of treatment intended, the compounds and other pharmacologically active agents of this disclosure may be administered at intervals of minutes, hours, days, or even weeks. Furthermore, the period may include administering one drug more frequently than another during a treatment period, and administering the drug at different doses each time.

[0153] In some cases, treatment regimens can be based on the individual's weight. For individuals identified as obese (BMI > 35), actual weight may need to be used. BMI is calculated as follows: BMI = weight (kg) / [height (m)] 2 For men, weight can be calculated as 50 kg + 2.3 kg. (For those exceeding 60 inches), or for women, this can be calculated as 45.5 kg + 2.3 kg. (Inches exceeding 60 inches). For individuals exceeding their ideal weight by 20%, an adjusted weight can be calculated. The adjusted weight can be the ideal weight + (0.4). The sum of (actual weight - ideal weight). In some cases, body surface area can be used to calculate the dose. Body surface area (BSA) can be calculated as follows: BSA (m²) 2 = √Height (cm) Weight(kg) / 3600.

[0154] In some aspects, this disclosure provides a method for modulating the activity of a PI3Kα protein, comprising contacting the PI3Kα protein with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof, thereby modulating the activity of the PI3Kα protein. In some embodiments, the subject method includes administration of additional agents or therapies.

[0155] In some aspects, this disclosure provides a method for modulating the activity of a PI3Kα protein, comprising contacting the PI3Kα protein with an effective amount of the compound or a pharmaceutically acceptable salt or solvate thereof, wherein the modulation comprises inhibiting RAS:PI3Kα interaction. In some aspects, this disclosure provides a method for inhibiting RAS:PI3Kα interaction, wherein the RAS is a wild-type RAS or RAS mutant protein (e.g., G12S, G12C, G12D, G12V, G13C, and / or G13D) of K-RAS, H-RAS, and / or N-RAS, the method comprising contacting the PI3Kα protein with an effective amount of the compound described herein or a pharmaceutically acceptable salt or solvate thereof.

[0156] In some aspects, this disclosure provides a method for reducing RAS-driven PI3Kα activation in cells, the method comprising contacting cells with the compounds described herein. The reduction in RAS-driven PI3Kα activation can be demonstrated by one or more of the following: (i) a decrease in phosphorylated AKTs473; (ii) a decrease (e.g., inhibition) in RAS-driven tumor cell growth; (iii) a decrease (e.g., inhibition) in HER2 / 3-driven tumor cell growth; (iv) a decrease in the interaction between RAS and PI3Kα; (v) no significant change in phosphorylated PIP2; (vi) no significant change in phosphorylated ERK; (vii) no significant inhibition of intrinsic PI3Kα kinase activity; (viii) no significant change in blood glucose levels; and (ix) no hyperglycemia. In some cases, the reduction in RAS-driven PI3Kα activation can be demonstrated by two, three, four, five, six, seven, eight, or all of the above (i)-(ix). In some embodiments, the reduction of any one or more of (i)-(iv) compared to a control not treated with the subject compound can be 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more. In some embodiments, the lack of significant change in any one or more of (v)-(viii) compared to the control not treated with the subject compound may be less than 0.5, 0.4, 0.3, 0.2, 0.1, 0.09, 0.07, 0.05, 0.03, or 0.0.01 times or less. The reduction in cell growth can be demonstrated by tumor cells or cell lines. Tumor cell lines can originate from tumors in one or more tissues such as the pancreas, lung, ovary, bile duct, intestine (e.g., small intestine, large intestine, colon), endometrium, stomach, hematopoietic tissue (e.g., lymphoid tissue), etc. Examples of tumor cell lines containing K-RAS mutations or amplifications include, but are not limited to, A549 (e.g., K-Ras G12S), AGS (e.g., K-Ras G12D), ASPC1 (e.g., K-Ras G12D), Calu-6 (e.g., K-Ras Q61K), CFPAC-1 (e.g., K-Ras G12V), CL40 (e.g., K-Ras G12D), COLO678 (e.g., K-Ras G12D), COR-L23 (e.g., K-Ras G12V), DAN-G (e.g., K-Ras G12V), DLD-1 (e.g., K-Ras G13D), FaDu (K-Ras amp.), GP2D (e.g., K-Ras G12D), GSU ​​(e.g., K-Ras G12F), H358 (e.g., K-Ras G12C), and H2122 (e.g., K-Ras G12F). G12C), HCT116 (e.g., K-Ras G13D), HEC1A (e.g., K-Ras G12D), HEC1B (e.g., K-Ras G12F), HEC50B (e.g., K-Ras G12F), HEYA8 (e.g., K-Ras G12D or G13D), HPAC (e.g., K-Ras G12D), HPAFII (e.g., K-Ras G12D), HUCCT1 (e.g., K-Ras G12D), KARPAS620 (e.g., K-Ras G13D), KOPN8 (e.g., K-Ras G13D), KP-3 (e.g., K-Ras G12V), KP-4 (e.g., K-Ras G12D), KYSE410 (e.g., K-Ras G12C), L3.3 (e.g., K-Ras G12D), LoVo (e.g., K-Ras G13D), LS180 (e.g., K-Ras G12D), LS513 (e.g., K-Ras G12D), MCAS (e.g., K-Ras G12D), NB4 (e.g., K-Ras A18D), NCI-H1355 (e.g., K-Ras G13C), NCI-H1573 (e.g., K-Ras G12A), NCI-H1944 (e.g., K-Ras G13D), NCI-H2009 (e.g., K-Ras G12A), NCI-H441 (e.g., K-Ras G12V), NCI-H747 (e.g., K-Ras G13D), NOMO-1 (e.g., K-Ras G12D), OV7 (e.g., K-Ras G12D), PANC0203 (e.g., K-Ras G12D), PANC0403 (e.g., K-Ras G12D), PANC0504 (e.g., K-Ras G12D), PANC0813 (e.g., K-Ras G12D), PANC1 (e.g., K-Ras G12D), Panc-10.05 (e.g., K-Ras G12D), PaTu-8902 (e.g., K-Ras G12V), PK1 (e.g., K-Ras G12D), PK45H (e.g., K-Ras G12D), PK59 (e.g., K-Ras G12D), PSN-1 (e.g., K-Ras G12R), SK-CO-1 (e.g., K-Ras G12V), SKLU1 (e.g., K-Ras G12D), SKM-1 (e.g., K-Ras K117N), SNU1 (e.g., K-Ras G12D), SNU1033 (e.g., K-Ras G12D), SNU1197 (e.g., K-Ras G12D), SNU407 (e.g., K-Ras G12D), SNU410 (e.g., K-Ras G12D), SNU601 (e.g., K-Ras G12D), SNU61 (e.g., K-Ras G12D), SNU8 (e.g., K-Ras G12D), SNU869 (e.g., K-Ras G12D), SNU-C2A (e.g., K-Ras G12D), SU.86.86 (e.g., K-Ras G12D), SUIT2 (e.g., K-Ras G12D), SW1116 (e.g., K-Ras G12A), SW1990 (e.g., K-Ras G12D), SW403 (e.g., K-Ras G12V), SW480 (e.g., K-Ras G12V), SW620 (e.g., K-Ras G12V), SW948 (e.g., K-Ras Q61L), T3M10 (e.g., K-Ras G12D), T24 (e.g., K-Ras G12V), T84 (e.g., K-Ras G13D), TCC-PAN2 (e.g., K-Ras G12R), TGBC11TKB (e.g., K-Ras G12D), and MIA Pa-Ca (e.g., MIA Pa-Ca 2 (e.g., K-Ras G12C)). Another suitable cell line for the subject-matter approach is H1975 (EGFR T790M, L858R; PI3KαG118D; TP53R273H).

[0157] In one aspect, a modified PI3Kα protein is provided comprising a compound described herein (or a residue of a compound described herein, wherein the residue is modified by the independent compound described herein through covalent binding to an amino acid corresponding to C242). In some embodiments, such covalently bound modified PI3Kα proteins exhibit reduced PI3Kα signal transduction output (e.g., compared to the corresponding unmodified PI3Kα without the covalently bound compound). In some embodiments, the modified PI3Kα protein comprises a compound described herein covalently bound to an amino acid residue corresponding to C242, wherein the PI3Kα protein is PI3Kα E542K. In some embodiments, the modified PI3Kα protein comprises a compound described herein covalently bound to an amino acid residue corresponding to C242, wherein the PI3Kα protein is PI3Kα E545K. In some embodiments, the modified PI3Kα protein comprises a compound described herein covalently bound to an amino acid residue corresponding to C242, wherein the PI3Kα protein is PI3KαH1047R. The subject compounds of this disclosure encompass both the compounds described herein prior to covalent binding to the PI3Kα protein and the resulting compounds covalently bound to the modified PI3Kα protein. For example, the subject compounds of this disclosure can be covalently bound to the PI3Kα protein to form the modified PI3Kα protein by adding a cysteine ​​residue to a double bond (e.g., the double bond of acrylamide) or by undergoing a substitution reaction with the cysteine ​​residue (which results in the loss of a leaving group upon covalent binding to the amino acid corresponding to C242). Compounds prior to and after such covalent binding are considered subject compounds of this disclosure. In some embodiments, the modified PI3Kα protein described herein is formed by contacting a compound described herein with a cysteine ​​residue of an unmodified PI3Kα protein, wherein the compound comprises a portion readily reacting with a nucleophilic cysteine ​​residue corresponding to C242. In some embodiments, the compound comprises a stationary group and a leaving group, and said contact results in the release of the leaving group and the formation of the modified protein.

[0158] In the embodiments of the modified PI3Kα protein described herein, the compound covalently binds in vitro to the cysteine ​​residue corresponding to C242 of the unmodified PI3Kα protein. In the embodiments of the modified PI3Kα protein described herein, the compound covalently binds in vivo to the cysteine ​​residue corresponding to C242 of the unmodified PI3Kα protein. In the embodiments of the modified PI3Kα protein described herein, the compound covalently binds in vitro or in vivo to the cysteine ​​residue corresponding to position 242 of the unmodified PI3Kα protein, which corresponds to PI3Kα or a PI3Kα mutant.

[0159] On one hand, a method is provided that includes RAS mutant proteins (e.g., KRAS G12D, KRAS G12C, KRASG12S, KRAS G12V, KRAS G13D, KRAS G13C, NRAS G12D, NRAS G12C, NRAS G12S, NRAS G13D, NRAS G13C, HRAS G12D, HRAS G12C, HRAS G12S, HRAS G13D, or HRAS G13C). A method for treating cancer in a subject, the method comprising modifying the PI3Kα protein of the subject by administering a compound described herein to the subject, wherein the compound is characterized in that, upon contact with the PI3Kα protein, the PI3Kα protein is covalently modified at a residue corresponding to residue 242, such that the modified PI3Kα protein exhibits reduced RAS-driven PI3Kα activation (e.g., compared to a control, such as unmodified PI3Kα protein not covalently bound to any compound (such as those disclosed herein)). In some aspects, a method is provided for treating cancer in a subject comprising a RAS mutant protein (e.g., a KRAS mutant protein comprising mutations in G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, or Q61H), the method comprising: inhibiting the interaction between the RAS mutant protein of the subject and the PI3Kα protein by administering to the subject a compound described herein or a salt or solvation thereof. In some embodiments, the cancer is a solid tumor or a hematologic cancer. In some aspects, this disclosure provides a method for modifying the PI3Kα protein, comprising contacting the PI3Kα protein with an effective amount of a compound disclosed herein or a salt or solvation thereof. In some embodiments, the kinase activity of the modified PI3Kα protein was not significantly inhibited, for example, the kinase activity was in the range of 0.5-fold, 0.4-fold, 0.3-fold, 0.2-fold, 0.1-fold, 0.09-fold, 0.07-fold, 0.05-fold, 0.03-fold, 0.01-fold or lower compared to the untreated control.

[0160] In some respects, the subject compound exhibits one or more of the following properties: it is capable of reacting with mutant PI3Kα proteins (e.g., E81K, E110del, K111E, K111N, G118D, N345K, C420R, E453K, E542K, E545A, E545G, E545K, Q546K, Q546P, Q546R, E726K, M1043I, N1044K, H1047L, H1047R, and / or G1049R) and covalently modifies such PI3Kα mutant proteins and / or the portion thereof containing nucleophilic amino acid residues readily reacting with the nucleophilic amino acid residue corresponding to position 242 of PI3Kα. In some embodiments, when used to modify PI3Kα proteins, the subject reduces the signal transduction output of the PI3Kα protein. In some embodiments, the subject compound exhibits an IC50 of less than 10 μM for PI3Kα, such as less than 5 μM, 1 μM, 500 nM, 100 nM, 50 nM, 10 nM, 5 nM, 1 nM, 500 pM, 50 pM, 10 pM or lower (as determined by the reduction of RAS:PI3Kα interaction).

[0161] In some embodiments, the modified PI3Kα protein disclosed herein exhibits reduced RAS-driven PI3Kα activation. This reduction in RAS-driven PI3Kα activation can be determined using a variety of methods known in the art. For example, one or more techniques, such as kinase activity assays, phosphorylation-specific antibodies, Western blotting, enzyme-linked immunosorbent assays (ELISA), cell-based ELISA, intracellular flow cytometry, mass spectrometry, and multianalyte analysis, can be used to detect and / or quantify phosphorylation of the substrate or specific amino acid residues thereof. Many readouts can demonstrate a reduction in RAS-driven PI3Kα activation, including but not limited to: (i) a reduction in phosphorylated AKTs473; (ii) a reduction (e.g., inhibition) in RAS-driven tumor cell growth; (iii) a reduction (e.g., inhibition) in HER2 / 3-driven tumor cell growth; (iv) a reduction in RAS-PI3Kα interaction; (v) no significant change in phosphorylated PIP2; (vi) no significant change in phosphorylated ERK; (vii) no significant inhibition of intrinsic PI3Kα kinase activity; (viii) no significant change in blood glucose levels; and (ix) no hyperglycemia. In some cases, a reduction in RAS-driven PI3Kα activation can be demonstrated by two, three, four, five, six, seven, eight, or all of the above (i)-(ix). In some embodiments, a reduction in RAS-driven PI3Kα activation can be demonstrated by any one of (i)-(ix) compared to a control unmodified PI3Kα protein that is not covalently bound to any of the compounds disclosed herein. For example, as described herein, the control PI3Kα protein may be a PI3Kα protein that is not complexed with any of the subject compounds of this disclosure (e.g., wild-type or mutant). The reduction in items (i) to (iv) compared to the control PI3Kα protein may be at least about 0.1-fold, 0.2-fold, 0.3-fold, 0.4-fold, 0.5-fold, 0.6-fold, 0.7-fold, 0.8-fold, 0.9-fold, 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold, 5000-fold, or more.

[0162] Pharmaceutical Compositions and Administration In one aspect, a pharmaceutical composition is provided comprising the compound described herein or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0163] In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are administered to the subject in a biocompatible form suitable for treatment or prevention of a disease, symptom, or condition. Administration of the compounds described herein may be in any pharmacological form, including alone or in combination with a pharmaceutically acceptable carrier, in a therapeutically effective amount of the compounds described herein, or their pharmaceutically acceptable salts or solvates.

[0164] In some embodiments, the compounds described herein are administered in the form of pure chemicals. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier), which is selected based on the chosen route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition MackPub. Co., Easton, PA (2005)).

[0165] Therefore, this document provides a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt described herein and one or more pharmaceutically acceptable excipients. An excipient (or carrier) is acceptable or suitable if it is compatible with the other components of the composition and is harmless to the recipient (i.e., the object) of the composition.

[0166] In some embodiments of the methods described herein, the compounds described herein are administered alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents to form a pharmaceutical composition. Administration of the compounds and compositions described herein can be achieved by any method that enables delivery of the compounds to the site of action. These methods include, but are not limited to, administration via the enteric route (including oral, gastric or duodenal feeding tubes, rectal suppositories, and rectal enemas), the parenteral route (injection or infusion, including intra-arterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrasheathal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalation, percutaneous, transmucosal, sublingual, buccal, and topical (including epidermal, dermal, enema, eye drops, ear drops, intranasal, and vaginal) administration, although the most suitable route may depend, for example, on the recipient's condition and illness. By way of example only, the compounds described herein can be administered topically to the area requiring treatment, for example, by local infusion during surgery, by topical application such as creams or ointments, by injection, by catheter, or by implantation. Administration can also be performed by direct injection at the site of the diseased tissue or organ. In some embodiments, the compounds described herein, or their pharmaceutically acceptable salts or solvates, are administered orally.

[0167] In some embodiments of the methods described herein, pharmaceutical compositions suitable for oral administration are provided in the following forms: discrete units, such as capsules, pouches, or tablets, each containing a predetermined amount of the active ingredient; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water or water-in-oil liquid emulsions. In some embodiments, the active ingredient is provided in the form of pills, electuals, or pastes.

[0168] Orally administered pharmaceutical compositions include tablets, push-fit capsules made of gelatin, and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. Tablets can be prepared by compression or molding, optionally with one or more excipients. Compressed tablets can be prepared by compression in a suitable machine of an active ingredient in a free-flowing form (such as powder or granules), optionally mixed with a binder, an inert diluent or lubricant, a surfactant, or a dispersant. Molded tablets can be prepared by molding in a suitable machine a mixture of powdered compounds moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and formulated to provide a slow or controlled release of the active ingredient therein. All formulations intended for oral administration should be dossier suitable for such administration. Push-fit capsules may contain the active ingredient blended with a filler (such as lactose), a binder (such as starch), and / or a lubricant (such as talc or magnesium stearate), and optionally a stabilizer. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added. The core of the sugar-coated pill is provided with a suitable coating. For this purpose, a concentrated sugar solution can be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to the coating of the tablet or sugar-coated pill to identify or characterize different combinations of active compound dosages.

[0169] In some embodiments of the methods described herein, the pharmaceutical composition is formulated for parenteral administration by injection, such as via bolus injection or continuous infusion. The injectable formulation may be provided in unit dosage forms, such as in ampoules or in multi-dose containers with added preservatives. The composition may be in the form of a suspension, solution, or emulsion, such as in an oily or aqueous medium, and may contain a formulatory agent, such as a suspending agent, stabilizer, and / or dispersant. The composition may be provided in unit-dose or multi-dose containers, such as sealed ampoules and vials, and may be stored in powder form or in a lyophilized (freeze-dried) state, requiring only the immediate addition of a sterile liquid carrier, such as saline or sterile pyrogen-free water, prior to use. Temporary injectable solutions and suspensions may be prepared from the previously described types of sterile powders, granules, and tablets.

[0170] Pharmaceutical compositions for parenteral administration include aqueous and non-aqueous (oil-based) sterile injectable solutions of an active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. Suitable lipophilic solvents or mediators include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

[0171] Pharmaceutical compositions can also be formulated into reservoir formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular implantation) or by intramuscular injection. Thus, for example, the compound can be formulated with suitable polymeric or hydrophobic materials (e.g., formulated as an emulsion in an acceptable oil) or ion exchange resin, or can be formulated as a slightly soluble derivative, such as a slightly soluble salt.

[0172] Example The following examples are provided for illustrative purposes only and do not limit the scope of the claims provided herein. Unless otherwise stated, all materials (such as reagents, starting materials, and solvents) were purchased from commercial suppliers such as Sigma-Aldrich, VWR, etc., and used without further purification. Unless otherwise stated, the reactions were carried out under a nitrogen atmosphere. The progress of the reactions was monitored by thin-layer chromatography (TLC), analytical high-performance liquid chromatography (analytical HPLC), and mass spectrometry, details of which are provided in specific examples.

[0173] The reaction is handled as specifically described in each preparation; typically, the reaction mixture is purified by extraction and other purification methods, such as temperature- and solvent-dependent crystallization and precipitation. Additionally, the reaction mixture is routinely purified by preparative HPLC, for example, using Microsorb C18 or Microsorb BDS column packing and conventional eluents. The progress of the reaction is typically monitored by liquid chromatography-mass spectrometry (LCMS). Characterization of isomers is typically performed by nuclear Overhauser effect spectroscopy (NOE). Characterization of reaction products is typically performed by mass spectrometry and / or... 1 H-NMR was performed. For NMR measurements, the sample was dissolved in a deuterated solvent (CD3OD, CDCl3, or DMSO). d6 )middle.

[0174] Example 1a: 1-(3-(3) 4-Fluoro-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecanoephedrine-9-ene-2 6 Synthesis of 7,8-dihydro-1,6-naphthidium-6(5H)-prop-2-en-1-one (105). Step A: To a solution of 4-fluoro-2-hydroxybenzaldehyde (1-1) (5.0 g, 35.71 mmol) in DMF (50 mL), add (2-bromoethoxy)(tert-butyl)dimethylsilane (10.2 g, 42.86 mmol) and Cs₂CO₃ (13.97 g, 42.86 mmol). The resulting mixture was stirred at 80 °C for 16 hours. The reaction mixture was partitioned between water and ethyl acetate (30 mL x 2). The combined organic layers were washed with aqueous NH₄Cl and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 10:1) to give 2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorobenzaldehyde (1-2, 6.6 g). ESI-MS m / z: 299 [M+H] + .

[0175] Step B: Under argon atmosphere, n-BuLi (7.1 mL, 2.5 M) was slowly added to a solution of N,N-diethylthiophene-3-carboxamide (2.5 g, 13.73 mmol) in anhydrous THF (33 mL) at -78 °C. After 45 minutes, 1–2 (4.5 g, 15.10 mmol) in THF (10 mL) was added. The resulting mixture was stirred at -78 °C to room temperature for 5 hours. The reaction mixture was partitioned between water and ethyl acetate. The combined organic layers were washed with aqueous NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 3:1) to give 2-((2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)(hydroxy)methyl)-N,N-diethylthiophene-3-carboxamide (1–3, 4 g). ESI-MS m / z : 482 [M+H] + .

[0176] Step C: At 0 °C, SiH(Et)3 (2.75 g, 23.70 mmol) was added to a solution of 1-3 (3.8 g, 7.90 mmol) in TFA (38 mL), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum. The mixture was dissolved in DCM, washed with aqueous NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 5:1) to give N,N-diethyl-2-(4-fluoro-2-(2-hydroxyethoxy)benzyl)thiophene-3-carboxamide (1-4, 2.5 g). ESI-MS m / z 352 [M+H] + .

[0177] Step D: At 0 °C, NaH (60%) (570 mg, 14.25 mmol) was added to a solution of 1-4 (2.5 g, 7.12 mmol) in anhydrous DMF (25 mL). After 25 minutes, 3-bromoprop-1-ene (1.11 g, 9.26 mmol) was added. The resulting mixture was stirred at 90 °C for 16 hours. The reaction mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with aqueous NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by rapid column chromatography on silica gel (PE / EA = 3:1) to give 2-(2-(2-(allyloxy)ethoxy)-4-fluorobenzyl)-N,N-diethylthiophene-3-carboxamide (1-5, 2.3 g). ESI-MS m / z 392 [M+H] + .

[0178] Step E: At -78 °C, n-BuLi (1.3 mL, 2.5 M) was slowly added to a solution of 1–5 (500 mg, 1.28 mmol) in anhydrous THF (4 mL). After 45 minutes, a solution of tert-butyl 3-cyano-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (333 mg, 1.28 mmol) in THF (1 mL) was added. The mixture was stirred at -78 °C to room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with aqueous NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1:2) to give tert-butyl 3-(7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1–6, 245 mg). ESI-MS m / z 578 [M+H] + .

[0179] Step F: At -78°C, add pyridine (67 mg, 0.85 mmol) and trifluoromethanesulfonic anhydride (156 mg, 0.55 mmol) to the solution of 1-6 (245 mg, 0.42 mmol) in anhydrous DCM (10 mL). Stir the resulting mixture at -78°C to room temperature for 1.5 hours. Quench the reaction mixture with 1 N HCl (aq) and extract with DCM (15 mL x 2). Wash the combined organic layers with brine, dry to Na2SO4, filter, and concentrate under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1:1) to give tert-butyl 3-(7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1-7, 155 mg). ESI-MS m / z 710 [M+H] + .

[0180] Step G: Add (2-hydroxyphenyl)boronic acid (71 mg, 0.51 mmol), K₂CO₃ (411 mg, 1.25 mmol), and Pd(Ph₃)₄ (30 mg, 0.01 mmol) to a solution of 1-7 (145 mg, 0.21 mmol) in dioxane (10 mL) and H₂O (1 mL). Stir the resulting mixture at 105 °C for 2.5 hours. Cool to room temperature and add ethyl acetate (15 mL). Wash the organic layer with brine, dry over Na₂SO₄, filter, and concentrate under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1:2) to give tert-butyl 3-(7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-4-(2-hydroxyphenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1–8, 114 mg). ESI-MS m / z 654 [M+H] + .

[0181] Step H: Cs₂CO₃ (114 mg, 0.35 mmol) and 3-bromoprop-1-ene (42 mg, 0.35 mmol) were added to a solution of 1-8 (114 mg, 0.18 mmol) in acetonitrile (10 mL), and the resulting mixture was stirred at 55 °C for 5 hours. It was cooled to room temperature, and ethyl acetate (10 mL) was added. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1:1) to give tert-butyl 3-(7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-4-(2-(allyloxy)phenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1-9, 110 mg). ESI-MS m / z 694 [M+H] + .

[0182] Step I: Grubbs II catalyst (6 mg) was added to a solution of 1-9 (20 mg, 0.03 mmol) in DCE (40 mL), and the resulting mixture was stirred at 80 °C for 16 hours under argon atmosphere. The reaction mixture was diluted with DCM, washed with aqueous NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1:2) to give 3-(3 4-Fluoro-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecanoephedrine-9-ene-2 6 tert-butyl 7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1-10, 14 mg). ESI-MS m / z 666 [M+H] + .

[0183] Step J: Add TFA (3 mL) to a solution of 1-10 (14 mg, 0.02 mmol) in DCM (10 mL), and stir the resulting mixture at 0 °C to room temperature for 2 hours. Dilute the reaction mixture with DCM, wash with aqueous NaHCO3 solution and brine, dry over Na2SO4, filter, and concentrate under vacuum. Purify the residue by rapid column chromatography on silica gel (DCM / MeOH = 10:1) to obtain 3 4 -Fluorine-2 6 -(5,6,7,8-Tetrahydro-1,6-naphthidin-3-yl)-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylheterocyclic dodecane-9-ene (8 mg). ESI-MS m / z :566 [M+H] + .

[0184] Step K: At 0°C, to 3 4 -Fluorine-2 6 -(5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylheterocyclic dodecane-9-ene (8 mg) was added to a solution in anhydrous DCM (5 mL) with TEA (4.3 mg, 0.04 mmol) and acrylic anhydride (2.2 mg, 0.017 mmol), and the resulting mixture was stirred at 0 °C to room temperature for 1 hour. The reaction mixture was quenched with 1 N HCl solution and extracted with DCM (15 mL x 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1:2) to give 105 (3.5 mg). ESI-MS m / z 620.4 [M+H] + .

[0185] Example 1b: 1-(3-(3) 4-Fluoro-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecaban-2 6 Synthesis of 7,8-dihydro-1,6-naphthidium-6(5H)-prop-2-en-1-one (106). Step A: Add Pd / C (6 mg) to a solution of 1-10 (20 mg, 0.03 mmol) in MeOH (10 mL) and react the resulting mixture in H2 for 2 hours. Filter the reaction mixture through diatomaceous earth. Concentrate the filtrate under vacuum. Purify the residue by rapid column chromatography on silica gel (PE / EA = 1:2) to obtain 3-(3 4 -Fluoro-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecaban-2 6 tert-butyl 7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (2-1,14 mg). ESI-MS m / z 668 [M+H] + .

[0186] Step B: Add TFA (3 mL) to the solution of 2-1 (14 mg, 0.02 mmol) in DCM (10 mL), and stir the resulting mixture at 0 °C to room temperature for 2 hours. Dilute the reaction mixture with DCM, wash with aqueous NaHCO3 solution and brine, dry over Na2SO4, filter, and concentrate under vacuum. Purify the residue by rapid column chromatography on silica gel (DCM / MeOH = 10:1) to obtain 3. 4 -Fluorine-2 6 -(5,6,7,8-Tetrahydro-1,6-naphthidin-3-yl)-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecanone (8 mg). ESI-MS m / z 568 [M+H] + .

[0187] Step C: At 0°C, to 3 4 -Fluorine-2 6-(5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylheterocyclic dodecanoate (8 mg, 0.014 mmol) was added to a solution in anhydrous DCM (5 mL) with TEA (4.3 mg, 0.04 mmol) and acrylic anhydride (2.2 mg, 0.017 mmol). The resulting mixture was stirred at 0 °C to room temperature for 1 hour. The reaction mixture was quenched with 1 N HCl solution and extracted with DCM (15 mL x 2). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel (PE / EA = 1:2) to give 106 (5.5 mg). ESI-MS m / z 622.3 [M+H] + ; 1 HNMR(400 MHz, CD3OD): δ 8.26 (s, 1H), 7.71 (s, 1H), 7.57-7.56 (d, J = 4 Hz, 1H), 7.47-7.35 (m, 3H), 7.11-7.07 (m, 3H), 6.75-6.71 (m, 3H), 6.17-6.10 (m,1H),5.70-5.67 (d, J = 12 Hz, 1H), 4.68-4.62 (m, 4H), 3.86-3.79 (m, 6H), 3.39-3.38(m, 2H), 2.97-2.8 5 (m,4H), 1.38-1.34 (m,2H).

[0188] Example 1c: (R)-1-(2-(3) 4 -Fluoro-4,7,13-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylheterocyclic tridecaban-9-ene-2 6 Synthesis of 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)prop-2-en-1-one (108). Step A: Add n-BuLi (4 mL) dropwise to a stirred solution of 1-4 (350 mg, 0.75 mmol) in THF (2 mL). Stir the mixture at -50 °C for 30 min, then add (R)-2-cyano-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (200 mg, 0.76 mmol). Stir the resulting mixture at 0 °C for 3 h, dilute with water, and extract with ethyl acetate (20 mL x 3). Wash the combined organic layers with brine, dry over anhydrous Na₂SO₄, and concentrate under vacuum. The residue was purified by rapid column chromatography on silica gel, eluting with ethyl acetate to give (4R)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (3-1,400 mg). ESI-MS m / z 655.27 [M+H] + .

[0189] Step B: At 0 °C, TEA (0.5 mL) and Tf₂O (0.4 mL) were added to a stirred solution of 3-1 (200 mg, 0.31 mmol) in DCM (4 mL). The mixture was stirred at 0 °C for 1 hour and then extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give (4R)-2-(7-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (3-2, 130 mg). ESI-MS m / z 673.13 [M+H] + .

[0190] Step C: A mixture of 3-2 (130 mg, 0.19 mmol), Pd(PPh3)4 (22 mg, 0.019 mmol), K2CO3 (80 mg, 0.58 mmol), and (2-hydroxyphenyl)boronic acid (54 mg, 0.38 mmol) in dioxane (10 mL) and water (10 mL) was stirred overnight at 105 °C. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel, eluting with PE / EA (1:1) to give (4R)-2-(7-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-4-(2-hydroxyphenyl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (3-3, 120 mg). ESI-MS m / z: 617.23 [M+H] + .

[0191] Step D: At 0°C, Cs₂CO₃ (111 mg, 0.33 mmol) and 4-bromobut-1-ene (30 mg, 0.22 mmol) were added to a stirred solution of 3-3 (70 mg, 0.11 mmol) in THF (4 mL), and the resulting mixture was stirred at 55°C for 3 hours. The mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to give (4R)-2-(4-(2-(but-3-en-1-yloxy)phenyl)-7-(4-fluoro-2-(2-hydroxyethoxy)phenyl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (3-4, 52 mg). ESI-MS m / z 671.26 [M+H] + .

[0192] Step E: At 0 °C, add NaH (31 mg, 1.1 mmol) and 3-bromoprop-1-ene (20 mg, 0.17 mmol) to a stirred solution of 3-4 (52 mg, 0.08 mmol) in THF. Stir the mixture overnight at 55 °C, dilute with water, and extract with DCM. Wash the combined organic layers with water and brine, dry over anhydrous Na2SO4, and concentrate under vacuum. Purify the residue by rapid column chromatography on silica gel, eluting with PE / EA (1:1) to give (4R)-2-(7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-4-(2-(but-3-en-1-yloxy)phenyl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (3-5, 35 mg). ESI-MS m / z 711.29 [M+H] + .

[0193] Step F: Add Grubbs-II catalyst (12 mg) to a stirred solution of 3-5 (35 mg, 0.05 mmol) in DCE (4 mL), and stir the resulting mixture overnight at 80 °C. Dilute the mixture with water and extract with DCM. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4, and concentrate under vacuum. Purify the residue by rapid column chromatography on silica gel, eluting with DCM / MeOH (20:1) to give (R)-2-(3 4 -Fluoro-4,7,13-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylheterocyclic tridecaban-9-ene-2 6 tert-butyl 5(4H)-carboxylate (3-6,22 mg). ESI-MS m / z 683.26 [M+H] + .

[0194] Step G: Add 2 mL of TFA to the stirred solution of 3-6 (22 mg, 0.03 mmol) in DCM (4 mL) and stir the resulting mixture at room temperature for 1 hour. Dilute the mixture with aqueous NaHCO3 solution and extract with DCM. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4 and concentrate under vacuum. Purify the residue by rapid column chromatography on silica gel, eluting with DCM / MeOH (10:1) to give (R)-3. 4 -Fluorine-2 6-(4-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-4,7,13-trioxa-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylheterocyclic tridecane-9-ene (3-7,11 mg). ESI-MS m / z 583.21 [M+H] + .

[0195] Step H: TEA (0.2 mL) and acryloyl chloride (0.15 mL) were added to a stirred solution of 3-7 (11 mg, 0.02 mmol) in DCM (4 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 hour. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by TLC (DCM / MeOH = 15:1) to give 10⁸ (2.2 mg). ESI-MS m / z 637.4 [M+H] + ; 1 HNMR (400 MHz, CD3OD): δ 7.70 (s, 1H), 7.53 (d, 1H), 7.46 (t,1H), 7.35 (m,2H), 7.18 (dd, 1H), 7.05 (m, 4H), 6.88 (d, 1H), 6.72 (s,1H), 6.19 (d, 1H),5.72 (dd, 1H), 5.45 (m,1H), 5.08 (m, 1H), 4.32 (m, 2H), 3.99 (m, 5H), 3.45(m, 5H), 2.09 (m, 2H), 1.50 (s, 3H).

[0196] Example 1d: 1-(3-(3) 4 -Fluoro-4,7-dioxa-12-aza-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecanoe-9-ene-2 6 Synthesis of 7,8-dihydro-1,6-naphthidium-6(5H)-prop-2-en-1-one (101). Step A: Add Pd(PPh3)4 (30 mg, 0.03 mmol) and K2CO3 (200 mg, 1.4 mmol) to a stirred solution of 1-7 (200 mg, 0.28 mmol) and (2-((tert-butoxycarbonyl)amino)phenyl)boronic acid (200 mg, 0.84 mmol) in dioxane (15 mL) and H2O (3 mL). Stir the mixture at 90-100 °C for 2 hours. Concentrate the mixture under vacuum to remove the solvent. The residue was purified by rapid column chromatography on silica gel, eluting with 30% EA / PE to give tert-butyl 3-(7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-4-(2-((tert-butoxycarbonyl)amino)phenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (4-1, 150 mg). ESI-MS m / z 753.1 [M+H] + .

[0197] Step B: Add NaH (24 mg, 0.6 mmol) to a stirred solution of 4-1 (150 mg, 0.20 mmol) in DMF (10 mL) at 0 °C and stir the resulting mixture for 30 min. Add 3-bromoprop-1-ene (60 mg, 0.5 mmol) to the reaction mixture. Stir the mixture at 40 °C for 2 h and then partition it between water and ethyl acetate. Concentrate the organic layer under vacuum. Purify the residue on silica gel by rapid column chromatography to give tert-butyl 3-(4-(2-(allyl(tert-butoxycarbonyl)amino)phenyl)-7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (4-2, 120 mg). ESI-MS m / z 793.2 [M+H] + .

[0198] Step C: Add Grubbs II catalyst (22 mg) to the stirred solution of 4-2 (65 mg, 0.082 mmol) in DCE (25 mL), and stir the resulting mixture overnight at 80 °C. Concentrate the mixture under vacuum, and purify the residue on silica gel by rapid column chromatography to obtain 2. 6 -(6-(tert-Butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-3 4-Fluoro-4,7-dioxa-12-aza-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecaneno-9-ene-12-carboxylic acid tert-butyl ester (4-3, 30 mg). ESI-MS m / z 765.2 [M+H] + .

[0199] Step D: Add TFA (1 mL) to the stirred solution of 4-3 (30 mg, 0.039 mmol) in DCM (5 mL) and stir the resulting mixture for 1 hour. Concentrate the mixture under vacuum to remove the solvent. Dilute the residue with aqueous NaHCO3 solution and extract with DCM. Concentrate the organic layer under vacuum and purify the residue on silica gel by rapid column chromatography to obtain 3. 4 -Fluorine-2 6 -(5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-4,7-dioxa-12-aza-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)diphenylhexacyclic dodecane-9-ene (14 mg). ESI-MS m / z 565.2 [M+H] + .

[0200] Step E: At 0°C, to 3 4 -Fluorine-2 6 -(5,6,7,8-tetrahydro-1,6-naphthidin-3-yl)-4,7-dioxa-12-aza-2(4,7)-thieno[3,2-c]pyridazine-1,3(1,2)-diphenylhexacyclic dodecaneno-9-ene (14 mg, 0.025 mmol) was added to a stirred solution of TEA (0.1 mL) and acrylic anhydride (0.1 mL) in DCM (5 mL). The mixture was stirred for 5 min, diluted with aqueous NaHCO3 solution, and extracted with DCM. The combined organic layers were concentrated under vacuum. The residue was purified by rapid column chromatography on silica gel to give 101 (5 mg). ESI-MS m / z 619.4 [M+H] + ; 1HNMR (400 MHz, CD3OD): δ 8.31 (s, 1H), 7.8 (m, 1H), 7.7 (m, 2H), 7.5 (d, J = 7.2 Hz, 1H), 7.4 (d, J = 4.8 Hz, 1H), 7.3 (t, J = 7.6 Hz, 1H), 6.8 (m, 4H), 6.6 (d, J =11.6 Hz, 1H), 6.2 (d, J = 16 Hz, 1H), 6.0 (d, J = 16.4 Hz, 1H), 5.8 (d, J =10.4 Hz, 1H), 5.5 (m, 1H), 4.81 (s, 1H), 4.6 (m, 2H), 3.9 (m, 8H), 3.4 (m, 2H), 2.9 (m, 2H).

[0201] Example 1e: (R)-1-(2-(3) 4 ,3 6 -Difluoro-1 1 -Methyl-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 Synthesis of 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)prop-2-en-1-one (148). Step A: At -78°C, n-BuLi (2.5 M, 4 mL) was slowly added to a stirred solution of 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorobenzyl)-N,N-diethylthiophene-3-carboxamide (5-1, 350 mg, 0.75 mmol) in THF (2 mL), and the resulting mixture was stirred at -50°C for 1 hour. Then, (R)-2-cyano-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (5-2, 200 mg, 0.76 mmol) was added. The mixture was stirred at 0°C for 3 hours, then diluted with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate to give (4R)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (5-3,320 mg). ESI-MS m / z 673.9 [M+H] + .

[0202] Step B: At 0°C, pyridine (0.5 mL) and Tf₂O (0.4 mL) were added to a stirred solution of 5-3 (320 mg, 0.48 mmol) in DCM (4 mL). The resulting mixture was stirred at 0°C for 1 hour, then diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and concentrated under vacuum to give (4R)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (300 mg). ESI-MS m / z 805.9 [M+H] + .

[0203] Step C: The mixture of (4R)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (300 mg, 0.37 mmol), Pd(PPh3)4 (43 mg, 0.04 mmol), K2CO3 (103 mg, 0.75 mmol) and (6-hydroxy-1-methyl-1H-indazol-5-yl)boronic acid (5-4, 255 mg, 0.93 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred overnight at 100 °C. The mixture was diluted with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, concentrated under vacuum, and purified by silica gel column chromatography, eluting with PE / EA (1:1) to give (4R)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (5-5, 320 mg). ESI-MS m / z: 804.0 [M+H] + .

[0204] Step D: Add TBAF (0.8 mL, 70%–75% w / w aq) to a stirred solution of 5–5 (320 mg, 0.40 mmol) in THF (4 mL) and stir the resulting mixture for 30 min. Dilute the mixture with water and extract with ethyl acetate (20 mL x 3). Wash the combined organic layers with brine, dry over anhydrous Na₂SO₄ and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (1:1) to give (4R)-2-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-carboxylic acid tert-butyl ester (250 mg). ESI-MS m / z: 689.7 [M+H] + .

[0205] Step E: To a stirred solution of (4R)-2-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-carboxylic acid tert-butyl ester (320 mg, 0.40 mmol) in THF (4 mL), 3-bromoprop-1-ene (240 mg, 2.0 mmol) and NaH (80 mg, 2.0 mmol) were added, and the resulting mixture was stirred overnight at 55 °C. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to give (4R)-2-(4-(6-(allyloxy)-1-methyl-1H-indazol-5-yl)-7-(2-(2-(allyloxy)ethoxy)-4,6-difluorophenyl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (5-6, 160 mg). ESI-MS m / z 769.8 [M+H] + .

[0206] Step F: Add Grubbs II catalyst (40 mg) to the stirred solution of 5-6 (160 mg, 0.21 mmol) in DCE (4 mL), and stir the resulting mixture overnight at 55 °C. Dilute the mixture with water and extract with DCM. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4 and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (2:1) to give (R,E)-2-(3 4 ,3 6 -Difluoro-1 1 -Methyl-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (5-7, 120 mg). ESI-MS m / z 741.8 [M+H] + .

[0207] Step G: Add 2 mL of TFA to the stirred solution of 5-7 (120 mg, 0.16 mmol) in DCM (4 mL) and stir the resulting mixture for 1 hour. Dilute the mixture with aqueous NaHCO3 solution and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4 and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give (R)-3. 4 ,3 6 -Difluoro-1 1 -Methyl-2 6 -(4-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzocyclododecano-9-ene (5-8, 100 mg). ESI-MS m / z 641.7 [M+H] + .

[0208] Step H: TEA (0.3 mL) and acryloyl chloride (0.2 mL) were added to a stirred solution of 5-8 (100 mg, 0.16 mmol) in DCM (4 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 1 hour. The mixture was diluted with aqueous NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA, to give (R)-1-(2-(3 4 ,3 6 -Difluoro-1 1 -Methyl-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 5-(4H)-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one (5-9, 80 mg). Compound 148 (24 mg) was obtained by chiral SFC separation of 5-9. ESI-MS m / z 695.35 [M+H] +;HNMR(400 MHz, CD3OD): δ 8.15 (s, 1H), 7.87 (d,1H), 7.50 (m, 1H), 7.07 (m, 1H), 7.00 (s, 1H), 6.71 (m, 2H), 6.58 (m, 1H), 6.17 (d, 1H), 6.04 (d, 1H), 5.70(m,1H), 5.53 (d, 2H), 4.88 (m, 1H), 4.36 (s, 2H), 4.12 (s, 3H), 3.88 (m, 7H),3.55 (m,1H), 3.32 (m, 2H), 1.34 (s, 3H).

[0209] Example 1f: 1-(3-(3) 4 ,3 6 -Difluoro-1 2 -Methyl-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 Synthesis of 7,8-dihydro-1,6-naphthidium-6(5H)-prop-2-en-1-one (111). Step A: Tribromoborane (8 mL, 41.32 mmol) was added to a solution of 5-bromo-6-methoxy-2-methyl-2H-indazole (6-1, 5 g, 20.66 mmol) in DCE (100 mL) at -78 °C, and the resulting mixture was stirred at 50 °C for 16 hours. The mixture was poured into ice water, and the solid was collected by filtration, washed with NaHCO3 aqueous solution (200 mL) and 30% EA / PE (100 mL), and dried to give 5-bromo-2-methyl-2H-indazole-6-ol (6-2, 4.5 g). ESI-MS m / z 228.0 [M+H] + .

[0210] Step B: To a solution of 6-2 (2 g, 8.81 mmol) in toluene (30 mL), add bis(neopentylethylene glycol)diboron (6 g, 26.43 mmol), KOAc (3.45 g, 35.24 mmol), and Pd(dppf)Cl2·CH2Cl2 (0.3 g), and stir the resulting mixture at 100 °C for 3 hours. Dilute the mixture with water and extract with ethyl acetate. Wash the combined organic layers with brine, dry to anhydrous Na2SO4, and concentrate under vacuum. Purify the residue by column chromatography (petroleum ether / EA = 10 / 1 to 1 / 2) to give 5-(5,5-dimethyl-1,3,2-dioxoboronyl-2-yl)-2-methyl-2H-indazole-6-ol (6-3, 1 g). ESI-MS m / z : 261.0 [M+H] + .

[0211] Step C: Following the procedure described for 5-3 in Example 1e, in the first step, tert-butyl 3-cyano-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate was used instead of 5-2 to prepare tert-butyl 3-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthidine-6(5H)-carboxylate (6-4). A mixture of 6-3 (300 mg, 0.93 mmol), Pd(PPh3)4 (43 mg, 0.04 mmol), K2CO3 (103 mg, 0.75 mmol), and 6-4 (300 mg, 0.37 mmol) in dioxane (10 mL) and water (1 mL) was stirred overnight at 100 °C. The mixture was diluted with water and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl 3-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(6-hydroxy-2-methyl-2H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (6-5, 280 mg). ESI-MS m / z 800.2 [M+H] + .

[0212] Step D: Add TBAF (1 mL) to a stirred solution of 6-5 (280 mg, 0.35 mmol) in THF (4 mL). Stir the resulting mixture for 30 min, then dilute with water and extract with ethyl acetate (20 mL x 3). Wash the combined organic layers with brine, dry over anhydrous Na2SO4 and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl 3-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-2-methyl-2H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (230 mg). ESI-MS m / z 686.2 [M+H] + .

[0213] Step E: Add NaH (80 mg, 2.0 mmol) to a stirred solution of tert-butyl 3-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-2-methyl-2H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (230 mg, 0.34 mmol) in DMF (10 mL), and stir the resulting mixture for 30 min. Then add 3-bromoprop-1-ene (240 mg, 2.0 mmol), and stir the mixture at 55 °C for an additional 2 h. Dilute the mixture with water and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry over anhydrous Na2SO4, and concentrate under vacuum. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (20:1) to give tert-butyl 3-(4-(6-(allyloxy)-2-methyl-2H-indazol-5-yl)-7-(2-(2-(allyloxy)ethoxy)-4,6-difluorophenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (6-6, 60 mg). ESI-MS m / z 766.2 [M+H] + .

[0214] Step F: Add Grubbs-II catalyst (10 mg) to a stirred solution of 6-6 (60 mg, 0.078 mmol) in DCE (4 mL), and stir the resulting mixture at 55 °C for 2 hours. Remove the solvent and purify the residue by silica gel column chromatography, eluting with PE / EA (1:2) to give 3-(3 4 ,3 6 -Difluoro-12 -Methyl-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 tert-butyl 7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (6-7, 35 mg). ESI-MS m / z 738.2 [M+H] + .

[0215] Step G: Add TFA (2 mL) to the stirred solution of 6-7 (35 mg, 0.047 mmol) in DCM (4 mL) and stir the resulting mixture for 1 hour. Dilute the mixture with aqueous NaHCO3 solution and then extract with ethyl acetate. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4 and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with DCM / MeOH (10:1) to give 3 4 ,3 6 -Difluoro-1 2 -Methyl-2 6 -(5,6,7,8-tetrahydro-1,6-naphthid-3-yl)-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzocyclododecano-9-ene (24 mg). ESI-MS m / z 666.2 [M+H] + .

[0216] Step H: At 0°C, to 3 4 ,3 6 -Difluoro-1 2 -Methyl-2 6 -(5,6,7,8-tetrahydro-1,6-naphthid-3-yl)-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene (24 mg, 0.036 mmol) was added to a stirred solution in DCM (5 mL) with TEA (0.3 mL) and acryloyl chloride (0.1 mL), and the resulting mixture was stirred at 0 °C for 1 hour. The mixture was diluted with aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by TLC to give 111 (18 mg). ESI-MS m / z 692.2 [M+H]+ ; 1 H NMR (400 MHz, CD3OD): δ 8.25 (d, J =1.6 Hz, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.8-7.7 (m, 1H), 7.58 (d, J = 5.6Hz, 1H), 7.15 (d, J = 5.6 Hz, 1H), 7.03 (s, 1H), 6.8-6.7 (m, 1H), 6.65-6.55(m, 2H), 6.15 (m, 1H). 5.75-5.6 (m, 2H), 5.15 (m, 1H), 4.65 (s, 1H), 4.4 (m,2H), 4.12 (s, 3H), 4.0-3.7 (m, 6H), 3.4-3.3 (m, 2H), 2.9-2.8 (m, 2H).

[0217] Example 1g: 1-(3-(1) 4 ,3 4 -difluoro-4,7,12-trioxa-2(1,4)-isoquinoline-1,3(1,2)-diphenylheterocyclic dodecane-9-ene-2 3 Synthesis of 7,8-dihydro-1,6-naphthidium-6(5H)-prop-2-en-1-one (154). Step A: TFA (2 mL) was added to a stirred solution of tert-butyl 3-bromo-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (7-1, 1 g) in DCM (10 mL), and the resulting mixture was stirred for 1 hour. The solvent was removed, and the residue was partitioned between DCM and an aqueous solution of NaHCO3. The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography to give 3-bromo-5,6,7,8-tetrahydro-1,6-naphthyl (680 mg). ESI-MS m / z 213.0 [M+H] + .

[0218] Step B: NaHCO3 (1.05 g, 12.5 mmol) was added to a stirred solution of 3-bromo-5,6,7,8-tetrahydro-1,6-naphthidine (680 mg, 3.21 mmol) in water (9 mL), and the resulting mixture was stirred for 10 min. Acryloyl chloride (577 mg, 6.42 mmol) in THF (6 mL) was added dropwise to the mixture at 0 °C. The mixture was stirred for 1 h, and then partitioned between ethyl acetate and the NaHCO3 aqueous solution. The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography to give 1-(3-bromo-7,8-dihydro-1,6-naphthidine-6(5H)-yl)prop-2-en-1-one (7-2,890 mg). ESI-MS m / z 267.0 [M+H] + .

[0219] Step C: Under Ar conditions, KOAc (656 mg, 6.69 mmol) and Pd(dppf)Cl2·DCM (273 mg, 0.33 mmol) were added to a stirred solution of 7-2 (890 mg, 3.35 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxoboronylcyclopentane) (765 mg, 3.01 mmol) in dioxane (10 mL). The mixture was stirred at 100 °C for 6 hours, then the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give (6-acryloyl-5,6,7,8-tetrahydro-1,6-naphthid-3-yl)boronic acid (7-3, 800 mg). ESI-MS m / z 233.1 [M+H] + .

[0220] Step D: Under Ar conditions, Pd(dppf)Cl2·DCM (1 g) and Na2CO3 (5.35 g) were added to a stirred solution of 1,3-dichloroisoquinoline (7-4.5 g) and (4-fluoro-2-hydroxyphenyl)boronic acid (3.55 g) in dioxane (50 mL) and H2O (10 mL). The mixture was stirred overnight at 80 °C. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 2-(3-chloroisoquinoline-1-yl)-5-fluorophenol (7-5.35 g). ESI-MS m / z 274.6 [M+H] + .

[0221] Step E: Add DIEA (4.96 g) and MOMBr (3.2 g, 25.6 mmol) to a stirred solution of 7-5 (3.5 g, 12.8 mmol) in DCM (30 mL). Stir the mixture for 3 hours, then remove the solvent under reduced pressure. Dilute the residue with aqueous NH4Cl solution and extract with DCM. Concentrate the combined organic layers under vacuum and purify the residue by silica gel column chromatography to give 3-chloro-1-(4-fluoro-2-(methoxymethoxy)phenyl)isoquinoline (3.6 g). ESI-MS m / z 318.0 [M+H] + .

[0222] Step F: tBuONa (3.3 g), tBuphos (254 mg), and Pd(OAc)2 (963 mg) were added to a stirred solution of 3-chloro-1-(4-fluoro-2-(methoxymethoxy)phenyl)isoquinoline (3.6 g) in dioxane (30 mL) and MeOH (30 mL), and the resulting mixture was stirred overnight at 80 °C under Ar conditions. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give 1-(4-fluoro-2-(methoxymethoxy)phenyl)-3-methoxyisoquinoline (7-6, (3.4 g)). ESI-MS m / z 314.0 [M+H] + .

[0223] Step G: Add NBS (1.9 g) to the stirred solution of 7-6 (3.4 g) in DMF (30 mL) and stir the resulting mixture overnight. Dilute the mixture with water and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry over anhydrous Na2SO4 and concentrate under vacuum. Purify the residue by silica gel column chromatography to give 4-bromo-1-(4-fluoro-2-(methoxymethoxy)phenyl)-3-methoxyisoquinoline (3.5 g). ESI-MS m / z 392.0 [M+H] + .

[0224] Step H: Under Ar conditions, Pd(PPh3)4 (295 mg) and Na2CO3 (1.08 g) were added to a stirred solution of 4-bromo-1-(4-fluoro-2-(methoxymethoxy)phenyl)-3-methoxyisoquinoline (1 g) and tert-butyl(2-(5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)phenoxy)ethoxy)dimethylsilane (7-7, 1.52 g) in dioxane (15 mL) and H2O (3 mL). The mixture was stirred overnight at 90 °C. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 4-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-1-(4-fluoro-2-(methoxymethoxy)phenyl)-3-methoxyisoquinoline (7-8, 1.05 g). ESI-MS m / z 582.2 [M+H] + .

[0225] Step I: Add 4 N HCl / dioxane (10 mL) to the stirred solution of 7-8 (1.05 g) in THF (10 mL) and stir the resulting mixture for 2 hours. Dilute the mixture with aqueous NaHCO3 solution and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry over anhydrous Na2SO4 and concentrate under vacuum. Purify the residue by silica gel column chromatography to give 5-fluoro-2-(4-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-3-methoxyisoquinoline-1-yl)phenol (930 mg). ESI-MS m / z 424.1 [M+H] + .

[0226] Step J: At 0 °C, NaH (264 mg, 6.6 mmol) was added to a stirred solution of 5-fluoro-2-(4-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-3-methoxyisoquinoline-1-yl)phenol (930 mg) in DMF (10 mL). The mixture was stirred for 30 min, and then 3-bromoprop-1-ene (798 mg, 6.6 mmol) was added to the reaction. The mixture was stirred overnight at 50 °C, then diluted with aqueous NH4Cl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 1-(2-(allyloxy)-4-fluorophenyl)-4-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-3-methoxyisoquinoline (7-9, 750 mg). ESI-MS m / z504.2 [M+H] + .

[0227] Step K: Add Grubbs II catalyst (150 mg) to the stirred solution of 7-9 (750 mg, 1.49 mmol) in DCE (100 mL), and stir the resulting mixture overnight at 80 °C under Ar. Remove the solvent under reduced pressure, and purify the residue by silica gel column chromatography to obtain 1 4 ,3 4 -Difluoro-2 3 -Methoxy-4,7,12-trioxa-2(1,4)-isoquinolina-1,3(1,2)-diphenylheterocyclic dodecane-9-ene (440 mg). ESI-MS m / z 476.1 [M+H] + .

[0228] Step L: To 1 4 ,3 4 -Difluoro-2 3 -Methoxy-4,7,12-trioxa-2(1,4)-isoquinolina-1,3(1,2)-diphenylheterocyclic dodecanoe-9-ene (440 mg, 0.93 mmol) was added to a stirred solution in MeCN (30 mL) with NaI (505 mg, 4.63 mmol) and TMSCl (417 mg, 2.78 mmol), and the resulting mixture was stirred at 65 °C for 30 min. The mixture was partitioned between ethyl acetate and ice water. The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography to give 1 4 ,3 4 -difluoro-4,7,12-trioxa-2(1,4)-isoquinoline-1,3(1,2)-diphenylheterocyclic dodecane-9-ene-2 3 - Alcohol (7-10, 370 mg). ESI-MS m / z 462.1 [M+H] + .

[0229] Step M: Add Et3N (0.1 mL) and (Tf)2O (0.1 mL) to a stirred solution of 7-10 (150 mg, 0.33 mmol) in DCM (10 mL) at -78 °C. Stir the mixture at -78 °C for 1 hour, then partition it between DCM and water. Concentrate the organic layer under vacuum, and purify the residue by silica gel column chromatography to obtain trifluoromethanesulfonic acid-1. 4 ,3 4-difluoro-4,7,12-trioxa-2(1,4)-isoquinoline-1,3(1,2)-diphenylheterocyclic dodecane-9-ene-2 3 -Base ester (50 mg). ESI-MS m / z 594.0 [M+H] + .

[0230] Step N: Under Ar conditions, add trifluoromethanesulfonic acid-1 4 ,3 4 -difluoro-4,7,12-trioxa-2(1,4)-isoquinoline-1,3(1,2)-diphenylheterocyclic dodecane-9-ene-2 3 β-methyl ester (50 mg, 0.084 mmol) and 7-3 (100 mg) were added to a stirred solution of xphos (8 mg) and Pd(OAc)2 (2 mg) in MeCN (2 mL) and H2O (0.2 mL), and the resulting mixture was stirred at 100 °C for 4 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography to give 154 (1.8 mg). ESI-MS m / z 632.2 [M+H] + .

[0231] Example 1h: 2 6 -(6-Acryloyl-5,6,7,8-tetrahydro-1,6-naphthid-3-yl)-1 4 ,3 4 -difluoro-4,12-dioxa-2(4,7)-thieno[3,2-c]pyridazine-6(4,1)-piperidazine-1,3(1,2)-diphenylhexacyclic dodecaneno-9-ene-6 2 Synthesis of -ketone (153). Step A: At -78°C under Ar conditions, n-BuLi (2.5 M, 5.2 mL) was added in portions to a solution of 2-(2-(benzyloxy)-4-fluorobenzyl)-N,N-diethylthiophene-3-carboxamide (8-1, 2.0 g, 5.12 mmol) in anhydrous THF (8 mL). After stirring for 45 minutes, a solution of tert-butyl 3-cyano-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1.2 g, 4.61 mmol) in THF (3 mL) was added. The mixture was stirred from -78°C to room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate (30 mL x 2), washed with aqueous NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:2) to give tert-butyl 3-(7-(2-benzyloxy)-4-fluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (8-2, 1.5 g). ESI-MS m / z 584 [M+H] + .

[0232] Step B: Under argon atmosphere at -78°C, add pyridine (1.5 mL) and trifluoromethanesulfonic anhydride (2.17 g, 7.71 mmol) to a solution of 8-2 (1.5 g, 2.57 mmol) in anhydrous DCM (10 mL). Stir the resulting mixture from -78°C to room temperature for 1.5 hours. Quench the reaction mixture with 2 N HCl aqueous solution (1.5 mL) and extract with DCM (15 mL x 2). Wash the combined organic layers with water and brine, dry to Na2SO4, filter, and concentrate under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give tert-butyl 3-(7-(2-(benzyloxy)-4-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1.26 g). ESI-MS m / z 716 [M+H] + .

[0233] Step C: To a solution of tert-butyl 3-(7-(2-benzyloxy)-4-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (1.26 g, 1.76 mmol) in dioxane (30 mL) and water (2 mL), (4-fluoro-2-hydroxyphenyl)boronic acid (845 mg, 3.52 mmol), K₂CO₃ (730 mg, 5.28 mmol), and Pd(PPh₃)₄ (200 mg, 0.17 mmol) were added. The resulting mixture was stirred at 105 °C under argon for 2.5 h, then cooled to room temperature and ethyl acetate (15 mL) was added. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:2) to give tert-butyl 3-(7-(2-benzyloxy)-4-fluorophenyl)-4-(4-fluoro-2-hydroxyphenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (8-3, 1.07 g). ESI-MS m / z 678 [M+H] + .

[0234] Step D: Cs₂CO₃ (1.54 g, 4.74 mmol) and SEMCl (338.2 mg, 2.05 mmol) were added to a solution of 8-3 (1.07 mg, 1.58 mmol) in acetonitrile (25 mL). The resulting mixture was stirred under argon for 3 hours, and then ethyl acetate (20 mL) was added. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give tert-butyl 3-(7-(2-(benzyloxy)-4-fluorophenyl)-4-(4-fluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthidium-6(5H)-carboxylate (867 mg). ESI-MS m / z 808 [M+H] + .

[0235] Step E: Pd / C (346.8 mg) was added to a solution of tert-butyl 3-(7-(2-(benzyloxy)-4-fluorophenyl)-4-(4-fluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (867 mg, 1.07 mmol) in EtOH (10 mL), and the resulting mixture was stirred at 65 °C under hydrogen for 16 hours. The reaction mixture was filtered through a silica gel pad and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:2) to give tert-butyl 3-(4-(4-fluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-(4-fluoro-2-hydroxyphenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (8-4,650 mg). ESI-MS m / z 718 [M+H] + .

[0236] Step F: Add 4-(hydroxymethyl)piperidin-2-one (585 mg, 1.8 mmol) and 2-(tributyl-λ5-phosphaneylidene)acetonitrile (216 mg, 1.8 mmol) to the solution of 8-4 (650 mg, 0.90 mmol) in toluene (10 mL). Stir the resulting mixture at 110 °C under argon for 16 hours, then cool to room temperature and add ethyl acetate (10 mL). Wash the organic layer with brine, dry over Na2SO4, filter, and concentrate under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give tert-butyl 3-(4-(4-fluoro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-7-(4-fluoro-2-((2-oxopiridin-4-yl)methoxy)phenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (8-5,527 mg). ESI-MS m / z 829 [M+H] + .

[0237] Step G: Add TBAF (15 mL) to the solution of 8-5 (527 mg, 0.63 mmol) in THF (5 mL). Stir the resulting mixture at 60 °C under argon for 16 hours, then extract with ethyl acetate (40 mL x 2), wash with brine, dry to Na₂SO₄, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography (PE / EA = 1:1) to give tert-butyl 3-(7-(4-fluoro-2-((2-oxopiridin-4-yl)methoxy)phenyl)-4-(4-fluoro-2-hydroxyphenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (395 mg). ESI-MS m / z : 699 [M+H] + .

[0238] Step H: Cs₂CO₃ (551 mg, 1.70 mmol) and 3-bromoprop-1-ene (157 mg, 1.13 mmol) were added to a solution of tert-butyl 3-(7-(4-fluoro-2-((2-oxopiridin-4-yl)methoxy)phenyl)-4-(4-fluoro-2-hydroxyphenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (395 mg, 0.57 mmol) in acetonitrile (10 mL). The resulting mixture was stirred at 55°C under argon for 3 hours, and then ethyl acetate (10 mL) was added. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give tert-butyl 3-(4-(2-(allyloxy)-4-fluorophenyl)-7-(4-fluoro-2-((2-oxopiridin-4-yl)methoxy)phenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (8-6, 320 mg). ESI-MS m / z 739 [M+H] + .

[0239] Step I: Under argon atmosphere at 0°C, NaH (80 mg, 0.86 mmol) and 4-bromobut-1-ene (132 mg, 0.86 mmol) were added to a solution of 8-6 (320 mg, 0.43 mmol) in anhydrous THF (50 mL). The resulting mixture was stirred from 0°C to 55°C for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give tert-butyl 3-(4-(2-(allyloxy)-4-fluorophenyl)-7-(2-((1-(but-3-en-1-yl)-2-oxopiperidin-4-yl)methoxy)-4-fluorophenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (227 mg). ESI-MS m / z 793 [M+H] + .

[0240] Step J: Grubbs II catalyst (68 mg, 0.4 mmol) was added to a solution of tert-butyl 3-(4-(2-(allyloxy)-4-fluorophenyl)-7-(2-((1-(but-3-en-1-yl)-2-oxopiperidin-4-yl)methoxy)-4-fluorophenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (227 mg, 0.29 mmol) in DCE (40 mL). The resulting mixture was stirred at 80 °C for 16 h under argon atmosphere. The reaction mixture was extracted with DCM (20 mL x 2), washed with aqueous NH4Cl solution and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:2) to give 3-(1 4 ,3 4 -Difluoro-6 2 -oxo-4,12-dioxa-2(4,7)-thieno[3,2-c]pyridaza-6(4,1)-piperidaza-1,3(1,2)-diphenylhexacyclic dodecane-9-ene-2 6 tert-butyl 7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (8-7, 127 mg). ESI-MS m / z :765 [M+H] + .

[0241] Step K: Add TFA (3 mL) to the solution of 8-7 (127 mg, 0.08 mmol) in DCM (10 mL). Stir the resulting mixture from 0 °C to room temperature for 2 hours. Dilute the reaction mixture with DCM, wash with aqueous NaHCO3 solution and brine, dry over Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography (DCM / MeOH = 10:1) to obtain 1 4 ,3 4 -Difluoro-2 6 -(5,6,7,8-Tetrahydro-1,6-naphthidin-3-yl)-4,12-dioxa-2(4,7)-thieno[3,2-c]pyridazine-6(4,1)-piperidinazine-1,3(1,2)-diphenylhexacyclic dodecaneno-9-ene-6 2 - Ketone (44.5 mg). ESI-MS m / z 665 [M+H] + .

[0242] Step L: At 0°C under argon atmosphere, to 1 4 ,3 4 -Difluoro-2 6 -(5,6,7,8-Tetrahydro-1,6-naphthidin-3-yl)-4,12-dioxa-2(4,7)-thieno[3,2-c]pyridazine-6(4,1)-piperidinazine-1,3(1,2)-diphenylhexacyclic dodecaneno-9-ene-6 2 -K-ketone (44.5 mg, 0.067 mmol) was added to a solution of TEA (21.4 mg, 0.2 mmol) and acrylic anhydride (8.7 mg, 0.067 mmol) in anhydrous DCM (5 mL). The resulting mixture was stirred from 0 °C to room temperature for 1 hour. The reaction mixture was quenched with 1 N HCl aqueous solution and extracted with DCM (15 mL x 2). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:2) to give 153 (13.4 mg). ESI-MS m / z 719.4 [M+H] + ;H NMR (400 MHz, DMSO- d6): δ 8.17 (s, 1H),7.83-7.82 (d, J = 4 Hz, 1H), 7.76-7.73 (d, 1H), 7.61 (s, 1H), 7.26 (s, 2H),7.17-7.10 (m, 2H), 6.96-6.87 (m, 2H), 6.18-6.14 (t, J = 16 Hz, 1H), 5.75-5.72(t, J =12 Hz,1H), 4.68 (s, 1H), 4.56-4.45 (m, 2H), 3.95 (s, 2H), 2.96-2.91(t, 4H), 2.69 (s, 1H), 2.19 (s, 2H), 1.97-1.93 (m, 2H), 1.74-1.67 (m, 1H), 1.43-1.31 (m, 7H), 0.86 (s, 2H).

[0243] Example 1i: 1-(3-(4-(3) 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzerocyclododecano-9-ene-2 6 Synthesis of 1-yl)piperazine-1-yl)azacyclobutane-1-yl)prop-2-en-1-one (166). Step A: To a solution of 3-bromo-6-chloro-2-methoxypyridine (9-1, 1.5 g, 6.8 mmol) in dioxane (50 mL) and water (3 mL), (4-fluoro-2-hydroxyphenyl)boronic acid (3 g, 20 mmol), K₂CO₃ (1.4 g, 10.2 mmol), and Pd(PPh₃)₄ (778 mg, 0.68 mmol) were added. The resulting mixture was stirred at 105 °C under argon for 2.5 h, then cooled to room temperature and ethyl acetate (50 mL) was added. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:1) to give 2-(6-chloro-2-methoxypyridine-3-yl)-5-fluorophenol (9-2, 1.2 g). ESI-MS m / z 254 [M+H] + .

[0244] Step B: Add (2-bromoethoxy)(tert-butyl)dimethylsilane (1.47 g, 6.17 mmol) and Cs₂CO₃ (2.0 g, 6.17 mmol) to a solution of 9-2 (1.2 g, 4.7 mmol) in ACN (36 mL), and stir the resulting mixture at 55 °C under argon for 6 hours. Dilute the reaction mixture with water and extract with EA (50 mL x 2). Wash the combined organic layers with brine, dry, and concentrate under vacuum. Purify the residue by silica gel column chromatography (PE / EA = 3:1) to give 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-6-chloro-2-methoxypyridine (1.1 g). ESI-MS m / z :412 [M+H] + .

[0245] Step C: K₂CO₃ (703 mg, 5.1 mmol) and Pd(PPh₃)₄ (286 mg, 0.25 mmol) were added to a solution of 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-6-chloro-2-methoxypyridine (700 mg, 1.7 mmol) in 1,4-dioxane (50 mL). The resulting mixture was stirred at 100 °C for 6 hours, then diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give 5-(5-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-6-methoxypyridin-2-yl)-1-methyl-1H-indazole-6-ol (9-3, 680 mg). ESI-MS m / z 524 [M+H] + .

[0246] Step D: Add TBAF (522 mg, 2 mmol) to a solution of 9-3 (680 mg, 1.3 mmol) in THF (50 mL) and stir the resulting mixture for 2 hours. Extract the reaction mixture with ethyl acetate (40 mL x 2), wash the combined organic layers with water and brine, dry to Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography (PE / EA = 1:1) to give 5-(5-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-6-methoxypyridin-2-yl)-1-methyl-1H-indazole-6-ol (400 mg). ESI-MS m / z : 410 [M+H] + .

[0247] Step E: Under argon atmosphere at 0 °C, NaH (80 mg, 2 mmol) and 3-bromoprop-1-ene (240 mg, 2 mmol) were added to a solution of 5-(5-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-6-methoxypyridin-2-yl)-1-methyl-1H-indazole-6-ol (400 mg, 0.97 mmol) in anhydrous THF (50 mL). The resulting mixture was stirred at 55 °C for 6 hours, then diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give 6-(allyloxy)-5-(5-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-6-methoxypyridin-2-yl)-1-methyl-1H-indazole (9-4, 380 mg). ESI-MS m / z : 490 [M+H] + .

[0248] Step F: Grubbs II catalyst (114 mg) was added to a solution of 9-4 (380 mg, 0.77 mmol) in DCE (40 mL) under argon atmosphere. The resulting mixture was stirred at 55 °C under argon atmosphere for 6 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 3:1) to give 3 4 -Fluorine-2 6 -Methoxy-1 1 -Methyl-1 1 H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzocyclododecano-9-ene (320 mg). ESI-MS m / z :462 [M+H] + .

[0249] Step G: To 3 4 -Fluorine-2 6 -Methoxy-1 1 -Methyl-1 1H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzerocyclododecano-9-ene (320 mg, 0.69 mmol) was added to a solution in ACN (40 mL) with NaH (120 mg, 2.1 mmol) and TMSCl (108 mg, 1.03 mmol), and the resulting mixture was stirred for 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 2:1) to give 3 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzerocyclododecano-9-ene-2 6 - Alcohol (9-5, 280 mg). ESI-MS m / z 448 [M+H] + .

[0250] Step H: Under argon atmosphere at -75°C, (Tf)₂O (282 mg, 0.99 mmol) and pyridine (1 mL) were added to a solution of 9-5 (280 mg, 0.66 mmol) in DCM (30 mL), and the resulting mixture was stirred from -75°C to room temperature for 30 minutes. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 5:1) to give trifluoromethanesulfonic acid-3. 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzerocyclododecano-9-ene-2 6 -Base ester (200 mg). ESI-MS m / z 580 [M+H] + .

[0251] Step I: Add trifluoromethanesulfonic acid-3 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzerocyclododecano-9-ene-2 6A solution of tert-butyl 3-(piperazin-1-yl)azacyclobutane-1-carboxylate (120 mg, 0.51 mmol), KI (56 mg, 0.34 mmol), and TMSCl (216 mg, 0.34 mmol) was added to ACN (10 mL). The resulting mixture was stirred at 130 °C under nitrogen for 8 h, then cooled to room temperature and ethyl acetate (30 mL) was added. The mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:2) to give 3-(4-(3-) 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzerocyclododecano-9-ene-2 6 tert-butyl 1-(1-yl)piperazine-1-yl)azacyclobutane-1-carboxylate (9-6, 70 mg). ESI-MS m / z 671 [M+H] + .

[0252] Step J: Add TFA (4 mL) to the solution of 9-6 (70 mg, 0.1 mmol) in DCM (15 mL), and stir the resulting mixture from 0 °C to room temperature for 2 hours. Extract the reaction mixture with DCM (20 mL x 2). Wash the combined organic layers with aqueous NaHCO3 solution, water, and brine, dry to Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography (DCM / MeOH = 10:1) to obtain 2 6 -(4-(azacyclobutane-3-yl)piperazin-1-yl)-3 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzocyclododecano-9-ene (50 mg). ESI-MS m / z 571 [M+H] + .

[0253] Step K: At 0°C under argon atmosphere, to 2 6 -(4-(azacyclobutane-3-yl)piperazin-1-yl)-3 4 -Fluorine-1 1 -Methyl-1 1H-4,7,12-trioxa-1(5,6)-indazaza-2(2,5)-pyridaza-3(1,2)-benzerocyclododecano-9-ene (50 mg, 0.08 mmol) was added to a solution of TEA (2 mL) and acrylic anhydride (14 mg, 0.16 mmol) in anhydrous DCM (10 mL). The resulting mixture was stirred from 0 °C to room temperature for 1 hour. The reaction mixture was quenched with 1 N HCl aqueous solution, extracted with DCM (15 mL x 2), and the combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE / EA = 1:2) to give 166 (40 mg). ESI-MS m / z 625.5 [M+H] + ; 1 HNMR (400 MHz, CD3OD): δ 7.86 (s, 1H), 7.67 (s, 1H), 7.41 (d, J = 7.6 Hz,1H), 7.27 (dd, J = 8.0, 6.8 Hz, 1H), 7.0 (s, 1H), 6.95 (d, J = 7.2 Hz, 1H),6.74-6.68 (m, 2H), 6.23-6.08 (m, 2H), 6.72-6.58 (m, 3H), 4.48 (s, 2H), 4.18-4.14 (m,1H), 3.97-3.95 (m, 8H), 3.74-3.70 (m, 1H), 3.58-3.54 (m, 3H), 3.10-3.07 (m, 5H), 2.16 (broads, 4H).

[0254] Example 1j: (S,E)-1-(2-(3) 4 ,3 6 -Difluoro-1 2 -Methyl-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 Synthesis of 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-yl)prop-2-en-1-one (149). Step A: n-BuLi (2.5 M, 6 mL, 15 mmol) was slowly added to a stirred solution of 5-1 (5 g, 10.33 mmol) in THF (40 mL) at -78 °C, and the resulting mixture was stirred at -50 °C for 1 h. Then, (S)-2-cyano-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (10-1, 2.4 g, 9.81 mmol, in 5 mL THF) was added at 0 °C. The resulting mixture was stirred at room temperature for 3 h, then diluted with water and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate, to give (4S)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (10⁻², 4.7 g). ESI-MS m / z 673.9 [M+H] + .

[0255] Step B: At 0 °C, pyridine (0.6 mL) and Tf₂O (0.6 mL) were added to a stirred solution of 10⁻² (1 g, 1.49 mmol) in DCM (20 mL). The mixture was stirred at 0 °C for 1 hour, then diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (10:1) to give (4S)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (940 mg). ESI-MS m / z 805.4 [M+H] + .

[0256] Step C: (4S)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (80 mg, 0.1 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol), K2CO3 (55 mg, 0.40 mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-2H-indazole-6-ol (10-3, 44 mg, 0.16 mmol) were placed in 1,4-dioxane (15 mL) and H2O (2 The mixture in mL was stirred overnight at 100 °C. The solvent was removed under reduced pressure, and the resulting residue was diluted with water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give (4S)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(6-hydroxy-2-methyl-2H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (10-4, 85 mg). ESI-MS m / z 803.3 [M+H] + .

[0257] Step D: Add TBAF (1 mL, 70%–75% w / w) to a stirred solution of 10⁻⁴ (100 mg, 0.13 mmol) in THF (15 mL). Stir the resulting mixture for 3 hours, then dilute with water and extract with ethyl acetate (10 mL x 3). Wash the combined organic layers with brine, dry to anhydrous Na₂SO₄, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (1:1) to give (4S)-2-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-2-methyl-2H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (75 mg). ESI-MS m / z 689.4 [M+H] + .

[0258] Step E: NaH (60% in mineral oil, 28 mg, 0.7 mmol) was added to a stirred solution of (4S)-2-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-2-methyl-2H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-carboxylic acid tert-butyl ester (60 mg, 0.087 mmol) in DMF (5 mL). After stirring for 30 minutes, 3-bromoprop-1-ene (84 mg, 0.7 mmol) was added to the reaction mixture. The resulting mixture was stirred at 55°C for 30 minutes, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (1:1 to 2:1) to give (4S)-2-(4-(6-(allyloxy)-2-methyl-2H-indazol-5-yl)-7-(2-(2-(allyloxy)ethoxy)-4,6-difluorophenyl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (10-5, 43 mg). ESI-MS m / z 769.4 [M+H] + .

[0259] Step F: Add 10 mg of Grubbs II catalyst to a stirred solution of 10⁻⁵ (40 mg, 0.039 mmol) in DCE (40 mL). Stir the resulting mixture overnight at 55 °C, then remove the solvent under reduced pressure. Purify the residue by silica gel column chromatography (eluting with EA / PE (2:1)) followed by preparative HPLC to obtain (S,E)⁻²⁻(3 4 ,3 6 -Difluoro-1 2 -Methyl-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 tert-butyl 5(4H)-carboxylic acid (10⁻⁶, 15 mg). ESI-MS m / z 741.4 [M+H] + .

[0260] Step G: Add 1 mL of TFA to a stirred solution of 10⁻⁶ (30 mg, 0.04 mmol) in DCM (5 mL). Stir the resulting mixture for 2 hours, then remove the solvent under reduced pressure. Dilute the mixture with an aqueous solution of NaHCO₃ and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry over anhydrous Na₂SO₄, filter, and concentrate under vacuum to give (S,E)⁻³ 4 ,3 6 -Difluoro-1 2 -Methyl-2 6 -(4-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzocyclododecano-9-ene (10⁻⁷, 25 mg). ESI-MS m / z 641.4 [M+H] + .

[0261] Step H: At 0 °C, DIEA (50 mg, 0.39 mmol) and acryloyl chloride (20 mg, 0.22 mmol) were added to a stirred solution of 10⁻⁷ (25 mg, 0.039 mmol) in DCM (10 mL). The resulting mixture was stirred at 0 °C for 1 hour, then diluted with aqueous NaHCO₃ solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 3% MeOH / DCM to give (S,E)⁻¹⁻(2⁻(3⁻ ... 4 ,3 6 -Difluoro-1 2 -Methyl-1 2 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 5(4H)-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-yl)prop-2-en-1-one (149, 18 mg). ESI-MS m / z 695.35 [M+H] + .

[0262] Example 1k: (R)-2-((S,E)-3 4 ,3 6 -Difluoro-1 1 5-Dimethyl-1 1H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 Synthesis of 197)-4-methyl-N-((R,Z)-4-(methylsulfonyl)but-3-en-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-formamide. Step A: n-BuLi (5.0 M, 1.2 mL, 6.0 mmol) was slowly added to a solution of (S)-2-(2-((1-((tert-butyldimethylsilyl)oxy)prop-2-yl)oxy)-4,6-difluorobenzyl)-N,N-diethylthiophene-3-carboxamide (11-1, 1.0 g, 2.08 mmol) in THF (10 mL) at -78 °C. The resulting mixture was stirred at -50 °C for 1 hour, and then 5-2 (488 mg, 1.86 mmol, in 2 mL THF) was added at 0 °C. The mixture was stirred at room temperature for 3 hours, then diluted with water and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate to give (4R)-2-(7-(2-(((S)-1-((tert-butyldimethylsilyl)oxy)prop-2-yl)oxy)-4,6-difluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (11-2,520 mg). ESI-MS m / z 686.28 [M+H] + .

[0263] Step B: Add pyridine (0.3 mL) and Tf2O (0.3 mL) to a solution of 11-2 (520 mg, 0.74 mmol) in DCM (10 mL). Stir the mixture at 0 °C for 1 hour, then dilute with water and extract with DCM. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (10:1) to give (4R)-2-(7-(2-(((S)-1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)oxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (360 mg). ESI-MS m / z 818.23 [M+H] + .

[0264] Step C: (4R)-2-(7-(2-(((S)-1-((tert-butyldimethylsilyl)oxy)prop-2-yl)oxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (360 mg, 0.44 mmol), Pd(PPh3)4 (50 mg, 0.044 mmol), K2CO3 (182 mg, 1.31 mmol), and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-indazole-6-ol (11-3, 180 mg, 0.65 mmol) A mixture of 1,4-dioxane (20 mL) and H2O (1 mL) was stirred overnight at 100 °C under argon. The solvent was removed, and the mixture was then diluted with water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give (4R)-2-(7-(2-(((S)-1-((tert-butyldimethylsilyl)oxy)propyl-2-yl)oxy)-4,6-difluorophenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (11-4,230 mg). ESI-MS m / z 816.33 [M+H] + .

[0265] Step D: Add TBAF (4.0 mL, 70%–75% w / w) to a solution of 11-4 (230 mg, 0.28 mmol) in THF (20 mL). Stir the resulting mixture at room temperature for 3 hours, then dilute with water and extract with ethyl acetate (10 mL x 3). Wash the combined organic layers with brine, dry to anhydrous Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (1:1) to give (4R)-2-(7-(2,4-difluoro-6-(((S)-1-hydroxypropyl-2-yl)oxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (180 mg). ESI-MS m / z 702.24 [M+H] + .

[0266] Step E: At 0 °C, NaH (60% in mineral oil, 61 mg, 2.56 mmol) was added to a stirred solution of (4R)-2-(7-(2,4-difluoro-6-(((S)-1-hydroxypropyl-2-yl)oxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (180 mg, 0.25 mmol) in THF (20 mL). After stirring for 30 min, 3-bromoprop-1-ene (155 mg, 1.28 mmol) was added to the mixture. The resulting mixture was stirred at 55 °C for 30 min, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (1:1) to give (4R)-2-(4-(6-(allyloxy)-1-methyl-1H-indazol-5-yl)-7-(2-(((S)-1-(allyloxy)prop-2-yl)oxy)-4,6-difluorophenyl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (11-5, 165 mg). ESI-MS m / z 782.31 [M+H] + .

[0267] Step F: Add Grubbs II catalyst (50 mg) to a solution of 11-5 (165 mg, 0.21 mmol) in DCE (20 mL). Stir the resulting mixture overnight at 55 °C, then remove the solvent under reduced pressure. Purify the residue by silica gel column chromatography (eluting with EA / PE (2:1)) followed by preparative HPLC to give (R)-2-((S,E)-3 4 ,3 6 -Difluoro-1 1 5-Dimethyl-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (11-6, 134 mg). ESI-MS m / z 754.27 [M+H] + .

[0268] Step G: Add TFA (5 mL) to a solution of 11-6 (134 mg, 0.13 mmol) in DCM (20 mL). Stir the resulting mixture at room temperature for 2 hours, then remove the solvent under reduced pressure. Dilute the mixture with an aqueous solution of NaHCO3 and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry over anhydrous Na2SO4, filter, and concentrate under vacuum to give (S,E)-3. 4 ,3 6 -Difluoro-1 1 5-Dimethyl-2 6 -((R)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene (130 mg, crude). ESI-MS m / z 654.22 [M+H] + .

[0269] Step H: At 0°C, towards (S,E)-3 4 ,3 6 -Difluoro-1 1 5-Dimethyl-2 6 -((R)-4-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1 1H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazona-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene (130 mg, 0.19 mmol) was added to a solution of H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazona-1(5,6)-indazona-3(1,2)-benzane(BTC) in 10 mL of THF. The resulting mixture was stirred at 0 °C for 30 min, then (R,Z)-4-(methylsulfonyl)but-3-en-2-amine (11-7, 73 mg, 0.38 mmol, in THF) and DIEA were added, and the resulting mixture was stirred at 55 °C for 16 h. The mixture was diluted with H₂O and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 3% MeOH / DCM to obtain (R)-2-((S,E)-3 4 ,3 6 -Difluoro-1 1 5-Dimethyl-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 (-yl)-4-methyl-N-((R,Z)-4-(methanesulfonyl)but-3-en-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxamide. ESI-MS m / z: 829.25 [M+H] + Compound 197 (45 mg) was obtained by chiral SFC separation at 11–8. ESI-MS m / z: 829.25 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ: 8.06 (s, 1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.30 (s, 1H), 7.04 (s, 1H), 6.89-6.86 (m, 3H), 6.76-6.66 (m, 2H),6.31 (s, 1H), 5.62-5.59 (d, J = 12 Hz, 1H), 5.32 (s, 1H), 4.57-4.41 (m, 6H),4.30-4.27 (d, J= 12 Hz,1H), 4.09 (s, 3H), 3.82 (s, 3H), 3.65-3.60 (m, 1H), 3.13-3.07 (m, 2H), 2.98 (s, 3H), 1.28-1.24 (m, 6H), 0.83 (s, 3H).

[0270] Example 11: (E)-1-(3-(3) 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,13-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclodeca-9-ene-2 6 Synthesis of 7,8-dihydro-1,6-naphthidium-6(5H)-prop-2-en-1-one (203). Step A: At -78°C, n-BuLi (2.5 M, 2 mL, 5 mmol) was slowly added to a stirred solution of 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorobenzyl)-N,N-diethylthiophene-3-carboxamide (12-1, 2 g, 4.13 mmol) in THF (16 mL). The resulting mixture was stirred at -50°C for 1 hour, and then tert-butyl 3-cyano-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (12-2, 0.96 g, 3.71 mmol, in 2 mL THF) was added at 0°C. The mixture was stirred at room temperature for 3 hours, then diluted with water and extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with ethyl acetate to give tert-butyl 3-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-4-hydroxythieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (12-3,2 g). ESI-MS m / z 652.26 [M+H] + .

[0271] Step B: Add pyridine (1 mL) and Tf2O (1 mL) to a stirred solution of 12-3 (350 mg, 0.53 mmol) in DCM (15 mL). Stir the mixture at 0 °C for 1 hour, then dilute with water and extract with DCM. Wash the combined organic layers with water and brine, dry to anhydrous Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (10:1) to give tert-butyl 3-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (380 mg). ESI-MS m / z 784.21 [M+H] + .

[0272] Step C: A mixture of tert-butyl 3-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (380 mg, 0.48 mmol), Pd(PPh3)4 (55 mg, 0.05 mmol), K2CO3 (100 mg, 0.72 mmol), and 11-3 (200 mg, 0.73 mmol) in 1,4-dioxane (20 mL) and H2O (1 mL) was stirred overnight at 100 °C. The solvent was removed under reduced pressure, and the resulting mixture was diluted with water and extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl 3-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-fluorophenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (12-4, 180 mg). ESI-MS m / z 782.32 [M+H] + .

[0273] Step D: Add TBAF (3 mL, 70%–75% w / w) to a stirred solution of 12–4 (180 mg, 0.23 mmol) in THF (15 mL). Stir the resulting mixture at room temperature for 3 hours, then dilute with water and extract with ethyl acetate (15 mL x 3). Wash the combined organic layers with brine, dry to anhydrous Na₂SO₄, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (1:1) to give tert-butyl 3-(7-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (100 mg). ESI-MS m / z 668.23 [M+H] + .

[0274] Step E: Cs₂CO₃ (97.80 mg, 0.3 mmol) and 4-bromobut-1-ene (43 mg, 0.3 mmol) were added to a stirred solution of tert-butyl 3-(7-(4-fluoro-2-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (100 mg, 0.15 mmol) in acetonitrile (15 mL). The resulting mixture was stirred at room temperature for 6 hours, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (2:1) to give tert-butyl 3-(4-(6-(but-3-en-1-yloxy)-1-methyl-1H-indazol-5-yl)-7-(4-fluoro-2-(2-hydroxyethoxy)phenyl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid (12-5, 75 mg). ESI-MS m / z 722.28 [M+H] + .

[0275] Step F: At 0 °C, NaH (60% mineral oil, 103 mg, 0.52 mmol) was added to a stirred solution of 12-5 (75 mg, 0.10 mmol) in DMF (15 mL). After stirring for 30 minutes, 3-bromoprop-1-ene (24.51 mg, 0.21 mmol) was added to the mixture. The resulting mixture was stirred at 55 °C for 30 minutes, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (1:1 to 2:1) to give 12-6 (70 mg) of tert-butyl 3-(7-(2-(2-(allyloxy)ethoxy)-4-fluorophenyl)-4-(6-(but-3-en-1-yloxy)-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-7,8-dihydro-1,6-naphthyl-6(5H)-carboxylic acid. ESI-MS m / z 762.31 [M+H] + .

[0276] Step G: Add Grubbs II catalyst (21 mg) to a stirred solution of 12-6 (70 mg, 0.09 mmol) in DCE (70 mL). Stir the resulting mixture overnight at 55 °C, then remove the solvent. Purify the residue by silica gel column chromatography (eluting with EA / PE (2:1)) followed by preparative HPLC to give (E)-3-(3 4 -Fluorine-1 1 -Methyl-1 1 H-4,7,13-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclodeca-9-ene-2 6 tert-butyl 7,8-dihydro-1,6-naphthyl-6(5H)-carboxylate (12-7, 40 mg). ESI-MS m / z 734.28 [M+H] + .

[0277] Step H: Add TFA (3 mL) to a stirred solution of 12-7 (20 mg, 0.027 mmol) in DCM (10 mL). Stir the resulting mixture at room temperature for 2 hours, then remove the solvent under reduced pressure. Dilute the mixture with an aqueous solution of NaHCO3 and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry over anhydrous Na2SO4, filter, and concentrate under vacuum to give (E)-3. 4 -Fluorine-1 1 -Methyl-26 -(5,6,7,8-tetrahydro-1,6-naphthid-3-yl)-1 1 H-4,7,13-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclodeca-9-ene (12-8, 16 mg). ESI-MS m / z 634.22 [M+H] + .

[0278] Step I: DIEA (0.5 mL) and acryloyl chloride (4.45 mg, 0.05 mmol) were added to a stirred solution of 12-8 (16 mg, 0.025 mmol) in DCM (8 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour, then diluted with aqueous NaHCO3 solution and extracted with DCM. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 3% MeOH / DCM to give 203 (6.3 mg). ESI-MS m / z 695.35 [M+H] + ; 1 HNMR (400 MHz, CD3OD): δ 8.25 (s, 1H), 7.92 (s,1H), 7.83 (s, 1H), 7.78 (s, 1H), 7.50-7.59 (d, J = 4 Hz, 1H), 7.34-7.29 (m,1H), 7.24-7.18 (m, 2H), 7.13-7.11 (m, 1H), 7.08 (s, 1H), 6.85-6.68 (m, 4H), 6.17-6.13 (m, 1H), 6.70-6.68 (m, 1H), 5.39 (s, 1H), 4.00 (s, 2H), 3.94-3.92(m, 2H), 3.86-3.83 (m, 3H), 3.77-3.73 (m, 1H), 3.62-3.52 (m, 3H), 2.91-2.85(m, 2H), 3.47-2.37 (m, 2H), 2.19-2.09 (m, 2H).

[0279] Example 1m: (S)-2-((E)-3 4 ,3 6 -Difluoro-1 1 -Methyl-1 1H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 Synthesis of 191-(R,E)-4-methyl-N-((R,E)-4-(methylsulfonyl)but-3-en-2-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-formamide. Step A: A mixture of (4S)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (13-1, 550 mg, 0.68 mmol), Pd(PPh3)4 (79 mg, 0.068 mmol), K2CO3 (377 mg, 2.74 mmol), and 11-3 (281 mg, 1.03 mmol) in 1,4-dioxane (15 mL) and H2O (1.5 mL) was stirred overnight at 100 °C. The solvent was removed under reduced pressure, and the resulting mixture was then diluted with water and extracted with ethyl acetate (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EA (1:1) to give (4S)-2-(7-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4,6-difluorophenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (13-2,560 mg). ESI-MS m / z 803.3 [M+H] + .

[0280] Step B: Add TBAF (1.5 mL, 70%–75% w / w) to a stirred solution of 13-2 (560 mg, 0.69 mmol) in THF (15 mL). Stir the resulting mixture for 3 hours, then dilute with water and extract with ethyl acetate (10 mL x 3). Wash the combined organic layers with brine, dry to anhydrous Na2SO4, filter, and concentrate under vacuum. Purify the residue by silica gel column chromatography, eluting with PE / EA (1:1) to give (4S)-2-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-carboxylic acid tert-butyl ester (450 mg). ESI-MS m / z 689.4 [M+H] + .

[0281] Step C: NaH (60% mineral oil, 183 mg, 4.57 mmol) was added to a stirred solution of (4S)-2-(7-(2,4-difluoro-6-(2-hydroxyethoxy)phenyl)-4-(6-hydroxy-1-methyl-1H-indazol-5-yl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-5(4H)-carboxylic acid tert-butyl ester (450 mg, 0.65 mmol) in DMF (10 mL) at 0 °C. After stirring for 30 min, 3-bromoprop-1-ene (628 mg, 5.23 mmol) was added to the reaction mixture. The resulting mixture was stirred at 55 °C for 30 min, then diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with EA / PE (1:1 to 2:1) to give (4S)-2-(4-(6-(allyloxy)-1-methyl-1H-indazol-5-yl)-7-(2-(2-(allyloxy)ethoxy)-4,6-difluorophenyl)thieno[3,2-c]pyridin-6-yl)-4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (13-3,400 mg). ESI-MS m / z 769.4 [M+H] + .

[0282] Step D: Add Grubbs II catalyst (80 mg) to a stirred solution of 13-3 (400 mg, 0.52 mmol) in DCE (20 mL). Stir the resulting mixture overnight at 55 °C, then remove the solvent under reduced pressure. Purify the residue by silica gel column chromatography (eluting with EA / PE (2:1)) followed by preparative HPLC to obtain (S,E)-2-(3 4 ,3 6 -Difluoro-1 1 -Methyl-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene-2 6 4-methyl-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (13-4, 240 mg). ESI-MS m / z 741.4 [M+H] + .

[0283] Step E: Add TFA (2 mL) to a stirred solution of 13-4 (100 mg, 0.13 mmol) in DCM (10 mL). Stir the resulting mixture for 2 hours, then remove the solvent under reduced pressure. Dilute the mixture with an aqueous solution of NaHCO3 and extract with ethyl acetate. Wash the combined organic layers with water and brine, dry over anhydrous Na2SO4, and concentrate under vacuum to give (S,E)-3. 4 ,3 6 -Difluoro-1 1 -Methyl-2 6 -(4-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1 1 H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridaza-1(5,6)-indazaza-3(1,2)-benzocyclododecano-9-ene (80 mg). ESI-MS m / z 641.4 [M+H] + .

[0284] Step F: At 0 °C, towards (S,E)-3 4 ,3 6 -Difluoro-1 1 -Methyl-2 6 -(4-Methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-1 1H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazona-1(5,6)-indazaza-3(1,2)-benzerocyclododecano-9-ene (80 mg, 0.12 mmol) was added to a stirred solution of H-4,7,12-trioxa-2(4,7)-thieno[3,2-c]pyridazona-1(5,6)-indazona-3(1,2)-benzane (BTC) in 10 mL of THF. The resulting mixture was stirred at 0 °C for 0.5 h, then (R,E)-4-(methylsulfonyl)but-3-en-2-amine (13-5, 100 mg, 0.67 mmol, in THF) and DIEA were added, and the resulting mixture was stirred at 55 °C for 16 h. The mixture was diluted with H₂O and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with 3% MeOH / DCM to give 191 (11 mg). ESI-MS m / z 816.24 [M+H] + ; 1 HNMR (400 MHz, CD3OD): δ 7.94-7.91 (m, 2H), 7.50-7.49 (dd, J = 4 Hz, 1H), 7.08-7.02 (m, 2H), 6.67-6.56 (m, 2H), 6.23-6.12 (m, 2H), 5.97-5.95 (d, J = 8 Hz, 1H), 5.56-5.51(d, J = 10 Hz, 1H), 5.25-5.18 (m, 2H), 4.94-4.89 (m, 1H), 4.48-4.39 (m, 2H),4.26-4.16 (m, 1H), 4.00-3.96 (m, 3H), 3.94-3.78 (m, 6H), 3.38-3.30 (m, 3H), 3.05-3.04 (d, J = 4 Hz, 3H), 1.27-1.18 (m, 6H).

[0285] Example 2: Disruption of PI3Kα:KRAS interaction by SPR inhibition assay SPR binding experiments were performed on a Biacore 8K instrument (Cytiva). Neutravidin (Pierce) was coupled to the carboxymethylated dextran surface of the CM5 sensor chip (Cytiva) using standard amine coupling chemistry. First, the CM5 chip surface was activated with 0.1 M N-hydroxysuccinimide and 0.4 M N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide at a flow rate of 20 µL / min, using 20 mM HEPES (pH 7.4) and 150 mM NaCl as the run buffer. Next, neutralvidin was diluted to 20 µg / mL in 10 mM sodium acetate (pH 4.5) and injected into all flow cells until a fixed density of approximately 10,000 response units (RUs) was achieved. The activated amines were quenched by injection of 1 M ethanolamine (pH 8.0). All flow cells were used to capture 300–500 RU of avi-labeled full-length PI3Kα in buffers of 20 mM HEPES (pH 7.4), 150 mM NaCl, 5 mM MgCl2, 1 mM TCEP, 0.05% Tween 20, and 5% DMSO. 20 µM of KRAS-Q25A was mixed with eight concentrations of the compound (50 nM–100 µM) and injected onto full-length PI3Kα at a flow rate of 30 µL / min at 25 °C. Steady-state levels of KRAS binding were recorded, and an IC50 was determined using a 4-parameter inhibition model. 50 value.

[0286] Example 3: PI3Kα (NCBI gene ID: 5290, Uniprot ID: P42336) compound modification assay The test compound was prepared as a 10 mM stock solution in dimethyl sulfoxide (DMSO; Fisher catalog number BP231-100). Human recombinant PIK3CA protein 157-300 was produced internally. The PIK3CA protein was diluted to 1 µM in buffer (20 mM Hepes pH 7.5, 150 mM NaCl, 1 mM MgCl2, 1 mM DTT). To test the PIK3CA modification, the compound was diluted to a 50X final test concentration in DMSO in a 96-well storage plate. 2 μL of the diluted 50X compound was added to the appropriate wells in a PCR plate (Fisher catalog number AB-0800). The stock protein solution (98 µL) was added to each well in the 96-well PCR plate. The reaction was then carefully mixed. The plate was sealed with an aluminum plate seal and stored in a drawer at room temperature. After different incubation times, the reaction was quenched by adding 5 µL of 2% formic acid (Fisher catalog number A117-50) in MilliQ H2O to each well and then mixing with a pipette. The plates were then resealed with aluminum sealant and stored until mass spectrometry analysis.

[0287] The degree of covalent modification of the PIK3CA protein was determined using a Thermo Q-Exactive Plus mass spectrometer via liquid chromatography-electrospray mass spectrometry (LC-ESMS) analysis of the intact protein. 10 or 20 µL of sample was injected into a bioZen 3.6 µm intact C4 column (Phenomenex catalog number 00B-4767-AN) placed in a column oven at 50 °C, and separation was performed using an LC gradient from 20% to 60% solvent B. Solvent A was 0.1% formic acid, and solvent B was 0.1% formic acid in acetonitrile. The sheath gas, auxiliary gas, and purge gas flow rates of the HESI source were set to 40, 5, and 1, respectively. The spray voltage was 4 kV, and the capillary temperature was 320 °C. The RF level of the S-lens was 50, and the auxiliary gas heater temperature was set to 200 °C. Mass spectrometry analysis was performed using a scan range of 650 to 1750 m / z with positive polarity at a mass resolution of 70,000, an AGC target with 1e6 ions, and a maximum injection time of 250 ms. Recorded protein mass spectra were deconvolved from the raw data files using Protein Deconvolution v4.0 (Thermo). Protein mass, adduct mass, and corresponding peak intensities were exported to Excel (Microsoft). The peak intensities of unmodified and modified proteins were used to calculate the percentage of covalent modification of the PIK3CA protein based on the following equation: %PIK3CA protein modification = ((PIK3CA-compound) / (PIK3CA) + (PIK3CA-compound)) × 100.

[0288] Table 2 shows the percentage of PI3Kα modification achieved by the selected compounds within 60 minutes using the above-described experimental methods. The compound numbers correspond to the numbers and structures provided in Table 1 and Example 1.

[0289] Table 2 Example 4: Cell-based pAKT HTRF assay in BT474 cells The effectiveness of the compound in interfering with PIK3CA / KRAS signaling in BT474 cells was determined using a pAKT HTRF assay (Perkin-Elmer). On day 1, cells were cultured at 2.5 x 10⁻⁶ cells / cells. 4 Cells / well were seeded into complete growth medium (DMEM, 10% FBS) in 96-well plates. On day 2, cells were treated with the presently disclosed test compound containing 0.25% DMSO. Source plates were created using the compound diluted 5-fold in medium to the final assay concentration. The compound was run as a 9-point concentration curve, starting at 3 μM and with 3-fold dilutions between concentrations. 20 µL was transferred to the cell plate (final volume in wells: 100 µL). The plate was harvested after 4 hours of incubation by aspirating the medium and adding 1x supplemental lysis buffer (75 µL per well) provided in the kit to all wells. The culture plate was then placed on a plate shaker and incubated for an additional 30 minutes at 850 rpm. An antibody mixture solution was prepared by aliquoting the d2 and Eu Cryptate antibodies 1:20 in the assay buffer provided in the kit, and then mixing the diluted antibody solution (1:1 v:v). 4 µL of this solution was then added to a 384-well assay plate (Perkin Elmer; 6008230). The samples were homogenized by pipetting up and down, and then (16 µL of cell lysate) were transferred from a 96-well cell culture plate to two wells of an HTRF 384-well assay plate containing antibody solution. The culture plates were centrifuged (524 g, 1 min) and incubated at room temperature for 4 to 24 hours. The plates were centrifuged again (524 g, 1 min) and analyzed using the following settings on an EnVision plate reader: excitation 320 nM, bandwidth 75 nM; emission 615 nM, bandwidth 85 nM, gain 100%, flash 100, hysteresis 60 µs.

[0290] Example 5: PI3Kα cell assay The ability of the compounds disclosed herein to inhibit...

Claims

1. A compound of formula (I): (I)， Or a pharmaceutically acceptable salt or solvate thereof, wherein: G is selected from C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R G replace; X 1 Selected from N and C(R) 1 ); X 2 Selected from N and C(R) 2 ); X 3 Selected from N, C(R) 3 ) and C(O); X is selected from N and C; J is selected from C 3-12 Carbocyclic rings and 3- to 12-membered heterocycles, each optionally bound by one or more R J replace; L 1 Selected from C 5-15 Alkylene, C 5-15 imidene group, C 5-15 Alynyl, 5- to 15-membered heteroalkyl, and 5- to 15-membered heteroenyl, each optionally bound by one or more R L1 replace; A 1 Selected from key, C 3-12 Carbon rings and 3- to 12-membered heterocycles, of which C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. A1 replace; L is selected from key, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -O-, -N(R) 12 -, -C(O)-, -C(R) 12 )=, -S-, -S(O)-, -S(O)2-, -P(O)R 12 -、-P(O)R 12 O-、-N(R 12 )C(O)-、-N(R 12 )S(O)-、-N(R 12 )S(O)2-、-N(R 12 )P(O)R 12 -、-OP(O)R 12 -、-C(O)N(R 12 )-、-S(O)N(R 12 )-、-S(O)2N(R 12 )- and -P(O)R 12 N(R 12 )-, where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl and 3- to 6-membered heteroynyl groups are each optionally surrounded by one, two or three R groups. L replace; A 2 Selected from C 3-12 Carbon rings and 3- to 12-membered heterocycles, each optionally bound by one, two, or three R... A2 replace; R A Selected from hydrogen, R 20 and E, where E is optionally connected to A. 2 The combination is the part that can covalently bind to the C242 residue of the PI3Kα protein; R 1 R 2 and R 3 Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)N(R 12 (R) 13 ), -N(R 12 )C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -S(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 -S(O)(NR) 12 )R 12 -S(O)2N(R) 12 (R) 13 ) and -S(O)(NR 12 )N(R 12 (R) 13 ), or R 1 and R 2 Together with the atoms they are attached to, they form C 5-8 Monocyclic carbon rings or 5- to 8-membered monocyclic heterocycles, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 5-8 Monocyclic carbon rings and 5- to 8-membered monocyclic heterocycles are each optionally divided by one, two, or three Rs. 20 replace; R G R L1 R J R A1 R L and R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SF5, -SR 12 -N(R) 12 (R) 13 =NR 12 =C(R) 14 )2、-C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)N(R 12 (R) 13 ), -N(R 12 )C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -S(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 -OS(O)2R 12 -S(O)(NR) 12 )R 12 -S(O)2N(R) 12 (R) 13 ), -S(O)(NR 12 )N(R 12 (R) 13 ), -N(R 12 )P(O)R 12 R 13 and -P(O)R 12 R 13 Two of them R L1 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; in which two Rs A1 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; in which two Rs A2 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; and C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace; R 12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl-(3- to 12-membered heterocyclic), wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles) are each optionally surrounded by one, two, or three R groups. 20 replace; R 13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; or R groups attached to the same nitrogen atom 12 and R 13 Formed by one, two or three R 20 Replacement of 3- to 10-membered heterocycles; R 14 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl group (3- to 12-membered heterocyclic rings), or two R groups 14 Together with the carbon atoms they are attached to, they form C 3-12 Carbon rings or 3- to 12-membered heterocycles, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocycles), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace; R 20 Each occurrence is independently selected from halogen, oxo, -CN, -NO2, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 22 -SF5, -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 Two of them R 20 Optional joining to form C 3-12 Carbon rings or 3- to 12-membered heterocycles; wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbide ring and the 3- to 12-membered heterocycles are each optionally and independently selected from halogens, oxocycles, -CN, -NO2, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 22 -SF5, -SR 22 -N(R) 22 (R) 23 =NR 22 =C(R) 21 )2、-C(O)OR 22 -OC(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)N(R 22 (R) 23 ), -N(R 22 )C(O)OR 22 -N(R) 22 )S(O)2R 22 -C(O)R 22 -S(O)R 22 -OC(O)R 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -N(R 22 )C(O)R 22 -S(O)2R 22 -OS(O)2R 22 -S(O)(NR) 22 )R 22 -S(O)2N(R) 22 (R) 23 -S(=O)(=NR) 22 )N(R 22 (R) 23 ), -N(R 22 )P(O)R 22 R 23 and -P(O)R 22 R 23 One or more substituents are substituted; R 21 Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl group (3- to 12-membered heterocycle), or two R groups 21 Together with the carbon atoms they are attached to, they form C 3-12 Carbon rings or 3- to 12-membered heterocycles, each optionally and independently selected from halogens, C 1-3 Alkyl, C 1-3 The alkyl halogroup and -OH are substituted with one, two or three substituents; R 22 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-(C 3-12 (Carbon ring) and -C 0-6 Alkyl groups (3- to 12-membered heterocycles); R 23 Each time it appears, it is independently selected from hydrogen and C. 1-6 Alkyl group; or R group attached to the same nitrogen atom 22 and R 23 Formation of 3- to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

2. The compound, salt, or solvate according to claim 1, wherein G is selected from phenyl and 5- to 10-membered heteroaryl groups, each optionally constituting one or more R groups. G replace.

3. The compound, salt, or solvate according to claim 1 or 2, wherein G is selected from phenyl and benzofuran, each optionally being reacted with one or more R G replace.

4. The compound, salt, or solvate according to any one of the preceding claims, having the structure of formula (I-1): (I-1)， Or a pharmaceutically acceptable salt or solvate thereof, wherein: g1 is 0, 1, 2, or 3.

5. The compound, salt, or solvate according to any one of the preceding claims, wherein R G Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic) and -OR 12 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heterokynyl, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace.

6. The compound, salt, or solvate according to any one of the preceding claims, wherein R G Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, 2- to 6-membered heteroalkyl and -OR 12 ; where C 1-6 Alkyl groups and 2- to 6-membered heteroalkyl groups are each optionally and independently selected from halogens, oxo groups, -CN groups, C groups. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted.

7. The compound, salt, or solvate according to any one of the preceding claims, wherein R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3.

8. The compound, salt, or solvate according to any one of the preceding claims, wherein X 1 It is C(R) 1 And X 2 It is C(R) 2 ).

9. The compound, salt, or solvate according to any one of the preceding claims, wherein R 1 and R 2 Each is hydrogen; or R 1 and R 2 Together with the atoms they are attached to, they form C6 aryl or 5-membered heteroaryl groups, each optionally bonded by one, two, or three R atoms. 20 replace.

10. The compound, salt, or solvate according to any one of the preceding claims, wherein R 1 and R 2 Together with the atoms they are attached to, they form thiophene, benzene, cyclopentene, or pyrazole.

11. The compound, salt, or solvate according to any one of the preceding claims, wherein X is C.

12. The compound, salt, or solvate according to any one of the preceding claims, having a structure of formula (I-2a), (I-2b), (I-2c), or (I-2d): (I-2a), (I-2b), (I-2c) or (I-2d), Or a pharmaceutically acceptable salt or solvate thereof, wherein: g1 is 0, 1, 2, or 3.

13. The compound, salt, or solvate according to any one of the preceding claims, wherein J is selected from phenyl, 5- to 6-membered monocyclic heterocycles, and 7- to 11-membered bicyclic heterocycles, each optionally being oxidized by one or more R J replace.

14. The compound, salt, or solvate according to any one of the preceding claims, wherein J is optionally reacted with one or more R J Substituted phenyl groups.

15. The compound, salt, or solvate according to any one of the preceding claims, wherein R J Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -N(R) 12 )S(O)2R 12 -C(O)R 12 -OC(O)R 12 -C(O)N(R) 12 (R) 13 ), -N(R 12 )C(O)R 12 -S(O)2R 12 and -S(O)2N(R 12 (R) 13 )-; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, -C 0-6 Alkyl-(C 3-12 (Carbocyclic), -(2- to 6-membered heteroalkyl)-(C 3-12 carbon ring), -C 0-6 Alkyl-(3- to 12-membered heterocyclic), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocyclic), C 3-12 The carbon ring and the 3- to 12-membered heterocycles are each optionally separated by one, two, or three Rs. 20 replace.

16. The compound, salt, or solvate according to any one of the preceding claims, wherein R J Selected from halogens and C 1-3 alkyl.

17. The compound, salt, or solvate according to any one of the preceding claims, having the structure of formula (I-3): (I-3)， Or its pharmaceutically acceptable salt, wherein: g1 is 0, 1, 2, or 3; and j1 is 0, 1, 2, 3 or 4.

18. The compound, salt, or solvate according to any one of the preceding claims, wherein X 3 It is N.

19. The compound, salt, or solvate according to any one of the preceding claims, wherein L 1 Selected from C 8-12 Alkylene, C 8-12 alkenyl, 8- to 12-membered heteroalkyl, and 8- to 12-membered heteroalkyl, each optionally bound by one or more R L1 replace.

20. The compound, salt, or solvate of claim 19, wherein the imenoyl and heteroenyl groups contain a carbon-carbon double bond.

21. The compound, salt, or solvate of claim 19, wherein the heteroalkyl and heteroenyl groups comprise at least one oxygen or nitrogen atom.

22. The compound, salt, or solvate according to any one of the preceding claims, wherein R L1 Each time it appears, it is independently selected from halogen, oxidative, and C. 1-6 Alkyl, C 1-6 Haloalkyl, (C 1-6 Alkyl)-OH and -OH.

23. The compound, salt, or solvate according to any one of the preceding claims, wherein A 1 Selected from bonds, 4- to 10-membered saturated heterocycles, and 5- to 8-membered partially unsaturated heterocycles, wherein the 4- to 10-membered saturated heterocycles and the 5- to 8-membered partially unsaturated heterocycles are each optionally bounded by one, two, or three R... A1 replace.

24. The compound, salt, or solvate according to any one of claims 1 to 23, wherein A 1 Selected from aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroaziridine, and 1,4-diazacycloheptane, each optionally separated by one, two, or three R... A1 replace.

25. The compound, salt, or solvate according to any one of claims 1 to 23, wherein A 1 It is a key.

26. The compound, salt, or solvate according to any one of the preceding claims, wherein R A1 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 Two of them R A1 Optionally joined to form bridges of 1 to 4 atoms; wherein C 1-6 Alkyl, C 2-6 The alkenyl group and the bridge of 1 to 4 atoms are each optionally and independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted.

27. The compound, salt, or solvate according to any one of the preceding claims, wherein L is selected from bonds, C 1-3 Alkyl and -C(O)-, where C 1-3 Alkyl groups are optionally surrounded by one, two, or three R groups. L replace.

28. The compound, salt, or solvate according to any one of the preceding claims, wherein R L Each time it appears, it is independently selected from halogen, oxo, -CN, and C. 1-6 alkyl.

29. The compound, salt or solvate according to any one of the preceding claims, wherein L is a bond.

30. The compound, salt, or solvate according to any one of the preceding claims, wherein A 2 It can be arbitrarily determined by one, two, or three Rs. A2 Replaced heterocyclic compounds ranging from 4 to 12.

31. The compound, salt, or solvate according to any one of the preceding claims, wherein A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 replace.

32. The compound, salt, or solvate according to any one of the preceding claims, wherein A 2 Selected from tetrahydronaphthyl, tetrahydropyrazolopyrazine, pyridone, pyrazole, aziridine, pyrrolidine, piperidine, piperazine, aziridine, 1,4-diazacycloheptane, and 2-azispiro[3.3]heptane, each optionally separated by one, two, or three R A2 replace.

33. The compound, salt, or solvate according to any one of the preceding claims, wherein A 2 Selected from tetrahydronaphthyl and tetrahydropyrazolopyrazine, each optionally constituting one, two, or three R... A2 replace.

34. The compound, salt, or solvate according to any one of the preceding claims, wherein R A2 Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl and -OR 12 Two of them R A2 Optionally joined to form bridges of 1 to 4 atoms; wherein C 1-6 Alkyl, C 2-6 The alkenyl group and the bridge of 1 to 4 atoms are each optionally and independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and -OR 22 One or more substituents are substituted.

35. The compound, salt, or solvate according to any one of the preceding claims, wherein R A It is E.

36. The compound, salt, or solvate according to any one of the preceding claims, wherein R A Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Each of them is optionally controlled by one or two R 20 replace.

37. The compound, salt, or solvate according to any one of the preceding claims, wherein R A yes .

38. The compound, salt, or solvate according to any one of claims 1, 4, 12, or 17, wherein: R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3; A 1 Selected from aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroazine, and 1,4-diazacycloheptane, wherein aziridine, pyrrolidine, dihydropyrrole, piperidine, tetrahydropyridine, piperazine, aziridine, tetrahydroazine, and 1,4-diazacycloheptane are each optionally separated by one, two, or three R... A1 replace; L is a bond; A 2 Selected from 9- to 10-membered bicyclic heterocycles and 4- to 8-membered monocyclic heterocycles, each optionally bounded by one, two, or three R... A2 Replace; and R A yes .

39. The compound, salt, or solvate according to any one of claims 1 to 35, wherein R A It is selected from , , , , , , , and .

40. The compound, salt, or solvate according to any one of claims 1 to 35, wherein R A It is selected from , , , , , , and .

41. The compound, salt, or solvate according to any one of claims 1 to 35, wherein R A yes .

42. The compound, salt, or solvate according to any one of claims 1, 4, 12, or 17, wherein: R G Each time it appears, it is independently selected from fluorine and -O(CH2)2OCH3; A 1 It is a key; L is a bond; A 2 Selected from one, two or three Rs A2 The replacement of 9- to 10-yuan bicyclic heterocyclic rings; and R A yes .

43. The compound according to claim 1, having the following formula: ， Or its pharmaceutically acceptable salts or solvates.

44. The compound according to claim 1, having the following formula: ， Or its pharmaceutically acceptable salts or solvates.

45. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

46. ​​A method of modifying PI3Kα protein, comprising contacting the PI3Kα protein with an effective amount of a compound, salt or solvate according to any one of claims 1 to 44.

47. The method of claim 46, wherein the kinase activity of the modified PI3Kα protein is not significantly inhibited.

48. A method for inhibiting the interaction between RAS protein and PI3Kα protein, the method comprising contacting the PI3Kα protein with an effective amount of the compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt or solvate thereof.

49. A method of treating cancer in a subject in need, comprising administering to said subject a therapeutically effective amount of the compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt or solvate thereof.

50. The method of claim 49, wherein the cancer exhibits one or more of abnormal activation of PI3Kα or PI3Kα mutation.

51. The method of claim 50, wherein the PI3Kα mutation is selected from E81K, E110del, K111E, K111N, G118D, N345K, C420R, E453K, E542K, E545A, E545G, E545K, Q546K, Q546P, Q546R, E726K, M1043I, N1044K, H1047L, H1047R, and G1049R.

52. The method according to any one of claims 49 to 51, wherein the cancer comprises a RAS mutant protein.

53. A method for treating cancer in a subject containing a RAS mutant protein, the method comprising: The interaction between the RAS mutant protein and the PI3Kα protein of the object is inhibited by applying the compound according to any one of claims 1 to 44 to the object.

54. The method according to claim 52 or 53, wherein the RAS mutant protein is a KRAS mutant protein comprising mutations of G12C, G12D, G12S, G12V, G12R, G12A, G13D, G13A, G13C, G13R, G13S, G13V, Q61E, Q61K, Q61L, Q61P, Q61R, or Q61H.

55. The method according to any one of claims 49 to 54, wherein the cancer is a solid tumor or a hematologic cancer.

56. A method for inhibiting cell growth, comprising administering an effective amount of the compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt or solvate thereof to cells expressing PI3Kα protein, thereby inhibiting the growth of said cells.

57. The method according to any one of claims 46 to 56, wherein the application of an additional agent is included.

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