SOS1 degradation agent and preparation method and application thereof

Abstract

The present invention discloses a SOS1 degrading agent and a preparation method and application thereof. Specifically, the present invention discloses a compound of formula I: S-L-E (I); wherein S is a small molecule compound capable of inhibiting the activity of SOS1 protein or binding to SOS1 protein; L is a connecting chain, which connects S and E through a covalent bond; and E is a structure shown in E7a. The compound of formula I of the present invention can degrade and / or inhibit SOS1 protein in cells, and can be used to treat and / or prevent related diseases or conditions mediated by SOS1 or caused by the interaction between SOS1 and Ras or SOS1 and Rac.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology. Specifically, the present invention relates to an SOS1 degrader, a preparation method thereof, and an application thereof as a therapeutic agent for preventing and / or treating cancer. Background Art

[0002] SOS1 (son of sevenless homolog 1) is a widely expressed regulatory protein in cells. As a key protein in signaling pathways, SOS1 plays an important role in regulating many intracellular signal transduction pathways, such as the Ras and Rac signaling pathways. SOS1 is composed of 1333 amino acids and contains a proline-rich domain (PxxP) at its C-terminus. This domain binds to growth factor receptor-bound protein 2 (Grb2), a protein in the Ras pathway, to form a Grb2-SOS1 complex. This brings SOS1 to the vicinity of Ras proteins on the cell membrane. SOS1 catalyzes the binding of Ras to GTP, promoting Ras activation and, in turn, activating multiple downstream signaling pathways, such as the Ras-Raf-Mek-Erk and Ras-PI3K-AKT-mTOR pathways. PxxP can also bind to the SH3 (Src homology 3) domain of proteins such as E3B1 in the Rac pathway to form an EPS8-E3B1-SOS1 complex. The EPS8-E3B1-SOS1 complex connects to actin filaments through EPS8, causing GTP conversion, thereby activating Rac and subsequently activating signaling pathways such as JNK and MAPK.

[0003] Ras mutations are considered major oncogenes with a high incidence in human cancers. Studies have shown that 20-30% of tumor patients harbor Ras mutations, with KRas mutations accounting for 85%, NRas and HRas mutations accounting for 12% and 3%, respectively. However, due to the picomolar affinity of GTP for its binding site and the smooth surface of the Ras protein lacking other suitable binding pockets, directly inhibiting Ras activity is considered extremely challenging.

[0004] Abnormal expression or mutation of SOS1 is also closely associated with the development of clinical diseases. Studies have shown that SOS1 mutations are present in patients with NS and CFC. HGF1 is a rare autosomal dominant genetic disease, the cause of which is also related to mutations in the PxxP domain of SOS1. In addition, abnormal expression or mutation of SOS1 is also associated with the development of cancer.

[0005] WO2018172250A1, WO2020173935A1, WO2019201848A1, WO2020180768A1, WO2020180770A1, WO2019122129A1 and EP3558979A1 disclose several types of SOS1 inhibitors, but so far, there have been no reports on SOS1 degraders. Proteolysis Targeting Chimeria (PROTAC) is a technology different from traditional small molecule inhibitors. Traditional small molecule inhibitors usually need to act on the active site of the target protein to inhibit its activity. PROTAC is a heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein through a connecting chain, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase. This bifunctional molecule recognizes the target protein and E3 ubiquitin ligase in vivo, brings the target protein and E3 ubiquitin ligase closer to form a ternary complex, ubiquitinates the target protein, and then degrades the target protein through the ubiquitin-proteasome pathway in vivo. Compared to traditional small molecule inhibitors, PROTAC only needs to bring the target protein closer to the E3 ubiquitin ligase to degrade the substrate. This mode of action allows this technology to be applied to some undruggable targets. On the other hand, since the target protein can be released after being degraded and continue to participate in the degradation process of the next protein, this catalytic degradation effect allows a smaller PROTAC drug dose to achieve efficient degradation. On the other hand, traditional small molecule inhibitors are prone to drug resistance, which is often due to point mutations, causing the small molecule inhibitors to lose their inhibitory effect on the target. PROTAC can directly degrade the target protein, which can avoid the drug resistance caused by point mutations to a certain extent. Therefore, compared to traditional small molecule inhibitors, the use of PROTAC technology for the development of new drug small molecules has high advantages and feasibility. Summary of the Invention

[0006] The present invention provides a compound of formula I, or a stereoisomer, enantiomer, diastereomer, deuterated form, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[0007] SLE

[0008] Ⅰ

[0009] in:

[0010] S is a small molecule compound that can inhibit the activity of SOS1 protein or bind to SOS1 protein;

[0011] L is a connecting chain, which connects S and E through a covalent bond;

[0012] E is E7a;

[0013]

[0014] Among them, E7a:

[0015] W is CH2, CR a R b , C(S), C(O) or SO2;

[0016] X is H2, CH2, O or S;

[0017] Z is H2, CH2, O or S;

[0018] G is selected from hydrogen, C1-C6 alkyl, OH, -CH2-heterocycloalkyl optionally substituted by R', -CH2-phenyl optionally substituted by R';

[0019] Q1, Q2, Q3, and Q4 are each independently carbon, nitrogen, or nitrogen oxides;

[0020] A is hydrogen, C1-C6 alkyl, cycloalkyl or halogen;

[0021] R is independently selected from hydrogen, hydroxy, halogen, -NH2, -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -CONR′R″, -OR′, -NR′R″, -SR′, -SO2R′, -SO2NR′R″, -CR′R″, -CR′NR′R″, aryl, heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, -P(O)(OR′)R″, -P(O)R′R″, -OP(O)(OR′)R″, -Cl, -F, -Br, -I, -CF3, -CN, -NR′SO2NR 'R", -NR'C(O)NR'R", -C(O)NR'C(O)R", -NR'C(=N-CN)NR'R", -C(=N-CN)NR'R", -NR'C(=N-CN)R", -NR'C(=C-N O2)NR′R″, -SO2NR′COR″, -NO2, -COR′, -C(C=N-OR′)R″, -CR′=CR′R″, -CCR′, -S(C=O)(C=NR′)R″, -SF5 or -OCF3;

[0022] R ′ and R″ are each independently selected from a bond, hydrogen, C1-C6 alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl;

[0023] n″ is an integer from 1 to 4;

[0024] ----- is a bond, which can be an R stereoisomer, an S stereoisomer or a non-stereoisomer. The present invention provides a compound of formula I, or a stereoisomer, enantiomer, diastereomer, deuterated substance, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof

[0025] SLE

[0026] Ⅰ

[0027] Wherein, the structures of S and L are as defined below;

[0028] E is E7a, and the structure of E7a is as defined above.

[0029] In certain embodiments of the present invention, in E7a, W is CH2 or C(O).

[0030] In certain embodiments of the present invention, in E7a, X is O or S.

[0031] In certain embodiments of the present invention, in E7a, X is O.

[0032] In certain embodiments of the present invention, in E7a, Z is O.

[0033] In certain embodiments of the present invention, in E7a, G is hydrogen.

[0034] In certain embodiments of the present invention, in E7a, Q1, Q2, Q3, and Q4 are each independently carbon or nitrogen.

[0035] In certain embodiments of the present invention, in E7a, Q1 is carbon.

[0036] In certain embodiments of the present invention, in E7a, Q2 is carbon.

[0037] In certain embodiments of the present invention, in E7a, Q3 is carbon.

[0038] In certain embodiments of the present invention, in E7a, Q4 is carbon.

[0039] In certain embodiments of the present invention, in E7a, Q1, Q2, Q3, and Q4 are carbon.

[0040] In certain embodiments of the present invention, in E7a, A is hydrogen.

[0041] In certain embodiments of the present invention, in E7a, R is hydrogen.

[0042] In certain embodiments of the present invention, said E is E7a';

[0043]

[0044] Wherein, in E7a', Q1, Q2, Q4, X, W, G, Z, R, n", A and ----- are as defined and described in E7a.

[0045] In certain embodiments of the present invention, said E is E7a″;

[0046]

[0047] In E7a″, Q1, Q2, Q3, X, W, G, Z, R, n″, A and ----- are as defined and described in E7a.

[0048] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E7a-1:

[0049]

[0050] Wherein said E7a-1:

[0051] Q1, Q2, Q3 and Q4 are each independently carbon or nitrogen;

[0052] W is C(O) or CH2;

[0053] A is hydrogen, C1-C6 alkyl or halogen (for example, A is hydrogen);

[0054] R is selected from hydrogen, hydroxy, halogen, -NH2, -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl;

[0055] n″ is 1, 2, 3 or 4;

[0056] ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.

[0057] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E7a-2:

[0058]

[0059] Wherein said E7a-2:

[0060] W is CH2 or C(O);

[0061] A is hydrogen, methyl, Cl or F (for example, A is hydrogen);

[0062] R is each independently selected from hydrogen, hydroxy, NH2, C1-C6 alkyl or C1-C6 alkoxy;

[0063] n″ is 1, 2, 3 or 4;

[0064] ----- is a bond, which may be an R stereoisomer, an S stereoisomer or a non-stereoisomer.

[0065] In certain embodiments of the present invention, when the carbon atom to which the ----- bond is attached has chirality, it is in the R configuration, the S configuration, or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).

[0066] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is any of the following structures:

[0067]

[0068] The carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).

[0069] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is the following structure:

[0070]

[0071] The carbon atoms marked with * are in R configuration, S configuration or a mixture thereof (eg, a mixture of 40%-60% R configuration and 60%-40% S configuration).

[0072] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is the following structure:

[0073]

[0074] Wherein, the carbon atom marked with * is in R configuration, S configuration, or a mixture thereof (e.g., a mixture of 40%-60% R configuration and 60%-40% S configuration). In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof, E is any of the following structures:

[0075]

[0076]

[0077] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E8r:

[0078]

[0079] Among them, E8r:

[0080] Q1, Q2, Q3, and Q4 are each independently carbon, N, or N substituted by R', or nitrogen oxide.

[0081] In a preferred embodiment of the compound of formula I of the present invention, its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs or pharmaceutically acceptable salts thereof, E is E9:

[0082]

[0083] Among them, E9:

[0084] R' is H.

[0085] Preferably, in certain embodiments of the present invention, S is S1:

[0086]

[0087] Wherein S1:

[0088] R1 is selected from hydrogen, halogen, -OH, -CN, -NO2, C1-C6 alkylthiol or -NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0089] R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, C3-C6 heterocycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C1-C6 haloalkyl, -COOH, -COOR c ; the R c is -C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl or -C4-C8 cycloalkenyl;

[0090] R1 is -NS(O)(R d )(R e ), the R d and R e Each is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0091] R1 is -NHC(O)-(C1-C6 alkyl), -NHC(O)-NR a R b , the R a and R b Each is independently hydrogen, -C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0092] R1 is -NH-(CH2) k -NH-C(O)-R aa , the R aa is C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl (for example, R aa is a C1-C6 alkyl), and k is 1 or 2;

[0093] R1 is -NH-(CH2) i -R f , i is 0, 1 or 2 and R f is a 4-7 membered heterocycloalkyl, heteroaryl, or C1-C6 alkylsulfonyl group;

[0094] In addition, the above-mentioned C1-C6 alkyl, C1-C6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally replaced by 1, 2 or 3 halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-7 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH2)-heteroaryl, -NHC(O)(C1-C6 alkyl), C3-C8 cycloalkoxy, phenoxy, heteroaryloxy or -NR a R b The group substituted; the R a and R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0095] R1 is -O-(CH2) z -phenyl, -O-(CH2) z-(4-7 membered heterocycloalkyl), -O-(CH2) z -heteroaryl, wherein z is 0, 1 or 2, and the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted by -OH, heterocycloalkyl or heterocycloalkenyl groups, and can be substituted by methyl or oxo groups;

[0096] Or R1 is

[0097]

[0098] Or two adjacent R1 together with the carbon atoms to which they are attached form a 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group;

[0099] And the x is 1, 2 or 3;

[0100] A1 is C4-C 12 cycloalkyl, heterocycloalkyl, aryl (e.g., phenyl), or heteroaryl (e.g., thienyl);

[0101] R2 is hydrogen, -OH, oxo, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C3-C8 cycloalkoxy, -C3-C8 halocycloalkoxy, -C4-C8 cycloalkenyl, 4-7 membered heterocycloalkyl, -O-CH2-4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, -C1-C6 haloalkyl, -C1-C6 haloalkoxy, -C1-C6 alkylsulfonyl;

[0102] R2 is -NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl or -C(O)C1-C3 alkyl;

[0103] R2 is -C(O)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0104] R2 is -C(O)OR g , the R g is hydrogen or C1-C6 alkyl;

[0105] R2 is -OR h ; the R h is a C1-C6 alkyl group;

[0106] R2 is -(CH2)NRa R b , the R a and R b each independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0107] and w is 1, 2, 3 or 4 (e.g., said w is 1, 2 or 3);

[0108] A2(R3) Y is hydrogen;

[0109] Or A2 is C4-C 12 cycloalkyl, heterocycloalkyl, aryl (e.g., phenyl), or heteroaryl, and

[0110] R3 is hydrogen, halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, C7-C8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C1-C6 haloalkyl;

[0111] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally substituted by 1, 2 or 3 halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, phenyl, heteroaryl or -C(O)NR i R j Substituents substituted, the R i and R j Each is independently hydrogen or C1-C6 alkyl;

[0112] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NR k R l Substituted, the R k and R l Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, phenyl, heteroaryl, -CH2-C(O)-R m 、-C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 groups selected from C1-C6 haloalkyl, -OH, oxo, phenyl, -CN, C1-C6 alkoxy or heteroaryl, and the heteroaryl is optionally substituted by methyl; and the R mis a bicyclic heteroaryl, a C1-C6 alkoxy group or a -NR n R o , the R n and R o Each is independently hydrogen, C1-C6 alkyl or phenyl, the alkyl group is optionally substituted by C1-C6 alkoxy or phenyl, or -NR n R o is a 4-7 membered nitrogen heterocycloalkyl group, the nitrogen heterocycloalkyl group is connected to other parts of the molecule through a nitrogen atom, and further contains one or more heteroatoms selected from N or O; the R p C1-C6 alkoxy, C1-C6 alkyl optionally substituted by 1, 2 or 3 -OH or C1-C6 alkoxy, monocyclic or bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R p -CH2-NR q R r , the R q and R r Each is independently selected from hydrogen, phenyl or C1-C6 alkyl optionally substituted by F;

[0113] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NR s R t Substituted, the -NR s R t It is a 4-7 membered azacycloalkyl group connected to other parts of the molecule through a nitrogen atom or a 6-10 membered azaspirocycloalkyl group connected to other parts of the molecule through a nitrogen atom, and further includes up to two heteroatoms selected from N or O, and is optionally substituted by 1, 2 or 3 groups selected from -OH, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl, -C(O)OR z Substituents substituted, the R z C1-C6 alkyl, halogen, -N(C1-C6 alkyl)2, -CH2N(C1-C6 alkyl)2, -C(O)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0114] or R3 is C(O)R v 、-C(O)NH2、-C(O)NHR v 、-C(O)NR v R w 、-C(O)OR v , the R v and Rw Each is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or -(CH2)2NR x R y , the R x and R y Each is independently hydrogen, C1-C4 alkyl or -(CH2)2N(CH3)2;

[0115] Or R3 is -NH2, -NHR z 、-NR z R za 、-NHC(O)R z 、-NHC(O)OR z 、-NHS(O)2R z , 4-7 membered heterocycloalkyl, heteroaryl, spiro heterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, said R z and R za Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0116] Or R3 is C1-C6 alkoxy, C1-C6 haloalkoxy, -O(CH2) s -C3-C8 cycloalkyl, -O(CH2) s -phenyl, -O(CH2) s -heterocycloalkyl, -O(CH2) s -heteroaryl, wherein s is 0, 1, 2 or 3;

[0117] Or R3 is -S(O)2R z 、-S(O)2NH2、-S(O)2NHR z 、-S(O)2NR z R za , the R z and R za Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0118] Y is 0, 1, 2, 3, 4, or 5 (e.g., Y is 0, 1, 2, or 3);

[0119] L' is a bond, -(CH2) k -、-O(CH2) k -、-(CH2) k -O- or -O-(CH2) k -O- (e.g., L' is a bond, -(CH2) k -or-O(CH2) k -), wherein k is 0, 1, 2 or 3, or L' is -CH=CH-(CH2)n -, where n is 0, 1 or 2;

[0120] R4 and R5 are each independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 cycloalkoxy, and the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally substituted by cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or halogen.

[0121] Preferably, in certain embodiments of the present invention, R4 and R5 in S1 are each independently a methyl group.

[0122] In some embodiments, in the definition of each group of S1, the R a and R b Each occurrence is independently hydrogen or C1-C6 alkyl.

[0123] In some embodiments, in the definition of each group of S1, the R d and R e Each occurrence is independently hydrogen or C1-C6 alkyl.

[0124] In certain embodiments of the present invention, in S1, R5 is a C1-C6 alkyl group, such as a methyl group.

[0125] In certain embodiments of the present invention, in S1, R4 is a C1-C6 alkyl group, such as a methyl group.

[0126] In certain embodiments of the present invention, in S1, R1 is hydrogen or C1-C6 alkoxy.

[0127] In certain embodiments of the present invention, in S1, A1 is an aryl group or a heteroaryl group.

[0128] In certain embodiments of the present invention, in S1, A1 is an aryl group, such as a phenyl group.

[0129] In certain embodiments of the present invention, in S1, A1 is a heteroaryl group, such as a thienyl group.

[0130] In certain embodiments of the present invention, in S1, R2 is hydrogen, halogen, C1-C6 alkyl or -C1-C6 haloalkyl.

[0131] In certain embodiments of the present invention, in S1, L' is a bond.

[0132] In certain embodiments of the present invention, in said S1, A2(R3) Y For hydrogen.

[0133] In certain embodiments of the present invention, in S1, A2 is an aryl group, such as a phenyl group.

[0134] In certain embodiments of the present invention, in S1, R3 is hydrogen, halogen or C1-C6 alkyl, and the alkyl is optionally replaced by -NR k R l Substituted; said R k and R l In certain embodiments of the present invention, in S7, R3 is hydrogen, F, Cl, methyl or ethyl, and the methyl and ethyl groups are replaced by -NR k R l Substitution; said R k is methyl or ethyl, R l is hydrogen, methyl or ethyl.

[0135] In certain embodiments of the present invention, in S1, R3 is hydrogen, Cl, -CH2NHCH3 or -CH2N(CH3)2.

[0136] In certain embodiments of the present invention, in S1, A1 is an aryl group, L' is a bond, A2(R3) Y For hydrogen.

[0137] In certain embodiments of the present invention, in said S1, A1 is a heteroaryl group, L' is a bond, A2 is an aryl group, R3 is hydrogen, halogen or C1-C6 alkyl, said alkyl group is optionally replaced by -NR k R l Substituted; said R k and R l Each is independently hydrogen or C1-C6 alkyl.

[0138] In certain embodiments of the present invention, the S is S1':

[0139]

[0140] Wherein, in S1', R1, R2, R3, R4, R5, L', A1, A2, w, x and Y are defined as described in S1.

[0141] In certain embodiments of the present invention, the S is S1″:

[0142]

[0143] Wherein, in said S1″, R1, R2, R3, R4, R5, L′, A1, A2, w and Y are as defined in S1.

[0144] In certain embodiments of the present invention, in S1′ or S1″, R1 is hydrogen, C1-C6 alkyl or C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by C1-C6 alkoxy (eg, methoxy).

[0145] In certain embodiments of the present invention, in said S1' or S1", R1 is hydrogen, methyl, methoxy or

[0146] In certain embodiments of the present invention, in said S1 and S1', The fragment is

[0147] In certain embodiments of the present invention, S is -X-S1', the structure of S1' is as described above; X is O, NH or S, preferably O.

[0148] In certain embodiments of the present invention, S is -X-S1", the structure of S1" is as described above; X is O, NH or S, preferably O.

[0149] Preferably, in certain embodiments of the present invention, the S is S1a

[0150]

[0151] wherein S1a:

[0152] R1 is selected from hydrogen, -OCH3, -OCH2CH3, -CH2OH, -C(O)OH, -C(O)OCH3, -Br, -OCH(CH3)2, -O(CH2)2CH(CH3)2, -O(CH2)3CH3, -O(CH2)2OCH3, -O(CH2)-phenyl, -N=S(O)(CH3)2, -CH3, cyclopropyl, -N(CH3)2, -NHCH3, -NH2, -C(CH3)2-OH, -NH(CH2)-NH-C(O)CH3, -NH(CH2)-morpholine, -NH-C(O)CH3, -NH-C(O)NHCH3, -NH-C(O)-N(CH3)2, nitro, -NH-S(O)2CH3, -N=S(O)(CH3)2, hydroxyl, -O-(CH2)2-S(O)2CH3, -F, Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azelanyl, piperidinyl, piperazinyl, oxetane, oxolanyl, oxhexanyl, thietanyl, thiolanyl, thiolanyl, azetidinyloxy, azelanyloxy, piperidinyloxy, piperazinyloxy, oxetaneoxy, oxolanyloxy, oxhexanyloxy, thietanyloxy, thiolanyloxy, thiolanyloxy, thiolanyloxy,

[0153]

[0154] -OCH2CH2CH3, -OCH2CH2CH2N(CH3)2, -OCH2CH2CH2OH, -OCH2CH2NC(O)CH3, -OCH2CH2N(CH3)2, -OCH2CH2OH, -SCH3, -N(CH3)2,

[0155] x is 1 or 2;

[0156] A1 is selected from

[0157] R2 is selected from: hydrogen, hydroxy, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(═CH2)CH3, -C(CH3)(═CH2)CH3, -CH═CH(CH2)2CH3, -CH═CHCH3, -CH═CH-cyclopropyl, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -OCH3, -CH2NH2, trifluoromethyl, methyl, trifluoromethoxy, or halogen (F, Cl, Br), -NH2, -NHC(O)CH3, -NHCH2CH3 or -NHCH(CH3)2;

[0158] w is 1, 2, or 3;

[0159] A2 is selected from

[0160] R 3-C(O)NH(CH2)2CH3, -C(O)N(CH3)2, -C(O)NH2, -C(O)NH(CH2)2N(CH3)2, -CH2C(O)NH2, hydrogen, -F, -Cl, -Br, cyano, -CF3, -CH3, -CH2CH3, -CH=CH2, -CH2CN, -CH(CH3)-NH2, -CH=CH-CN, -C(O)-OH, -C(O)OCH3, -C(O)CH3, -C(CH3)2-C(O)-OCH3, -C(CH3)2-CN, oxo, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, -NH2, -NH-C(O)CH3, -NH-S(O)2CH3, -NH-C(O)OC(CH3)3, -S(O)2CH3, -S(O)2NCH3, -S(O)2NH2, -OCH2CH3, -O(CH2)2CH3, -OCF3, -OCH2 cyclopropyl, -OCH3, -O(CH2)3CH3, -OCH2 phenyl, -O-phenyl, -(CH2)-OH, -(CH2)2-OH, -(CH2)-OCH3, -(CH2)-OCH2CH3, -CH(OH)-CH2-phenyl, -CH(OH)-CH2CH3, -CH(OH)-CH2CH2CH3, -CH(OH)-CH2CH2CH2CH3, -CH(OH)-CH(CH3)2, -CH(OH)-phenyl, -CH(OH)-CN, -CH(OH)-CH2-OH, -CH(OH)-CF3, -CH(OH)-(CH2)2-phenyl, ＊ -CH(OH)-C≡CH、-CH(NH2)-CH2-C(O)OH、-CH2-NH-S(O)2-CH3、-CH2-NH-(CH2)3CH3、-CH2-NH-CH3、-CH2-N(CH3)2、-CH2-NH-CH2CH3、-CH(CH3)-NH2、-CH2-NH2、-CH2CH2-NH2、-CH2NH-CH2-phenyl、-CH2N(CH2CH3)2、-CH2NH-cyclopropyl、-C H2NH-cyclobutyl, -CH2NH-cyclopentyl, -CH2NH-pyridyl, -CH2NH-phenyl, -CH2NH-(CH2)2-OH, -CH2N(CH3)-(CH2)2-OH, -CH2NH-CH2-CN, -CH2N(CH3)-CH2-CN, -CH2N(CH3)-CH2-CF3, -CH2N(CH3)-CH2-CF2H, -CH2NH-CH2-CF2H, -CH2NH-(CH2)2-OCH3, -CH2NH-C(O)-OC(CH3)3, -CH2CH2NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH2NOH, -CH2NH-C(O)-CH2OCH3, -CH(CH3)NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH3, -CH2NHCH2-C(O)-NH2, -CH2NHCH2-C(O)-(CH3)2, -CH2NHCH2-C(O)-OCH3, -CH2NHCH2-C(O)-NHCH3, -CH2NHCH2-C(O)-NH(CH2)2-OCH3, -CH2NHCH2-C(O)-NHCH2-phenyl, -CH2NHCH2-C(O)-NH-phenyl, -CH2NH-C(O)-CH2NH-phenyl, or -CH2NH-C(O)-CH2NH-CH2CF3;

[0161] Y is 1 or 2;

[0162] L' is a bond, -(CH2) k -or-O(CH2) k -, k is 1 or 2, or L' is -CH=CH-(CH2) n -, wherein n is 0, 1 or 2.

[0163] In some embodiments, in S1a, R2 is selected from: hydrogen, hydroxyl, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(=CH2)CH3, -C(CH3)(=CH2)CH3, -CH=CH(CH2)2CH3, -CH=CHCH3, -CH=CH-cyclopropyl, -C(O)NH2, -C(O)OCH3, -S(O)2CH3, -OCH3, -CH2NH2, trifluoromethyl, methyl, trifluoromethoxy, halogen (F, Cl, Br).

[0164] In certain embodiments of the present invention, in S1a, w is 1 or 2.

[0165] In certain embodiments of the present invention, in S1a, R1 is hydrogen, -CH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -O(CH2)2CH(CH3)2 or -O(CH2)3CH3, for example, -OCH3.

[0166] In certain embodiments of the present invention, in said S1a, A1 is

[0167] In certain embodiments of the present invention, in said S1a, A1 is

[0168] In certain embodiments of the present invention, in S1a, R2 is hydrogen, halogen, -NH2, C1-C6 alkyl or -C1-C6 haloalkyl.

[0169] In certain embodiments of the present invention, in S1a, L' is a bond.

[0170] In certain embodiments of the present invention, in said S1a, A2(R3) Y For hydrogen.

[0171] In certain embodiments of the present invention, in said S1a, A2 is

[0172] In certain embodiments of the present invention, in S1a, R3 is hydrogen, -F, -Cl, -Br, -CH2-NH-(CH2)3CH3, -CH2-NH-CH3, -CH2-N(CH3)2 or -CH2-NH-CH2CH3.

[0173] In certain embodiments of the present invention, in S1a, R3 is hydrogen, Cl, -CH2NHCH3 or -CH2N(CH3)2.

[0174] In certain embodiments of the present invention, in said S1a, A1 is L' is a bond, A2(R3) Y For hydrogen.

[0175] In certain embodiments of the present invention, in said S1a, A1 is L' is a key, A2 is R3 is hydrogen, -F, -Cl, -Br, -CH2-NH-(CH2)3CH3, -CH2-NH-CH3, -CH2-N(CH3)2 or -CH2-NH-CH2CH3.

[0176] In certain embodiments of the present invention, the S is S1a':

[0177]

[0178] Wherein, in said S1a', R1, R2, R3, L', A1, A2, w, x and Y are defined as described in S1 or S1a.

[0179] In certain embodiments of the present invention, the S is S1a":

[0180]

[0181] Wherein, in said S1a″, R1, R2, R3, L′, A1, A2, w and Y are as defined in S1 or S1a.

[0182] In certain embodiments of the present invention, in S1a' and S1a", R1 is hydrogen, C1-C6 alkyl or C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by C1-C6 alkoxy (e.g., methoxy).

[0183] In certain embodiments of the present invention, in said S1a', S1a", R1 is hydrogen, methyl, methoxy or

[0184] In certain embodiments of the present invention, in said S1a, S1a', and S1a", The fragment is

[0185] In certain embodiments of the present invention, S is -X-S1a', the structure of S1a' is as described above; X is O, NH or S, preferably O.

[0186] In certain embodiments of the present invention, S is -X-S1a", the structure of S1a" is as described above; X is O, NH or S, preferably O.

[0187] More preferably, in certain embodiments of the present invention, S1 is the specific compound of Example 1 to Example 458 in WO2018172250A1 (the entire text of which is incorporated herein by reference).

[0188] Preferably, in certain embodiments of the present invention, said S is S2:

[0189]

[0190] Wherein S2:

[0191] R1 is hydrogen, halogen, -OH, -CN, -NO2, C1-C6 alkylthiol or -NR a R b ; the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0192] R1 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyloxy, C3-C6 heterocycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C1-C6 haloalkyl, -COOH, -COOR c ; the R c is -C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl or -C4-C8 cycloalkenyl;

[0193] R1 is -NS(O)(R d )(R e ), the R d and R e Each is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl;

[0194] R1 is -NHC(O)-(C1-C6 alkyl), -NHC(O)-NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0195] R1 is -NH-(CH2) k -NH-C(O)-(C1-C6 alkyl), wherein k is 1 or 2;

[0196] R1 is -NH-(CH2) i -R f , i is 0, 1 or 2 and R f is a 4-7 membered heterocycloalkyl, heteroaryl, or C1-C6 alkylsulfonyl group;

[0197] In addition, the above-mentioned C1-C6 alkyl, C1-C6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally replaced by 1, 2 or 3 halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-7 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH2)-heteroaryl, -NHC(O)(C1-C6 alkyl), C3-C8 cycloalkoxy, phenoxy, heteroaryloxy or -NR a R b The group substituted; the R aand R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0198] R1 is -O-(CH2) z -phenyl, -O-(CH2) z -(4-7 membered heterocycloalkyl), -O-(CH2) z -heteroaryl, wherein z is 0, 1 or 2, and the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted by -OH, heterocycloalkyl or heterocycloalkenyl groups, and can be substituted by methyl or oxo groups;

[0199] Or R1 is

[0200] L2a is C(O), L2b is a bond or a C1-C6 alkylene group, and X2 is

[0201] Rx2 is

[0202] Or R1 is

[0203]

[0204] Or two adjacent R1 together with the carbon atoms to which they are attached form a 5-7 membered cycloalkyl group or a 5-7 membered heterocycloalkyl group;

[0205] and x is 1, 2, 3 or 4 (for example, x is 1, 2 or 3);

[0206] A1 is C4-C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl;

[0207] R2 is hydrogen, -OH, oxo, halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C3-C8 cycloalkoxy, -C3-C8 halocycloalkoxy, -C4-C8 cycloalkenyl, 4-7 membered heterocycloalkyl, -O-CH2-4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, -C1-C6 haloalkyl, -C1-C6 haloalkoxy, -C1-C6 alkylsulfonyl;

[0208] R2 is -NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0209] R2 is -C(O)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0210] R2 is -C(O)OR g , the R g is hydrogen or C1-C6 alkyl;

[0211] R2 is -OR h ; the R h is a C1-C6 alkyl group;

[0212] R2 is -(CH2)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0213] and w is 1, 2, 3 or 4 (e.g., said w is 1 or 2);

[0214] A2(R3) Y is hydrogen;

[0215] Or A2 is C4-C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and

[0216] R3 is hydrogen, halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, C2-C8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C1-C6 haloalkyl;

[0217] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally substituted by 1, 2 or 3 halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, phenyl, heteroaryl or -C(O)NR i R j Substituents substituted, the R i and R j Each is independently hydrogen or C1-C6 alkyl;

[0218] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NRk R l Substituted, the R k and R l Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, phenyl, heteroaryl, -CH2-C(O)-R m 、-C(O)R p or 4-7 membered heterocycloalkyl, and the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 groups selected from C1-C6 haloalkyl, -OH, oxo, phenyl, -CN, C1-C6 alkoxy or heteroaryl, and the heteroaryl is optionally substituted by methyl; and the R m is a bicyclic heteroaryl, a C1-C6 alkoxy group or a -NR n R o , the R n and R o Each is independently hydrogen, C1-C6 alkyl or phenyl, the alkyl group is optionally substituted by C1-C6 alkoxy or phenyl, or -NR n R o is a 4-7 membered nitrogen heterocycloalkyl group, the nitrogen heterocycloalkyl group is connected to other parts of the molecule through a nitrogen atom, and further contains one or more heteroatoms selected from N or O; the R p C1-C6 alkoxy, C1-C6 alkyl optionally substituted by 1, 2 or 3 -OH or C1-C6 alkoxy, monocyclic or bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R p -CH2-NR q R r , the R q and R r Each is independently selected from hydrogen, phenyl or C1-C6 alkyl optionally substituted by F;

[0219] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NR s R t Substituted, the -NR s R t It is a 4-7 membered azacycloalkyl group connected to other parts of the molecule through a nitrogen atom or a 6-10 membered azaspirocycloalkyl group connected to other parts of the molecule through a nitrogen atom, and further includes up to two heteroatoms selected from N or O, and is optionally substituted by 1, 2 or 3 groups selected from -OH, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl, -C(O)OR z Substituents substituted, the R zC1-C6 alkyl, halogen, -N(C1-C6 alkyl)2, -CH2N(C1-C6 alkyl)2, -C(O)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0220] or R3 is C(O)R v 、-C(O)NH2、-C(O)NHR v 、-C(O)NR v R w 、-C(O)OR v , the R v and R w Each is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or -(CH2)2NR x R y , the R x and R y Each is independently hydrogen, C1-C4 alkyl or -(CH2)2NH(CH3)2;

[0221] Or R3 is -NH2, -NHR z 、-NR z R za 、-NHC(O)R z 、-NHC(O)OR z 、-NHS(O)2R z , 4-7 membered heterocycloalkyl, heteroaryl, spiro heterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, said R z and R za Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0222] Or R3 is C1-C6 alkoxy, C1-C6 haloalkoxy, -O(CH2) s -C3-C8 cycloalkyl, -O(CH2) s -phenyl, -O(CH2) s -heterocycloalkyl, -O(CH2) s -heteroaryl, wherein s is 0, 1, 2 or 3;

[0223] Or R3 is -S(O)2R z 、-S(O)2NH2、-S(O)2NHR z 、-S(O)2NR z R za , the R z and Rza Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0224] Y is 0, 1, 2, 3, 4 or 5 (e.g., Y is 0, 1, 2 or 3);

[0225] L' is a bond, -(CH2) k -、-O(CH2) k -、-(CH2) k -O- or -O-(CH2) k -O- (for example, the L' is a bond, -(CH2) k -or-O(CH2) k -), wherein k is 0, 1, 2 or 3, or L' is -CH=CH-(CH2) n -, where n is 0, 1 or 2;

[0226] R4 and R5 are each independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 cycloalkoxy, wherein the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally substituted with cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or halogen;

[0227] Both T and V are N, or T is C and V is N, or T is N and V is C.

[0228] Preferably, in certain embodiments of the present invention, R4 and R5 in S2 are each independently a methyl group.

[0229] In some embodiments, in the definition of each group of S2, the R a and R b Each occurrence is independently hydrogen or C1-C6 alkyl.

[0230] In certain embodiments of the present invention, in S2, both T and V are N.

[0231] In certain embodiments of the present invention, in S2, T is C and V is N.

[0232] In certain embodiments of the present invention, in S2, T is N, and V is C.

[0233] In certain embodiments of the present invention, in S2, R5 is a C1-C6 alkyl group, such as a methyl group.

[0234] In certain embodiments of the present invention, in S2, R4 is a C1-C6 alkyl group, such as a methyl group.

[0235] In certain embodiments of the present invention, in S2, R1 is hydrogen or C1-C6 alkoxy.

[0236] In certain embodiments of the present invention, in S2, A1 is an aryl group or a heteroaryl group.

[0237] In certain embodiments of the present invention, in S2, A1 is an aryl group, such as a phenyl group.

[0238] In certain embodiments of the present invention, in S2, A1 is a heteroaryl group, such as a thienyl group.

[0239] In certain embodiments of the present invention, in S2, R2 is hydrogen, halogen, C1-C6 alkyl or -C1-C6 haloalkyl.

[0240] In certain embodiments of the present invention, in S2, L' is a bond.

[0241] In certain embodiments of the present invention, in said S2, A2(R3) Y For hydrogen.

[0242] In certain embodiments of the present invention, in S2, A2 is an aryl group, such as a phenyl group.

[0243] In certain embodiments of the present invention, in said S2, R3 is hydrogen, halogen or C1-C6 alkyl, said alkyl is optionally replaced by -NR k R l Substituted; said R k and R l In certain embodiments of the present invention, in S7, R3 is hydrogen, F, Cl, methyl or ethyl, and the methyl and ethyl groups are replaced by -NR k R l Substituted; said R k is methyl or ethyl, R l is hydrogen, methyl or ethyl.

[0244] In certain embodiments of the present invention, in S2, R3 is hydrogen, Cl, -CH2NHCH3 or -CH2N(CH3)2.

[0245] In certain embodiments of the present invention, in S2, A1 is an aryl group, L' is a bond, A2(R3) Y For hydrogen.

[0246] In certain embodiments of the present invention, in said S2, A1 is a heteroaryl group, L' is a bond, A2 is an aryl group, R3 is hydrogen, halogen or C1-C6 alkyl, said alkyl group is optionally replaced by -NR k R l Substituted; said R k and R lEach is independently hydrogen or C1-C6 alkyl.

[0247] In certain embodiments of the present invention, S is S2':

[0248]

[0249] Wherein, in S2', T, V, R1, R2, R3, R4, R5, L', A1, A2, w, x and Y are defined as described in S2.

[0250] In certain embodiments of the present invention, the S is S2″:

[0251]

[0252] Wherein, in said S2″, R2, R3, R4, R5, L′, A1, A2, w and Y are as defined in S2.

[0253] In certain embodiments of the present invention, in S2, S2', and S2", R1 is hydrogen, C1-C6 alkyl, or C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by C1-C6 alkoxy (e.g., methoxy).

[0254] In certain embodiments of the present invention, in said S2, S2', S2", R1 is hydrogen, methyl, methoxy or

[0255] In certain embodiments of the present invention, in said S2 and S2', The fragment is

[0256] In certain embodiments of the present invention, S is -X-S2', the structure of S2' is as described above; X is O, NH or S, preferably O.

[0257] In certain embodiments of the present invention, S is -X-S2", where the structure of S2" is as described above; X is O, NH or S, preferably O.

[0258] Preferably, in certain embodiments of the present invention, said S is S2a,

[0259]

[0260] wherein S2a:

[0261] T and V are both N, or T is C and V is N, or T is N and V is C;

[0262] R1 is selected from hydrogen, -OCH3, -OCH2CH3, -CH2OH, -C(O)OH, -C(O)OCH3, -Br, -OCH(CH3)2, -O(CH2)2CH(CH3)2, -O(CH2)3CH3, -O(CH2)2OCH3, -O(CH2) z -phenyl, -N=S(O)(CH3)2, -CH3, cyclopropyl, -N(CH3)2, -NHCH3, -NH2, -C(CH3)2-OH, -NH(CH2)-NH-C(O)CH3, -NH(CH2)-morpholine, -NH-C(O)CH3, -NH-C(O)NHCH3, -NH-C(O)-N(CH3)2, nitro, -NH-S(O)2CH3, -N=S(O)(CH3)2, hydroxyl, -O-(CH2)2-S(O)2CH3, -F, Cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, azetidinyl, azelanyl, piperidinyl, piperazinyl, oxetane, oxolanyl, oxhexanyl, thietanyl, thiolanyl, thiolanyl, azetidinyloxy, azelanyloxy, piperidinyloxy, piperazinyloxy, oxetaneoxy, oxolanyloxy, oxhexanyloxy, thietanyloxy, thiolanyloxy, thiolanyloxy, thiolanyloxy,

[0263]

[0264] -OCH2CH2CH3, -OCH2CH2CH2N(CH3)2, -OCH2CH2CH2OH, -OCH2CH2NC(O)CH3, -OCH2CH2N(CH3)2, -OCH2CH2OH, -SCH3, -N(CH3)2,

[0265] z is 1 or 2;

[0266] x is 1 or 2;

[0267] A1 is selected from

[0268] R2 is selected from: hydrogen, hydroxy, oxo, cyano, cyclopropyl, 1,1-dimethylcyclopropyl, -C(═CH2)CH3, -C(CH3)(═CH2)CH3, -CH═CH(CH2)2CH3, -CH═CHCH3, -CH═CH-cyclopropyl, -C(O)NH2, trifluoromethyl, methyl, trifluoromethoxy, -C(O)OCH3, -S(O)2CH3, -OCH3, -CH2NH2 or halogen (F, Cl, Br);

[0269] w is 1, 2, or 3;

[0270] A2 is selected from

[0271] R 3 -C(O)NH(CH2)2CH3, -C(O)N(CH3)2, -C(O)NH2, -C(O)NH(CH2)2N(CH3)2, -CH2C(O)NH2, hydrogen, -F, -Cl, -Br, cyano, -CF3, -CH3, -CH2CH3, -CH=CH2, -CH2CN, -CH(CH3)-NH2, -CH=CH-CN, -C(O)-OH, -C(O)OCH3, -C(O)CH3, -C(CH3)2-C(O)-OCH3, -C(CH3)2-CN, oxo, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl, -NH2, -NH-C(O)CH3, -NH-S(O)2CH3, -NH-C(O)OC(CH3)3, -S(O)2CH3, -S(O)2NCH3, -S(O)2NH2, -OCH2CH3, -O(CH2)2CH3, -OCF3, -OCH2 cyclopropyl, -OCH3, -O(CH2)3CH3, -OCH2 phenyl, -O-phenyl, -(CH2)-OH, -(CH2)2-OH, -(CH2)-OCH3, -(CH2)-OCH2CH3, -CH(OH)-CH2-phenyl, -CH(OH)-CH2CH3, -CH(OH)-CH2CH2CH3, -CH(OH)-CH2CH2CH2CH3, -CH(OH)-CH(CH3)2, -CH(OH)-phenyl, -CH(OH)-CN, -CH(OH)-CH2-OH, -CH(OH)-CF3, -CH(OH)-(CH2)2-phenyl, ＊-CH(OH)-C≡CH、-CH(NH2)-CH2-C(O)OH、-CH2-NH-S(O)2-CH3、-CH2-NH-(CH2)3CH3、-CH2-NH-CH3、-CH2-N(CH3)2、-CH2-NH-CH2CH3、-CH(CH3)-NH2、-CH2-NH2、-CH2CH2-NH2、-CH2NH-CH2-phenyl、-CH2N(CH2CH3)2、-CH2NH-cyclopropyl、-C H2NH-cyclobutyl, -CH2NH-cyclopentyl, -CH2NH-pyridyl, -CH2NH-phenyl, -CH2NH-(CH2)2-OH, -CH2N(CH3)-(CH2)2-OH, -CH2NH-CH2-CN, -CH2N(CH3)-CH2-CN, -CH2N(CH3)-CH2-CF3, -CH2N(CH3)-CH2-CF2H, -CH2NH-CH2-CF2H, -CH2NH-(CH2)2-OCH3, -CH2NH-C(O)-OC(CH3)3, -CH2CH2NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH2NOH, -CH2NH-C(O)-CH2OCH3, -CH(CH3)NH-C(O)-OC(CH3)3, -CH2NH-C(O)-CH3, CH2NHCH2-C(O)-NH2、-CH2NHCH2-C(O)-(CH3)2、-CH2NHCH2-C(O)-OCH3、-CH2NHCH2-C(O)-NHCH3、-CH2NHCH2-C(O)-NH(CH2)2-OCH3、-CH2NHCH2-C(O)-NHCH2-phenyl、 -CH2NHCH2-C(O)-NH-phenyl, -CH2NH-C(O)-CH2NH-phenyl, or -CH2NH-C(O)-CH2NH-CH2CF3;

[0272] Y is 1 or 2;

[0273] L' is a bond, -(CH2) k -or-O(CH2) k -, k is 1 or 2, or L' is -CH=CH-(CH2) n , the n is 0 or 1.

[0274] More preferably, in certain embodiments of the present invention, S2 is the specific compound of Example 1 to Example 100 in WO2019201848A1 (the entire text of which is incorporated herein by reference).

[0275] In certain embodiments of the present invention, in S2a, w is 1 or 2.

[0276] In certain embodiments of the present invention, in S2a, R1 is hydrogen, methyl, -OCH3, -OCH2CH3, -OCH(CH3)2, -O(CH2)2CH(CH3)2 or -O(CH2)3CH3, for example, -OCH3.

[0277] In certain embodiments of the present invention, in said S2a, A1 is

[0278] In certain embodiments of the present invention, in said S2a, A1 is

[0279] In certain embodiments of the present invention, in S2a, R2 is hydrogen, halogen, -NH2, C1-C6 alkyl or -C1-C6 haloalkyl.

[0280] In certain embodiments of the present invention, in S2a, L' is a bond.

[0281] In certain embodiments of the present invention, in said S2a, A2(R3) Y For hydrogen.

[0282] In certain embodiments of the present invention, in said S2a, A2 is

[0283] In certain embodiments of the present invention, in S2a, R3 is hydrogen, -F, -Cl, -Br, -CH2-NH-(CH2)3CH3, -CH2-NH-CH3, -CH2-N(CH3)2 or -CH2-NH-CH2CH3.

[0284] In certain embodiments of the present invention, in S2a, R3 is hydrogen, Cl, -CH2NHCH3 or -CH2N(CH3)2.

[0285] In certain embodiments of the present invention, in said S2a, A1 is L' is a bond, A2(R3) Y For hydrogen.

[0286] In certain embodiments of the present invention, in said S2a, A1 is L' is a key, A2 is R3 is hydrogen, -F, -Cl, -Br, -CH2-NH-(CH2)3CH3, -CH2-NH-CH3, -CH2-N(CH3)2 or -CH2-NH-CH2CH3.

[0287] In certain embodiments of the present invention, the S is S2a',

[0288]

[0289] Wherein, in S2a', T, V, R1, R2, R3, L', A1, A2, w, x and Y are defined as described in S2 or S2a.

[0290] In certain embodiments of the present invention, the S is S2a″,

[0291]

[0292] Wherein, in said S2a″, T, V, R2, R3, L′, A1, A2, w and Y are as defined in S2 or S2a.

[0293] In certain embodiments of the present invention, in S2a' and S2a", R1 is hydrogen, C1-C6 alkyl or C1-C6 alkoxy, and the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by C1-C6 alkoxy (e.g., methoxy).

[0294] In certain embodiments of the present invention, in S2a' and S2a", R1 is hydrogen, methyl, methoxy or

[0295] In certain embodiments of the present invention, in said S2a, S2a', and S2a", The fragment is

[0296] In certain embodiments of the present invention, S is -X-S2a', the structure of S2a' is as described above; X is O, NH or S, preferably O.

[0297] In certain embodiments of the present invention, S is -X-S2a", the structure of S2a" is as described above; X is O, NH or S, preferably O.

[0298] Preferably, in certain embodiments of the present invention, the S is S3:

[0299]

[0300] Among them, S3:

[0301] Q 1 and Q 2Each independent CH or N;

[0302] Q 3 , Q 4 and Q 7 Each independently is C or N, the Q 3 and Q 4 At least one of the C, Q 3 , Q 4 and Q 7 Not all are N;

[0303] Q 5 is CH, N, NH, O or S;

[0304] Q 6 is CH, N, NH, N(C1-C6 alkyl), N(C1-C6 heteroalkyl), N(3-7 membered cycloalkyl), N(3-7 membered heterocycle), O or S;

[0305] The Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 and Q 7 At least one of them is N, NH, O or S;

[0306] R 1 Selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halogen, -NHR 1a 、-OR 1a , C3-C6 cycloalkyl, C3-C6 cycloalkoxy or -CN; the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl and C3-C6 cycloalkoxy are optionally selected from halogen, -NHR 1a OR 1a Substituents substituted; said R 1a is hydrogen, C1-C6 alkyl, 3-6 membered heterocycle or C1-C6 haloalkyl;

[0307] L 2 Selected from a bond, -C(O)-, -C(O)O-, -C(O)NH(CH2) o -, -S(O)2-, -S(O)-, -S(=O)(=NH)-, -S(=O)[=N(C1-C6 alkyl)]-, -N(C1-C6 alkyl)-, -C(O)(CH2) p -、-(CH2) p - or O; said o is 0, 1 or 2; said p is an integer from 1 to 6;

[0308] R 2Selected from hydrogen, halogen, -CN, -NO2, C1-C6 alkylthiol, C2-C6 alkynyl, C1-C6 alkyl, C2-C6 alkenyl, -NR 2b R 2c 、-OR 2a , 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; the C1-C6 alkyl, C2-C6 alkenyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally selected from C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OR 2a , oxo, halogen, -C(O)R 2a 、-C(O)OR 2a 、-C(O)NR 2b R 2c 、-CN、-NR 2b R 2c , 3-6 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said R 2a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3-7 membered heterocycloalkyl, or -(CH2) r OCH3, wherein r is 1, 2 or 3;

[0309] The R 2b is hydrogen or C1-C6 alkyl;

[0310] The R 2c is hydrogen or C1-C6 alkyl;

[0311] R 2 -NHC(O)-(C1-C6 alkyl), -NHC(O)-NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl (for example, the R a and R b Each independently is hydrogen or C1-C6 alkyl);

[0312] R 2 -NH-(CH2) k -NH-C(O)-(C1-C6 alkyl), wherein k is 1 or 2;

[0313] R 2 -NH-(CH2) i -R f , i is 0, 1 or 2 and Rf is a 4-7 membered heterocycloalkyl, heteroaryl, or C1-C6 alkylsulfonyl group;

[0314] R 3 and R 4 Each independently represents hydrogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkoxy; the R 3 and R 4 At least one is not hydrogen, or the R 3 and R 4 Together with the atoms to which they are attached, they form a 3-6 membered cycloalkyl group; the alkyl, alkoxy, cycloalkyl and cycloalkoxy groups are optionally substituted with cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or halogen;

[0315] A is an optionally substituted (eg, optionally substituted by one or more R2, R2 is as defined in S1) 6-membered aryl or an optionally substituted (eg, optionally substituted by one or more R2, R2 is as defined in S1) 5-6-membered heteroaryl.

[0316] Preferably, in certain embodiments of the present invention, said S is S3a,

[0317]

[0318] In S3a:

[0319] Q 1 and Q 2 Each independent CH or N;

[0320] Q 3 and Q 4 Each independently is C or N, the Q 3 and Q 4 At least one is C;

[0321] Q 6 is CH, N, NH, O or S;

[0322] Q 5 is CH, N, NH, O or S;

[0323] The Q 1 , Q 2 , Q 3 , Q 4 , Q 5 and Q 6 At least one of them is N, NH, O or S;

[0324] R 1 Selected from hydrogen, C1-C6 alkyl, halogen, -OR 1a, cyclopropyl or -CN; said R 1a is hydrogen or C1-C6 alkyl;

[0325] L 2 Selected from a bond, -C(O)-, -C(O)O-, -C(O)NH(CH2) o -、-S(O)2-、-C(O)(CH2) p -、-(CH2) p - or O; said o is 0, 1 or 2; said p is an integer from 1 to 6;

[0326] R 2 Selected from hydrogen, -(CH2) q CH3, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; said q is an integer from 1 to 5; said 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally selected from C1-C6 alkyl, -OH, halogen, -C(O)R 2a 、-C(O)NR 2b R 2c Substituents substituted; said R 2a C1-C6 alkyl or -(CH2) r OCH3, wherein r is 1, 2 or 3; wherein R 2b is hydrogen or C1-C6 alkyl; said R 2c is hydrogen or C1-C6 alkyl;

[0327] R 3 and R 4 Each independently represents hydrogen or C1-C6 alkyl, the R 3 and R 4 At least one is not hydrogen, or the R 3 and R 4 Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl group;

[0328] A is optionally substituted (eg, optionally substituted by one or more R2, R2 is as defined in S1) phenyl or optionally substituted (eg, optionally substituted by one or more R2, R2 is as defined in S1) 5-6 membered heteroaryl.

[0329] More preferably, in certain embodiments of the present invention, S3 is the specific compound of Example 1 to Example 103 in WO2020180768A1 (the entire text of which is incorporated herein by reference).

[0330] Preferably, in certain embodiments of the present invention, the S is S4:

[0331]

[0332] In S4:

[0333] Q 1 is CH or N;

[0334] Q 4 is CH, C or N;

[0335] Each Q 2 Each is independent of CR 1 Or N, the Q 2 One of them is N and the other is Q 2 CR 1 ;

[0336] Each Q 3 and Q 5 The molecule is independent of C(R QC )2、NR QN , C(O), O, S or SO2, the R QC Each independently represents hydrogen, F, Cl, Br, or a 6-10 membered aryl group, wherein R QN Each is independently hydrogen, C1-C6 alkyl or 6-10 membered aryl;

[0337] The Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 At least one is N or NR QN , O or SO2;

[0338] m is 0, 1, 2, or 3;

[0339] n is 0, 1, 2, or 3;

[0340] And when m is 0, n is not 0;

[0341] R 1 Selected from hydrogen, C1-C6 alkyl, halogen, -C(O)NHR 1a 、-NHR 1a 、-OR 1a , cyclopropyl, azetidine or -CN; the C1-C6 alkyl and azetidine are optionally selected from halogen, R 1a 、-NHR 1a OR 1a Substituents substituted; said R 1ais hydrogen, C1-C6 alkyl, cyclopropyl, 3-6 membered heterocycle or C1-C6 haloalkyl;

[0342] L 2 Selected from a bond, -C(O)-, -C(O)O-, -C(O)NH(CH2) o -, -S(O)2-, -S(O)-, -S(=O)(=NH)-, -S(=O)[=N(C1-C6 alkyl)]-, -N(C1-C6 alkyl)-, -C(O)(CH2) p -、-(CH2) p - or O; said o is 0, 1 or 2; said p is an integer from 1 to 6;

[0343] R 2 Selected from hydrogen, C1-C6 alkyl, -NR 2b R 2c 、-OR 2a , 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; the C1-C6 alkyl, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl are each independently optionally selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 methoxyalkyl, -OH, -OR 2a , oxo, halogen, =N, -C(O)R 2a 、-C(O)OR 2a 、-C(O)NR 2b R 2c 、-S(O)2R 2a 、-CN、-NR 2b R 2c , 3-6 membered cycloalkyl, 3-7 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl; said R 2a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 3-7 membered heterocycloalkyl, or -(CH2) r OCH3, wherein r is 1, 2 or 3;

[0344] The R 2b is hydrogen or C1-C6 alkyl;

[0345] The R 2c is hydrogen or C1-C6 alkyl;

[0346] R 3 and R 4 Each independently represents hydrogen, C1-C6 alkyl optionally substituted by halogen or -OH, wherein R 3 and R4 At least one is hydrogen, or the R 3 and R 4 Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl group;

[0347] A is an optionally substituted (e.g., optionally substituted by one or more R2, R2 is as defined in S1) 6-membered aryl or an optionally substituted (e.g., optionally substituted by one or more R2, R2 is as defined in S1) 5-6-membered heteroaryl;

[0348] The condition is when for When R 1 Not hydrogen.

[0349] Preferably, in certain embodiments of the present invention, the S is S4a

[0350]

[0351] In S4a:

[0352] Q 1 is CH or N;

[0353] Q 4 is CH, C or N;

[0354] Each Q 2 Each is independent of CR 1 or N;

[0355] Each Q 3 and Q 5 The molecule is independent of C(R QC )2、NR QN , C(O), O, S or SO2, the R QC Each independently represents hydrogen, F, Cl, Br, or a 6-10 membered aryl group, wherein R QN Each is independently hydrogen, C1-C6 alkyl or 6-10 membered aryl;

[0356] The Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 At least one is N or NR QN , O or SO2;

[0357] R 1 Selected from hydrogen, C1-C6 alkyl, halogen, cyclopropyl, cyano or -OR 1a , the R 1a is hydrogen or C1-C6 alkyl;

[0358] L 2 Selected from a bond, -C(O)-, -C(O)O-, -C(O)NH(CH2) o -、-S(O)2-、-C(O)(CH2) p -、-(CH2) p - or O; said o is 0, 1 or 2; said p is an integer from 1 to 6;

[0359] R 2 Selected from hydrogen, -(CH2) q CH3, 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; said q is a multiple of 1 to 5; said 3-14 membered cycloalkyl, 3-14 membered cycloalkenyl, 3-14 membered heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl are each independently selected from C1-C6 alkyl, hydroxyl, halogen, -C(O)R 2a or -C(O)NR 2b R 2c The group substituted; the R 2a Selected from C1-C6 alkyl or -(CH2) r OCH3; said r is 1, 2 or 3; said R 2b and R 2c Each is independently hydrogen or C1-C6 alkyl;

[0360] R 3 and R 4 Each independently represents hydrogen or C1-C6 alkyl, the R 3 and R 4 At least one is hydrogen, or the R 3 and R 4 Together with the atoms to which it is attached, it forms a 3-6 membered cycloalkyl group;

[0361] A is an optionally substituted (eg, optionally substituted by one or more R2, R2 is as defined in S1) 6-membered aryl or an optionally substituted (eg, optionally substituted by one or more R2, R2 is as defined in S1) 5-6-membered heteroaryl.

[0362] Preferably, in certain embodiments of the present invention, R 3 and R 4 Each independently represents hydrogen or methyl, the R 3 and R 4 At least one is hydrogen.

[0363] More preferably, in certain embodiments of the present invention, S4 is the specific compound of Example 1 to Example 540 in WO2020180770A1 (the entire text of which is incorporated herein by reference).

[0364] Preferably, in certain embodiments of the present invention, the S is S5:

[0365]

[0366] Among them, S5:

[0367] The R 1 is hydrogen or R a1 ;

[0368] R a1 Selected from C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C1-C6 alkynyl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl or 5-10 membered heteroaryl, the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C1-C6 alkynyl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted by one or more identical or different R b1 and / or R c1 replace;

[0369] Each R b1 Each independent is -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 、-N(C1-C4 alkyl)C(O)R c1 、-NHC(O)OR c1 or -N(C1-C4 alkyl)C(O)OR c1 ;

[0370] Each R c1Each is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl; the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl and 5-10 membered heteroaryl are each independently optionally substituted by one or more identical or different R d1 and / or R e1 ;

[0371] Each R d1 Each independent is -OR e1 、-NR e1 R e1 , halogen, -CN, -C(O)R e1 、-C(O)OR e1 、-C(O)NR e1 R e1 、-S(O)2R e1 、-S(O)2NR e1 R e1 、-NHC(O)R e1 、-N(C1-C4 alkyl)C(O)R e1 、-NHC(O)OR e1 or -N(C1-C4 alkyl)C(O)OR e1 ;

[0372] Each R e1 Each is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl, 3-10 membered heterocycloalkyl, C6-C 10 Aryl or 5-10 membered heteroaryl;

[0373] R 2 is selected from hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl or halogen;

[0374] Ring A is selected from C6-C 10 aryl, 5-10 membered heteroaryl or 9-10 membered biheterocycloalkyl;

[0375] p is 1, 2, or 3;

[0376] Each R 4 Each is independently hydrogen, hydroxy, oxo, halogen, cyano, C1-C4 alkyl, -NH2, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 hydroxyalkyl, hydroxy-C1-C4 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, 3-6 membered heterocycloalkyl, C3-C6 hydroxycycloalkyl, C1-C4 haloalkyl substituted by 3-6 membered heterocycloalkyl, 3-6 membered heterocycloalkyl substituted by hydroxy, halogen, -NH2, -S(O)2-(C1-C4 alkyl) or oxo, and the oxo is substituted only on the non-aromatic ring;

[0377] R 4 -NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0378] R 4 -C(O)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0379] R 4 -C(O)OR g , the R g is hydrogen or C1-C6 alkyl;

[0380] R 4 For-OR h ; the R h is a C1-C6 alkyl group;

[0381] or R 4 -(CH2)NR a R b , the R a and R b each independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0382] R 3 and R 5 Each is independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 cycloalkoxy, and the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally substituted by cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or halogen.

[0383] Preferably, in certain embodiments of the present invention, R 5 It is a methyl group.

[0384] In some embodiments, in the definition of each group of S5, the R a and R b Each occurrence is independently hydrogen or C1-C6 alkyl.

[0385] In certain embodiments of the present invention, the S is S5':

[0386]

[0387] wherein said S5', said R 2 、R 3 、R 4 、R 5 , Ring A and p are as defined and described in S5.

[0388] In certain embodiments of the present invention, S is -X-S5', the structure of S5' is as described above; X is O, NH or S, preferably O.

[0389] Preferably, in certain embodiments of the present invention, the S is S5a:

[0390]

[0391] Among them, the R 1 、R 2 、R 3 、R 4 , Ring A and p are as defined and described in S5.

[0392] In certain embodiments of the present invention, the S is S5a':

[0393]

[0394] wherein said S5a', said R 2 、R 3 、R 4 、R 5 , Ring A and p are as defined and described in S5a.

[0395] In certain embodiments of the present invention, S is -X-S5a', the structure of S5a' is as described above; X is O, NH or S, preferably O.

[0396] More preferably, in certain embodiments of the present invention, S5 is a specific compound of I-1 to I-179 in WO2019122129A1 (the entire content of which is incorporated herein by reference).

[0397] Preferably, in certain embodiments of the present invention, the S is S6:

[0398]

[0399] Among them, S6:

[0400] R2 is selected from hydrogen, halogen, -OH, -CN, -NO2, C1-C6 alkylthiol or -NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0401] R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C3-C6 heterocycloalkoxy (e.g. ), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 4-7 membered heterocycloalkyl (e.g. ), 5-10 membered heterocycloalkene, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C1-C6 haloalkyl, -COOH, -COOR c ; the R c is -C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl or -C4-C8 cycloalkenyl;

[0402] R2 is -NS(O)(R d )(R e ), the R d and R e Each is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0403] R2 is -NHC(O)-(C1-C6 alkyl), -NHC(O)-NR a R b , the R a and R b Each is independently hydrogen, -C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0404] R2 is -NH-(CH2) k -NH-C(O)-R aa , the R aa is a C1-C6 alkyl, a C3-C8 heterocycloalkyl or a C3-C8 cycloalkyl, and k is 1 or 2;

[0405] R2 is -NH-(CH2) i -R f , i is 0, 1 or 2 and R f is a 4-7 membered heterocycloalkyl, heteroaryl, or C1-C6 alkylsulfonyl group;

[0406] In addition, the above-mentioned C1-C6 alkyl, C1-C6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally replaced by 1, 2 or 3 halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-7 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH2)-heteroaryl, -NHC(O)(C1-C6 alkyl), C3-C8 cycloalkoxy, phenoxy, heteroaryloxy or -NR a R b The group substituted; the R a and R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0407] R2 is -O-(CH2) z -phenyl, -O-(CH2) z -(4-7 membered heterocycloalkyl), -O-(CH2) z -heteroaryl, wherein z is 0, 1 or 2, and the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted by -OH, heterocycloalkyl or heterocycloalkenyl groups, and can be substituted by methyl or oxo groups;

[0408] Or R2 is

[0409]

[0410] R1 is hydrogen or -OR A ;

[0411] R A For hydrogen, C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl; the C3-C 10 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more identical or different R a1 and / or R c1 replace;

[0412] Each R a1 Each is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are each independently optionally substituted by one or more identical or different R b1 and / or R c1 replace;

[0413] Each R b1 Each independent is -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 、-N(C1-C4 alkyl)C(O)R c1 , oxo, and the oxo is only substituted on the non-aromatic ring;

[0414] Each R c1 Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0415] or R1 is selected from C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted by one or more R a2 and / or R b2 replace;

[0416] Each R a2 Each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R c2 and / or R b2 replace;

[0417] Each R b2 Each independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-OC(O)R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 、-N(C1-C4 alkyl)C(O)R c2 、-NHC(O)OR c2 , oxo, =NH, and the oxo, =NH are only substituted on the non-aromatic ring;

[0418] Each R c2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R d2 and / or R e2 replace;

[0419] Each R d2 Each independent is -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 Re2 、-NHC(O)R e2 、-N(C1-C4 alkyl)C(O)R e2 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0420] Each R e2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R f2 and / or R g2 replace;

[0421] Each R f2 Each independently selected from -OR g2 、-NR g2 R g2 , halogen, -CN, -C(O)R g2 、-C(O)OR g2 、-C(O)NR g2 R g2 、-S(O)2R g2 、-S(O)2NR g2 R g2 、-NHC(O)R g2 、-N(C1-C4 alkyl)C(O)R g2 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0422] Each R g2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0423] or R1 is selected from C2-C4 alkyl, C2-C4 alkenyl; said C2-C4 alkyl and C2-C4 alkenyl optional R b3 replace;

[0424] R b3 Selected from -C(O)R c3 、-C(O)OR c3 、-C(O)NR c3 R c3、-C(O)NHOR c3 or -C(O)N(C1-C4 alkyl)OR c3 ;

[0425] Each R c3 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R d3 and / or R e3 replace;

[0426] Each R d3 Each independently selected from -OR e3 、-NR e3 R e3 , halogen, -CN, -C(O)R e3 、-C(O)OR e3 、-C(O)NR e3 R e3 、-S(O)2R e3 、-S(O)2NR e3 R e3 、-NHC(O)R e3 、-N(C1-C4 alkyl)C(O)R e3 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0427] Each R e3 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0428] R3 is selected from hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen;

[0429] R5 is selected from hydrogen, hydroxy or -NHR';

[0430] R' is selected from hydrogen, C1-C3 alkyl and -C(O)C1-C3 alkyl;

[0431] R4 is selected from C1-C4 alkyl, hydroxy, oxo, cyano, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, hydroxy-C1-C4 haloalkyl, C2-C6 alkenyl, -C2-C6 alkynyl, C3-C6 cycloalkyloxy, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, 3-6 membered hydroxyheterocycloalkyl, halogen or -SO2-C1-C4 alkyl;

[0432] R6 is selected from hydrogen, C1-C4 alkyl or halogen;

[0433] Or R4, R6 together with the carbon atom to which they are attached form an optionally substituted (e.g. unsubstituted or oxo) C5-C6 cycloalkyl (e.g. ) and a 5-6 membered heterocycloalkyl group, wherein the heteroatoms in the 5-6 membered heterocycloalkyl group are selected from heteroatoms or heteroatom groups independently selected from -NH, -O-, -S- and N;

[0434] R7 and R8 are each independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 cycloalkoxy, and the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally substituted by cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or halogen.

[0435] In some embodiments, in S6, when R4, R6 and the carbon atom to which they are attached together form an optionally substituted C5-C6 cycloalkyl and 5-6 membered heterocycloalkyl, the substitution refers to substitution by 1, 2, 3 or 4 =0.

[0436] In some embodiments, in said S6, when R4, R6 and the carbon atom to which they are attached together form an optionally substituted 5-6 membered heterocycloalkyl, The fragment is For example

[0437] In some embodiments, in S6, R1 is hydrogen or -OR A , R A For hydrogen.

[0438] In some embodiments, in S6, R1 is hydrogen.

[0439] In some embodiments, in S6, R2 is hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen, and the C1-C4 alkyl and -O(C1-C4 alkyl) are each independently optionally substituted by -O(C1-C4 alkyl).

[0440] In some embodiments, in S6, R2 is hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen.

[0441] In some embodiments, in S6, R2 is hydrogen, C1-C4 alkyl or -O(C1-C4 alkyl), and the -O(C1-C4 alkyl) is optionally substituted by -O(C1-C4 alkyl).

[0442] In other embodiments, in S6, R2 is

[0443] In some embodiments, in S6, R3 is hydrogen.

[0444] In some embodiments, in S6, R5 is hydrogen or -NHR'.

[0445] In some embodiments, in said S6, R4 is C1-C4 haloalkyl; R6 is hydrogen or halogen; or, R4, R6 and the carbon atom to which they are attached form a ring so that The fragment is

[0446] In some embodiments, in S6, R7 is C1-C6 alkyl.

[0447] In some embodiments, in S6, R8 is C1-C6 alkyl.

[0448] In some embodiments, in S6, R1 is hydrogen or -OR A ;

[0449] R A is hydrogen;

[0450] R2 is hydrogen, C1-C4 alkyl or -O(C1-C4 alkyl) (e.g., methoxy), wherein the -O(C1-C4 alkyl) is optionally substituted with -O(C1-C4 alkyl) (e.g., methoxy);

[0451] R3 is hydrogen;

[0452] R5 is hydrogen or -NHR';

[0453] R' is selected from hydrogen, C1-C3 alkyl and -C(O)C1-C3 alkyl;

[0454] R4 is a C1-C4 haloalkyl group;

[0455] R6 is hydrogen or halogen;

[0456] Or R4, R6 and the carbon atoms to which they are connected form a ring so that S6 The fragment is

[0457] R7 is a C1-C6 alkyl group;

[0458] R8 is a C1-C6 alkyl group.

[0459] In some embodiments, in S6, when R2 is a C1-C4 alkyl group, the C1-C4 alkyl group may be a methyl group.

[0460] In some embodiments, in S6, when R2 is -O(C1-C4 alkyl), the -O(C1-C4 alkyl) may be -OCH3.

[0461] In some embodiments, in S6, R2 is hydrogen, methyl, -OCH3 or

[0462] In some embodiments, in S6, R2 is hydrogen, methyl or -OCH3.

[0463] In some embodiments, in S6, R3 is hydrogen.

[0464] In some embodiments, in S6, when R' is a C1-C3 alkyl group, the C1-C3 alkyl group may be an ethyl group or an isopropyl group.

[0465] In some embodiments, in S6, when R' is -C(O)C1-C3 alkyl, the -C(O)C1-C3 alkyl may be -C(O)CH3.

[0466] In some embodiments, in S6, R5 is hydrogen or -NHR', wherein R' is hydrogen, ethyl, isopropyl or -C(O)CH3.

[0467] In some preferred embodiments, in S6, R5 is -NHR', wherein R' is hydrogen.

[0468] In some embodiments, in S6, R4 is C1-C4 haloalkyl;

[0469] R6 is hydrogen or halogen;

[0470] Or R4, R6 and the carbon atoms to which they are connected form a ring so that S6 The fragment is

[0471] In some embodiments, in S6, when R4 is a C1-C4 haloalkyl group, the C1-C4 haloalkyl group may be a C1-C4 fluoroalkyl group, such as a trifluoromethyl group.

[0472] In some embodiments, in S6, R7 is C1-C6 alkyl.

[0473] In some embodiments, in S6, when R7 is a C1-C6 alkyl group, the C1-C6 alkyl group may be a methyl group.

[0474] In some embodiments, in S6, R8 is C1-C6 alkyl.

[0475] In some embodiments, in S6, when R8 is a C1-C6 alkyl group, the C1-C6 alkyl group may be a methyl group.

[0476] In some embodiments, the S6 The fragment can be

[0477] In some embodiments, the S6 The fragment is preferably

[0478] In some embodiments, the S6 The fragment is preferably

[0479] In some embodiments, the S6 The fragment can be Preferably

[0480] In some preferred embodiments, the S6 The fragment is

[0481] In some more preferred embodiments, the S6 The fragment is

[0482] Preferably, in certain embodiments of the present invention, R8 in S6 is methyl.

[0483] In certain embodiments of the present invention, the S is S6':

[0484]

[0485] In S6', R2, R3, R4, R5, R6, and R7 are as defined and described in S6.

[0486] In certain embodiments of the present invention, in S6 and S6', The fragment is

[0487] In certain embodiments of the present invention, S is -X-S6', the structure of S6' is as described above; X is O, NH or S, preferably O.

[0488] Preferably, in certain embodiments of the present invention, the S is S6a:

[0489]

[0490] In S6a, R1, R2, R3, R4, R5, R6, and R7 are as defined and described in S6.

[0491] Preferably, in certain embodiments of the present invention, in S6 or S6a, R 1 is hydrogen; R 2 Selected from -O(C1-C4 alkyl); R 3 is hydrogen; R 4 is a C1-C4 haloalkyl group; R 5 is selected from -NH2; R 7 Selected from C1-C4 alkyl or C1-C4 haloalkyl.

[0492] Preferably, in certain embodiments of the present invention, the S is S6b:

[0493]

[0494] In S6b, R1, R2, R3, R4, R5, R6 and R7 are as defined and described in S6.

[0495] Preferably, in certain embodiments of the present invention, S is S6c:

[0496]

[0497] In S6c, R2, R3, R4, R5, R6 and R7 are as defined and described in S6.

[0498] In certain embodiments of the present invention, S is -X-S6c, and the structure and definition of S6c are as described above; wherein X is O, NH or S, preferably O.

[0499] Preferably, in certain embodiments of the present invention, S is S6d:

[0500]

[0501] In S6d, X is O, NH or S, preferably O; R2, R3, R4, R5, R6 and R7 are as defined and described in S6.

[0502] Preferably, in certain embodiments of the present invention, the S6 is a specific compound of I-1 to I-383 in WO2018115380A1 (the entire text of which is incorporated herein by reference). Preferably, in certain embodiments of the present invention, the S is S6e:

[0503]

[0504] In S6e, R2, R3 and R7 are as defined and described in any of the schemes of S6.

[0505] Preferably, in certain embodiments of the present invention, S is -X-S6e, and the structure and definition of S6e are as described above; wherein X is O, NH or S, preferably O.

[0506] Preferably, in certain embodiments of the present invention, in S6e, R2 is -O(C1-C4 alkyl); R3 is hydrogen; and R7 is C1-C6 alkyl.

[0507] Preferably, in certain embodiments of the present invention, in S6e, R2 is -OCH3; R3 is hydrogen; and R7 is methyl.

[0508] In certain embodiments of the present invention, S6, S6', S6a or S6c is any of the following structures:

[0509]

[0510] Preferably, in certain embodiments of the present invention, said S6, S6', S6a or S6c is

[0511] Preferably, in certain embodiments of the present invention, said S6, S6', S6a, S6c or S6e is

[0512] In certain embodiments of the present invention, the S is

[0513] In certain embodiments of the present invention, the S is S6″:

[0514]

[0515] In S6″, R1, R3, R4, R5, R6, R7 and R8 are as defined and described in S6.

[0516] In certain embodiments of the present invention, the S is S6″′:

[0517]

[0518] In S6″′, R3, R4, R5, R6, R7 and R8 are as defined and described in S6.

[0519] In certain embodiments of the present invention, in S6″ and S6′″, The fragment is

[0520] In certain embodiments of the present invention, S is -X-S6', and the structure of S6'" is as described above; wherein X is O, NH or S, preferably O.

[0521] Preferably, in certain embodiments of the present invention, said S6″ is

[0522] Preferably, in certain embodiments of the present invention, S is S6a":

[0523]

[0524] In S6a″, R1, R3, R4, R5, R6, and R7 are as defined and described in S6.

[0525] Preferably, in certain embodiments of the present invention, the S is S6b":

[0526]

[0527] In S6b″, R1, R3, R4, R5, R6 and R7 are as defined and described in S6.

[0528] Preferably, in certain embodiments of the present invention, S is S6c":

[0529]

[0530] In S6c″, R3, R4, R5, R6 and R7 are as defined and described in S6.

[0531] Preferably, in certain embodiments of the present invention, S is -X-S6c", the structure and definition of S6c are as described above; wherein X is O, NH or S, preferably O.

[0532] Preferably, in certain embodiments of the present invention, S is S6d":

[0533]

[0534] In S6d″, X is O, NH or S, preferably O; R3, R4, R5, R6 and R7 are as defined and described in S6.

[0535] Preferably, in certain embodiments of the present invention, the S is S6e":

[0536]

[0537] In S6e″, R3 and R7 are as defined and described in S6.

[0538] Preferably, in certain embodiments of the present invention, S is -X-S6e", the structure and definition of S6e" are as described above; wherein X is O, NH or S, preferably O.

[0539] Preferably, in certain embodiments of the present invention, in S6e″, R3 is hydrogen; and R7 is a C1-C6 alkyl.

[0540] Preferably, in certain embodiments of the present invention, in S6e″, R3 is hydrogen; R7 is methyl.

[0541] Preferably, in certain embodiments of the present invention, said S6", S6c" or S6e" is

[0542] Preferably, in certain embodiments of the present invention, said S is

[0543]

[0544] More preferably, in certain embodiments of the present invention, said S is

[0545]

[0546] More preferably, in certain embodiments of the present invention, said S is

[0547] In certain embodiments of the present invention, the S is S7:

[0548]

[0549] Wherein said S7:

[0550] R2 is selected from hydrogen, halogen, -OH, -CN, -NO2, C1-C6 alkylthiol or -NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0551] R2 is selected from C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, C3-C6 heterocycloalkoxy (e.g. ), C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 4-7 membered heterocycloalkyl (e.g. ), 5-10 membered heterocycloalkene, spiroheterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, phenyl, heteroaryl, C1-C6 haloalkyl, -COOH, -COOR c ; the R c is -C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C8 cycloalkyl or -C4-C8 cycloalkenyl;

[0552] R2 is -NS(O)(R d )(R e ), the R d and R e Each is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, 6-10 membered aryl or 5-10 membered heteroaryl;

[0553] R2 is -NHC(O)-(C1-C6 alkyl), -NHC(O)-NR a R b , the R a and R b Each is independently hydrogen, -C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0554] R2 is -NH-(CH2) k -NH-C(O)-R aa , the R aa is a C1-C6 alkyl, a C3-C8 heterocycloalkyl or a C3-C8 cycloalkyl, and k is 1 or 2;

[0555] R2 is -NH-(CH2) i -R f , i is 0, 1 or 2 and R f is a 4-7 membered heterocycloalkyl, heteroaryl, or C1-C6 alkylsulfonyl group;

[0556] In addition, the above-mentioned C1-C6 alkyl, C1-C6 alkoxy, 4-7 membered heterocycloalkyl and heteroaryl are optionally replaced by 1, 2 or 3 halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 4-7 membered heterocycloalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkylsulfonyl, phenyl, benzyl, heteroaryl, -(CH2)-heteroaryl, -NHC(O)(C1-C6 alkyl), C3-C8 cycloalkoxy, phenoxy, heteroaryloxy or -NRa R b The group substituted; the R a and R b Each is independently selected from hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl;

[0557] R2 is -O-(CH2) z -phenyl, -O-(CH2) z -(4-7 membered heterocycloalkyl), -O-(CH2) z -heteroaryl, wherein z is 0, 1 or 2, and the phenyl, heterocycloalkyl and heteroaryl groups are optionally substituted by -OH, heterocycloalkyl or heterocycloalkenyl groups, and can be substituted by methyl or oxo groups;

[0558] Or R2 is

[0559]

[0560] R1 is hydrogen or -OR A ;

[0561] R A For hydrogen, C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl; the C3-C 10 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more identical or different R a1 and / or R c1 replace;

[0562] Each R a1 Each is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are each independently optionally substituted by one or more identical or different R b1 and / or R c1 replace;

[0563] Each R b1 Each independent is -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 、-N(C1-C4 alkyl)C(O)R c1 , oxo, and the oxo is only substituted on the non-aromatic ring;

[0564] Each R c1 Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0565] or R1 is selected from C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted by one or more R a2 and / or R b2 replace;

[0566] Each R a2 Each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R c2 and / or R b2 replace;

[0567] Each R b2 Each independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-OC(O)R c2 、-S(O)2R c2 、-S(O)2NRc2 R c2 、-NHC(O)R c2 、-N(C1-C4 alkyl)C(O)R c2 、-NHC(O)OR c2 , oxo, =NH, and the oxo, =NH are only substituted on the non-aromatic ring;

[0568] Each R c2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R d2 and / or R e2 replace;

[0569] Each R d2 Each independent is -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 R e2 、-NHC(O)R e2 、-N(C1-C4 alkyl)C(O)R e2 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0570] Each R e2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R f2 and / or R g2 replace;

[0571] Each Rf2 Each independently selected from -OR g2 、-NR g2 R g2 , halogen, -CN, -C(O)R g2 、-C(O)OR g2 、-C(O)NR g2 R g2 、-S(O)2R g2 、-S(O)2NR g2 R g2 、-NHC(O)R g2 、-N(C1-C4 alkyl)C(O)R g2 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0572] Each R g2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0573] or R1 is selected from C2-C4 alkyl, C2-C4 alkenyl; the C2-C4 alkyl and C2-C4 alkenyl optional R b3 replace;

[0574] R b3 Selected from -C(O)R c3 、-C(O)OR c3 、-C(O)NR c3 R c3 、-C(O)NHOR c3 or -C(O)N(C1-C4 alkyl)OR c3 ;

[0575] Each R c3 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R d3 and / or R e3 replace;

[0576] Each R d3 Each independently selected from -OR e3、-NR e3 R e3 , halogen, -CN, -C(O)R e3 、-C(O)OR e3 、-C(O)NR e3 R e3 、-S(O)2R e3 、-S(O)2NR e3 R e3 、-NHC(O)R e3 、-N(C1-C4 alkyl)C(O)R e3 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0577] Each R e3 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0578] R4 is selected from hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen;

[0579] A2(R3) Y is hydrogen;

[0580] Or A2 is C4-C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and

[0581] R3 is hydrogen, halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, C7-C8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C1-C6 haloalkyl;

[0582] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally substituted by 1, 2 or 3 halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, phenyl, heteroaryl or -C(O)NR i R j Substituents substituted, the R i and R j Each is independently hydrogen or C1-C6 alkyl;

[0583] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NR k R l Substituted, the R k and R l Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, phenyl, heteroaryl, -CH2-C(O)-R m 、-C(O)R p or 4-7 membered heterocycloalkyl, and each of the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl is independently optionally substituted by 1, 2 or 3 substituents selected from C1-C6 haloalkyl, -OH, oxo, phenyl, -CN, C1-C6 alkoxy or heteroaryl, and the heteroaryl is optionally substituted by methyl; and the R m is a bicyclic heteroaryl, a C1-C6 alkoxy group or a -NR n R o , the R n and R o Each is independently hydrogen, C1-C6 alkyl or phenyl, the alkyl group is optionally substituted by C1-C6 alkoxy or phenyl, or -NR n R o is a 4-7 membered nitrogen heterocycloalkyl group, the nitrogen heterocycloalkyl group is connected to other parts of the molecule through a nitrogen atom, and further contains one or more heteroatoms selected from N or O; the R p C1-C6 alkoxy, C1-C6 alkyl optionally substituted by 1, 2 or 3 -OH or C1-C6 alkoxy, monocyclic or bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R p -CH2-NR q R r , the R q and R r Each is independently selected from hydrogen, phenyl or C1-C6 alkyl optionally substituted by F;

[0584] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NR s R t Substituted, the -NR s R tIt is a 4-7 membered azacycloalkyl group connected to other parts of the molecule through a nitrogen atom or a 6-10 membered azaspirocycloalkyl group connected to other parts of the molecule through a nitrogen atom, and further includes up to two heteroatoms selected from N or O, and is optionally substituted by 1, 2 or 3 groups selected from -OH, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl, -C(O)OR z Substituents substituted, the R z C1-C6 alkyl, halogen, -N(C1-C6 alkyl)2, -CH2N(C1-C6 alkyl)2, -C(O)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl (for example, the R a and R b Each independently is hydrogen or C1-C6 alkyl);

[0585] or R3 is C(O)R v 、-C(O)NH2、-C(O)NHR v 、-C(O)NR v R w 、-C(O)OR v , the R v and R w Each is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or -(CH2)2NR x R y , the R x and R y Each is independently hydrogen, C1-C4 alkyl or -(CH2)2N(CH3)2;

[0586] Or R3 is -NH2, -NHR z 、-NR z R za 、-NHC(O)R z 、-NHC(O)OR z 、-NHS(O)2R z , 4-7 membered heterocycloalkyl, heteroaryl, spiro heterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, said R z and R za Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0587] Or R3 is C1-C6 alkoxy, C1-C6 haloalkoxy, -O(CH2) s -C3-C8 cycloalkyl, -O(CH2) s-phenyl, -O(CH2) s -heterocycloalkyl, -O(CH2) s -heteroaryl, wherein s is 0, 1, 2 or 3;

[0588] Or R3 is -S(O)2R z 、-S(O)2NH2、-S(O)2NHR z 、-S(O)2NR z R za , the R z and R za Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0589] Y is 0, 1, 2, 3, 4, or 5;

[0590] L' is a bond, -(CH2) k -or-O(CH2) k -, wherein k is 0, 1, 2 or 3, or L' is -CH=CH-(CH2) n , said n is 0, 1 or 2;

[0591] R7 and R8 are each independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 cycloalkoxy, and the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally substituted by cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or halogen.

[0592] Preferably, in certain embodiments of the present invention, the S is S7:

[0593]

[0594] Wherein said S7:

[0595] R1 is hydrogen or -OR A ;

[0596] R A For hydrogen, C3-C 10 Cycloalkyl or 3-10 membered heterocycloalkyl; the C3-C 10 Cycloalkyl and 3-10 membered heterocycloalkyl are optionally substituted by one or more identical or different R a1 and / or R c1 replace;

[0597] Each R a1 Each is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are each independently optionally substituted by one or more identical or different R b1 and / or R c1 replace;

[0598] Each R b1 Each independent is -OR c1 、-NR c1 R c1 , halogen, -CN, -C(O)R c1 、-C(O)OR c1 、-C(O)NR c1 R c1 、-S(O)2R c1 、-S(O)2NR c1 R c1 、-NHC(O)R c1 、-N(C1-C4 alkyl)C(O)R c1 , oxo, and the oxo is only substituted on the non-aromatic ring;

[0599] Each R c1 Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0600] or R1 is selected from C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the C3-C 10 Cycloalkyl, C3-C 10 Cycloalkenyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted by one or more R a2 and / or R b2 replace;

[0601] Each R a2 Each independently selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R c2 and / or R b2 replace;

[0602] Each R b2 Each independently selected from -OR c2 、-NR c2 R c2 , halogen, -CN, -C(O)R c2 、-C(O)OR c2 、-C(O)NR c2 R c2 、-OC(O)R c2 、-S(O)2R c2 、-S(O)2NR c2 R c2 、-NHC(O)R c2 、-N(C1-C4 alkyl)C(O)R c2 、-NHC(O)OR c2 , oxo, =NH, and the oxo, =NH are only substituted on the non-aromatic ring;

[0603] Each R c2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R d2 and / or R e2 replace;

[0604] Each R d2 Each independent is -OR e2 、-NR e2 R e2 , halogen, -CN, -C(O)R e2 、-C(O)OR e2 、-C(O)NR e2 R e2 、-S(O)2R e2 、-S(O)2NR e2 Re2 、-NHC(O)R e2 、-N(C1-C4 alkyl)C(O)R e2 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0605] Each R e2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R f2 and / or R g2 replace;

[0606] Each R f2 Each independently selected from -OR g2 、-NR g2 R g2 , halogen, -CN, -C(O)R g2 、-C(O)OR g2 、-C(O)NR g2 R g2 、-S(O)2R g2 、-S(O)2NR g2 R g2 、-NHC(O)R g2 、-N(C1-C4 alkyl)C(O)R g2 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0607] Each R g2 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0608] or R1 is selected from C2-C4 alkyl, C2-C4 alkenyl; said C2-C4 alkyl and C2-C4 alkenyl optional R b3 replace;

[0609] R b3 Selected from -C(O)R c3 、-C(O)OR c3 、-C(O)NR c3 R c3、-C(O)NHOR c3 or -C(O)N(C1-C4 alkyl)OR c3 ;

[0610] Each R c3 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl are optionally substituted with one or more R d3 and / or R e3 replace;

[0611] Each R d3 Each independently selected from -OR e3 、-NR e3 R e3 , halogen, -CN, -C(O)R e3 、-C(O)OR e3 、-C(O)NR e3 R e3 、-S(O)2R e3 、-S(O)2NR e3 R e3 、-NHC(O)R e3 、-N(C1-C4 alkyl)C(O)R e3 , oxo, wherein the oxo is substituted only on the non-aromatic ring;

[0612] Each R e3 Each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl;

[0613] R2 is selected from hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen;

[0614] R4 is selected from hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen;

[0615] A2(R3) Y is hydrogen;

[0616] Or A2 is C4-C 12 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and

[0617] R3 is hydrogen, halogen, -OH, oxo, -CN, -NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, C7-C8 cycloalkynyl, 4-7 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, phenyl, heteroaryl, C1-C6 haloalkyl;

[0618] The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally substituted by 1, 2 or 3 halogen, -OH, oxo, -CN, -C1-C6 alkyl, -C1-C6 alkoxy, -C1-C6 haloalkyl, phenyl, heteroaryl or -C(O)NR i R j Substituents substituted, the R i and R j Each is independently hydrogen or C1-C6 alkyl;

[0619] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NR k R l Substituted, the R k and R l Each is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkylsulfonyl, phenyl, heteroaryl, -CH2-C(O)-R m 、-C(O)R p or 4-7 membered heterocycloalkyl, and each of the alkyl, alkynyl, alkenyl, cycloalkyl, phenyl, heteroaryl and heterocycloalkyl is independently optionally substituted by 1, 2 or 3 substituents selected from C1-C6 haloalkyl, -OH, oxo, phenyl, -CN, C1-C6 alkoxy or heteroaryl, and the heteroaryl is optionally substituted by methyl; and the R m is a bicyclic heteroaryl, a C1-C6 alkoxy group or a -NR n R o , the R n and R o Each is independently hydrogen, C1-C6 alkyl or phenyl, the alkyl group is optionally substituted by C1-C6 alkoxy or phenyl, or -NR n R o is a 4-7 membered nitrogen heterocycloalkyl group, the nitrogen heterocycloalkyl group is connected to other parts of the molecule through a nitrogen atom, and further contains one or more heteroatoms selected from N or O; the R pC1-C6 alkoxy, C1-C6 alkyl optionally substituted by 1, 2 or 3 -OH or C1-C6 alkoxy, monocyclic or bicyclic heteroaryl, 4-7 membered heterocycloalkyl or R p -CH2-NR q R r , the R q and R r Each is independently selected from hydrogen, phenyl or C1-C6 alkyl optionally substituted by F;

[0620] or the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkenyl, cycloalkynyl and heterocycloalkenyl groups are optionally replaced by -NR s R t Substituted, the -NR s R t It is a 4-7 membered azacycloalkyl group connected to other parts of the molecule through a nitrogen atom or a 6-10 membered azaspirocycloalkyl group connected to other parts of the molecule through a nitrogen atom, and further includes up to two heteroatoms selected from N or O, and is optionally substituted by 1, 2 or 3 groups selected from -OH, oxo, C1-C6 alkyl, C1-C6 hydroxyalkyl, -C(O)OR z Substituents substituted, the R z C1-C6 alkyl, halogen, -N(C1-C6 alkyl)2, -CH2N(C1-C6 alkyl)2, -C(O)NR a R b , the R a and R b Each is independently hydrogen, C1-C6 alkyl, C3-C8 heterocycloalkyl or C3-C8 cycloalkyl (for example, the R a and R b Each independently is hydrogen or C1-C6 alkyl);

[0621] or R3 is C(O)R v 、-C(O)NH2、-C(O)NHR v 、-C(O)NR v R w 、-C(O)OR v , the R v and R w Each is independently hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, phenyl or -(CH2)2NR x R y , the R x and R y Each is independently hydrogen, C1-C4 alkyl or -(CH2)2N(CH3)2;

[0622] Or R3 is -NH2, -NHR z 、-NR z R za 、-NHC(O)R z 、-NHC(O)OR z 、-NHS(O)2R z , 4-7 membered heterocycloalkyl, heteroaryl, spiro heterocycloalkyl, fused heterocycloalkyl, bridged heterocycloalkyl, said R z and R za Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0623] Or R3 is C1-C6 alkoxy, C1-C6 haloalkoxy, -O(CH2) s -C3-C8 cycloalkyl, -O(CH2) s -phenyl, -O(CH2) s -heterocycloalkyl, -O(CH2) s -heteroaryl, wherein s is 0, 1, 2 or 3;

[0624] Or R3 is -S(O)2R z 、-S(O)2NH2、-S(O)2NHR z 、-S(O)2NR z R za , the R z and R za Each is independently C1-C4 alkyl, C1-C4 haloalkyl or phenyl;

[0625] Y is 0, 1, 2, 3, 4, or 5;

[0626] L' is a bond, -(CH2) k -or-O(CH2) k -, wherein k is 0, 1, 2 or 3, or L' is -CH=CH-(CH2) n , said n is 0, 1 or 2;

[0627] R7 and R8 are each independently C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl or C3-C6 cycloalkoxy, and the alkyl, alkoxy, cycloalkyl and cycloalkoxy are optionally substituted by cyano, hydroxy, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy or halogen.

[0628] In certain embodiments of the present invention, in S7, R1 is hydrogen.

[0629] In certain embodiments of the present invention, in S7, R2 is hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen, and the C1-C4 alkyl and -O(C1-C4 alkyl) are each independently optionally substituted by -O(C1-C4 alkyl).

[0630] In certain embodiments of the present invention, in S7, R2 is hydrogen, C1-C4 alkyl, -O(C1-C4 alkyl), -NH2, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2 or halogen.

[0631] In certain embodiments of the present invention, in S7, R2 is hydrogen, C1-C4 alkyl or -O(C1-C4 alkyl), and the -O(C1-C4 alkyl) is optionally substituted by -O(C1-C4 alkyl).

[0632] In certain embodiments of the present invention, in said S7, R2 is

[0633] In certain embodiments of the present invention, in S7, R2 is -O(C1-C4 alkyl).

[0634] In certain embodiments of the present invention, in S7, R4 is hydrogen.

[0635] In certain embodiments of the present invention, in said S7, R3 is hydrogen, halogen or C1-C6 alkyl, said alkyl is optionally replaced by -NR k R l Substitution; said R k and R l Each is independently hydrogen or C1-C6 alkyl.

[0636] In certain embodiments of the present invention, in S7, A2 is an aryl group.

[0637] In certain embodiments of the present invention, in S7, Y is 0, 1, 2 or 3.

[0638] In certain embodiments of the present invention, in S7, L' is a bond.

[0639] In certain embodiments of the present invention, in S7, R7 is a C1-C6 alkyl group.

[0640] In certain embodiments of the present invention, in S7, R8 is a C1-C6 alkyl group.

[0641] In certain embodiments of the present invention, in S7:

[0642] R1 is hydrogen;

[0643] R2 is hydrogen, C1-C4 alkyl or -O(C1-C4 alkyl) (e.g., methoxy), wherein the -O(C1-C4 alkyl) is optionally substituted with -O(C1-C4 alkyl) (e.g., methoxy);

[0644] R4 is hydrogen;

[0645] R3 is hydrogen, halogen or C1-C6 alkyl, the alkyl group is optionally replaced by -NR k R l Substitution; said R k and R l Each is independently hydrogen or C1-C6 alkyl;

[0646] A2 is an aryl group;

[0647] Y is 0, 1, 2, or 3;

[0648] L' is a bond;

[0649] R7 is a C1-C6 alkyl group;

[0650] R8 is a C1-C6 alkyl group.

[0651] In certain embodiments of the present invention, in said S7, R2 is hydrogen, methyl, -OCH3 or

[0652] In certain embodiments of the present invention, in S7, R2 is -O(C1-C4 alkyl), for example -OCH3.

[0653] In certain embodiments of the present invention, in said S7, R3 is hydrogen, F, Cl, methyl or ethyl, and said methyl and ethyl are replaced by -NR k R l Substitution; said R k is methyl or ethyl, R l is hydrogen, methyl or ethyl.

[0654] In certain embodiments of the present invention, in S7, R3 is hydrogen, Cl, -CH2NHCH3 or -CH2N(CH3)2.

[0655] In certain embodiments of the present invention, in S7, A2 is phenyl.

[0656] In certain embodiments of the present invention, in S7, R7 is methyl.

[0657] Preferably, in certain embodiments of the present invention, in S7, R8 is methyl.

[0658] Preferably, in certain embodiments of the present invention, S is S7':

[0659]

[0660] wherein R2, R3, R4, R7, R8, Y, A2 and L' are as defined and described in S7.

[0661] In certain embodiments of the present invention, in S7 and S7', The fragment is

[0662] In certain embodiments of the present invention, the S is -O-S7', wherein the structure and definition of S7' are as described above.

[0663] Preferably, in certain embodiments of the present invention, the S is S7″:

[0664]

[0665] wherein R2, R3, R4, R7, Y, A2 and L' are as defined and described in S7.

[0666] In certain embodiments of the present invention, the S is -O-S7", wherein the structure and definition of S7 are as described above.

[0667] Preferably, in certain embodiments of the present invention, the S is S7a:

[0668]

[0669] wherein R1, R2, R3, R4, R7, R8 and Y are as defined and described in S7.

[0670] Preferably, in certain embodiments of the present invention, S is S7a':

[0671]

[0672] wherein R2, R3, R4, R7, R8 and Y are as defined and described in S7.

[0673] In certain embodiments of the present invention, in S7a and S7a', The fragment is

[0674] In certain embodiments of the present invention, the S is -O-S7a', wherein the structure and definition of S7a' are as described above.

[0675] Preferably, in certain embodiments of the present invention, S is S7a":

[0676]

[0677] wherein R2, R3, R4, R7 and Y are as defined and described in S7.

[0678] In certain embodiments of the present invention, the S is -O-S7a", wherein the structure and definition of S7a" are as described above.

[0679] In certain embodiments of the present invention, in S7a, S7a' and S7a", The fragment is R 3a and R 3b The definition of R is independently as described in R3. In certain embodiments of the present invention, R 3b is a C1-C6 alkyl group, wherein the alkyl group is replaced by -NR k R l Substitution; said R k and R l Each is independently hydrogen or C1-C6 alkyl. In certain embodiments of the present invention, R 3b is methyl or ethyl, said methyl and ethyl being -NHR l or -NR k R l Substitution; said R k and R l Each independently is methyl or ethyl. In certain embodiments of the present invention, R 3b is -CH2NHCH3 or -CH2N(CH3)2. In certain embodiments of the present invention, R 3a is hydrogen or a halogen, such as H or Cl.

[0680] Preferably, in certain embodiments of the present invention, said S, S7, S7', S7", S7a, S7a' and S7a" are any of the following structures:

[0681]

[0682] Preferably, in certain embodiments of the present invention, said S, S7, S7', S7", S7a, S7a' and S7a" are

[0683]

[0684] Preferably, in certain embodiments of the present invention, S, S7, S7', S7", S7a, S7a' and S7a" are the following structures:

[0685]

[0686] Preferably, in certain embodiments of the present invention, S, S7, S7', S7", S7a, S7a' and S7a" are the following structures:

[0687]

[0688] In certain embodiments of the present invention, the S is

[0689]

[0690] In certain embodiments of the present invention, L is a bond.

[0691] In certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -, -O-, -S-, -S(O)-, -S(O)NR 3’ -、-NR 3’ S(O)-, -S(O)2-, -S(O)2NR 3’ -、-NR 3’ S(O)2-、-NR 4’ S(O)2NR 3’ -、-CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -NR 3’ C(O)O-、-OC(O)NR 3’ -、-C(O)NR 3’ -、-NR 3’ C(O)-、-NR 4’ C(O)NR 3’ -, -P(O)-, -P(O)O-, -OP(O)-, -OP(O)O-, vinylene, ethynylene, 3-12 membered cycloalkylene, 3-12 membered heterocycloalkylene containing one or more heteroatoms selected from N, O or S, 6-10 membered arylene or 5-10 membered heteroarylene groups, wherein the vinylene, cycloalkylene, heterocycloalkylene, arylene and heteroarylene groups are each independently optionally replaced by one or more halogen, -OR 3’ 、-NR 3’ R 4’ , oxo, nitro, cyano, C1-C6 alkyl, -S(C1-C6 alkyl), C3-C10 cycloalkyl, C3-C10 heterocycloalkyl, 6-10 aryl, 5-10 membered heteroaryl, -C(O)R 1’ 、-C(O)OR 3’ 、-OC(O)R 1’ 、-C(O)NR 3’ 、-NR 3’ C(O)R 1’ 、-S(O)R 1’ 、-S(O)NR 3’ 、-S(O)2R 1’、-S(O)2NR 3’ 、-NR 3’ S(O)2R 1’ 、-NR 4’ S(O)2NR 3’ 、-OC(O)NR 3’ 、-NR 4’ C(O)NR 3’ The alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are each independently optionally substituted by one or more substituents selected from halogen, -OH, -NR 3’ R 4’ , oxo, nitro, cyano, C1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Substituted by a heterocycloalkyl, a 6-10 membered aryl, or a 5-10 membered heteroaryl; R 1’ 、R 2’ Each is independently halogen, -OH, -NR 3’ R 4’ , C1-C6 alkyl, chloro C1-C6 alkyl, hydroxy C1-C6 alkyl, -O(C1-C6 alkyl), -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, C3-C 10 Cycloalkyl, -O(C3-C 10 Cycloalkyl), -NH(C3-C 10 Cycloalkyl), C3-C 10 Heterocycloalkyl, -O(C3-C 10 Heterocycloalkyl), -NH(C3-C 10 heterocycloalkyl), 6-10 membered aryl, -O(6-10 membered aryl), -NH(6-10 membered aryl), 5-10 membered heteroaryl, -O(5-10 membered heteroaryl), -NH(5-10 membered heteroaryl), R 3’ 、R 4’ Each independently represents hydrogen, deuterium, C1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 heterocycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl; j is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25.

[0692] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -、-O-、-CR 1’ R 2’-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -、-NR 3’ C(O)-、-S(O)2NR 3’ -、-NR 3’ S(O)2-, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 4-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-2 independent heteroatoms selected from nitrogen, oxygen or sulfur, atom, a 5-11 membered saturated or partially unsaturated fused heterocycloalkylene having 1-2 independently selected nitrogen, oxygen or sulfur heteroatoms, an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene having 1-2 independently selected nitrogen, oxygen or sulfur heteroatoms, a 5-6 membered heteroarylene having 1-4 independently selected nitrogen, oxygen or sulfur heteroatoms, or an 8-10 membered bicyclic heteroaryl having 1-5 selected nitrogen, oxygen or sulfur heteroatoms, wherein the vinylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, spiroheterocycloalkylene, fused cycloalkylene and heteroarylene are each independently optionally substituted by one or more selected from halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , nitro, -CN, C1-C6 alkyl, C3-C 10 Cycloalkyl, C3-C 10 The alkyl, cycloalkyl, and heterocycloalkyl groups are optionally substituted by one or more substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, and C3-C6 cycloalkyl groups, R 1’ 、R 2’ Each is independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), C3-C6 heterocycloalkyl, -O(C3-C6 heterocycloalkyl), -NH(C3-C6 cycloalkyl); R 3’ 、R 4’ Each is independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

[0693] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -One or more methylene groups are optionally selected from -NR 3’ -、-O-、-CR 1’ R 2’ -, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -、-NR 3’ C(O)-、-S(O)2NR 3’ -、-NR 3’ S(O)2-, vinylene, ethynylene, phenyl, 8-10 membered bicyclic arylene, 3-7 membered saturated or partially unsaturated monocyclic cycloalkylene, 5-11 membered saturated or partially unsaturated spirocycloalkylene, 5-11 membered saturated or partially unsaturated fused cycloalkylene, 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene, 5-7 membered saturated or partially unsaturated heterocycloalkylene having 1-2 independently selected from nitrogen or oxygen heteroatoms, 5-11 membered saturated or partially unsaturated spiroheterocycloalkylene having 1-2 independently selected from nitrogen or oxygen heteroatoms, substituted by a 5-11 membered saturated or partially unsaturated fused heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen or oxygen, a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen or oxygen, or a 8-10 membered bicyclic heteroaryl having 1-5 heteroatoms selected from nitrogen or oxygen, wherein the vinylene, ethynylene, cycloalkylene, heterocycloalkylene, phenyl, spiroheterocycloalkylene, fused heterocycloalkylene, fused cycloalkylene, spiroheterocycloalkylene and heteroarylene are each independently optionally substituted by one or more halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , nitro, -CN, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl substituted, the alkyl, cycloalkyl, heterocycloalkyl optionally substituted with one or more substituents selected from halogen, -OH, -NH2, -CN, C1-C4 alkyl, C3-C6 cycloalkyl, R 1’ 、R 2’Each is independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), C3-C6 heterocycloalkyl, -O(C3-C6 heterocycloalkyl), -NH(C3-C6 cycloalkyl); R 3’ 、R 4’ Each is independently hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0694] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -, 1, 2, 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, vinylene, ethynylene, cyclopropylene, cyclobutylene, cyclopentylene, Cyclohexylene, oxiranediylene, oxetanediylene, oxolanediylene, oxhexylene, aziridinediylene, aziridinediylene, piperidinylene, piperazinylene, morpholinylene, homomorpholinylene, phenylene, pyrrolylene, thienylene, furanylene, imidazolylene, pyrazolylene, triazolylene, tetrazolylene, oxazolylene, isoxazolylene, thiazolylene, isothiazolylene, pyridinylene, pyrimidinylene, pyridazinylene, pyrazinylene, The substituent group is optionally replaced by one or more halogen, oxo, -NR 3’ R 4’ 、-OR 3’ , C1-C4 alkyl substituents, wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH2, R 3’ 、R 4’ Each is independently hydrogen, deuterium, or C1-C4 alkyl, and j is 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0695] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j-, 1, 2, 3, 4 or 5 methylene groups are optionally selected from -NH-, -NCH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, oxetane, oxolanyl, oxhexylene, aziridine, aziridine, aziridine, aziridine, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, The substituent group is optionally replaced by one or more groups selected from F, Cl, oxo, -NR 3’ R 4’ 、-OR 3’ , C1-C4 alkyl substituents, wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, -NH2, R 3’ 、R 4’ Each is independently hydrogen, deuterium, methyl, ethyl, or propyl, and j is 3, 4, 5, 6, 7, 8, 9, or 10.

[0696] Preferably, in certain embodiments of the present invention, L is -(CH2) j -, the -(CH2) j -1, 2, 3, 4 or 5 methylene groups are optionally selected from -O-, -NH-, -NCH3-, -C(O)-, -C(O)NH-, -NHC(O)-, -NCH3C(O)-, -C(O)NCH3-, cyclohexylene, aziridine, aziridinyl, aziridine, piperidinyl, piperazinyl, and j is 4, 5, 6, 7, 8, 9 or 10.

[0697] Preferably, in certain embodiments of the present invention, L is selected from -(CH2) j-1 -C(O)-, said -(CH2) j-1 The methylene group in -C(O)- is as defined in the above L, and is optionally substituted by one or more groups, and the j is as defined in the above L.

[0698] Preferably, in certain embodiments of the present invention, L is selected from

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726] In certain embodiments of the present invention, L is any of the following structures:

[0727]

[0728]

[0729] Preferably, in certain embodiments of the present invention, said L is LA,

[0730]

[0731] Among them, LA:

[0732] Ring A is a bond, C3-C 12 Cycloalkylene (e.g. wherein the a end is connected to S and the b end is connected to X″′) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g. wherein the a end is connected to S and the b end is connected to X″′), the cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0733] Ring B is a bond, C3-C 12 Cycloalkylene (e.g., wherein the c-terminal is connected to X″′ and the d-terminal is connected to L3) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g. wherein the c-terminus is connected to X″′ and the d-terminus is connected to L3), the cycloalkylene and heterocycloalkylene are optionally substituted with a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0734] Ring C is C3-C 12 Cycloalkylene (e.g. wherein the e end is connected to L3 and the f end is connected to X″) or a 3-12 membered heterocycloalkylene group containing 1-2 heteroatoms selected from N, O or S (e.g. wherein the e end is connected to L3 and the f end is connected to X″), the cycloalkylene and heterocycloalkylene are optionally substituted by a substituent selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0735] X″ is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, or -C(O)CH2O-;

[0736] L3 is -(CH2) k , one or two methylene groups in L3 are optionally selected from -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -C(O)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 0, 1, 2, 3, 4, 5, 6 or 7;

[0737] X″′ is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -CH2NCH3-, -NHC(O)- or -NCH3C(O)-.

[0738] In some embodiments, in the LA:

[0739] Ring A is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0740] Ring B is C3-C 12 Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0741] Ring C is C3-C 12Cycloalkylene or 3-12 membered heterocycloalkylene containing 1-2 heteroatoms selected from N, O or S, wherein the cycloalkylene and heterocycloalkylene are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0742] X″ is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, or -NCH3C(O)-;

[0743] L3 is -(CH2) k , one or two methylene groups in L3 are optionally selected from -O-, -NH-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 0, 1, 2, 3 or 4;

[0744] X″′ is a bond, -NH-, -NCH3-, -O-, -C(CH3)2-, -S-, -C=C-, -C≡C-, -CHF-, -CHCF3-, -C(O)-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)- or -NCH3C(O)-.

[0745] In certain embodiments of the present invention, in the LA, L3 is -(CH2) k , one or two methylene groups in L3 are optionally replaced by -O-, -NH-, -C≡C-, -N(C1-C6 alkyl)-, -N(C1-C6 haloalkyl)-, -N(C1-C6 hydroxyalkyl)- or -N(C3-C8 cycloalkyl)-, and k is 0, 1, 2, 3, 4, 5, 6 or 7.

[0746] Preferably, in certain embodiments of the present invention, in said LA, ring A is a bond.

[0747] Preferably, in certain embodiments of the present invention, in LA, ring A is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0748] Preferably, in certain embodiments of the present invention, in LA, ring A is a 3-6 membered saturated cycloalkylene group or a 4-7 membered saturated monocyclic heterocycloalkylene group having 1 or 2 heteroatoms independently selected from nitrogen atoms.

[0749] Preferably, in certain embodiments of the present invention, in the LA, ring A is a cyclohexylene group (e.g., cyclohexane-1,4-diyl, e.g., trans-cyclohexane-1,4-diyl), a piperidinylene group (e.g., piperidinyl-1,4-diyl) or a piperazinylene group (e.g., piperazine-1,4-diyl).

[0750] In certain embodiments of the present invention, in the LA, ring A is The a-terminal is connected to S, and the b-terminal is connected to X″′.

[0751] In certain embodiments of the present invention, in the LA, ring A is The a-terminal is connected to S, and the b-terminal is connected to X″′.

[0752] In certain embodiments of the present invention, in the LA, ring A is The a-terminal is connected to S, and the b-terminal is connected to X″′.

[0753] Preferably, in certain embodiments of the present invention, in LA, ring B is a bond.

[0754] Preferably, in certain embodiments of the present invention, in LA, ring B is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0755] Preferably, in certain embodiments of the present invention, in LA, ring B is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a condensed heterocycloalkylene group.

[0756] Preferably, in certain embodiments of the present invention, in LA, ring B is a piperidinylene group (eg, piperidine-1,4-diyl) or a piperazinylene group (eg, piperazine-1,4-diyl).

[0757] In certain embodiments of the present invention, in the LA, ring B is The c-terminal is connected to X″′, and the d-terminal is connected to L3.

[0758] Preferably, in certain embodiments of the present invention, ring B is The c-terminal is connected to X″′, and the d-terminal is connected to L3.

[0759] Preferably, in certain embodiments of the present invention, in the LA, ring C is a 3-7 membered saturated or partially unsaturated cycloalkylene group, a 4-11 membered saturated or partially unsaturated spirocycloalkylene group, a 4-11 membered saturated or partially unsaturated fused cycloalkylene group, an 8-10 membered bicyclic saturated or partially unsaturated cycloalkylene group, a 4-7 membered saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated spiroheterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-11 membered saturated or partially unsaturated fused heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic saturated or partially unsaturated heterocycloalkylene group having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0760] Preferably, in certain embodiments of the present invention, in LA, ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a condensed heterocycloalkylene group.

[0761] Preferably, in certain embodiments of the present invention, in the LA, ring C is piperidinylene (e.g., piperidine-1,4-diyl), piperazinylene (e.g., piperazine-1,4-diyl), (For example ), (For example ), (For example ), (For example ), (For example ), (For example ), (For example )or (For example ).

[0762] In certain embodiments of the present invention, in the LA, ring C is The e end is connected to L3, and the f end is connected to X″.

[0763] In certain embodiments of the present invention, in the LA, ring C is The e end is connected to L3, and the f end is connected to X″.

[0764] Preferably, in certain embodiments of the present invention, in LA, X″ is a bond or -C(O)-.

[0765] Preferably, in certain embodiments of the present invention, in LA, X" is a bond.

[0766] Preferably, in certain embodiments of the present invention, in said LA, X″ is -C(O)-.

[0767] Preferably, in certain embodiments of the present invention, in LA, X'' is a bond or -C(O)-.

[0768] Preferably, in certain embodiments of the present invention, in LA, X'' is a bond.

[0769] Preferably, in certain embodiments of the present invention, in the LA, X'' is -C(O)-.

[0770] Preferably, in certain embodiments of the present invention, in said LA, k is 1, 2, 3, 4 or 5.

[0771] Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k , k is 1, 2, 3, 4 or 5.

[0772] Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k , one or two methylene groups in L3 are optionally replaced by -O-, -NH-, -C≡C- or -N(C1-C6 alkyl)- (e.g., -N(CH3)-), and k is 1, 2, 3, 4 or 5.

[0773] Preferably, in certain embodiments of the present invention, in said LA, k is 1, 2, 3 or 4. Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k -, wherein one or two CH2 contained in said L3 are each independently optionally replaced by -O-, -NH- or -N(C1-C6 alkyl)- (e.g. -N(CH3)-), or one -CH2CH2- contained in said L3 is optionally replaced by -C≡C-; k is 1, 2, 3 or 4.

[0774] Preferably, in certain embodiments of the present invention, in said LA, L3 is -(CH2) k -, a methylene group in L3 is optionally replaced by a group of -O-, -NH- or -N(C1-C6 alkyl)- (e.g., -N(CH3)-); k is 1, 2, 3 or 4.

[0775] Preferably, in certain embodiments of the present invention, ring A in LA is a 3-6 membered saturated cycloalkylene group; ring B is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms; ring C is a 4-7 membered saturated monocyclic heterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, a 7-11 membered spiroheterocycloalkylene group containing 1 or 2 nitrogen heteroatoms, or a fused heterocycloalkylene group; X″ is a bond or -C(O)-; L3 is -(CH2) k , k is 1, 2, 3, 4 or 5 (e.g., k is 1, 2, 3 or 4).

[0776] Preferably, in certain embodiments of the present invention, the LA is LA-1:

[0777]

[0778] wherein Ring A, Ring B, Ring C, L3, and X″ are as defined and described in LA.

[0779] In certain embodiments of the present invention, the LA is LA-2:

[0780]

[0781] Among them, ring A is Wherein end a is connected to S, and end b is connected to X″′;

[0782] X″′ is —C(O)—;

[0783] Ring B is The c-terminus is connected to X″′, and the d-terminus is connected to L3;

[0784] L3 is -(CH2) k -, wherein one or two CH2 contained in said L3 are each independently optionally replaced by -O-, -NH- or -N(C1-C6 alkyl)- (e.g. -N(CH3)-); k is 1, 2, 3 or 4;

[0785] Ring C is The e end is connected to L3, and the f end is connected to X″;

[0786] X″ is a bond or -C(O)-.

[0787] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, ring A is The a-terminal is connected to S, and the b-terminal is connected to X″′.

[0788] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, ring B is The c-terminal is connected to X″′, and the d-terminal is connected to L3.

[0789] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, k is 2, 3 or 4.

[0790] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 is -(CH2) k -, wherein one CH2 contained in L3 is optionally replaced by -O-; k is 2, 3 or 4.

[0791] In certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 can be -(CH2)2-, -(CH2)3-, -(CH2)4-, The k″ end is connected to ring B, and the k' end is connected to ring C.

[0792] Preferably, in certain embodiments of the present invention, in LA, LA-1 and LA-2, ring C is The e end is connected to L3, and the f end is connected to X″.

[0793] In certain embodiments of the present invention, the LA-2 is any of the following structures:

[0794]

[0795] In certain embodiments of the present invention, the LA is LA-4:

[0796]

[0797] Among them, ring A is Wherein end a is connected to S, and end b is connected to X″′;

[0798] X″′ is a bond;

[0799] Ring B is a bond;

[0800] L3 is -(CH2) k -, wherein one or two CH2 contained in said L3 are each independently optionally replaced by -O-, -NH- or -N(C1-C6 alkyl)- (e.g. -N(CH3)-); k is 1, 2, 3 or 4;

[0801] Ring C is The e end is connected to L3, and the f end is connected to X″;

[0802] X″ is a bond.

[0803] In certain embodiments of the present invention, in LA, LA-1 and LA-2, ring A is The a-terminal is connected to S, and the b-terminal is connected to X″′.

[0804] In certain embodiments of the present invention, in LA, LA-1 and LA-2, ring B is The c-terminal is connected to X″′, and the d-terminal is connected to L3.

[0805] In certain embodiments of the present invention, in LA, LA-1 and LA-2, k is 2, 3 or 4.

[0806] In certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 is -(CH2) k -, wherein one CH2 contained in L3 is optionally replaced by -O-; k is 2, 3 or 4.

[0807] In certain embodiments of the present invention, in LA, LA-1 and LA-2, L3 may be -(CH2)2- or -(CH2)3-.

[0808] In certain embodiments of the present invention, in LA, LA-1 and LA-2, ring C is The e end is connected to L3, and the f end is connected to X″.

[0809] In certain embodiments of the present invention, the LA-4 is any of the following structures:

[0810]

[0811] Preferably, in certain embodiments of the present invention, the LA is any of the following structures:

[0812]

[0813]

[0814]

[0815] Preferably, in certain embodiments of the present invention, the compound of formula I is any one of the following compounds:

[0816]

[0817]

[0818]

[0819] In certain embodiments, the deuterated compound is a structure in which 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 H in the compound structure (e.g., L, e.g., ring A, ring B, L3, ring C in LA, LA-1, LA-2, LA-4) is replaced by deuterium. In certain embodiments, the deuterated LA structure is

[0820] The present invention provides a method for preparing a compound of formula I and / or its stereoisomers, enantiomers, diastereomers, deuterated products, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts.

[0821] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0822] The present invention provides a method for degrading SOS1 protein, comprising contacting a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated substances, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof with SOS1 protein.

[0823] The present invention provides a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts, or pharmaceutical compositions thereof for use as a drug for treating or preventing SOS1-mediated diseases or conditions.

[0824] The present invention provides a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts, or pharmaceutical compositions thereof for use as a drug for treating or preventing diseases or conditions (cancer) caused by the interaction between SOS1 and Ras (e.g., KRAS) or between SOS1 and Rac (e.g., KRAS).

[0825] The present invention provides use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of a medicament for treating or preventing SOS1-mediated diseases or conditions (e.g., cancer).

[0826] The present invention provides the use of a compound of Formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of a medicament for treating or preventing a disease or condition (e.g., cancer) caused by the interaction between SOS1 and Ras (e.g., KRAS) or between SOS1 and Rac (e.g., KRAS).

[0827] The present invention provides use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated products, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts, or pharmaceutical compositions thereof, in the preparation of drugs for treating or preventing cancer.

[0828] The present invention provides use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0829] The present invention provides use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-cutaneous syndrome (CFC), Leggs syndrome and hereditary gingival fibromatosis.

[0830] The present invention provides a method for treating or preventing a disease or condition mediated by SOS1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0831] The present invention provides a method for treating or preventing a disease or condition (e.g., cancer) regulated by the interaction between SOS1 and Ras (e.g., KRAS) or SOS1 and Rac (e.g., KRAS), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterates, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof.

[0832] In certain embodiments of the present invention, the cancer may be selected from:

[0833] Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma group;

[0834] Lung: bronchial cancer (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar carcinoma (bronchiolar carcinoma), bronchial adenoma, sarcoma, lymphoma, enchondroma, hamartoma, mesothelioma;

[0835] Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma);

[0836] Genitourinary system: kidney (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);

[0837] Liver: liver cancer (hepatocellular carcinoma), bile duct cancer, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;

[0838] Biliary tract: gallbladder cancer, ampullary cancer, bile duct cancer;

[0839] Bone: osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, enchondroma (osteochondral exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor;

[0840] Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomas), brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germinal cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, congenital tumors), spinal neurofibromas, meningiomas, gliomas, sarcomas);

[0841] Gynecology: uterus (endometrial cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-Leydig cell tumor, germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma);

[0842] Hematology: Blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma);

[0843] Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplasia, lipoma, hemangioma, dermatofibroma, keloid, psoriasis;

[0844] Adrenal gland: neuroblastoma.

[0845] In certain embodiments of the present invention, the cancer can be selected from pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer and sarcoma.

[0846] The present invention also provides the use of the aforementioned compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, prodrugs and / or pharmaceutically acceptable salts thereof, or the aforementioned pharmaceutical compositions in the preparation of a medicament for treating and / or preventing KRAS-mediated diseases or conditions.

[0847] The present invention also provides a method for treating and / or preventing KRAS-mediated diseases or conditions, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0848] In certain embodiments of the present invention, the KRAS may be a mutant KRAS, preferably one or more of KRAS G12C, KRAS G12D, KRAS G13D, and KRAS G12V.

[0849] The present invention provides a method for preparing a compound of formula I, or its stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, or pharmaceutically acceptable salts:

[0850] When S is S6c L stands for LA When ring B contains an NH group, the preparation method is:

[0851]

[0852] INT-A and INT-B undergo a reductive amination reaction to obtain the target compound; wherein the reducing agent for the reductive amination is but not limited to Pd / C, sodium borohydride, sodium cyanoborohydride, borane, sodium triacetoxyborohydride. refers to ring B containing an NH group; R2, R3, R4, R5, R6, and R7 are as defined and described in S6b; refers to L3 containing an aldehyde group; Ring A, Ring B, Ring C, and X″ are as defined in LA; E is as defined and described in the present invention, and preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb, E21-1cc, E21-1dd, E21-1ee, E21-1ff, E21-1gg or E21-1hh.

[0853] When S is S6c L stands for LA When ring C contains an NH group and X″ is C(O), the preparation method is:

[0854]

[0855] INT-C and INT-D undergo substitution reaction under alkaline conditions to obtain the target compound; wherein the base includes but is not limited to triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate. Refers to the ring C containing the NH group; P 100 is pentafluorophenyl or p-nitrophenyl; R2, R3, R4, R5, R6, R7 are as defined and described in S6b; Ring A, Ring B, Ring C, L3 are as defined in LA; E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb, E21-1cc, E21-1dd, E21-1ee, E21-1ff, E21-1gg or E21-1hh.

[0856] When S is S6d L stands for LA When ring C contains an NH group and X″ is C(O), the preparation method is:

[0857]

[0858] INT-E and INT-D undergo substitution reaction under alkaline conditions to obtain the target compound; wherein the base includes but is not limited to triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate. Refers to the ring C containing the NH group; P 100 is pentafluorophenyl or p-nitrophenyl; R2, R3, R4, R5, R6, R7 are as defined and described in S6d; Ring A, Ring B, Ring C, L3 are as defined in LA; E is as defined and described in the present invention, preferably E is E7, E7a, E7b, E7c, E7d, E7e, E7a-1, E7a-2, E21, E21-1a, E21-1b, E21-1c, E21-1d, E21-1e, E21-1f, E21-1g, E21-1h, E21-1aa, E21-1bb, E21-1cc, E21-1dd, E21-1ee, E21-1ff, E21-1gg or E21-1hh.

[0859] DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0860] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched alkyl groups; C1-C8 alkyl refers to an alkyl group containing 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched chain isomers thereof; preferably C1-C6 alkyl; more preferably C1-C4 alkyl. The alkyl group may be substituted or unsubstituted. In some embodiments, the alkyl group is C1, C2, C3, C4, C5, C6, C7 or C8 alkyl.

[0861] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent; "C3-C 11 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 11 carbon atoms; "C3-C8 cycloalkyl" refers to a cycloalkyl group containing 3 to 8 carbon atoms; "C5-C 10 "Cycloalkyl" refers to a cycloalkyl group comprising 5 to 10 carbon atoms;

[0862] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8 membered cycloalkyl; more preferably C3-C6 membered cycloalkyl.

[0863] Polycyclic cycloalkyl includes cycloalkyl of spiro ring, fused ring and bridged ring. "Spiroalkyl" refers to a polycyclic group in which a carbon atom (called spiro atom) is shared between the monocyclic rings. They may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spiroalkyl is divided into monospiroalkyl, bispiroalkyl or polyspiroalkyl according to the number of spiro atoms shared between the rings, preferably 7-12 membered bispiroalkyl. Non-limiting examples of spiroalkyl include:

[0864]

[0865] "Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Depending on the number of constituent rings, fused cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic, preferably bicyclic. Non-limiting examples of fused cycloalkyl groups include:

[0866]

[0867] "Bridged cycloalkyl" refers to a fully carbon-containing polycyclic group in which any two rings share two carbon atoms that are not directly connected. They may contain one or more double bonds, but no ring has a completely conjugated π electron system. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl. Non-limiting examples of bridged cycloalkyl groups include:

[0868]

[0869] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl can be optionally substituted or unsubstituted.

[0870] In some embodiments, the cycloalkyl group is C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 、C 12 Monocyclic or polycyclic (eg, spirocyclic, fused or bridged) cycloalkyl groups.

[0871] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent in which one or more (e.g., 2, 3, 4, or 5) ring atoms are selected from nitrogen, oxygen, or S(O) r (wherein r is an integer of 0, 1 or 2), but does not contain a ring portion of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. "3-11-membered heterocycloalkyl" refers to a ring group containing 3 to 11 ring atoms, "5-10-membered heterocycloalkyl" refers to a ring group containing 5 to 10 ring atoms, and "3-8-membered heterocycloalkyl" refers to a ring group containing 3 to 8 ring atoms, preferably a "3-11-membered heterocycloalkyl" containing 1-2 heteroatoms selected from N, O or S, and more preferably a 3-11-membered heterocycloalkyl containing 1 or 2 N atoms.

[0872] Monocyclic heterocycloalkyl is preferably a 3-8 membered monocyclic heterocycloalkyl containing 1-2 N heteroatoms; non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl and piperazinyl.

[0873] Polycyclic heterocycloalkyl groups include spiro, fused and bridged heterocycloalkyl groups. "Spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which the single rings share an atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). r (wherein r is an integer 0, 1, 2), and the remaining ring atoms are carbon. They may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spirocycloalkyl groups are divided into monospiroheterocycloalkyl, bispiroheterocycloalkyl or polyspiroheterocycloalkyl groups according to the number of spiro atoms shared between the rings, preferably saturated "3-11 membered bispiroheterocycloalkyl groups" containing 1-2 heteroatoms selected from N, O or S; more preferably saturated "7-11 membered bispiroheterocycloalkyl groups" containing 1 or 2 N atoms. Non-limiting examples of spiroheterocycloalkyl groups include:

[0874]

[0875] "Fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) r(where r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of constituent rings, fused heterocycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably "3-11-membered bicyclic fused heterocycloalkyl groups" containing 1-3 heteroatoms selected from N, O, or S; and more preferably "3-11-membered bicyclic fused heterocycloalkyl groups" containing 1 or 2 saturated N atoms. Non-limiting examples of fused heterocycloalkyl groups include:

[0876]

[0877] "Bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two atoms that are not directly connected, they may contain one or more double bonds, but no ring has a completely conjugated π electron system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, or 2), and the remaining ring atoms are carbon. Depending on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged heterocycloalkyl groups include:

[0878]

[0879] The heterocycloalkyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocycloalkyl, non-limiting examples of which include:

[0880] The heterocycloalkyl group may be optionally substituted or unsubstituted.

[0881] In some embodiments, the heterocycloalkyl group is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered monocyclic or polycyclic (e.g., spirocyclic, fused, or bridged) heterocycloalkyl group, wherein the number of heteroatoms can be 1, 2, 3, 4, or 5, each heteroatom being independently nitrogen, oxygen, or S(O). r (where r is an integer 0, 1, or 2).

[0882] "Aryl" refers to an all-carbon monocyclic ring or a fused polycyclic ring (i.e., a ring that shares adjacent pairs of carbon atoms) with a conjugated π electron system. "6-10 membered aryl" refers to an all-carbon aromatic group containing 6-10 carbon atoms, such as phenyl and naphthyl; preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, where the ring attached to the parent structure is the aryl ring. Non-limiting examples include:

[0883] The aryl group may be optionally substituted or unsubstituted. In some embodiments, the aryl group is a 6-10 membered aryl group.

[0884] "Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen or S(O) r (wherein r is an integer of 0, 1, or 2), a 5-6 membered heteroaryl group refers to a heteroaromatic system containing 5-6 ring atoms, and a 5-10 membered heteroaryl group refers to a heteroaromatic system containing 5-10 ring atoms, preferably a 5-6 membered heteroaryl group; more preferably a 5-6 membered heteroaryl group containing 1 or 2 N atoms; non-limiting examples include furanyl, thienyl, pyridinyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl, etc.; preferably pyridinyl. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include:

[0885]

[0886] The heteroaryl group may be optionally substituted or unsubstituted. In some embodiments, the heteroaryl group is a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group, wherein the number of heteroatoms may be 1, 2, 3, 4, or 5, each heteroatom being independently nitrogen, oxygen, or S.

[0887] "Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. 2-8 "Alkenyl" refers to a straight or branched chain alkenyl containing 2 to 8 carbon atoms, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably "C 2-6 Alkenyl", more preferably "C 2-4 The alkenyl group may be substituted or unsubstituted. In some embodiments, the alkenyl group is a C2, C3, C4, C5, C6, C7, or C8 alkenyl group.

[0888] "Alkynyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond. 2-8 "Alkynyl" refers to a straight or branched chain alkynyl containing 2 to 8 carbon atoms, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C 2-6 Alkynyl", more preferably "C 2-4 The alkynyl group can be substituted or unsubstituted. In some embodiments, the alkynyl group is a C2, C3, C4, C5, C6, C7, or C8 alkynyl group.

[0889] "Ylene" refers to a divalent group, such as alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkylene refers to a divalent cycloalkyl group, heterocycloalkylene refers to a divalent heterocycloalkyl group, arylene refers to a divalent aryl group, and heteroarylene refers to a divalent heteroaryl group. The alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are as defined above, and the alkylene group may be optionally substituted or unsubstituted.

[0890] "Haloalkyl" refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein alkyl is as defined above, non-limiting examples of which include difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl and the like.

[0891] "Hydroxyalkyl" refers to an alkyl group optionally substituted with one or more -OH groups, wherein alkyl is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl.

[0892] "Alkoxy" refers to an -O-alkyl group wherein alkyl is as defined above, non-limiting examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0893] "Cycloalkoxy" refers to an -O-cycloalkyl group wherein the cycloalkyl group is as defined above. Non-limiting examples include cyclopropaneoxy, cyclobutaneoxy, cyclopentaneoxy, cyclohexaneoxy, and the like.

[0894] "Heterocycloalkoxy" refers to an -O-heterocycloalkyl group, wherein the heterocycloalkyl group is as defined above, non-limiting examples of which include azetidinyloxy, azeolanyloxy, piperidinyloxy, piperazinyloxy, oxolanyloxy, oxhexyloxy, and the like.

[0895] "-C(O)C1-C3 alkyl" refers to -C(O)-CH3, -C(O)-CH2CH3 and the like.

[0896] "Cyano" refers to -CN.

[0897] "Hydroxyl" refers to -OH.

[0898] "Sulfonyl" refers to -S(O)2-.

[0899] "Carboxy" or "carboxylic acid" refers to -COOH.

[0900] "Oxo" refers to a =0 group.

[0901] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0902] "Pd(PPh3)2Cl2" refers to (dichlorobis(triphenylphosphine)palladium).

[0903] "TEA" refers to triethylamine.

[0904] "EA or EtOAc" refers to ethyl acetate.

[0905] "THF" refers to tetrahydrofuran.

[0906] "NaBH4" refers to sodium borohydride.

[0907] "DCM" refers to dichloromethane.

[0908] "Tf2O" refers to trifluoromethanesulfonic anhydride.

[0909] "(Bpin)2" refers to bispinacol borate.

[0910] "Pd(dppf)2Cl2" refers to 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride.

[0911] "KOAc" refers to potassium acetate.

[0912] "DMF" refers to N,N-dimethylformamide.

[0913] "NBS" refers to N-bromosuccinimide.

[0914] "EtOH" refers to ethanol.

[0915] "MeOH" refers to methanol.

[0916] "Pd / C" refers to palladium / carbon.

[0917] "Pd(OH)2 / C" refers to palladium hydroxide on carbon.

[0918] "DMSO" refers to dimethyl sulfoxide.

[0919] "HATU" refers to 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0920] "TFA" refers to trifluoroacetic acid.

[0921] "NMP" refers to N-methylpyrrolidone.

[0922] "IBX" refers to 2-iodoacylbenzoic acid.

[0923] "DIEA" refers to N,N-diisopropylethylamine.

[0924] "STAB" refers to sodium triacetoxyborohydride.

[0925] "T3P" refers to 2,4,6-tripropyl-1,3,5,2,4,6-trioxytriphosphate-2,4,6-trioxide.

[0926] "NaOH" refers to sodium hydroxide.

[0927] "DMAP" refers to 4-dimethylaminopyridine.

[0928] "TPSC1" refers to 2,4,6-triisopropylbenzenesulfonyl chloride.

[0929] "DPBS" refers to Dulbecco's phosphate buffered saline.

[0930] "Dess-Martin" refers to Dess-Martin reagent.

[0931] "PBS" refers to phosphate buffered saline.

[0932] "SDS-PAGE" refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

[0933] "PVDF" refers to polyvinylidene fluoride.

[0934] "PE" refers to petroleum ether.

[0935] "NaHCO3" refers to sodium bicarbonate.

[0936] "Na2SO4" refers to sodium sulfate.

[0937] "NH4Cl" refers to ammonium chloride.

[0938] "AcOH" refers to acetic acid.

[0939] "HCl" refers to hydrochloric acid.

[0940] "DCC" refers to N,N'-dicyclohexylcarbodiimide.

[0941] "Ti(OEt)4" refers to tetraethyl titanate.

[0942] "L-Selectride" refers to lithium triisobutylborohydride.

[0943] "BOP" refers to benzotriazol-1-oxytris(dimethylamino)phosphine hexafluorophosphate

[0944] "DBU" refers to 1,8-diazacyclo[5,4,0]undecene-7-ene

[0945] "LiOH.H2O" refers to lithium hydroxide monohydrate

[0946] "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0947] "NIS" N-iodosuccinimide.

[0948] "Ac2O" refers to acetic anhydride.

[0949] "HOAc" refers to acetic acid.

[0950] "Hantzsch-ester" refers to diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.

[0951] "DMA" refers to dimethylacetamide.

[0952] "NiBr2(dtbpy)" refers to 4,4-di-tert-butylbipyridinium nickel dibromide.

[0953] "K2CO3" refers to potassium carbonate.

[0954] "9-BBN" refers to 9-borabicyclo[3.3.1]nonane.

[0955] "MTBE" refers to methyl tert-butyl ether.

[0956] "LiOH" refers to lithium hydroxide.

[0957] "DCE" refers to dichloroethane.

[0958] "NaBH3CN" refers to sodium cyanoborohydride.

[0959] "CBr4" refers to carbon tetrabromide.

[0960] "PPh3" refers to triphenylphosphine.

[0961] "n-BuLi" refers to n-butyllithium.

[0962] "NaH" refers to sodium hydrogen.

[0963] "i-PrOH" refers to isopropyl alcohol.

[0964] "ACN" refers to acetonitrile.

[0965] "NH4HCO3" refers to ammonium bicarbonate.

[0966] "m-CPBA" refers to meta-chloroperbenzoic acid.

[0967] "KI" refers to potassium iodide.

[0968] "IPA" refers to isophthalic acid

[0969] "N2H4-H2O" refers to hydrazine hydrate.

[0970] "NMI" refers to N-methylimidazole.

[0971] "TCFH" refers to tetramethylchlorouronium hexafluorophosphonate

[0972] "Ruphos Pd G2" refers to chloro(2-dicyclohexylphosphino-2',6'-di-isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II).

[0973] "K3PO4" refers to potassium phosphate.

[0974] "(Boc)2O" refers to di-tert-butyl dicarbonate.

[0975] "Prep-HPLC" refers to preparative high performance liquid chromatography.

[0976] "Sat." refers to a saturated solution.

[0977] "aq" refers to aqueous solution.

[0978] In the chemical structures herein, "-" as a connecting bond represents a single bond, and "=" represents a double bond (which may be trans or cis if the configuration is not limited).

[0979] "Optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocycloalkyl group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocycloalkyl group is substituted with an alkyl group and instances where the heterocycloalkyl group is not substituted with an alkyl group.

[0980] "Substituted" means that one or more hydrogen atoms, preferably up to five, and more preferably one to three, in a group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g., olefinic) bonds.

[0981] As used herein, the term "optionally substituted" may be unsubstituted or substituted unless otherwise indicated; when substituted, the substituents may be one or more (e.g., 2, 3, 4, 5, or 6) independently selected from alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, said alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl optionally substituted with one or more (e.g., 2, 3, 4, 5, or 6) cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl optionally substituted with one or more groups selected from alkyl, alkenyl, alkynyl, hydroxy, hydroxyalkyl, haloalkyl, alkoxy, amino, aminoalkyl, cyano, halogen, oxo.

[0982] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, and other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[0983] The present invention also provides pharmaceutically acceptable salts of compounds of formula (I). The term "pharmaceutically acceptable salt" refers to acid addition salts or base addition salts of relatively nontoxic compounds of the present invention. The acid addition salts are salts formed between compounds of formula (I) of the present invention and suitable inorganic or organic acids. These salts can be prepared during the final separation and purification of the compound, or can be prepared by reacting the purified compound of formula (I) in its free base form with a suitable organic or inorganic acid. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobionate, and laurylsulfonate. The base addition salt is a salt formed by the compound of formula (I) with a suitable inorganic base or organic base, including, for example, salts formed with alkali metals, alkaline earth metals, and quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, tetramethylammonium salts, tetraethylammonium salts, etc.; amine salts include salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.

[0984] The compounds of the present invention or their pharmaceutically acceptable salts can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powders, ointments or drops), or intratumorally.

[0985] The compound of the present invention can be administered at a dosage of approximately 0.05-300 mg / kg body weight / day, preferably 10-300 mg / kg body weight / day, more preferably 10-200 mg / kg body weight / day.

[0986] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules and the like. In these solid dosage forms, the compound of formula (I) of the present invention is mixed as an active ingredient with at least one conventional inert excipient (or carrier), for example, sodium citrate or dicalcium phosphate, or with the following ingredients: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (2) binders, such as hydroxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (3) humectants, such as glycerol; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates and sodium carbonate; (5) solubilizers, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) adsorbents, such as kaolin; and (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. Capsules, tablets and pills may also contain buffering agents.

[0987] Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be coated or microencapsulated with coatings and shell materials such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active ingredient can also be microencapsulated with one or more of the above-mentioned excipients.

[0988] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration, including but not limited to pharmaceutically acceptable emulsions, solutions, suspensions, syrups and tinctures. In addition to the active ingredient, the compound of formula (I) or its pharmaceutically acceptable salt, the liquid dosage form may contain inert diluents such as water and other solvents, solubilizers and emulsifiers conventionally used in the art, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures of these substances. In addition to these inert diluents, the liquid dosage form of the present invention may also contain conventional adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and spices.

[0989] The suspending agent includes ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol, microcrystalline cellulose, aluminum methylate and agar or a mixture of these substances.

[0990] The compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into dosage forms for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0991] The compounds of the present invention or their pharmaceutically acceptable salts can also be formulated into dosage forms for topical administration including ointments, powders, suppositories, drops, sprays and inhalants, etc. The active ingredient, the compound of formula (I) of the present invention or its pharmaceutically acceptable salt is mixed under sterile conditions with a physiologically acceptable carrier and optional preservatives, buffers, or propellants that may be required if necessary.

[0992] The present invention also provides a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient, or diluent. When preparing the pharmaceutical composition, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof is typically mixed with a pharmaceutically acceptable carrier, excipient, or diluent.

[0993] The composition of the present invention can be formulated into conventional pharmaceutical preparations according to conventional preparation methods, such as tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, sprays, etc.

[0994] The compounds of the present invention or their pharmaceutically acceptable salts can be administered alone or, if necessary, in combination with other pharmaceutically acceptable therapeutic agents, such as other anti-tumor drugs. The components to be combined can be administered simultaneously or sequentially, in the form of a single formulation or in the form of different formulations. The combination can include not only a combination of a compound of the present invention and one other active agent, but also a combination of a compound of the present invention and two or more other active agents.

[0995] In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrader compound of formula (I) may be: EGFR and / or its mutant inhibitors, ErbB2 (Her2) and / or its mutant inhibitors, ALK and / or its mutant inhibitors, MEK and / or its mutant inhibitors, Kras and / or its mutant inhibitors, BCR-ABL and / or its mutant inhibitors, FGFR1 / FGFR2 / FGFR3 and / or its mutant inhibitors, ROS1 and / or its mutant inhibitors, c-MET and / or its mutant inhibitors, AXL and / or its mutant inhibitors, NTRK1 and / or its mutant inhibitors, RET and / or its mutant inhibitors, taxanes, platinum-containing compounds, antimetabolites, mitotic kinase inhibitors, immunotherapeutics, anti-angiogenic drugs, topoisomerase inhibitors, A-Raf / B-Raf / C-RAf and / or its mutant inhibitors, ERK and / or its mutant inhibitors, apoptosis inhibitors, mTOR inhibitors, epigenetic regulators, IGF1 / 2 and / or IGF1-R inhibitors, RasGEF and / or its mutant inhibitors, PI3K and / or its mutant inhibitors.

[0996] In the present invention, other pharmaceutically acceptable therapeutic agents that can be used together or in combination with the SOS1 degrading agent compound of formula (I) can be: afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, EGF-816, trastuzumab, pertuzumab, crizotinib, alectinib, entrectinib, brigatinib, ib), trametinib, cobimetinib, binimetinib, selumetinib, refametinib, imatinib, dasatinib, nilotinib, nintedanib, crizotinib, lorlatinib, ceritinib, merestinib, paclitaxel, nab-paclitaxel, docetaxel el), cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, capecitabine, floxuridine, cytarabine, gemcitabine, a combination of trifluridine and tipiracil (=TAS102), palbociclib, ribociclib, abemaciclib, ipilimumab, nivolumab ), pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, PDR-001 (=spartalizumab), bevacizumab, irinotecan, liposomal irinotecan, topotecan, ulixertinib, rapamycin, temsirolimus, everolimus,ridaforolimus, JQ-1, GSK 525762, OTX 015 (=MK8628), CPI 0610, TEN-010 (=RO6870810), xentuzumab (antibody 60833 in WO2010 / 066868), or MEDI-573 (=dusigitumab).

[0997] The present invention demonstrates that the compounds of Formula I described herein can effectively bind to or inhibit the SOS1 target protein through SOS1 kinase activity assays. Western-blot analysis demonstrates that the compounds of Formula I described herein can effectively and specifically degrade SOS1 protein in NCI-H358 cells. The compounds of Formula I described herein, and / or their stereoisomers, enantiomers, diastereomers, deuterated forms, hydrates, solvates, metabolites, prodrugs, and / or pharmaceutically acceptable salts, can effectively degrade SOS1 protein, thereby preventing or treating diseases or conditions associated with SOS1 or caused by the interaction between SOS1 and Ras or SOS1 and Rac. DETAILED DESCRIPTION

[0998] The present invention will be further described in detail and completely below with reference to the examples, but the present invention is by no means limited thereto, and the present invention is not limited thereto. The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using methods known in the art. Unless otherwise specified, the experimental methods in the examples of the present invention that do not specify specific conditions are generally prepared under conventional conditions or under conditions recommended by the raw material or commodity manufacturer.

[0999] Ⅰ Compound Preparation Examples

[1000] Intermediate 1: Preparation of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride

[1001] Step 1: Preparation of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-one

[1002]

[1003] Under nitrogen protection, the reaction mixture of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (18 g, 66.7 mmol), tributyl (1-ethoxyvinyl) stannane (31 g, 86.7 mmol), Pd (PPh3) 2Cl2 (4.7 g, 6.67 mmol) and TEA (13.5 g, 133 mmol) in 1,4-dioxane (200 mL) solution was stirred at 80 ° C overnight. The reaction solution was quenched with potassium fluoride (saturated aqueous solution, 300 mL) and extracted with EA (200 mL × 3). The organic layer was collected and concentrated under reduced pressure. The concentrate was dissolved in THF (180 mL), hydrochloric acid (100 mL, 6 M) was added, and stirred at room temperature for 3 h. The mixture was then quenched with water (300 mL) and extracted with EA (200 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Crude product

[1004] The product was purified by column chromatography to obtain the target product 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-one.

[1005] 1 H NMR (400MHz, CDCl3) δ8.95 (t, J = 1.6 Hz, 1H), 8.69 (s, 1H), 8.54 (d, J = 0.5 Hz, 1H), 2.76 (s, 3H).

[1006] Step 2: Preparation of (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propyl-2-sulfenamide

[1007]

[1008] A reaction mixture of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-one (10.6 g, 45.5 mmol), (R)-2-methylpropyl-2-sulfenamide (8.3 g, 68.2 mmol), and tetraethyl titanate (25.9 g, 114 mmol) in THF (200 mL) was stirred at 60°C for 2 h. The reaction mixture was quenched with water (300 mL) and extracted with EA (200 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to yield the desired product, (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propyl-2-sulfenamide.

[1009] 1 H NMR (400MHz, DMSO-d6) δ8.87(s,1H),8.61(s,1H),8.43(s,1H),2.90(s,3H),1.37(s,9H).

[1010] Step 3: Preparation of (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propyl-2-sulfenamide

[1011]

[1012] To a mixture of (R,E)-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethylidene)propyl-2-sulfenamide (10 g, 30.7 mmol) in THF (100 mL) and water (20 mL) was added NaBH4 (1.28 g, 33.7 mmol). The reaction mixture was stirred at -10°C for 1 minute, then quenched with water (300 mL) and extracted with EA (200 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to yield the desired product, (R)-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propyl-2-sulfenamide.

[1013] 1 H NMR (400MHz, CDCl3) δ8.45–8.42(m,2H),7.96(s,1H),4.76–4.68(m,1H),3.56(d,J=4.2Hz,1H),1.62(d,J=6.7Hz,3H),1.26(s,9H).

[1014] Step 4: Preparation of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride

[1015]

[1016] (R)-2-Methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)propyl-2-sulfenamide (5.5 g, 16.3 mmol) was placed in a solution of hydrochloric acid (80 mL, 4 M) in dioxane and stirred at 25°C for 2 h. The crude product was filtered and washed with petroleum ether (100 mL) to obtain the desired product, (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride.

[1017] LC-MS:(ESI,m / z):[M+H] + =235.2.

[1018] Intermediate 2: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid ethyl ester

[1019] Step 1: Preparation of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

[1020]

[1021] To a stirred mixture of ethyl 4-oxocyclohexane-1-carboxylate (5 g, 32.0 mmol) and 2,6-lutidine (4.6 g, 42.9 mmol) in DCM (60 mL) was added Tf2O (9 g, 32.0 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h. The reaction mixture was then stirred at 25 ° C for 15 minutes, and Tf2O (7 g, 25.6 mmol) was added. The reaction mixture was then stirred at 25 ° C overnight. The reaction mixture was concentrated, quenched with water (300 mL), and extracted with EA (200 mL × 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate.

[1022] 1 H NMR(400MHz,DMSO-d6)δ5.90(d,J=3.9Hz,1H),4.14–4.02(m,2H),2.68–2.60(m,1H) ),2.47–2.27(m,4H),2.08–1.98(m,1H),1.88–1.76(m,1H),1.19(t,J=7.1Hz,3H).

[1023] Step 2: Preparation of ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

[1024]

[1025] A mixture of ethyl 4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (4.7 g, 16.8 mmol), (Bpin)2 (6.4 g, 25.2 mmol), Pd(dppf)2Cl2 (1.2 g, 1.68 mmol), and KOAc (4.9 g, 50.4 mmol) in 1,4-dioxane (80 mL) was stirred at 90°C overnight. The reaction was quenched with water (300 mL) and extracted with EA (200 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to yield ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[1026] 1H NMR (400MHz, DMSO-d6) δ6.42 (d, J = 2.2Hz, 1H), 4.11-4.02 (m, 2H), 2.33-1.95 (m, 4H), 1.93-1.83 (m, 1H), 1.53-1.38 (m, 1H), 1.21-1.14 (m, 16H).

[1027] Intermediate 3: ((1R,4R)-4-(4-(((R)-1-(3-amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone

[1028] Step 1: Preparation of 2-amino-5-bromo-4-methoxybenzoic acid

[1029]

[1030] To a stirred solution of 2-amino-4-methoxybenzoic acid (30 g, 179 mmol) in DMF (600 mL) at 0°C was added NBS (35 g, 197 mmol). The reaction mixture was stirred at 25°C for 1 h. The reaction solution was quenched with sodium thiosulfate (saturated aqueous solution, 500 mL) and extracted with EA (500 mL x 3). The organic layer was collected, washed with sodium chloride (saturated aqueous solution, 500 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude 2-amino-5-bromo-4-methoxybenzoic acid, which was used directly in the next step without further purification.

[1031] LC-MS:(ESI,m / z):[M+H] + =246.0.

[1032] Step 2: Preparation of 6-bromo-7-methoxy-2-methylquinazolin-4(3H)-one

[1033]

[1034] To a stirred solution of 2-amino-5-bromo-4-methoxybenzoic acid (17.0 g, 69.1 mmol) in methanol (170 mL) was added ammonium acetate (53.2 g, 691 mmol) and trimethyl orthoacetate (83.0 g, 691 mmol). The resulting reaction mixture was stirred in a sealed container at 120°C for 24 hours. The reaction mixture was poured into water (1 L), and the solid product was filtered. The crude product was washed with EA (1 L) to obtain the desired product, 6-bromo-7-methoxy-2-methylquinazolin-4(3H)-one. The crude product was used directly in the next reaction without purification.

[1035] LC-MS:(ESI,m / z):[M+H] + =268.9.

[1036] Step 3: Preparation of 6-bromo-4-chloro-7-methoxy-2-methylquinazoline

[1037]

[1038] A mixture of 6-bromo-7-methoxy-2-methylquinazolin-4(3H)-one (10 g, 37.2 mmol) in phosphorus oxychloride (200 mL) was stirred at 105°C overnight. The reaction mixture was concentrated, quenched with sodium bicarbonate (saturated aqueous solution, 500 mL), and extracted with EA (300 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the desired product, 6-bromo-4-chloro-7-methoxy-2-methylquinazoline.

[1039] LC-MS:(ESI,m / z):[M+H] + =287.0.

[1040] Step 4: Preparation of (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine

[1041]

[1042] To a mixture of 6-bromo-4-chloro-7-methoxy-2-methylquinazoline (1.8 g, 6.27 mmol) in EtOH (12 mL) was added (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride (1.7 g, 7.52 mmol) and DIEA (1.6 g, 12.5 mmol). The reaction mixture was stirred at 100°C in a microwave for 5 h. The reaction was quenched with water (300 mL) and extracted with EA (300 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to yield (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazoline-4-amine as a yellow oil.

[1043] LC-MS:(ESI,m / z):[M+H] + =484.9.

[1044] Step 5: Preparation of ethyl 4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohex-3-ene-1-carboxylate

[1045]

[1046] A reaction mixture of (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (2 g, 4.12 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (2.31 g, 8.24 mmol), sodium carbonate (873 mg, 8.24 mmol), and Pd(dppf)2Cl2 (300 mg, 0.41 mmol) in DMF (24 mL) and water (3 mL) was stirred at 110°C overnight. The reaction was quenched with water (300 mL). The solution was extracted with EA (300 mL × 3) and washed with sodium chloride (saturated aqueous solution, 500 mL × 3). The organic layers were combined. The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give ethyl 4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohex-3-ene-1-carboxylate.

[1047] LC-MS:(ESI,m / z):[M+H] + =559.7.

[1048] Step 6: Preparation of (R)-ethyl 4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate

[1049]

[1050] To a mixture of ethyl 4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohex-3-ene-1-carboxylate (1.7 g, 3.04 mmol) in MeOH (60 mL) was added Pd / C (1.02 g, 0.6 w / w). The reaction mixture was stirred at 50°C under a hydrogen atmosphere for 4 days. The crude product was filtered to obtain ethyl (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate.

[1051] LC-MS:(ESI,m / z):[M+H] + =531.2.

[1052] Step 7: Preparation of (1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid

[1053]

[1054] To a mixture of (R)-ethyl 4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (1.5 g, 2.82 mmol) in methanol (8 mL), THF (8 mL), and water (16 mL) was added lithium hydroxide (203 mg, 8.46 mmol). The reaction mixture was stirred at 60°C overnight. The crude product was purified by preparative HPLC to give (1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid.

[1055] LC-MS:(ESI,m / z):[M+H] + =503.2.

[1056] 1 H NMR (400MHz, DMSO-d6) δ8.13(d,J=8.0Hz,1H),8.06(s,1H),6.99(s,1H),6.88(s,1H),6.86(s,1H),6.69(s,1H),5.56(dd,J=13.6,5.8Hz,3H) ,3.88(s,3H),2.92(t,J=11.7Hz,1H),2.35(s,3H),2.24(t,J=11.8Hz,1H),2.05(d,J=10.8Hz,2H),1.87(d,J=11.8Hz,2H),1.66–1.40(m,7H).

[1057] Step 8: tert-Butyl 4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate

[1058]

[1059] To a mixture of (1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (220 mg, 0.44 mmol) in EA (12 mL) were added tert-butyl piperazine-1-carboxylate (163 mg, 0.88 mmol), DIEA (169 mg, 1.31 mmol), and T3P (209 mg, 0.66 mmol). The reaction mixture was stirred at 0°C for 3 h. The reaction was quenched with water (100 mL) and extracted with EA (100 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give tert-butyl 4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate.

[1060] LC-MS:(ESI,m / z):[M+H] + =671.3.

[1061] 1 H NMR (400MHz, DMSO-d6) δ8.19–8.07(m,2H),6.99(s,1H),6.86(d,J=10.5Hz,2H),6.70(s,1H),5.56(dd,J=16.7,9.3Hz,3H),3.89(s, 3H),3.47(m,4H),3.32(m,4H),2.95(s,1H),2.67(s,1H),2.36(s,3H),1.83(d,J=14.5Hz,4H),1.59(t,J=22.3Hz,7H),1.41(s,9H).

[1062] Step 9: Preparation of ((1R,4R)-4-(4-(((R)-1-(3-amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone

[1063]

[1064] A mixture of tert-butyl 4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7)methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate (220 mg, 0.33 mmol) in ethyl acetate and hydrochloric acid (3M, 10 mL) was stirred at 25°C for 2 h. The reaction was concentrated to give ((1R,4R)-4-(4-(((R)-1-(3-amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone, which was used in the next reaction without further purification.

[1065] LC-MS:(ESI,m / z):[M+H] + =571.2.

[1066] Intermediate 4: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[1067] Step 1: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione

[1068]

[1069] To a solution of 4-fluorophthalic acid (5.52 g, 0.03 mol) in acetic acid (50 mL) were added 3-aminopiperidine-2,6-dione hydrochloride (5.0 g, 0.03 mol) and potassium acetate (8.8 g, 0.09 mol). The reaction mixture was stirred at 120°C overnight. The reaction mixture was concentrated under reduced pressure, diluted with water (100 mL), stirred at room temperature for 30 minutes, filtered, and the solid was washed with water (50 mL x 2). Drying under reduced pressure gave the product.

[1070] LC-MS:(ESI,m / z):[M+H] + =277.1

[1071] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione

[1072]

[1073] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol), 2-(piperidin-4-yl)ethyl-1-ol (280 mg, 2.17 mmol), and DIEA (701 mg, 5.43 mmol) in NMP (5 mL) was reacted in a microwave reactor at 140°C for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was collected and washed with water (100 mL x 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified on a silica gel column to obtain the product.

[1074] LC-MS:(ESI,m / z):[M+H] + =386.1.

[1075] Step 3: Preparation of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[1076]

[1077] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (300 mg, 0.78 mmol) and IBX (436 mg, 1.56 mmol) in acetonitrile (6 mL) was stirred at 80°C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was collected and washed with water (50 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the product.

[1078] LC-MS:(ESI,m / z):[M+H] + =384.1.

[1079] 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),9.69(t,J=1.6Hz,1H),7.65(d,J=8.6Hz,1 H),7.31(d,J=2.0Hz,1H),7.23(dd,J=8.6,2.2Hz,1H),5.06(dd,J=12.9,5.4Hz,1 H),4.03(dd,J=10.3,2.9Hz,2H),3.04–2.82(m,3H),2.65–2.52(m,2H),2.41(dd ,J=6.7,1.6Hz,2H),2.17–1.97(m,2H),1.73(d,J=11.1Hz,2H),1.2-1.18(m,2H).

[1080] Intermediate 5: 2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undec-9-yl)acetaldehyde

[1081] Step 1: Preparation of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid

[1082]

[1083] 3-Amino-4-chlorobenzoic acid (5.0 g, 2.93 mmol) was suspended in acrylic acid (8.05 mL, 117 mmol) and stirred at 100°C for 3 hours. The reaction mixture was then cooled to room temperature with stirring. Acetic acid (33 mL) was added, and the stirred suspension was heated at 100°C for 10 minutes. Urea (11.00 g, 183 mmol) was added, and the reaction mixture was stirred at 120°C overnight. The reaction mixture was added to a mixture of ice water and concentrated hydrochloric acid (37%) and stirred. The resulting suspension was stored in a refrigerator at 5°C overnight, then filtered, washed with water, and dried to obtain a solid. The solid was triturated in hydrochloric acid (0.05 M), filtered, washed with methyl tert-butyl ether, and dried under reduced pressure at 40°C to obtain the desired product.

[1084] LC-MS:(ESI,m / z):[M+H] + =269.0

[1085] Step 2: Preparation of pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate

[1086]

[1087] A mixture of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (2.0 g, 7.58 mmol), 2,3,4,5,6-pentafluorophenol (1.67 g, 9.09 mmol), and N,N'-dicyclohexylcarboximide (1.87 g, 9.09 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 3 hours. The reaction mixture was poured into water (200 mL) and stirred for 0.5 hours. The solution was then extracted with ethyl acetate (200 mL x 3). The organic phase was collected, washed with water (500 mL x 2) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the desired product.

[1088] LC-MS:(ESI,m / z):[M+H] + =435.0

[1089] Step 3: Preparation of 2-(3-aza[5.5]undec-9-yl)ethan-1-ol

[1090]

[1091] To a mixture of benzyl 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylate (1.0 g, 3 mmol) in EA (10 mL) was added Pd(OH)2 / C (200 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 h. The mixture was filtered, and the filtrate was concentrated to obtain the desired product.

[1092] Step 4: Preparation of 1-(2-chloro-5-(9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1093]

[1094] To a mixture of 2-(3-azaspiro[5.5]undec-9-yl)ethan-1-ol (500 mg, 2.5 mmol) in DMSO (5 mL) was added pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (1.0 g, 2.5 mmol) and DIEA (0.5 mL). The reaction was quenched with water (30 mL) and extracted with EA (10 mL x 3). The organic layer was collected and washed with water (10 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to obtain the title compound.

[1095] LC-MS:(ESI,m / z):[M+H] +=448.1

[1096] Step 5: Preparation of 2-(3-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undec-9-yl)acetaldehyde

[1097]

[1098] To a mixture of 1-(2-chloro-5-(9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (700 mg, 1.56 mmol) in THF (12 mL) was added IBX (873 mg, 3.1 mmol). The reaction mixture was stirred at 80°C for 2 h. The reaction was quenched with water (30 mL), and the solution was extracted with EA (10 mL x 3). The organic layer was collected and washed with water (10 mL x 2) and saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to obtain the title compound.

[1099] LC-MS:(ESI,m / z):[M+H] + =446.1

[1100] Intermediate 6: 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde

[1101] Step 1: Preparation of tert-butyl 4-(2,2-dimethoxyethyl)piperazine-1-carboxylate

[1102]

[1103] To a mixture of tert-butyl piperazine-1-carboxylate (2.0 g, 10.75 mmol), potassium carbonate (4.45 g, 32.26 mmol), and potassium iodide (892 mg, 5.38 mmol) in acetone (20 mL) was added 2-bromo-1,1-dimethoxyethane (3.63 g, 21.51 mmol). The reaction was stirred at 80°C overnight. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (50 mL) and washed with water (50 mL x 2) and saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the desired product.

[1104] LC-MS:(ESI,m / z):[M+H] + =275.0.

[1105] Step 2: Preparation of 1-(2,2-dimethoxyethyl)piperazine

[1106]

[1107] A mixture of tert-butyl 4-(2,2-dimethoxyethyl)piperazine-1-carboxylate (2.2 g, 8.03 mmol) in hydrochloric acid / dioxane (4 M, 10 mL) was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to afford the desired product (1.5 g, crude). The crude product was used directly in the next step.

[1108] Step 3: Preparation of 5-(4-(2,2-dimethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1109]

[1110] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.48 g, 5.36 mmol), 1-(2,2-dimethoxyethyl)piperazine (1.4 g, 8.05 mmol), and DIEA (4.15 g, 36.16 mmol) in NMP (10 mL) was reacted at 140°C for 5 h in a microwave reactor. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was collected and washed with water (100 mL x 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the desired product.

[1111] LC-MS:(ESI,m / z):[M+H] + =431.1.

[1112] Step 4: Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde

[1113]

[1114] A mixture of 5-(4-(2,2-dimethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.8 g, 4.19 mmol) in trifluoroacetic acid / dichloromethane (5 mL / 5 mL) was stirred at room temperature for 60 h. The mixture was concentrated under reduced pressure, water was added, and the pH was adjusted to 8 with sodium bicarbonate (aqueous solution). The mixture was extracted with ethyl acetate (100 mL x 2). The organic phase was collected, washed with water (100 mL x 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified on a silica gel column to obtain the desired product.

[1115] LC-MS:(ESI,m / z):[M+H] + =285.0.

[1116] Intermediate 7: 2-(9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undec-3-yl)acetaldehyde

[1117] Step 1: Preparation of tert-butyl 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

[1118]

[1119] To a solution of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (1.0 g, 3.78 mmol) in N,N-dimethylformamide (10 mL) at room temperature under nitrogen was added HATU (1.66 g, 4.37 mmol), tert-butyl 3,9-diazaspiro[5.5]undecyl-3-carboxylate (0.96 g, 3.78 mmol), and N-methylmorpholine (0.8 g, 7.92 mmol). After stirring for 2 h, the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The organic layer was collected, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the desired product.

[1120] LC-MS:(ESI,m / z):[M+H] + =505.2

[1121] Step 2: Preparation of 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecyl-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1122]

[1123] A solution of tert-butyl 9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1.56 g, 3.1 mmol) in trifluoroacetic acid / dichloromethane (2.5 mL / 5 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain the crude target compound. The crude product was used directly in the next reaction.

[1124] LC-MS:(ESI,m / z):[M+H] + =405.1

[1125] Step 3: Preparation of 1-(2-chloro-5-(9-(2,2-dimethoxyethyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1126]

[1127] To a mixture of 1-(2-chloro-5-(3,9-diazaspiro[5.5]undecyl-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (200 mg, 0.25 mmol), potassium carbonate (155 mg, 1.25 mmol), and potassium iodide (19 mg, 0.11 mmol) in acetone (4 mL) was added 2-bromo-1,1-dimethoxyethane (46 mg, 0.3 mmol). The reaction mixture was stirred at 80°C for 3 h and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to yield the title compound.

[1128] LC-MS:(ESI,m / z):[M+H] + =493.3.

[1129] Step 4: Preparation of 2-(9-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3,9-diazaspiro[5.5]undec-3-yl)acetaldehyde

[1130]

[1131] A mixture of 1-(2-chloro-5-(9-(2,2-dimethoxyethyl)-3,9-diazaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (121 mg, 0.246 mmol) in trifluoroacetic acid / dichloromethane (1 mL / 2 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain the title compound.

[1132] LC-MS:(ESI,m / z):[M+H] + =447.1.

[1133] Intermediate 8: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanal

[1134] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione

[1135]

[1136] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol), 3-(piperidin-4-yl)propyl-1-ol (310 mg, 2.17 mmol), and DIEA (701 mg, 5.43 mmol) in NMP (5 mL) was reacted in a microwave reactor at 140°C for 5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was collected and washed with water (100 mL x 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified on a silica gel column to obtain the desired product.

[1137] LC-MS:(ESI,m / z):[M+H] + =400.2.

[1138] Step 2: Preparation of 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanal

[1139]

[1140] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione (310 mg, 0.78 mmol) and IBX (436 mg, 1.56 mmol) in acetonitrile (6 mL) was stirred at 80°C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was collected and washed with water (50 mL x 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by silica gel column chromatography to obtain the product.

[1141] LC-MS:(ESI,m / z):[M+H] +=398.2.

[1142] Intermediate 9: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-yl)quinazolin-4-amine

[1143] Step 1: Preparation of 2-amino-5-bromo-4-methoxybenzoic acid

[1144]

[1145] To a stirred solution of 2-amino-4-methoxybenzoic acid (16.7 g, 100.0 mmol) in DMF (300 mL) at 0°C was added NBS (19.6 g, 110.0 mmol). The reaction mixture was stirred at 25°C for 1 h and quenched with water (300 mL). The mixture was extracted with EA (300 mL x 3). The organic layer was collected and washed with sodium chloride (saturated aqueous solution, 300 mL x 3), dried over anhydrous ammonium sulfate, and concentrated to yield the desired crude product. The crude product was used directly in the next step without purification.

[1146] LC-MS:(ESI,m / z):[M+H] + =247.4.

[1147] Step 2: Preparation of 6-bromo-7-methoxy-2-methylquinazolin-4-ol

[1148]

[1149] To a mixture of 2-amino-5-bromo-4-methoxybenzoic acid (19.5 g, 79.3 mmol) in MeOH (195 mL) was added ammonium acetate (61.0 g, 793 mmol) and trimethyl orthoacetate (95.1 g, 793 mmol). The reaction mixture was stirred in a sealed container at 120°C for 24 hours. The reaction mixture was poured into water (500 mL), and the solid product was filtered. The crude product was washed with EA to obtain the desired crude product, which was used directly in the next reaction without purification.

[1150] LC-MS:(ESI,m / z):[M+H] + =271.0.

[1151] Step 3: Preparation of tert-butyl 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1152]

[1153] To a mixture of 6-bromo-7-methoxy-2-methylquinazolin-4-ol (1.5 g, 3.09 mmol) in DMF (30 mL) and water (4 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.73 g, 6.18 mmol), sodium carbonate (982 mg, 9.27 mmol), and Pd(dppf)2Cl2 (226 mg, 0.319 mmol). The reaction mixture was stirred at 110°C overnight. The reaction mixture was quenched with water (300 mL) and extracted with EA (200 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the desired product.

[1154] LC-MS:(ESI,m / z):[M+H] + =372.2.

[1155] Step 4: Preparation of tert-butyl 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)piperidine-1-carboxylate

[1156]

[1157] To a solution of tert-butyl 4-(4-hydroxy-7-methoxyquinazolin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate (500 mg, 0.894 mmol) in MeOH (20 mL) was added Pd / C (300 mg). The reaction mixture was stirred at 50°C under an H2 atmosphere for 2 days. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain the desired product, tert-butyl 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)piperidine-1-carboxylate. The crude product was used directly in the next reaction.

[1158] LC-MS:(ESI,m / z):[M+H] + =374.2.

[1159] Step 5: Preparation of tert-butyl 4-(7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)piperidine-1-carboxylate

[1160]

[1161] To a solution of tert-butyl 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)piperidine-1-carboxylate (250.0 mg, 0.76 mmol), TPSCl (295.0 mg, 1.0 mmol), and DMAP (13.0 mg, 0.1 mmol) in DCM (5.0 mL) was added TEA (0.3 mL, 2.4 mmol). The reaction mixture was stirred at room temperature for 12 h. The reaction solution was diluted with DCM and washed with saturated NaHCO₃ solution. The organic phase was dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by column chromatography (eluent system: EA / PE) to obtain tert-butyl 4-(7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)piperidine-1-carboxylate.

[1162] LC-MS:(ESI,m / z):[M+H] + =640.0.

[1163] Step 6: Preparation of (R)-tert-butyl 4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidine-1-carboxylate

[1164]

[1165] To a solution of tert-butyl 4-(7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)piperidine-1-carboxylate (400 mg, 0.03 mmol) in DMSO (8 mL) was added (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (203 mg, 0.75 mmol) and TEA (0.8 mL). The reaction mixture was stirred at 90°C overnight. The reaction was quenched with water and extracted with EA. The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by forward column chromatography to afford the desired product, tert-butyl (R)-4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidine-1-carboxylate.

[1166] LC-MS:(ESI,m / z):[M+H] + =590.3.

[1167] Step 7: Preparation of (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)quinazolin-4-amine

[1168]

[1169] To a solution of (R)-tert-butyl 4-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)piperidine-1-carboxylate (220 mg, 0.328 mmol) in DCM was added TFA. The reaction mixture was stirred at 25°C for 2 h. After concentration, the desired product, (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)quinazolin-4-amine, was obtained. The crude product was used directly in the next reaction.

[1170] LC-MS:(ESI,m / z):[M+H] + =490.2

[1171] Step 8: Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-yl)quinazolin-4-amine

[1172]

[1173] To a solution of (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-yl)quinazolin-4-amine (124 mg, 0.25 mmol) in EtOH / H₂O (3 mL / 1 ml) was added NH₄Cl (135.6 mg, 2.5 mmol) and Fe powder (141.5 mg, 2.5 mmol). The reaction mixture was stirred at 70°C under a N₂ atmosphere for 2 h. The reaction mixture was filtered and concentrated to obtain a crude product. The crude product was purified by preparative HPLC to yield the desired product, (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-yl)quinazolin-4-amine.

[1174] LC-MS:(ESI,m / z):[M+H] + =460.2.

[1175] 1 H NMR (400MHz, DMSO-d6) δ8.32(s,1H),8.09(s,1H),7.03(s,1H),6.88(d,J=11.1Hz,1H),6.70(s,1H),5.57(d,J=6.9Hz,1H),3 .89(s,3H),3.39–3.25(m,2H),3.22–3.13(m,1H),3.07–2.95(m,2H),2.36(s,3H),2.03–1.85(m,4H),1.56(d,J=7.0Hz,3H).

[1176] Intermediate 10: (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-oxy)quinazolin-4-amine

[1177] Step 1: tert-Butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate

[1178]

[1179] To a mixture of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.0 g, 49.7 mmol) and TEA (15.0 g, 149.1 mmol) in DCM (100 mL) was added dropwise methanesulfonyl chloride (7.4 g, 64.9 mmol) dissolved in DCM (20.0 mL) at 0°C. The reaction mixture was stirred at room temperature overnight, then water (200 mL) was added and the mixture was extracted with DCM (200 mL x 2). The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography to obtain the desired product.

[1180] LC-MS:(ESI,m / z):[M+H] + =280.1.

[1181] Step 2: Preparation of 6,7-dimethoxy-2-methylquinazolin-4-ol

[1182]

[1183] To a mixture of 2-amino-4,5-dimethoxybenzoic acid (20.0 g, 0.1 mol) in 2-methoxyethanol (120.0 mL) was added acetamidine hydrochloride (19.0 g, 0.2 mol) and sodium acetate (16.4 g, 0.2 mol). The reaction mixture was stirred at 140°C overnight. The reaction mixture was poured into water (250 mL) and stirred at room temperature for 10 minutes. The mixture was then filtered, the filter cake washed with water, and the solid dried under vacuum to yield the desired product.

[1184] LC-MS:(ESI,m / z):[M+H] + =221.2.

[1185] Step 3: Preparation of 7-methoxy-2-methylquinazoline-4,6-diol

[1186]

[1187] A reaction mixture of 6,7-dimethoxy-2-methylquinazolin-4-ol (9.1 g, 41.4 mmol) and DL-methionine (10.5 g, 70.4 mmol) in methanesulfonic acid (50 mL) was stirred at 80°C overnight. The reaction was quenched with ice water and basified with sodium hydroxide (2N) solution. The precipitate was filtered to obtain the desired crude product.

[1188] LC-MS:(ESI,m / z):[M+H] + =207.2.

[1189] Step 4: Preparation of tert-butyl 4-((4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidine-1-carboxylate

[1190]

[1191] A reaction mixture of 7-methoxy-2-methylquinazoline-4,6-diol (1.4 g, 6.8 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2.2 g, 8.2 mmol), and potassium carbonate (1.8 g, 13.6 mmol) in NMP (10.0 mL) was stirred at 100°C overnight. Water (50.0 mL) was then added, and the mixture was extracted with EA (50 mL x 3). The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by reverse-phase column chromatography (acetonitrile:water = 0-100%) to obtain the desired product.

[1192] LC-MS:(ESI,m / z):[M+H] + =390.2.

[1193] Step 5: Preparation of tert-butyl 4-((7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)oxy)piperidine-1-carboxylate

[1194]

[1195] A reaction mixture of tert-butyl 4-((4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidine-1-carboxylate (800.0 mg, 2.0 mmol), 2,4,6-triisopropylbenzenesulfonyl chloride (748.0 mg, 2.4 mmol), DMAP (125.0 mg, 0.4 mmol), and TEA (623.0 mg, 6.0 mmol) in DCM (10.0 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and the concentrate was purified by column chromatography to obtain the desired product.

[1196] LC-MS:(ESI,m / z):[M+Na] + =678.1.

[1197] Step 6: Preparation of (R)-tert-butyl 4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidine-1-carboxylate

[1198]

[1199] A reaction mixture of tert-butyl 4-((7-methoxy-2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)quinazolin-6-yl)oxy)piperidine-1-carboxylate (0.8 g, 1.2 mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride (0.43 g, 1.8 mmol), and TEA (1.1 g, 10.8 mmol) in DMSO (15.0 mL) was stirred at 90°C overnight. Water (50.0 mL) was then added, and the mixture was extracted with EA (50 mL x 3). The organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by reverse-phase column chromatography (acetonitrile-water = 0-100%) to obtain the desired product.

[1200] LC-MS:(ESI,m / z):[M+H] + =606.0.

[1201] Step 7: Preparation of (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-oxy)quinazolin-4-amine

[1202]

[1203] A mixture of (R)-tert-butyl 4-((7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)piperidine-1-carboxylate (140 mg, 0.23 mmol) in DCM (5.0 mL) and TFA (1.0 mL) was stirred at room temperature for 2.0 h. The reaction was concentrated under reduced pressure to obtain (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-oxy)quinazolin-4-amine.

[1204] LC-MS:(ESI,m / z):[M+H] + =506.1.

[1205] Step 8: Preparation of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-oxy)quinazolin-4-amine

[1206]

[1207] A reaction mixture of (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(piperidin-4-oxy)quinazolin-4-amine (100.0 mg, 0.19 mmol) and Pd / C (20.0 mg) in methanol (5.0 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The reaction mixture was filtered, the filtrate was concentrated, and the concentrate was purified by preparative HPLC to obtain the desired product.

[1208] LC-MS:(ESI,m / z):[M+H] + =476.3.

[1209] 1 H NMR (400MHz, DMSO-d6) δ7.91(d,J=7.9Hz,1H),7.78(s,1H),7.04(s,1H),6.88(s,1H),6.85(s,1H),6.69(s,1H),5.66-5.46(m, 3H),4.54-5.48(m,1H),3.87(s,3H),3.01-2.93(m,2H),2.64-2.53(m,2H),2.35(s,3H),1.93-1.89(m,2H),1.58-1.44(m,5H).

[1210] Intermediate 11: Pentafluorophenyl 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate

[1211] Step 1: Preparation of 4-((2-carboxyethyl)amino)benzoic acid

[1212]

[1213] Acrylic acid (23.62 g, 328.1 mmol) was added to a solution of 4-aminobenzoic acid (15.0 g, 109.4 mmol) in AcOH / H2O (40 ml / 200 mL). The mixture was stirred at 110°C for 12 hours. The reaction mixture was cooled and filtered to obtain the target product, 4-((2-carboxyethyl)amino)benzoic acid.

[1214] LC-MS:(ESI,m / z):[M+H] + =210.0.

[1215] Step 2: Preparation of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid

[1216]

[1217] Urea (114.83 g, 1913.8 mmol) was added to a solution of 4-((2-carboxyethyl)amino)benzoic acid (20.0 g, 95.69 mmol) in AcOH (240 mL) and stirred at 110 ° C for 24 h. After the reaction solution was cooled, HCl solution was added to adjust the pH to 1-2. The precipitated solid was filtered to obtain the target product 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid.

[1218] LC-MS:(ESI,m / z):[M+H] + =233.1.

[1219] Step 3: Preparation of pentafluorophenyl 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate

[1220]

[1221] Pentafluorophenol (12.97 g, 70.51 mmol) and DCC (14.52 g, 70.51 mmol) were added to a solution of 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoic acid (15.0 g, 64.1 mmol) in DMF (200 mL), stirred at room temperature overnight, extracted with ethyl acetate (100 mL × 3), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 3:7) to obtain the target product, pentafluorophenyl 4-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate.

[1222] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),8.20(d,J=8.7Hz,2H),7.64(d,J=8.7Hz,2H),3.94(t,J=6.6Hz,2H),2.76(t,J=6.6Hz,2H).

[1223] Intermediate 12: tert-Butyl (R)-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl)carbamate

[1224] Step 1: Preparation of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one

[1225]

[1226] A reaction mixture of 1-bromo-3-nitro-5-(trifluoromethyl)benzene (50.0 g, 185.1 mmol), Pd(PPh3)2Cl2 (12.9 g, 18.5 mmol), TEA (37.4 g, 370.2 mmol), and tributyl(1-ethoxyvinyl)stannane (86.6 g, 240.6 mmol) in dioxane (300 mL) was stirred at 80°C for 16 h. The reaction mixture was quenched with water (900 mL) and washed with EA (500 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was stirred in a mixture of 6N HCl (200 mL) and THF (200 mL) for 30 min. Water (500 mL) and EA (500 mL x 2) were then added. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE=0-1:9) to give 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one.

[1227] 1 H NMR (400MHz, CDCl3) δ8.95(s,1H),8.69(s,1H),8.53(s,1H),2.75(s,3H).

[1228] Step 2: Preparation of 1-(3-amino-5-(trifluoromethyl)phenyl)ethan-1-one

[1229]

[1230] A mixture of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-one (1.5 g, 6.4 mmol) and Pd / C (400 mg) in THF (30 mL) was stirred at 60°C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to yield 1-(3-amino-5-(trifluoromethyl)phenyl)ethan-1-one. The product was used directly in the next reaction.

[1231] LC-MS:(ESI,m / z):[M+H] + =203.0.

[1232] Step 3: Preparation of tert-butyl (3-acetyl-5-(trifluoromethyl)phenyl)carbamate

[1233]

[1234] A mixture of 1-(3-amino-5-(trifluoromethyl)phenyl)ethan-1-one (1.1 g, 5.4 mmol) and (Boc)2O (5.9 g, 27.0 mmol) in dioxane (20 mL) was stirred at 80°C for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (EA:PE = 0 to 3:17) to provide tert-butyl (3-acetyl-5-(trifluoromethyl)phenyl)carbamate.

[1235] LC-MS:(ESI,m / z):[M+H] + =303.0.

[1236] 1 H NMR (400MHz, DMSO-d6) δ8.26(s,1H),8.18(d,J=6.5Hz,1H),8.05(s,1H),2.67(d,J=11.4Hz,3H),1.41(d,J=11.7Hz,9H).

[1237] Step 4: Preparation of tert-butyl (S,E)-(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-(trifluoromethyl)phenyl)carbamate

[1238]

[1239] A mixture of tert-butyl (3-acetyl-5-(trifluoromethyl)phenyl)carbamate (1.0 g, 3.3 mmol), Ti(OEt)4 (1.8 g, 6.6 mmol), diethylene glycol dimethyl ether (2.3 g, 17.5 mmol), and (S)-propane-2-sulfenamide (1.2 g, 9.9 mmol) in THF (10 mL) was stirred at 70°C for 12 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with EA (30 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 0 to 1:4) to yield tert-butyl (S,E)-(3-(1-((tert-butylsulfinyl)imino)ethyl)-5-(trifluoromethyl)phenyl)carbamate.

[1240] LC-MS:(ESI,m / z):[M+H] + =407.0.

[1241] Step 5: Preparation of tert-butyl (3-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate

[1242]

[1243] To a solution of tert-butyl (S,E)-(3-(1-((tert-butylsulfinylsulfinyl)imino)ethyl)-5-(trifluoromethyl)phenyl)carbamate (1.0 g, 2.4 mmol) in THF (20 mL) at -78°C was added L-Selectride (1.0 mol / L / THF, 3.6 mL). The reaction was stirred at -78°C for 50 min. Water (50 mL) was added to the reaction solution to quench the reaction. The mixture was then extracted with EA (50 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE = 0 to 1:1) to afford tert-butyl (3-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate.

[1244] LC-MS:(ESI,m / z):[M+H] + =409.0.

[1245] 1 H NMR (400MHz, DMSO-d6) δ9.71 (s, 1H), 7.74 (d, J = 5.1Hz, 2H), 7.39 (s, 1H), 4.15 (q,J=6.7Hz,1H),1.48(s,15H),1.31(d,J=6.7Hz,3H),1.11(d,J=2.1Hz,3H).

[1246] Step 6: Preparation of tert-butyl (R)-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl)carbamate

[1247]

[1248] Tert-butyl (3-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate (1.0 g, 2.4 mmol) was stirred in 1N HCl / EtOAc (20 mL) at 0°C for 3 h. The reaction solution was quickly filtered through a chromatography column, rinsed first with EtOAc and then with a 5 / 1 DCM / MeOH mixture. The filtrate was basified with 7N NH3 / MeOH, and the organic phase was washed with water, dried over anhydrous Na2SO4, filtered, and concentrated to provide tert-butyl (R)-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl)carbamate.

[1249] LC-MS:(ESI,m / z):[M+H] + =305.1.

[1250] 1H NMR (400MHz, DMSO-d6) δ9.63(s,1H),7.71(s,1H),7.69(s,1H),7.35(s,1H),4.02–3.99(m,1H),1.48(s,9H),1.23(d,J=6.6Hz,3H).

[1251] Intermediate 13: (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[1252]

[1253] To a stirred solution of methyl (1R,4R)-4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (330 mg, 1.0 mmol) in DMF (5 mL) was added BOP (574 mg, 1.3 mmol) and DBU (380 mg, 2.5 mmol). After stirring for 15 min, tert-butyl (R)-(3-(1-aminoethyl)-5-(trifluoromethyl)phenyl)carbamate hydrochloride (396 mg, 1.3 mmol) was added. The reaction mixture was stirred at 70°C for 12 h. The reaction mixture was quenched by adding water (10 mL) and then extracted with EA (30 mL x 3). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (EA:PE=0-1) to give (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester.

[1254] LC-MS:(ESI,m / z):[M+H] + =617.4.

[1255] 1 H NMR(400MHz, DMSO-d6)δ9.69(s,1H),8.12(s,1H),7.77(d,J=25.2Hz,2H),7.41(s,1H),7.01(s,1H),5.71–5.55(m,1H),3.90(s,3H),3.6 2(s,3H),2.96(d,J=11.8Hz,1H),2.39(d,J=10.4Hz,4H),2.06(d,J=12.0Hz,2H),1.89(d,J=14.0Hz,2H),1.64–1.50(m,7H),1.46(s,9H).

[1256] Intermediate 14: (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid

[1257]

[1258] To a solution of methyl (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (250 mg, 0.4 mmol) in THF / H2O (10 mL / 5 mL) was added LiOH.H2O (48 mg, 1.2 mmol), and the reaction solution was stirred at 40°C overnight. The reaction solution was adjusted to pH 5.8 with 10% citric acid, then extracted with EtOAc (30 mL × 3). The organic phases were combined, washed with saturated brine, and concentrated under reduced pressure to give (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid.

[1259] LC-MS:(ESI,m / z):[M+H] + =603.1.

[1260] 1 H NMR (400MHz, DMSO-d6) δ9.67(s,1H),8.20(d,J=7.4Hz,1H),8.07(s,1H),7.77(d,J=24.0Hz,2H),7.41(s,1H),7.00(s,1H),5.68–5.5 2(m,1H),3.89(s,3H),2.95(d,J=11.3Hz,1H),2.40–2.23(m,4H),2.06(d,J=12.0Hz,2H),1.88(d,J=12.0Hz,2H),1.67–1.41(m,16H).

[1261] Intermediate 15: (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid

[1262] Step 1: Preparation of methyl (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylate

[1263]

[1264] To a solution of (1R,4R)-4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (500 mg, 1.52 mmol) in DMF (10 mL) was added BOP (871 mg, 1.97 mmol) and DBU (577 mg, 3.80 mmol) with stirring. Stirring was continued for 15 min, followed by the addition of (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine (461 mg, 1.97 mmol). The reaction mixture was then stirred at 70°C overnight. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with EA (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column (EA:PE=0-1) to give (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester.

[1265] LC-MS:(ESI,m / z):[M+H] + =547.1.

[1266] 1 H NMR (400MHz, DMSO-d6) δ8.62(s,1H),8.34(d,J=6.0Hz,3H),8.04(s,1H),7.01(s,1H),5.68(p,J=6.9Hz,1H),3.89(s,3H),3.64(s,3H),2. 94(t,J=11.4Hz,1H),2.48–2.37(m,1H),2.34(s,3H),2.08(d,J=12.0Hz,2H),1.97–1.86(m,2H),1.69(d,J=7.1Hz,3H),1.65–1.47(m,4H).

[1267] Step 2: Preparation of (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid

[1268]

[1269] To a solution of methyl (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylate (300 mg, 0.55 mmol) in THF / H₂O (15 mL, 1:2) was added LiOH.H₂O (240 mg, 8.0 mmol). The reaction mixture was then stirred at 50°C overnight. Water (50 mL) was added to quench the reaction mixture, and the mixture was extracted with EA (50 mL x 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid.

[1270] LC-MS:(ESI,m / z):[M+H] + =533.3.

[1271] 1 H NMR (400MHz, DMSO-d6) δ12.09(s,1H),8.89(s,1H),8.63(s,1H),8.36(d,J=10.6Hz,2H),8.14(s,1H),7.02(s,1H),5.89–5.64(m,1H),3.92(s,3 H),2.95(t,J=11.6Hz,1H),2.41(s,3H),2.37–2.26(m,1H),2.08(d,J=1 0.7Hz, 2H), 1.96–1.85 (m, 2H), 1.72 (d, J = 7.1Hz, 3H), 1.68–1.44 (m, 4H).

[1272] Intermediate 16: (1R,4R)-4-(4-(((R)-1-(4-bromothien-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid

[1273] Step 1: Preparation of 1-(1,3-dicarbonylisoindolin-2-yl)4-methyl(1R,4R)-cyclohexane-1,4-dicarboxylate

[1274]

[1275] To a solution of (1R,4R)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (20 g, 107.4 mmol) and 2-hydroxyisoindole-1,3-dione (20 g, 107.4 mmol) in DCM (300 mL) was added EDCI (34.7 g, 118.2 mmol) and DMAP (1.3 g, 10.7 mmol). The reaction mixture was then stirred at room temperature for 2 h. Brine and DCM were added to the reaction mixture. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM) to yield 1-(1,3-dicarbonylisoindole-2-yl) 4-methyl (1R,4R)-cyclohexane-1,4-dicarboxylate.

[1276] LC-MS:(ESI,m / z):[M+Na] + =354.1.

[1277] Step 2: Preparation of 2-amino-5-iodo-4-methoxybenzonitrile

[1278]

[1279] To a solution of 2-amino-4-methoxybenzonitrile (86.3 g, 582 mmol) in DMF (1000 mL) was added NIS (133 g, 613 mmol). The reaction was then stirred at room temperature for 2 h. Brine and DCM were added to the reaction mixture. The organic layer was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to yield 2-amino-5-iodo-4-methoxybenzonitrile.

[1280] LC-MS:(ESI,m / z):[M+Na] + =296.9.

[1281] Step 3: Preparation of N-(2-cyano-4-iodo-5-methoxyphenyl)acetamide

[1282]

[1283] To a solution of 2-amino-5-iodo-4-methoxybenzonitrile (160 g, 580 mmol) in HOAc (1600 mL) was added AcO (71.3 g, 700 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated to yield N-(2-cyano-4-iodo-5-methoxyphenyl)acetamide.

[1284] LC-MS:(ESI,m / z):[M+H] + =317.0.

[1285] Step 4: Preparation of (1R,4R)-4-(4-acetylamino-5-cyano-2-methoxyphenyl)cyclohexane-1-carboxylic acid methyl ester

[1286]

[1287] To a solution of N-(2-cyano-4-iodo-5-methoxyphenyl)acetamide (15.0 g, 47.45 mmol), 1-(1,3-dicarbonylisoindolin-2-yl)-4-methyl (1R,4R)-cyclohexane-1,4-dicarboxylate (31.40 g, 94.90 mmol), and Hantzsch-ester (24.00 g, 94.90 mmol) in DMA (237 mL, 0.2 M) was added NiBr(dtbpy) (2.31 g, 4.75 mmol). The reaction solution was flushed with N for 5 minutes and irradiated with two Kessil PR160-purple LED lamps (30 W High Luminous DEX2100 LED, λmax = 390 nm) for 16 hours. The reaction temperature was controlled at 30-40°C. After the reaction is completed, the reaction solution is poured into water (1L) and then extracted with EtOAc (150mLx3). The organic phases are combined and washed with saturated brine (400mLx3), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product is purified by chromatography (MeOH:DCM=1:99). The eluate containing the product is concentrated to 80mL, filtered, and the filtrate is concentrated to obtain a mixture with a cis-trans ratio of 1:1. The filter cake is a mixture with a cis-trans ratio of 15:1. The mixture with a cis-trans ratio of 15:1 is dissolved in DMA (85mL), and then 0.5M K2CO3 aqueous solution (200mL) is added. The resulting mixture is stirred at room temperature for 2 hours, filtered to obtain a mixture with a cis-trans ratio of 20:1, and this mixture is recrystallized from acetonitrile (180mL) to obtain the target product (cis-trans ratio of 97:2).

[1288] LC-MS:(ESI,m / z):[M+H] + =331.1.

[1289] 1 H NMR(400MHz, CDCl3)δ8.04(s,1H),7.55(s,1H),7.29(s,1H),3.89(s,3H),3.69(s,3H),2.90-2.84(m,1H),2 .35-2.26(m,1H),2.25(s,3H),2.11-2.08(m,2H),1.92-1.89(m,2H),1.63-1.56(m,2H),1.39-1.33(m,2H).

[1290] Step 5: Preparation of methyl (1R,4R)-4-(7-methoxy-2-methyl-4-carbonyl-3,4-dihydroquinazolin-6-yl)cyclohexane-1-carboxylate

[1291]

[1292] Methyl (1R,4R)-4-(4-acetylamino-5-cyano-2-methoxyphenyl)cyclohexane-1-carboxylate (3 g, 9.08 mmol) was added to i-PrOH (80 mL), and then HCl gas was passed through at room temperature for 1 hour. The reaction mixture was filtered and dried to yield methyl (1R,4R)-4-(7-methoxy-2-methyl-4-carbonyl-3,4-dihydroquinazolin-6-yl)cyclohexane-1-carboxylate.

[1293] LC-MS:(ESI,m / z):[M+H] + =331.1.

[1294] 1 H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.23(s,1H),3.95(s,3H),3.61(s,3H),2.98-2.87(m,1 H),2.58(s,3H),2.47-2.39(m,1H),2.06-1.98(m,2H),1.88-1.80(m,2H),1.59-1.42(m,4H).

[1295] Step 6: Preparation of (R,Z)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfenamide

[1296]

[1297] A reaction mixture of 1-(4-bromothiophen-2-yl)ethan-1-one (10.0 g, 48.80 mmol), (R)-2-methylpropane-2-sulfinamide (8.90 g, 73.20 mmol), and Ti(OEt)4 (27.8 g, 122.00 mmol) in THF (70 mL) was stirred at 80°C for 3 h. The reaction mixture was quenched with water (200 mL) and then extracted with EA (100 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 100:1) to afford (R,Z)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide.

[1298] 1H NMR (400MHz, DMSO-d6) δ7.96 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 1.2 Hz, 1H), 2.68 (s, 3H), 1.19 (s, 9H).

[1299] Step 7: Preparation of (R)-N-((R)-1-(4-bromothien-2-yl)ethyl)-2-methylpropane-2-sulfenamide

[1300]

[1301] To a solution of (R,Z)-N-(1-(4-bromothiophen-2-yl)ethylidene)-2-methylpropane-2-sulfinamide (7.0 g, 22.7 mmol) in THF (10 mL) was added 9-BBN / THF (0.5 M, 200 mL). The reaction was stirred at 25°C for 0.5 h. The reaction was quenched by the addition of MeOH (10 mL), followed by the addition of water (100 mL) and extraction with EA (100 mL x 3). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH = 100:1) to afford (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfinamide.

[1302] 1 H NMR (400MHz, DMSO-d6) δ7.54(d,J=1.2Hz,1H),7.08(s,1H),5.93(d,J=7.2Hz,1H),4.64-4.58(m,1H),1.48(d,J=6.8Hz,3H),1.12(s,9H).

[1303] Step 8: Preparation of (R)-1-(4-bromothiophen-2-yl)ethane-1-amine hydrochloride

[1304]

[1305] To a solution of (R)-N-((R)-1-(4-bromothiophen-2-yl)ethyl)-2-methylpropane-2-sulfenamide (6.0 g, 19.34 mmol) in 1,4-dioxane (60 mL) was added HCl (12 M, 454 mmol). The reaction mixture was then stirred at 25°C for 2 h. The reaction mixture was then concentrated. The resulting crude product was stirred in MTBE (100 mL), filtered, and dried to yield (R)-1-(4-bromothiophen-2-yl)ethane-1-amine hydrochloride.

[1306] 1H NMR (400MHz, DMSO-d6) δ8.62(s,3H),7.71(s,1H),7.32(s,1H),4.71-4.67(m,1H),1.57(d,J=6.8Hz,3H).

[1307] Step 9: Preparation of (1R,4R)-4-(4-(((R)-1-(4-bromothien-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[1308]

[1309] To a solution of (1R,4R)-4-(7-methoxy-2-methyl-4-carbonyl-3,4-dihydroquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (3.00 g, 9.07 mmol) and BOP (5.21 g, 11.79 mmol) in DMF (35 mL) was added DBU (3.45 g, 22.67 mmol) at room temperature. After stirring for 15 minutes, a solution of (R)-1-(4-bromothiophen-2-yl)ethane-1-amine hydrochloride (2.86 g, 11.79 mmol) in DMF (35 mL) was added dropwise. The reaction solution was stirred at room temperature for 20 minutes and then heated to 70°C and stirred for 8 hours. The reaction solution was purified by reverse phase column to obtain methyl (1R,4R)-4-(4-(((R)-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate.

[1310] LC-MS:(ESI,m / z):[M+H] + =518.0,520.0.

[1311] Step 10: Preparation of (1R,4R)-4-(4-(((R)-1-(4-bromothiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid

[1312]

[1313] To a solution of (1R,4R)-4-(4-(((R)-1-(4-bromothien-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester (2.00 g, 3.86 mmol) in THF / H₂O (20.0 mL / 20.0 mL) was added LiOH (0.81 g, 19.30 mmol). The reaction mixture was stirred at 25°C for 16 h. The reaction mixture was acidified with 2N HCl solution, resulting in the formation of a precipitate. The residue was filtered, and the filter cake was dried under vacuum to yield (1R,4R)-4-(4-(((R)-1-(4-bromothien-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid.

[1314] LC-MS:(ESI,m / z):[M+H] + =504.0,506.0.

[1315] Intermediate 17: Pentafluorophenyl 4-(2,6-dioxopiperidin-3-yl)benzoate

[1316] Step 1: Preparation of methyl 4-(4-cyano-1-methoxy-1-oxobutan-2-yl)benzoate

[1317]

[1318] Benzyltrimethylammonium hydroxide (6.03 g, 36.057 mmol) and acrylonitrile (5.727 g, 79.32 mmol) were added to a toluene solution (200 mL) of methyl 4-(2-methoxy-2-oxoethane)benzoate (15.0 g, 72.12 mmol), stirred at 30 ° C for 16 h, extracted with ethyl acetate (100 mL × 5), and the organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA: PE = 3:7) to obtain the target product, methyl 4-(4-cyano-1-methoxy-1-oxobutan-2-yl)benzoate.

[1319] 1 H NMR(400MHz,DMSO-d6)δ7.95(d,J=4.0Hz,2H),7.46(d,J=6.0Hz,2H),3.90-3.8 0(m,4H),3.62(s,3H),2.48-2.38(m,2H),2.36-2.26(m,1H),2.10-1.96(m,1H).

[1320] Step 2: Preparation of 4-(2,6-dioxopiperidin-3-yl)benzoic acid

[1321]

[1322] Methyl 4-(4-cyano-1-methoxy-1-oxobutan-2-yl)benzoate (8.5 g, 32.56 mmol) was dissolved in acetic acid (30 mL), sulfuric acid (15 mL) was added, and the mixture was stirred at 110°C for 12 h. The mixture was extracted with dichloromethane / methanol (10 / 1, 150 ml × 3), and the organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH:DCM=1:10) to obtain 4-(2,6-dioxopiperidin-3-yl).

[1323] 1 H NMR (400MHz, DMSO-d6) δ12.89(s,1H),10.89(s,1H),7.91(d,J=4.0Hz,2H),7.36(d,J=4.0Hz,2H) ,4.02-3.92(m,1H),2.72-2.63(m,1H),2.56-2.45(m,1H),2.30-2.20(m,1H),2.10-2.00(m,1H).

[1324] Step 3: Preparation of pentafluorophenyl 4-(2,6-dioxopiperidin-3-yl)benzoate

[1325]

[1326] 4-(2,6-dioxopiperidin-3-yl)benzoic acid (1.3 g, 5.579 mmol) was dissolved in DMF (100 mL), pentafluorophenol (1.129 g, 6.14 mmol) and DCC (1.265 g, 6.14 mmol) were added, and the mixture was stirred at room temperature overnight. The mixture was extracted with ethyl acetate (100 mL × 3), and the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA: PE = 3:7) to obtain pentafluorophenyl 4-(2,6-dioxopiperidin-3-yl)benzoate.

[1327] 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),8.17(d,J=4.0Hz,2H),7.56(d,J=4.0Hz,2H),4.14- 4.08(m,1H),2.79-2.69(m,1H),2.66-2.55(m,1H),2.30-2.23(m,1H),2.15-2.05(m,1H).

[1328] Intermediate 18: Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate

[1329] Step 1: Preparation of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid

[1330]

[1331] 3-Amino-4-methoxybenzoic acid (5.0 g, 2.93 mmol) was suspended in acrylic acid (8.05 mL, 117 mmol) and stirred at 100°C for 3 hours. The reaction mixture was then cooled to room temperature with stirring. Acetic acid (33 mL) was added, and the stirred suspension was heated at 100°C for 10 minutes. Urea (11.00 g, 183 mmol) was added, and the reaction mixture was stirred at 120°C overnight. The reaction mixture was added to a mixture of ice water and concentrated hydrochloric acid (37%) and stirred. The resulting suspension was stored in a refrigerator at 5°C overnight, then filtered, washed with water, and dried to obtain a solid. The solid was triturated in hydrochloric acid (0.05 M), filtered, washed with methyl tert-butyl ether, and dried under reduced pressure at 40°C to obtain the desired product.

[1332] 1 H NMR (400MHz, DMSO-d6) δ12.70(s,1H),10.34(s,1H),7.92(dd,J=8.6,2.2Hz,1H),7.83(d,J =2.2Hz,1H),7.21(d,J=8.8Hz,1H),3.94-3.82(m,3H),3.60(t,J=6.7Hz,2H),2.69(s,2H).

[1333] Step 2: Preparation of pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate

[1334]

[1335] A mixture of 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoic acid (2.0 g, 7.58 mmol), 2,3,4,5,6-pentafluorophenol (1.67 g, 9.09 mmol), and N,N'-dicyclohexylcarboximide (1.87 g, 9.09 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 3 h. The reaction solution was poured into water (200 mL) and stirred for 0.5 h. The solution was extracted with ethyl acetate (200 mL x 3). The organic phase was collected, washed with water (500 mL x 2) and saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was purified by column chromatography to obtain the desired product, pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-methoxybenzoate.

[1336] LC-MS:(ESI,m / z):[M+H] + =431.1.

[1337] Intermediate 19: Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-4-fluorobenzoate

[1338]

[1339] Prepared according to the method of Intermediate 18.

[1340] LC-MS:(ESI,m / z):[M+H] + =419.0.

[1341] Intermediate 20: Pentafluorophenyl 3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate

[1342]

[1343] Prepared according to the method of Intermediate 18.

[1344] LC-MS:(ESI,m / z):[M+H] + =401.0.

[1345] Intermediate 21: (1R,4R)-4-(4-(((R)-1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[1346] Step 1: Preparation of (1R,4R)-4-(4-(((R)-1-(4-(2-formylphenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[1347]

[1348] To a solution of methyl (1R,4R)-4-(4-(((R)-1-(4-bromothien-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (250 mg, 0.48 mmol) in 1,4-dioxane / H2O (1.5 mL / 0.5 mL) was added K3PO4 (255 mg, 1.2 mmol), (PPh3)2PdCl2 (34 mg, 0.048 mmol), and (2-formylphenyl)boronic acid (87 mg, 0.58 mmol). The reaction was stirred at 100°C overnight. The reaction solution was concentrated and then purified by column chromatography (PE / EA=2 / 1 to 1 / 2) to obtain methyl (1R,4R)-4-(4-(((R)-1-(4-(2-formylphenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate.

[1349] LC-MS:(ESI,m / z):[M+H] + =544.1.

[1350] Step 2: Preparation of (1R,4R)-4-(4-(((R)-1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[1351]

[1352] To a mixture of methyl (1R,4R)-4-(4-(((R)-1-(4-(2-formylphenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (200 mg, 0.36 mmol) and dimethylamine hydrochloride (60 mg, 0.74 mmol) was added MeOH (3 mL), DCE (3 mL), and AcOH (5 drops). The solution was stirred at room temperature for 1 hour, then NaBH3CN (46 mg, 0.74 mmol) was added and the reaction mixture was stirred at room temperature for an additional 3 hours. DCM and water were added to the reaction mixture, and the organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give methyl (1R,4R)-4-(4-(((R)-1-(4-(2-((dimethylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate.

[1353] LC-MS:(ESI,m / z):[M+H] + =573.3

[1354] 1H NMR (400MHz, CDCl3) δ7.44-7.34(m,3H),7.33-7.28(m,4H),7.12(s,1H),6.1 1-6.02(m,1H),5.69-5.60(m,1H),3.92(s,3H),3.69(s,3H),3.38(s,2H),3. 04-2.98(m,1H),2.63(s,3H),2.44-2.33(m,1H),2.24-2.18(m,6H),2.16-2. 07(m,2H),2.05-1.95(m,2H),1.82-1.79(d,J=6.8Hz,3H),1.67-1.60(m,4H).

[1355] Intermediate 22: tert-Butyl 4-(3-bromoprop-1-yn-1-yl)piperidine-1-carboxylate

[1356] Step 1: Preparation of tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate

[1357]

[1358] To a solution of CBr4 (14.0 g, 42.24 mmol) in DCM (200 mL) was added PPh3 (22.13 g, 84.48 mmol) with stirring at 0°C. Stirring was continued at 0°C for 30 min, followed by the addition of tert-butyl 4-formylpiperidine-1-carboxylate (6.0 g, 28.16 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA (200 mL) and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (EA:PE = 0 to 3:7) to afford tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate.

[1359] LC-MS:(ESI,m / z):[M-tBu] + =313.9.

[1360] Step 2: Preparation of tert-butyl 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate

[1361]

[1362] To a solution of tert-butyl 4-(2,2-dibromovinyl)piperidine-1-carboxylate (4.0 g, 10.86 mmol) in THF (60 mL) at -78°C was added n-BuLi (13.6 mL, 1.6 M / n-hexane). The mixture was stirred at -78°C for 1 hour, followed by the addition of paraformaldehyde (977 mg, 32.60 mmol). The reaction was stirred at room temperature overnight. NH4Cl (100 mL) was added to the reaction mixture to quench the reaction, which was then extracted with EA (100 mL x 3). The combined organic phases were washed with saturated brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (EA:PE = 0 to 4:1) to afford tert-butyl 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate.

[1363] LC-MS:(ESI,m / z):[M-Boc] + =140.2.

[1364] 1 H NMR(400MHz, DMSO-d6)δ5.04(t,J=5.9Hz,1H),4.04(dd,J=5.8,2.0Hz,2H),3.65–3.55(m,2H),3 .04(t,J=10.1Hz,2H),2.60(ddd,J=8.8,7.0,3.5Hz,1H),1.77–1.64(m,2H),1.43–1.31(m,11H).

[1365] Step 3: Preparation of tert-butyl 4-(3-bromoprop-1-yn-1-yl)piperidine-1-carboxylate

[1366]

[1367] To a solution of tert-butyl 4-(3-hydroxyprop-1-yn-1-yl)piperidine-1-carboxylate (700 mg, 2.92 mmol) and PPh3 (1.94 g, 5.83 mmol) in DCM (10 mL) was added CBr4 (1.94 g, 5.83 mmol) at 0°C with stirring. The reaction mixture was stirred at room temperature overnight. EA (10 mL) was added to the reaction mixture, which was then filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography (EA:PE = 0 to 3:7) to afford tert-butyl 4-(3-bromoprop-1-yn-1-yl)piperidine-1-carboxylate.

[1368] LC-MS:(ESI,m / z):[M-tBu] + =246.0.

[1369] 1H NMR (400MHz, DMSO-d6) δ4.24(d,J=2.0Hz,2H),3.64–3.54(m,2H),3.13–3.00(m,2H),2.75–2.65(m,1H),1.78–1.68(m,2H),1.44–1.33(m,11H).

[1370] Intermediate 23: tert-Butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate

[1371] Step 1: Preparation of tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate

[1372]

[1373] To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (1.0 g, 4.36 mmol) in THF (20 mL) at 0°C was added NaH (60%, 1.2 g, 30.58 mmol). The mixture was stirred at 0°C for 20 minutes. After warming to room temperature, 4-(bromomethyl)pyridinium hydrobromide (1.3 g, 5.13 mmol) was added, and the reaction mixture was stirred at room temperature overnight. Water (30 mL) was added to the reaction solution, and the mixture was extracted with EA (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The concentrate was purified by flash column chromatography (EA:PE = 0 to 4:1) to obtain the desired product, tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate.

[1374] LC-MS:(ESI,m / z):[M+H] + =321.1.

[1375] 1 H NMR (400MHz, CDCl3) δ8.57(d,J=5.9Hz,2H),7.24(d,J=5.7Hz,2H),4.51(s,2H),4.09(d,J=15.9Hz,2H),3.55(t,J=6.1 Hz,2H),2.70(t,J=12.2Hz,2H),1.66(d,J=13.9Hz,2H),1.58(m,2H),1.45(s,9H),1.26(m,1H),1.13(d,J=8.4Hz,2H).

[1376] Step 2: Preparation of tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate

[1377]

[1378] A mixture of tert-butyl 4-(2-(pyridin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (1.9 g, 5.9 mmol) and Pd / C (570 mg) in i-PrOH / H₂O (30 mL / 35 mL) was stirred at 75°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated to yield the desired product, tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate. The resulting product was used directly in the next reaction without purification.

[1379] LC-MS:(ESI,m / z):[M+H] + =327.2.

[1380] Intermediate 24: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde

[1381] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione

[1382]

[1383] To a solution of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.0 g, 3.6 mmol) in DMF (10 mL) was added 2-(piperidin-4-yl)ethan-1-ol (467 mg, 3.6 mmol) and DIEA (1.4 g, 10.8 mmol). The reaction mixture was stirred at 100°C overnight. Water (100 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with EA (20 mL x 3). The combined organic phases were washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (EA:PE = 0 to 1:1) to afford 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione.

[1384] LC-MS:(ESI,m / z):[M+H] + =386.1.

[1385] Step 2: Preparation of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde

[1386]

[1387] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (1.1 g, 3.0 mmol) in ACN (20 mL) was added IBX (1.7 g, 6.0 mmol). The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography (EA:PE = 0 to 1:1) to afford 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)acetaldehyde.

[1388] LC-MS:(ESI,m / z):[M+H] + =384.0.

[1389] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.72(s,1H),7.77–7.58(m,1H),7.34(dd,J=7.7,4.9Hz,2H),5.09(dd,J=12.9,5.4Hz,1H),3.68( d,J=11.8Hz,2H),2.97-2.82(m,3H),2.64–2.53(m,2H),2.45(d,J=6.6Hz,2H),2.13–1.99(m,3H),1.82-1.72(m,2H),1.50-1.30(m,2H).

[1390] Intermediate 25: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanal

[1391] Step 1: Preparation of 3-(piperidin-4-yl)propan-1-ol

[1392]

[1393] To tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (930.0 mg, 3.8 mmol) in DCM (8.00 mL) was added TFA (4.0 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was directly concentrated to afford 3-(piperidin-4-yl)propan-1-ol. The crude product was used directly in the next reaction.

[1394] LC-MS:(ESI,m / z):[M+H] + =144.2.

[1395] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione

[1396]

[1397] To a stirred solution of 3-(piperidin-4-yl)propan-1-ol (730 mg, TFA salt, 3.8 mmol) in DMF (10 mL) was added 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (1.0 g, 3.8 mmol) and DIEA (1.5 g, 11.4 mmol). The reaction mixture was stirred at 100°C overnight. Water (100 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with EA (20 mL x 3). The organic phase was washed with saturated brine (60 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash column chromatography (EA:PE = 0 to 1:1) to afford 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione.

[1398] LC-MS:(ESI,m / z):[M+H] + =400.0.

[1399] Step 3: Preparation of 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanal

[1400]

[1401] To a stirred solution of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(3-hydroxypropyl)piperidin-1-yl)isoindoline-1,3-dione (700 mg, 1.7 mmol) in ACN (20 mL) was added IBX (982 mg, 3.5 mmol). The reaction mixture was stirred at 80°C for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by flash column chromatography (EA:PE = 0 to 1:1) to afford 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)piperidin-4-yl)propanal.

[1402] LC-MS:(ESI,m / z):[M+H] + =398.0.

[1403] 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),9.71(t,J=1.4Hz,1H),7.74–7.60(m,1H),7.33(dd,J=7.7,3.4Hz,2H),5.09(dd,J=12.9,5.4Hz,1H),3.69 (d,J=11.9Hz,2H),2.93-2.79(m,3H),2.64–2.46(m,4H),2.07–2.00(m, 1H),1.80-1.72(m,2H),1.54(dd,J=14.0,7.1Hz,2H),1.40-1.27(m,3H)

[1404] Intermediate 26: Benzyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate

[1405] Step 1: Preparation of tert-butyl 9-((4-(((9H-fluoren-9-yl)methoxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[1406]

[1407] tert-Butyl 9-formyl-3-azaspiro[5.5]undecane-3-carboxylate (1.0 g, 3.56 mmol) and (9H-fluoren-9-yl)methylpiperazine-1-carboxylate (1.35 g, 3.91 mmol) were dissolved in THF (20 mL), and STAB (2.26 g, 10.68 mmol) was added. The mixture was stirred at room temperature overnight, and water (100 mL) was added. The mixture was extracted with ethyl acetate (100 mL×3), and the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PE=3:2) to give tert-butyl 9-((4-(((9H-fluoren-9-yl)methoxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[1408] LC-MS:(ESI,m / z):[M+H] + =574.2.

[1409] Step 2: Preparation of (9H-fluoren-9-yl)methyl 4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carboxylate

[1410]

[1411] tert-Butyl 9-((4-(((9H-fluoren-9-yl)methoxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (1.1 g, 1.92 mmol) was dissolved in DCM (10 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give (9H-fluoren-9-yl)methyl 4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carboxylate, which was used directly in the next step.

[1412] LC-MS:(ESI,m / z):[M+H] + =474.1.

[1413] Step 3: Preparation of benzyl 9-((4-(((9H-fluoren-9-yl)methoxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate

[1414]

[1415] (9H-fluoren-9-yl)methyl 4-((3-azaspiro[5.5]undec-9-yl)methyl)piperazine-1-carboxylate (1.1 g, 2.33 mmol) was dissolved in ACN (20 mL), and a saturated NaHCO3 solution (20 mL) was added. CbzCl (0.60 g, 3.50 mmol) was added with stirring and allowed to react overnight at room temperature. The acetonitrile was removed by concentration under reduced pressure, and water (50 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (EA / PE = 11:9) to obtain benzyl 9-((4-(((9H-fluoren-9-yl)methoxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[1416] LC-MS:(ESI,m / z):[M+H] + =608.1.

[1417] Step 4: Preparation of benzyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate

[1418]

[1419] Benzyl 9-((4-(((9H-fluoren-9-yl)methoxy)carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carboxylate (0.97 g, 1.60 mmol) was dissolved in ACN (10 mL), piperidine (2 mL) was added, and the mixture was stirred at room temperature for 3 h. The solvent was removed by concentration under reduced pressure, water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified using a column chromatography column (MeOH / DCM = 3:17) to obtain benzyl 9-(piperazin-1-ylmethyl)-3-azaspiro[5.5]undecane-3-carboxylate.

[1420] LC-MS:(ESI,m / z):[M+H] + =386.1.

[1421] Intermediate 27: 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester

[1422] Step 1: Preparation of methyl 4-(((trifluoromethoxy)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate

[1423]

[1424] 2,6-dimethyl-1λ 2 -Piperazine (51.4 g, 480.37 mmol) and Tf2O (90.38 g, 320.50 mmol) were added to 4-oxocyclohexane-1-carboxylic acid methyl ester (50.0 g, 320.51 mmol) in dichloromethane (500 ml), stirred at 0 ° C for 1 h, and then Tf2O (72.3 g, 256.38 mmol) was added. The mixture was stirred at room temperature overnight, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EA = 5: 1) to give 4-(((trifluoromethoxy)sulfonyl)oxy)cyclohex-3-ene-1-carboxylic acid methyl ester.

[1425] 1 H NMR (400MHz, DMSO-d6) δ5.90(s,1H),3.63(s,3H),2.70–2.60(m,1H),2.47–2.28(m,4H),2.11–1.98(m,1H),1.81(tt,J=8.9,6.0Hz,1H).

[1426] Step 2: Preparation of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate

[1427]

[1428] (Bpin)2 (39.1 g, 153.94 mmol), Pd(dppf)2Cl2 (7.5 g, 10.24 mmol) and potassium acetate (30.4 g, 310.2 mmol) were added to a solution of methyl 4-(((trifluoromethoxy)sulfonyl)oxy)cyclohex-3-ene-1-carboxylate (30.0 g, 104.17 mmol) in dioxane (500 ml), and the mixture was stirred at 90°C overnight. The reaction solution was diluted with water (2 L), extracted with ethyl acetate (500 mL×3), washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=0:100) to obtain methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate.

[1429] 1 H NMR (400MHz, CDCl3) δ6.53(s,1H),3.71–3.64(m,3H),2.61–2.46(m,1H),2.42–1.95(m,6H),1.28–1.19(m,12H).

[1430] Step 3: Preparation of methyl 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylate

[1431]

[1432] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate (25.0 g, 93.98 mmol), Pd(dppf)2Cl2 (5.3 g, 7.24 mmol) and Na2CO3 (15.3 g, 144.34 mmol) were added to a D solution of 6-bromo-7-methoxy-2-methylquinazolin-4-ol (19.4 g, 72.12 mmol). The reaction mixture was added to MF / H2O (300ml / 30ml) and stirred at 110°C overnight. The reaction solution was diluted with water (1L) and extracted with ethyl acetate (500mL×3). The organic phase was washed with saturated brine (500mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=0:100) to give a crude product of 4-(4-hydroxy-7-methoxy-2-methylquinazolin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester.

[1433] LC-MS:(ESI,m / z):[M+H] + =329.0.

[1434] Intermediate 28: (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylic acid methyl ester

[1435]

[1436] Methyl (1R,4R)-4-(4-(((R)-1-(4-(2-formaldehydephenyl)thiophen-2-yl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylate (180 mg, 0.33 mmol) and methylamine solution (0.33 ml, 0.66 mmol, 2M in THF) were added to MeOH / DCE (2 mL / 2 mL), followed by a few drops of AcOH (4 drops). The mixture was stirred at room temperature for 1 h, then NaBH3CN (42 mg, 0.66 mmol) was added and the reaction was stirred for 3 h. DCM and water were added to the reaction solution, and the organic phase was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give methyl (1R,4R)-4-(7-methoxy-2-methyl-4-(((R)-1-(4-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)cyclohexane-1-carboxylate.

[1437] LC-MS:(ESI,m / z):[M+H] + =559.4.

[1438] 1 H NMR (400MHz, CDCl3) δ7.42-7.39(m,1H),7.35-7.26(m,5H),7.24-7.20(m,1H),7.10(s,1H),6.08-6.01(m,1H),5.65-5.60(m,1H),3.92(s ,3H),3.73-3.69(m,5H),3.04-2.98(m,1H),2.63(s,3H),2.44-2.36(m,4H),2.14-1.99(m,4H),1.80(d,J=6.8Hz,3H),1.70-1.53(m,4H).

[1439] Example 1: 5-(4-(2-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1440]

[1441] A reaction mixture of ((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone (50 mg, 0.09 mmol), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (40 mg, 0.09 mmol), and STAB (55 mg, 0.27 mmol) in THF (3 mL) was stirred at 25°C for 1 hour. The reaction was quenched with water (50 mL) and extracted with EA (50 mL x 3). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by preparative HPLC (acetonitrile / 0.08% aqueous ammonium bicarbonate, 5% to 95%) to give 5-(4-(2-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[1442] LC-MS:(ESI,m / z):[M+H] + =938.3.

[1443] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.11(d,J=7.7Hz,1H),8.07(s,1H),7.65(d,J=8.6Hz,1H),7.31(s,1 H),7.23(d,J=8.1Hz,1H),7.00(s,1H),6.88(s,1H),6.86(s,1H),6.70(s,1H),5.66–5.47(m,3H),5.12–5.0 1(m,1H),4.11–3.96(m,2H),3.89(s,3H),3.57–3.40(m,4H),3.04–2.80(m,4H),2.72–2.57(m,3H),2.45–2 .25(m,9H),2.07–1.95(m,1H),1.93–1.73(m,6H),1.71–1.49(m,8H),1.45–1.35(m,2H),1.27–1.11(m,2H).

[1444] Example 2: 5-(4-(2-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)ethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1445]

[1446] Prepared according to the method of Example 1.

[1447] LC-MS:(ESI,m / z):[M+H] + =939.6.

[1448] 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),8.11(d,J=9.0Hz,1H),8.07(s,1H),7.68(d,J=8.4Hz ,1H),7.34(s,1H),7.26(d,J=8.4Hz,1H),7.00(s,1H),6.88(s,1H),(s,1H),6.70(s,1H),5. 63–5.49(m,3H),5.15–5.01(m,1H),3.89(s,3H),3.55–3.38(m,8H),3.01–2.83(m,2H),2.72 –2.53(m,6H),2.47–2.27(m,11H),2.07–1.97(m,1H),1.91–1.77(m,4H),1.73–1.48(m,8H).

[1449] Example 3: 5-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1450]

[1451] Prepared according to the method of Example 1.

[1452] LC-MS:(ESI,m / z):[M+H] + =952.5

[1453] 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.16–8.01(m,2H),7.65(d,J=8.6Hz,1H),7.30(d,J=2.0Hz,1H),7. 22(dd,J=8.7,2.1Hz,1H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.62-5.48(m,3H),5.06(dd ,J=12.9,5.4Hz,1H),4.04(d,J=13.0Hz,2H),3.88(s,3H),3.55-4.32(m,4H),3.25-3.22(m,1H),2.98-2.8 2(m,4H),2.68-2.53(m,2H),2.38-2.25(m,9H),2.03-1.97(m,1H),1.92-1.42(m,16H),1.26–1.12(m,4H).

[1454] Example 4: 5-(4-(2-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1455]

[1456] A mixture of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-oxy)quinazolin-4-amine (50 mg, 0.105 mmol), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (48 mg, 0.126 mmol), and STAB (31 mg, 0.24 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction solution was concentrated, and the concentrate was purified by preparative HPLC to obtain the target product 5-(4-(2-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[1457] LC-MS:(ESI,m / z):[M+H] + =843.3.

[1458] 1H NMR(400MHz,DMSO-d6)δ11.06(s,1H),7.92–7.88(m,1H),7.78(s,1H),7.65(d,J=8.6Hz,1H),7.33–7.18(m,2H) ,7.04(s,1H),6.87(s,1H),6.84(s,1H),6.69(s,1H),5.61–5.46(m,3H),5.10–5.02(m,1H),4.51–4.45(m,1H), 4.08–4.01(m,2H),3.87(s,3H),2.99–2.81(m,3H),2.78–2.65(m,2H),2.63–2.55(m,2H),2.42–2.32(m,5H),2. 28–2.18(m,2H),2.05–1.92(m,3H),1.81–1.65(m,4H),1.62–1.52(m,4H),1.45–1.36(m,2H),1.25–1.13(m,2H).

[1459] Example 5: 5-(4-(3-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)propyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1460]

[1461] A mixture of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-oxy)quinazolin-4-amine (50 mg, 0.105 mmol), 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanal (50 mg, 0.12 mmol), and STAB (67 mg, 0.31 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction solution was concentrated, and the concentrate was purified by preparative HPLC to give the target product 5-(4-(3-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxo)piperidin-1-yl)propyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[1462] LC-MS:(ESI,m / z):[M+H] + =857.3.

[1463] 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),7.93–7.89(m,1H),7.78(s,1H),7.65(d,J=8.6Hz,1H),7.33–7.18(m ,2H),7.05(s,1H),6.88(s,1H),6.84(s,1H),6.70(s,1H),5.61–5.46(m,3H),5.10–5.02(m,1H),4.51–4.4 5(m,1H),4.08–4.01(m,2H),3.87(s,3H),2.99–2.81(m,2H),2.78–2.65(m,2H),2.63–2.55(m,2H),2.43–2 .30(m,7H),2.28–2.18(m,2H),2.05–1.92(m,4H),1.81–1.52(m,7H),1.45–1.36(m,2H),1.25–1.13(m,2H).

[1464] Example 6: 4-(4-(2-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxy)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1465]

[1466] A mixture of (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(piperidin-4-oxy)quinazolin-4-amine (50 mg, 0.10 mmol), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)acetaldehyde (48 mg, 0.12 mmol), and STAB (65 mg, 0.30 mmol) in THF (5 mL) was stirred at room temperature overnight. The reaction solution was concentrated, and the concentrate was purified by preparative HPLC (acetonitrile / 0.08% NH4HCO3 aqueous solution, 5% to 95%) to give the target product 4-(4-(2-(4-((4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)oxo)piperidin-1-yl)ethyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[1467] LC-MS:(ESI,m / z):[M+H]+ =843.3.

[1468] 1 H NMR(400MHz, DMSO-d6)δ11.08(s,1H),7.91(d,J=7.7Hz,1H),7.79(s,1H),7.71–7.64(m,1H),7.36–7.29 (m,2H),7.05(s,1H),6.87(s,1H),6.84(s,1H),6.69(s,1H),5.62–5.47(m,3H),5.15-5.05(m,1H),4.55 -4.45(m,1H),3.87(s,3H),3.68(d,J=10.9Hz,2H),2.91–2.82(m,3H),2.79–2.68(m,2H),2.65-2.55(m, 2H),2.45-2.20(m,6H),2.09-1.89(m,4H),1.85-1.66(m,4H),1.55(d,J=7.0Hz,3H),1.50-1.31(m,5H).

[1469] Example 7: 4-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1470]

[1471] A mixture of ((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone (80 mg, 0.14 mmol), 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)propanal (56 mg, 0.14 mmol), and STAB (89 mg, 0.42 mmol) in THF (5 mL) was stirred at 25°C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with EA (50 mL × 3). The organic phase was dried over Na2SO4, filtered, and concentrated. The crude product was purified by preparative HPLC (acetonitrile / 0.08% NH4HCO3 aqueous solution, 5% to 95%) to give the target product 4-(4-(3-(4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)propyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[1472] LC-MS:(ESI,m / z):[M+H] + =952.4.

[1473] 1 H NMR(400MHz,DMSO-d6)δ8.11(d,J=7.6Hz,1H),8.06(s,1H),7.71–7.64(m,1H),7.32(dd,J=7.6,5.2Hz ,2H),6.99(s,1H),6.88(s,1H),6.85(s,1H),6.70(s,1H),5.66–5.46(m,3H),5.12–5.03(m,1H),3.89 (s,3H),3.69(d,J=11.4Hz,2H),3.55–3.40(m,4H),3.00–2.79(m,4H),2.70–2.54(m,3H),2.42–2.26( m,9H),2.07–1.98(m,1H),1.92–1.73(m,6H),1.72–1.61(m,2H),1.61–1.40(m,8H),1.38–1.23(m,4H).

[1474] Example 8: 5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1475] Step 1: Preparation of tert-butyl 4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate

[1476]

[1477] Dissolve tert-butyl 4-(2-(piperidin-4-ylmethoxy)ethyl)piperidine-1-carboxylate (500 mg, 1.533 mmol) in DMF (3 mL), then add 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (846 mg, 3.066 mmol) and DIEA (593 mg, 4.599 mmol). Stir at 110°C overnight. Dilute with water (20 mL) and extract with EA (20 mL x 2). Dry the organic phase over anhydrous NaSO, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (MeOH:DCM=3:97) to give tert-butyl 4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate.

[1478] LC-MS:(ESI,m / z):[M+H] + =583.2.

[1479] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione

[1480]

[1481] Tert-butyl 4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carboxylate (500 mg, 1.533 mmol) was dissolved in DCM (3 mL), followed by the addition of TFA (1 mL) and stirring at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to afford 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindolin-1,3-dione.

[1482] LC-MS:(ESI,m / z):[M+H] + =483.3.

[1483] Step 3: Preparation of tert-butyl (3-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate

[1484]

[1485] (1R,4R)-4-(4-(((R)-1-(3-(tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (200 mg, 0.331 mmol) was dissolved in DMF (3 mL), followed by the addition of DIEA (128.4 mg, 0.993 mmol) and HATU (164.0 mg, 0.431 mmol). The mixture was stirred for 20 minutes, followed by the addition of 2-(2,6-dioxopiperidin-3-yl)-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)isoindoline-1,3-dione (192 mg, 0.397 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with DCM (30 mL × 2). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH:DCM = 0 to 1:9) to obtain tert-butyl (3-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate.

[1486] LC-MS:(ESI,m / z):[M+H] + =1067.6.

[1487] Step 4: Preparation of 5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[1488]

[1489] Tert-butyl (3-((1R)-1-((6-((1R,4R)-4-(4-(2-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methoxy)ethyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carbamate (200 mg, 0.331 mmol) was dissolved in DCM (3 mL), and TFA (3 mL) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (acetonitrile / 0.05% NH4HCO3 aqueous solution, 5% to 95%) to give 5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione.

[1490] LC-MS:(ESI,m / z):[M+H] + =967.5.

[1491] 1H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.37-8.07(m,2H),7.64(d,J=8.5Hz,1H),7.30(s,1H),7.22(d,J=8.7Hz,1H ),6.99(s,1H),6.86(d,J=10.3Hz,2H),6.70(s,1H),5.65–5.48(m,3H),5.06(dd,J=12.8,5.5Hz,1H),4.39(d,J=11 .9Hz,1H),4.05(d,J=12.8Hz,2H),3.95-3.83(m,4H),3.41(t,J=6.3Hz,2H),3.23(d,J=6.2Hz,2H),3.09–2.80(m, 6H),2.70-2.60(m,2H),2.35(s,3H),2.04-1.96(m,1H),1.87–1.50(m,18H),1.50–1.41(m,2H),1.25–1.15(m,2H).

[1492] Example 9: 1-(5-(9-(2-(4-((1S,4S)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1493] Step 1: Preparation of (R)-tert-butyl 4-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate

[1494]

[1495] (R)-4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (220 mg, 0.44 mmol) was dissolved in ethyl acetate (12 mL) and cooled to 0°C. N-Boc piperazine (163 mg, 0.88 mmol), DIEA (169 mg, 1.31 mmol) and T3P (209 mg, 0.66 mmol) were added to the reaction mixture. The mixture was stirred at 0°C for 3 hours, quenched with water (30 mL), extracted with ethyl acetate (30 mL×3), and the organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (PE:EA=10:1) to give (R)-tert-butyl 4-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate.

[1496] LC-MS:(ESI,m / z):[M+H] + =671.3.

[1497] Step 2: Preparation of (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone

[1498]

[1499] To tert-Butyl (R)-4-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazine-1-carboxylate (220 mg, 0.33 mmol) was added a solution of hydrogen chloride in ethyl acetate (3M / EA, 10 mL). The reaction solution was stirred at room temperature for 2 hours and concentrated under reduced pressure to give (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone, which was used in the next step without purification.

[1500] Step 3: Preparation of 1-(5-(9-(2-(4-((1S,4S)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1501]

[1502] (R)-(4-(4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexyl)(piperazin-1-yl)methanone (115 mg, 0.165 mmol) was dissolved in tetrahydrofuran (5 mL), and 2-(3-(4-chloro-3-(2,4-oxotetrahydropyrimidin-1(2H)-yl)benzoyl)-3-azaspiro[5.5]undec-9-yl)acetaldehyde (39 mg, 0.09 mmol) and sodium triacetoxyborohydride (55 mg, 0.27 mmol) were added in sequence, and the reaction solution was stirred at room temperature. The reaction mixture was stirred for 2 hours, quenched with water (10 mL), extracted with dichloromethane (30 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase preparation (first purified by formic acid system, then purified by ammonium bicarbonate system) to give 1-(5-(9-(2-(4-((1S,4S)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)ethyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1503] LC-MS:(ESI,m / z):[M+H] + =1000.1.

[1504] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.31(d,J=7.9Hz,1H),7.95(s,1H),7.63(d,J=8.2Hz,1H), 7.54(d,J=1.9Hz,1H),7.38(dd,J=8.2,1.8Hz,1H),6.98(s,1H),6.88(s,1H),6.84(s,1H),6.69( s,1H),5.66–5.42(m,3H),3.87(s,3H),3.75-3.50(m,5H),3.50-3.40(m,5H),3.00-2.70(m,5H), 2.39-2.23(m,7H),2.00-1.84(m,4H),1.75-1.63(m,6H),1.59-1.18(m,13H),1.13-0.96(m,4H).

[1505] Example 10: 1-(2-chloro-5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1506]

[1507] To a solution of 1-(5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione (70 mg, 0.071 mmol) in THF (3 ml) was added acetaldehyde (40% aqueous solution, 16 mg, 0.142 mmol). The mixture was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (75 mg, 0.355 mmol) was added and stirred at room temperature overnight. The reaction solution was diluted with water (15 mL), extracted with DCM (20×3 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC to give 1-(2-chloro-5-(9-((4-((1R,4R)-4-(4-(((R)-1-(3-(ethylamino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)-3-azaspiro[5.5]undecane-3-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1508] LC-MS:(ESI,m / z):[M+H] + =1014.3.

[1509] 1H NMR (400MHz, DMSO-d6) δ10.52(s,1H),8.13(s,1H),8.07(s,1H),7.64(d,J=8.3Hz,1H),7.55(s,1H),7. 39(d,J=8.0Hz,1H),7.00(s,1H),6.90(d,J=6.5Hz,2H),6.64(s,1H),6.05(s,1H),5.60(t,J=6.4Hz,1H) ,3.89(s,3H),3.75-3.40(m,8H),3.11–3.00(m,2H),3.00-2.90(m,1H),2.87-2.70(m,2H),2.70-2.60( m,1H),2.40-2.25(m,7H),2.18-2.07(m,2H),1.90-1.75(m,4H),1.75-1.20(m,18H),1.18-0.96(m,7H).

[1510] Example 11: 1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1511] Step 1: Preparation of 5-amino-2-chloropyridine-4-carboxamide

[1512]

[1513] 5-Amino-2-chloropyridine-4-carboxylic acid (14.0 g, 81.13 mmol) was dissolved in DCM (200 mL), HOBt (13.2 g, 97.67 mmol) and EDCI (18.7 g, 97.67 mmol) were added, and the mixture was stirred at room temperature for 1 h. NH3H2O ​​(200 mL) was added and stirred for 2 h. The mixture was filtered and concentrated under reduced pressure to give crude 5-amino-2-chloropyridine-4-carboxamide.

[1514] LC-MS:(ESI,m / z):[M+H] + =172.0.

[1515] Step 2: Preparation of methyl 4-(5-amino-4-carbamoylpyridin-2-yl)cyclohex-3-ene-1-carboxylate

[1516]

[1517] 5-Amino-2-chloropyridine-4-carboxamide (5.0 g, 29.24 mmol) was dissolved in Dioxane / H2O (200 mL / 20 ml), Cs2CO3 (47.51 g, 146.18 mmol), Pd(dppf)Cl2 (2.67 g, 3.65 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexane-3-yl -ene-1-carboxylic acid methyl ester (10.1 g, 38.1 mmol) was added separately, the reaction solution was heated to 100 ° C under nitrogen protection and stirred overnight, diluted with water (500 ml), extracted with ethyl acetate (600 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (PE: EA = 1: 3) to obtain 4-(5-amino-4-aminoformylpyridin-2-yl)cyclohex-3-ene-1-carboxylic acid methyl ester.

[1518] LC-MS:(ESI,m / z):[M+H] + =276.0.

[1519] Step 3: Preparation of methyl 4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohex-3-ene-1-carboxylate

[1520]

[1521] 4-(5-amino-4-carbamoylpyridin-2-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (4.0 g, 14.55 mmol) was added to a solution of trimethyl orthoacetate (17.46 g, 145.5 mmol) in methanol (100 ml), stirred overnight at 120 ° C in a sealed pot, cooled and concentrated under reduced pressure to obtain a crude product of 4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester.

[1522] LC-MS:(ESI,m / z):[M+H] + =300.0.

[1523] Step 4: Preparation of methyl (1R,4R)-4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate

[1524]

[1525] 4-(4-Hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (800 mg, 3.33 mmol) and Pd(OH)2 (320 mg) were added to a methanol (50 mL) solution. The reaction solution was replaced with hydrogen three times, heated to 70°C and stirred overnight, filtered, and concentrated under reduced pressure. The crude product was dissolved in methanol (40 mL), sodium methoxide (1 mL, 5.4 mmol / L) was added, and stirred at 70°C overnight. The pH was adjusted to 3-4 with H2SO4, stirred at 50°C overnight, concentrated under reduced pressure, and purified by reverse phase preparative method to obtain (1R,4R)-4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester.

[1526] LC-MS:(ESI,m / z):[M+H] + =302.1.

[1527] Step 5: Preparation of methyl (1R,4R)-4-(2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate

[1528]

[1529] 2,4,6-Triisopropylphenylsulfonyl chloride (1.0 g, 3.3 mmol), DMAP (20.3 mg, 0.165 mmol) and TEA (503 mg, 4.98 mmol) were added to a solution of (1R,4R)-4-(4-hydroxy-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester (500 mg, 1.66 mmol) in dichloromethane (30 ml). The mixture was stirred at room temperature overnight. The organic phase was washed with water (50 ml) and saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography (PE:EA=1:3) to give (1R,4R)-4-(2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid methyl ester.

[1530] LC-MS:(ESI,m / z):[M+H] + =568.2.

[1531] Step 6: Preparation of methyl (1R,4R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate

[1532]

[1533] Methyl (1R,4R)-4-(2-methyl-4-(((2,4,6-triisopropylphenyl)sulfonyl)oxy)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate (800 mg, 1.41 mmol) and TEA (546.1 mg, 4.23 mmol) were added to a solution of 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl-1-amine (462 mg, 1.97 mmol) in DMSO (20 mL). The mixture was stirred at room temperature overnight. The crude product was purified by reverse phase column chromatography (ACN / H2O=2 / 1) to give methyl (1R,4R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate.

[1534] LC-MS:(ESI,m / z):[M+H] + =518.4.

[1535] Step 7: Preparation of (1R,4R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid

[1536]

[1537] Methyl (1R,4R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylate (400 mg, 0.774 mmol) was dissolved in THF / H2O (40 ml / 10 ml) solution, and LiOH (93 mg, 3.87 mmol) was added. The reaction solution was heated to 50°C and stirred overnight. The pH was adjusted to neutral with HCl (1 M), and the mixture was dissolved in water (50 ml). The mixture was extracted with ethyl acetate (100 ml) and concentrated under reduced pressure to give crude (1R,4R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid.

[1538] LC-MS:(ESI,m / z):[M+H] + =504.2.

[1539] Step 8: Preparation of 1-(2-methoxy-5-(4-((2-(1-((1R,4R)-4-(2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1540]

[1541] (1R,4R)-4-(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carboxylic acid (180 mg, 0.357 mmol), HATU (203.5 mg, 0.536 mmol) and DIEA (138.2 mg, 1.07 mmol) were added to 1-(2-methoxy-5-(4-((2-(piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione in DMF (6 ml) The solution was stirred at room temperature overnight, dissolved in water (50 ml), extracted with dichloromethane (30 ml×3), concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (ACN / H2O=1 / 2) to give 1-(2-methoxy-5-(4-((2-(1-((1R,4R)-4-(2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1542] LC-MS:(ESI,m / z):[M+H] + =958.5.

[1543] Step 9: Preparation of 1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1544]

[1545] 1-(2-methoxy-5-(4-((2-(1-((1R,4R)-4-(2-methyl-4-(((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg, 0.313 mmol) was dissolved in ethanol (20 ml) and Raney-Ni (aq., 1 mL). , hydrazine hydrate (0.5 mL) was added, the reaction solution was stirred at room temperature for 1 hour, filtered, and concentrated under reduced pressure. The crude product was purified by reverse phase preparative method to give 1-(5-(4-((2-(1-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)cyclohexane-1-carbonyl)piperidin-4-yl)ethoxy)methyl)piperidine-1-carbonyl)-2-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1546] LC-MS:(ESI,m / z):[M+H] + =928.5.

[1547] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),8.91(s,1H),8.58(d,J=7.9Hz,1H),8.10(s,1H),7.36(dd,J=8.4,1.9Hz,1H),7 .32(d,J=1.9Hz,1H),7.15(d,J=8.5Hz,1H),6.89(s,1H),6.85(s,1H),6.71(s,1H),5.57–5.51(m,3H),4.45-4.33(m, 1H),4.00-3.90(m,1H),3.84(s,3H),3.59(t,J=6.6Hz,2H),3.41(t,J=6.2Hz,2H),3.24(d,J=6.2Hz,2H),3.05-2.95( m,2H),2.83-2.70(m,2H),2.70-2.65(m,3H),2.43(s,3H),2.05-1.96(m,2H),1.88-1.40(m,20H),1.23-0.89(m,4H).

[1548] Example 12: 1-(5-(2-(4-((4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1549] Step 1: Preparation of tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate

[1550]

[1551] A mixture of tert-butyl 4-((1-((benzyloxy)carbonyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (500 mg, 1.20 mmol) and Pd / C (100 mg) in MeOH (10 mL) was stirred at room temperature under a H atmosphere for 2.0 h. The reaction mixture was filtered and concentrated under reduced pressure to provide tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate.

[1552] LC-MS:(ESI,m / z):[M+H] + =284.1.

[1553] Step 2: Preparation of tert-butyl 4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate

[1554]

[1555] A mixture of 2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetic acid (240 mg, 0.805 mmol), tert-butyl 4-(piperidin-4-ylmethyl)piperazine-1-carboxylate (251 mg, 0.886 mmol), HATU (612 mg, 1.61 mmol), and DIEA (312 mg, 2.42 mmol) in DMF (5 mL) was stirred at room temperature for 3 h. The reaction was quenched by adding water (20 mL) and extracted with DCM (20 mL x 2). The organic phase was separated, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH:DCM=0-1:24) to give tert-butyl 4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate.

[1556] LC-MS:(ESI,m / z):[M+H] + =564.2.

[1557] Step 3: Preparation of 1-(2-chloro-5-(2-oxo-2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1558]

[1559] A mixture of tert-butyl 4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazine-1-carboxylate (350 mg, 0.622 mmol) in TFA / DCM (10 mL / 3 mL) was stirred at room temperature for 2 h. The reaction solution was directly concentrated to afford 1-(2-chloro-5-(2-oxo-2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1560] LC-MS:(ESI,m / z):[M+H] + =464.2.

[1561] Step 4: Preparation of tert-butyl (3-((R)-1-((6-((1R,4R)-4-(4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate

[1562]

[1563] To a solution of 1-(2-chloro-5-(2-oxo-2-(4-(piperazin-1-ylmethyl)piperidin-1-yl)ethoxy)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (260 mg, 0.562 mmol), HATU (426 mg, 1.12 mmol), and DIEA (217 mg, 3.36 mmol) in DMF (3 mL) was added (1R,4R)-4-(4-(((R)-1-(3-((tert-butoxycarbonyl)amino)-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carboxylic acid (405.6 mg, 0.674 mmol). The reaction was then stirred at room temperature for 1 h. The reaction mixture was quenched by adding water (20 mL) and extracted with DCM (20 mL × 2). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (MeOH:DCM = 0-2:23) to give tert-butyl (3-((R)-1-((6-((1R,4R)-4-(4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate.

[1564] LC-MS:(ESI,m / z):[M+H] + =1048.6.

[1565] Step 5: Preparation of 1-(5-(2-(4-((4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1566]

[1567] A solution of tert-butyl (3-((R)-1-((6-((1R,4R)-4-(4-((1-(2-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenoxy)acetyl)piperidin-4-yl)methyl)piperazine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate (140 mg, 0.13 mmol) in DCM / TFA (3 mL / 1 mL) was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by Prep-HPLC (acetonitrile / 0.05% NH4HCO3 aqueous solution, 5% to 95%) to give 1-(5-(2-(4-((4-((1R,4R)-4-(4-(((R)-1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylquinazolin-6-yl)cyclohexane-1-carbonyl)piperazin-1-yl)methyl)piperidin-1-yl)-2-oxoethoxy)-2-chlorophenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1568] LC-MS:(ESI,m / z):[M+H] + =948.4.

[1569] 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),8.24-7.87(m,2H),7.45(d,J=8.9Hz,1H),7.11(d,J=2.9Hz,1H) ,6.99(s,1H),6.93(dd,J=9.0,3.0Hz,1H),6.86(d,J=10.9Hz,2H),6.70(s,1H),5.67-5.40(m,3H),4.9 3–4.63(m,2H),4.40-4.24(m,1H),3.89(s,3H),3.82-3.65(m,2H),3.63-3.42(m,4H),3.09-2.89(m,2 H),2.77-2.55(m,5H),2.41-2.25(m,7H),2.12(d,J=6.5Hz,2H),1.9-1.48(m,14H),1.15-0.88(m,2H).

[1570] Example 13: tert-Butyl (3-((R)-1-((6-((1R,4R)-4-(4-(3-((1-(4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)phenyl)piperidin-4-yl)(methyl)amino)propyl)piperidine-1-carbonyl)cyclohexyl)-7-methoxy-2-methylquinazolin-4-yl)amino)ethyl)-5-(trifluoromethyl)phenyl)carboxylate

[1571] Step 1: Preparation of 1-(2-chloro-5-(hydroxymethyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione

[1572]

[1573] Pentafluorophenyl 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzoate (2.0 g, 4.61 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL). The mixture was cooled to -60°C under nitrogen and a solution of lithium aluminum hydride in tetrahydrofuran (9.22 mL, 1.0 mmol / L) was added dropwise to the solution with stirring. After stirring at -60°C for 1 hour, saturated aqueous ammonium chloride (20 mL) was added dropwise to the reaction mixture. The mixture was filtered, and the mother liquor was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (methanol:dichloromethane = 1:9) to afford 1-(2-chloro-5-(hydroxymethyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[1574] LC-MS:(ESI,m / z):[M+H] + =255.0

[1575] Step 2: Preparation of 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzaldehyde

[1576]

[1577] 1-(2-Chloro-5-(hydroxymethyl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (450 mg, 1.76 mmol) was dissolved in acetonitrile (20 mL), and IBX (988 mg, 3.53 mmol) was added. The mixture was heated to 80°C and stirred for 1 hour. The reaction mixture was filtered, and the filter cake was washed with methanol (20 mL x 3). The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (methanol:dichloromethane = 1:9) to obtain 4-chloro-3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)benzaldehyde.

[1578] LC-MS:(ESI,m / z):[M+H] + =253.0.

[1579] 1H NMR (400MHz, DMSO-d6) δ10.57(s,1H),10.01(s,1H),8.06(d,J=1.8Hz,1H),7.93(dd,J=8.2,1.9Hz,1H),7.8 4(d,J=8.2Hz,1H), 3.80(dd,J=16.6,9.3Hz,1H), 3.64(dt,J=12.1,6.1Hz...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof: SLE Ⅰ in: The S is S6' or S7'; in: R2 is selected from C1-C6 alkoxy; R3 is selected from hydrogen; R5 is selected from NHR'; R' is selected from hydrogen; R4 is selected from C1-C4 haloalkyl; R6 is selected from hydrogen; R7 and R8 are each independently C1-C6 alkyl; in: R2 is selected from C1-C6 alkoxy; R4 is selected from hydrogen; A2 is and R3 is independently halogen or C1-C6 alkyl; The alkyl group is optionally replaced by -NR k R l Substitution, the R k and R l Each is independently hydrogen or C1-C6 alkyl; Y is 1 or 2; L' is a bond; R7 and R8 are each independently C1-C6 alkyl; L is a connecting chain, which connects S and E through a covalent bond; E is any of the following structures: Among them, the carbon atoms marked with * are in R configuration, S configuration or a mixture thereof; The L is LA: Among them, the LA: Ring A is Wherein the a end is connected to S, and the b end is connected to X''; Ring B is The c-terminal is connected to X"', and the d-terminal is connected to L3; Ring C is Wherein the e end is connected to L3, and the f end is connected to X"; X" is a bond or -C(O)-; L3 is -(CH2) k , one or two methylene groups in L3 are optionally replaced by -O- or -NH-, k is 2, 3, 4 or 5; X"' is -C(O)-; ----- is a bond, which is an R stereoisomer, an S stereoisomer or a non-stereoisomer.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: E is the following structure: Among them, the carbon atom marked with * is in R configuration, S configuration or a mixture thereof.

3. A compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: The S is S6c, In S6c: R2 is selected from C1-C6 alkoxy; R3 is selected from hydrogen; R5 is selected from NHR'; R' is selected from hydrogen; R4 is selected from C1-C4 haloalkyl; R6 is selected from hydrogen; R7 and R8 are each independently a C1-C6 alkyl group.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein: R1 is hydrogen; R2 is -O(C1-C4 alkyl); R3 is hydrogen; R5 is hydrogen or -NHR'; R' is selected from hydrogen; R4 is a C1-C4 haloalkyl group; R6 is hydrogen; R7 is a C1-C6 alkyl group; R8 is a C1-C6 alkyl group.

5. The compound of formula I or a pharmaceutically acceptable salt thereof as claimed in claim 3, wherein R7 is methyl.

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein: Each S structure The fragment is 7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, wherein: The S6' is 8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: In said S7', R1 is hydrogen; R2 is selected from -O(C1-C4 alkyl); R4 is selected from hydrogen; A2 is and R3 is halogen or C1-C6 alkyl; The alkyl group is optionally replaced by -NR k R l Substitution, the R k and R l Each is independently hydrogen or C1-C6 alkyl; Y is 2; L' is a bond; R7 and R8 are each independently a C1-C6 alkyl group.

9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 8, wherein: In said S7', The fragment is 10. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 8, wherein: In the S7', R2 is -O(C1-C4 alkyl); Or, in said S7', R3 is F, Cl, methyl or ethyl, and said methyl and ethyl are -NR k R l Substitution; said R k is methyl or ethyl, R l is hydrogen, methyl or ethyl; Or, in said S7', R7 is methyl; Or, in said S7', R8 is methyl.

11. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 8, wherein: R2 is -OCH3; Or, R3 is Cl, -CH2NHCH3 or -CH2N(CH3)2.

12. A compound of formula I or a pharmaceutically acceptable salt thereof as claimed in any one of claims 8 to 11, wherein: Said S is S7a' or S7a"; wherein R2, R3, R4, R7, R8 and Y are as defined in any one of claims 8-11.

13. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The S is any of the following structures:

14. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: In the LA, ring A is Wherein the a end is connected to S, and the b end is connected to X''; Or, in the LA, ring B is The c-terminal is connected to X"', and the d-terminal is connected to L3; Or, in the LA, L3 is -(CH2) k -, wherein one CH2 contained in L3 is optionally replaced by -O-; k is 2, 3 or 4.

15. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 14, wherein: The LA is any of the following structures:

16. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: The compound of formula I is any of the following compounds:

17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

18. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by SOS1, or a disease or condition caused by the interaction of SOS1 with Ras or SOS1 with Rac.

19. The use as claimed in claim 18, wherein: The disease is cancer.

20. The use as claimed in claim 19, wherein: The cancer is pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer or sarcoma.

21. The use as claimed in claim 20, wherein: The uterine cancer is endometrial cancer.

22. Use of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the preparation of a drug for treating and / or preventing neurofibromatosis type 1, Noonan syndrome, Noonan syndrome with lentigines, capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardiofacial-cutaneous syndrome, Leggs syndrome and hereditary gingival fibromatosis.

23. Use of the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 17 in the preparation of a medicament for treating and / or preventing a KRAS-mediated disease or condition.

24. The use according to claim 23, wherein: The KRAS is mutant KRAS.

25. The use according to claim 24, wherein: The mutant KRAS is one or more of KRAS G12C, KRAS G12D, KRASG13D and KRAS G12V.

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